Case Reports

Dislocation of the knee is a severe injury that usually results from high-energy blunt trauma.¹ Recognition of knee dislocations has increased with expansion of the definition beyond radiographically confirmed loss of tibiofemoral articulation to include injury of multiple knee ligaments with multidirectional joint instability, or the rupture of the anterior and posterior cruciate ligaments (ACL, PCL) when no gross dislocation can be identified² (though knee dislocations without rupture of either ligament have been reported^3,4). Knee dislocations account for 0.02% to 0.2% of orthopedic injuries.⁵ These multiligamentous injuries are rare, but their clinical outcomes are often complicated by arthrofibrosis, pain, and instability, as surgeons contend with the competing interests of long-term joint stability and range of motion (ROM).^6-9

Whereas treatment standards for acute knee dislocations are becoming clearer, treatment of subacute and chronic tibiofemoral dislocations and subluxations is less defined.⁵ Success with articulated external fixation originally across the ankle and elbow inspired interest in its use for the knee.^10-12 Richter and Lobenhoffer¹³ and Simonian and colleagues¹⁴ were the first to report on the postoperative use of a hinged external fixation device to help maintain the reduction of chronic fixed posterior knee dislocations. The literature has even supported nonoperative reduction of small fixed anterior or posterior (sagittal) subluxations with knee bracing alone.^15,16 However, there are no reports on treatment of chronic tibial subluxation in the coronal plane.

We report a case of a hinged-knee external fixator (HEF) used alone to reduce a chronic medial tibia subluxation that presented after initial repair of a knee dislocation sustained in a motor vehicle accident. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 51-year-old healthy woman who was traveling out of state sustained multiple orthopedic injuries in a motor vehicle accident. She had a pelvic fracture, a contralateral femoral shaft fracture, significant multiligamentous damage to the right knee, and a cavitary impaction fracture of the tibial eminence with resultant coronal tibial subluxation. Initial magnetic resonance imaging (MRI) showed the tibia injury likely was the result of varus translation, as the medial femoral condyle impacted the tibial spine, disrupting the ACL (Figures 1A, 1B).

On initial presentation to our clinic 5 weeks after injury, x-rays showed progressive medial subluxation of the tibia in relation to the femur with translation of about a third of the tibial width medially (Figures 2A, 2B).

Discussion

Although knee dislocations with multiligamentous involvement are rare, their outcomes can be poor. Fortunately, the principles of managing these complex injuries in the acute stage are becoming clearer. In a systematic review, Levy and colleagues¹⁸ found that operative treatment of a dislocated knee within 3 weeks after injury, compared with nonoperative or delayed treatment, resulted in improved functional outcomes. Ligament repair and reconstruction yielded similar outcomes, though repair of the posterolateral corner had a comparatively higher rate of failure. For associated lateral injuries, Shelbourne and colleagues¹⁷ advocated en masse repair in which the healing tissue complex is reattached to the tibia nonanatomically, without dissecting individual structures—a technique used in the original repair of our patient’s injuries.

Originally designed for other joints, hinged external fixators are now occasionally used for rehabilitation after traumatic knee injury. Stannard and colleagues⁹ recently confirmed the utility of the HEF as a supplement to ligament reconstruction for recovery from acute knee dislocation.⁹ Compared with postoperative use of a hinged-knee brace, HEF use resulted in fewer failed ligament reconstructions as well as equivalent joint ROM and Lysholm and IKDC scores at final follow-up. This clinical outcome is supported by results of kinematic studies of these hinged devices, which are capable of rigid fixation in all planes except sagittal and can reduce stress on intra-articular and periarticular ligaments when placed on the appropriate flexion-extension axis of the knee.^19,20Unfortunately, the situation is more complicated for subacute or chronic tibial subluxation than for acute subluxation. Maak and colleagues¹⁶ described 3 operative steps that are crucial in obtaining desired outcomes in this setting: complete release of scar tissue, re-creation of knee axis through ACL and PCL reconstruction, and postoperative application of a HEF or knee brace. These recommendations mimic the management course described by Richter and Lobenhoffer¹³ and Simonian and colleagues,¹⁴ who treated chronic fixed posterior tibial subluxations with arthrolysis, ligament reconstruction, and use of HEFs for 6 weeks, supporting postoperative rehabilitation. All cases maintained reduction at follow-up after fixator removal.

It is also possible for small fixed anterior or posterior tibial subluxations to be managed nonoperatively. Strobel and colleagues¹⁵ described a series of 109 patients with fixed posterior subluxations treated at night with posterior tibial support braces. Mean subluxation was reduced from 6.93 mm to 2.58 mm after an average treatment period of 180 days. Although 60% of all subluxations were completely reduced, reductions were significantly more successful for those displaced <10 mm.

Management of subacute or chronic fixed coronal tibial subluxations is yet to be described. In this article, we have reported on acceptable reduction of a subacute medial tibial subluxation with use of a HEF for 6 weeks after arthroscopic débridement of a deformed subacute bucket-handle lateral meniscus tear. Our case report is unique in that it describes use of a HEF alone for the reduction of a subacute tibial subluxation in any plane without the need for more extensive ligament reconstruction.

The injury here was primarily a lateral ligamentous injury. In the nonanatomical repair that was performed, the LCL and the iliotibial band were reattached to the proximal-lateral tibia. Had we started treating this injury from the time of the patient’s accident, then, depending on repair integrity, we might have considered acute augmentation of the anatomical repair of LCL with Larson-type reconstruction of the LCL and the popliteofibular ligament. Alternatively, acute reconstruction of the LCL and popliteus would be considered if the lateral structures were either irreparable or of very poor quality. In addition, had we initially seen the coronal instability/translation, we might have acutely considered either a staged procedure of a multiplanar external fixator or a HEF.

Given the narrowed lateral joint space, the débridement of the lateral meniscus, and the risk of developing posttraumatic arthritis, our patient will probably need total knee arthroplasty (TKA) at some point. We informed her that she had advanced lateral compartment joint space narrowing and arthritic progression and that she would eventually need TKA based on pain or dysfunction. We think the longevity of that TKA will be predictable and good, as she now had improved tibiofemoral alignment and stability of the collateral ligamentous structures. If she had been allowed to maintain the coronally subluxed position, it would have led to medial ligamentous attenuation and would have compromised the success and longevity of the TKA. In essence, a crucial part of the utility of the HEF was improved coronal tibiofemoral alignment and, therefore, decreased abnormal forces on both the repaired lateral ligaments and the native medial ligamentous structures. Although temporary external fixation issues related to infection risk and patient discomfort are recognized,^21-23 use of HEF alone can be part of the treatment considerations for fixed tibial subluxations in any plane when they present after treatment for multiligamentous injury.

Am J Orthop. 2016;45(7):E497-E502. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Dislocation of the knee is a severe injury that usually results from high-energy blunt trauma.¹ Recognition of knee dislocations has increased with expansion of the definition beyond radiographically confirmed loss of tibiofemoral articulation to include injury of multiple knee ligaments with multidirectional joint instability, or the rupture of the anterior and posterior cruciate ligaments (ACL, PCL) when no gross dislocation can be identified² (though knee dislocations without rupture of either ligament have been reported^3,4). Knee dislocations account for 0.02% to 0.2% of orthopedic injuries.⁵ These multiligamentous injuries are rare, but their clinical outcomes are often complicated by arthrofibrosis, pain, and instability, as surgeons contend with the competing interests of long-term joint stability and range of motion (ROM).^6-9

Whereas treatment standards for acute knee dislocations are becoming clearer, treatment of subacute and chronic tibiofemoral dislocations and subluxations is less defined.⁵ Success with articulated external fixation originally across the ankle and elbow inspired interest in its use for the knee.^10-12 Richter and Lobenhoffer¹³ and Simonian and colleagues¹⁴ were the first to report on the postoperative use of a hinged external fixation device to help maintain the reduction of chronic fixed posterior knee dislocations. The literature has even supported nonoperative reduction of small fixed anterior or posterior (sagittal) subluxations with knee bracing alone.^15,16 However, there are no reports on treatment of chronic tibial subluxation in the coronal plane.

We report a case of a hinged-knee external fixator (HEF) used alone to reduce a chronic medial tibia subluxation that presented after initial repair of a knee dislocation sustained in a motor vehicle accident. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 51-year-old healthy woman who was traveling out of state sustained multiple orthopedic injuries in a motor vehicle accident. She had a pelvic fracture, a contralateral femoral shaft fracture, significant multiligamentous damage to the right knee, and a cavitary impaction fracture of the tibial eminence with resultant coronal tibial subluxation. Initial magnetic resonance imaging (MRI) showed the tibia injury likely was the result of varus translation, as the medial femoral condyle impacted the tibial spine, disrupting the ACL (Figures 1A, 1B).

On initial presentation to our clinic 5 weeks after injury, x-rays showed progressive medial subluxation of the tibia in relation to the femur with translation of about a third of the tibial width medially (Figures 2A, 2B).

Discussion

Although knee dislocations with multiligamentous involvement are rare, their outcomes can be poor. Fortunately, the principles of managing these complex injuries in the acute stage are becoming clearer. In a systematic review, Levy and colleagues¹⁸ found that operative treatment of a dislocated knee within 3 weeks after injury, compared with nonoperative or delayed treatment, resulted in improved functional outcomes. Ligament repair and reconstruction yielded similar outcomes, though repair of the posterolateral corner had a comparatively higher rate of failure. For associated lateral injuries, Shelbourne and colleagues¹⁷ advocated en masse repair in which the healing tissue complex is reattached to the tibia nonanatomically, without dissecting individual structures—a technique used in the original repair of our patient’s injuries.

Originally designed for other joints, hinged external fixators are now occasionally used for rehabilitation after traumatic knee injury. Stannard and colleagues⁹ recently confirmed the utility of the HEF as a supplement to ligament reconstruction for recovery from acute knee dislocation.⁹ Compared with postoperative use of a hinged-knee brace, HEF use resulted in fewer failed ligament reconstructions as well as equivalent joint ROM and Lysholm and IKDC scores at final follow-up. This clinical outcome is supported by results of kinematic studies of these hinged devices, which are capable of rigid fixation in all planes except sagittal and can reduce stress on intra-articular and periarticular ligaments when placed on the appropriate flexion-extension axis of the knee.^19,20Unfortunately, the situation is more complicated for subacute or chronic tibial subluxation than for acute subluxation. Maak and colleagues¹⁶ described 3 operative steps that are crucial in obtaining desired outcomes in this setting: complete release of scar tissue, re-creation of knee axis through ACL and PCL reconstruction, and postoperative application of a HEF or knee brace. These recommendations mimic the management course described by Richter and Lobenhoffer¹³ and Simonian and colleagues,¹⁴ who treated chronic fixed posterior tibial subluxations with arthrolysis, ligament reconstruction, and use of HEFs for 6 weeks, supporting postoperative rehabilitation. All cases maintained reduction at follow-up after fixator removal.

It is also possible for small fixed anterior or posterior tibial subluxations to be managed nonoperatively. Strobel and colleagues¹⁵ described a series of 109 patients with fixed posterior subluxations treated at night with posterior tibial support braces. Mean subluxation was reduced from 6.93 mm to 2.58 mm after an average treatment period of 180 days. Although 60% of all subluxations were completely reduced, reductions were significantly more successful for those displaced <10 mm.

Management of subacute or chronic fixed coronal tibial subluxations is yet to be described. In this article, we have reported on acceptable reduction of a subacute medial tibial subluxation with use of a HEF for 6 weeks after arthroscopic débridement of a deformed subacute bucket-handle lateral meniscus tear. Our case report is unique in that it describes use of a HEF alone for the reduction of a subacute tibial subluxation in any plane without the need for more extensive ligament reconstruction.

The injury here was primarily a lateral ligamentous injury. In the nonanatomical repair that was performed, the LCL and the iliotibial band were reattached to the proximal-lateral tibia. Had we started treating this injury from the time of the patient’s accident, then, depending on repair integrity, we might have considered acute augmentation of the anatomical repair of LCL with Larson-type reconstruction of the LCL and the popliteofibular ligament. Alternatively, acute reconstruction of the LCL and popliteus would be considered if the lateral structures were either irreparable or of very poor quality. In addition, had we initially seen the coronal instability/translation, we might have acutely considered either a staged procedure of a multiplanar external fixator or a HEF.

Given the narrowed lateral joint space, the débridement of the lateral meniscus, and the risk of developing posttraumatic arthritis, our patient will probably need total knee arthroplasty (TKA) at some point. We informed her that she had advanced lateral compartment joint space narrowing and arthritic progression and that she would eventually need TKA based on pain or dysfunction. We think the longevity of that TKA will be predictable and good, as she now had improved tibiofemoral alignment and stability of the collateral ligamentous structures. If she had been allowed to maintain the coronally subluxed position, it would have led to medial ligamentous attenuation and would have compromised the success and longevity of the TKA. In essence, a crucial part of the utility of the HEF was improved coronal tibiofemoral alignment and, therefore, decreased abnormal forces on both the repaired lateral ligaments and the native medial ligamentous structures. Although temporary external fixation issues related to infection risk and patient discomfort are recognized,^21-23 use of HEF alone can be part of the treatment considerations for fixed tibial subluxations in any plane when they present after treatment for multiligamentous injury.

Am J Orthop. 2016;45(7):E497-E502. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Dislocation of the knee is a severe injury that usually results from high-energy blunt trauma.¹ Recognition of knee dislocations has increased with expansion of the definition beyond radiographically confirmed loss of tibiofemoral articulation to include injury of multiple knee ligaments with multidirectional joint instability, or the rupture of the anterior and posterior cruciate ligaments (ACL, PCL) when no gross dislocation can be identified² (though knee dislocations without rupture of either ligament have been reported^3,4). Knee dislocations account for 0.02% to 0.2% of orthopedic injuries.⁵ These multiligamentous injuries are rare, but their clinical outcomes are often complicated by arthrofibrosis, pain, and instability, as surgeons contend with the competing interests of long-term joint stability and range of motion (ROM).^6-9

Whereas treatment standards for acute knee dislocations are becoming clearer, treatment of subacute and chronic tibiofemoral dislocations and subluxations is less defined.⁵ Success with articulated external fixation originally across the ankle and elbow inspired interest in its use for the knee.^10-12 Richter and Lobenhoffer¹³ and Simonian and colleagues¹⁴ were the first to report on the postoperative use of a hinged external fixation device to help maintain the reduction of chronic fixed posterior knee dislocations. The literature has even supported nonoperative reduction of small fixed anterior or posterior (sagittal) subluxations with knee bracing alone.^15,16 However, there are no reports on treatment of chronic tibial subluxation in the coronal plane.

We report a case of a hinged-knee external fixator (HEF) used alone to reduce a chronic medial tibia subluxation that presented after initial repair of a knee dislocation sustained in a motor vehicle accident. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 51-year-old healthy woman who was traveling out of state sustained multiple orthopedic injuries in a motor vehicle accident. She had a pelvic fracture, a contralateral femoral shaft fracture, significant multiligamentous damage to the right knee, and a cavitary impaction fracture of the tibial eminence with resultant coronal tibial subluxation. Initial magnetic resonance imaging (MRI) showed the tibia injury likely was the result of varus translation, as the medial femoral condyle impacted the tibial spine, disrupting the ACL (Figures 1A, 1B).

On initial presentation to our clinic 5 weeks after injury, x-rays showed progressive medial subluxation of the tibia in relation to the femur with translation of about a third of the tibial width medially (Figures 2A, 2B).

Discussion

Although knee dislocations with multiligamentous involvement are rare, their outcomes can be poor. Fortunately, the principles of managing these complex injuries in the acute stage are becoming clearer. In a systematic review, Levy and colleagues¹⁸ found that operative treatment of a dislocated knee within 3 weeks after injury, compared with nonoperative or delayed treatment, resulted in improved functional outcomes. Ligament repair and reconstruction yielded similar outcomes, though repair of the posterolateral corner had a comparatively higher rate of failure. For associated lateral injuries, Shelbourne and colleagues¹⁷ advocated en masse repair in which the healing tissue complex is reattached to the tibia nonanatomically, without dissecting individual structures—a technique used in the original repair of our patient’s injuries.

Originally designed for other joints, hinged external fixators are now occasionally used for rehabilitation after traumatic knee injury. Stannard and colleagues⁹ recently confirmed the utility of the HEF as a supplement to ligament reconstruction for recovery from acute knee dislocation.⁹ Compared with postoperative use of a hinged-knee brace, HEF use resulted in fewer failed ligament reconstructions as well as equivalent joint ROM and Lysholm and IKDC scores at final follow-up. This clinical outcome is supported by results of kinematic studies of these hinged devices, which are capable of rigid fixation in all planes except sagittal and can reduce stress on intra-articular and periarticular ligaments when placed on the appropriate flexion-extension axis of the knee.^19,20Unfortunately, the situation is more complicated for subacute or chronic tibial subluxation than for acute subluxation. Maak and colleagues¹⁶ described 3 operative steps that are crucial in obtaining desired outcomes in this setting: complete release of scar tissue, re-creation of knee axis through ACL and PCL reconstruction, and postoperative application of a HEF or knee brace. These recommendations mimic the management course described by Richter and Lobenhoffer¹³ and Simonian and colleagues,¹⁴ who treated chronic fixed posterior tibial subluxations with arthrolysis, ligament reconstruction, and use of HEFs for 6 weeks, supporting postoperative rehabilitation. All cases maintained reduction at follow-up after fixator removal.

It is also possible for small fixed anterior or posterior tibial subluxations to be managed nonoperatively. Strobel and colleagues¹⁵ described a series of 109 patients with fixed posterior subluxations treated at night with posterior tibial support braces. Mean subluxation was reduced from 6.93 mm to 2.58 mm after an average treatment period of 180 days. Although 60% of all subluxations were completely reduced, reductions were significantly more successful for those displaced <10 mm.

Management of subacute or chronic fixed coronal tibial subluxations is yet to be described. In this article, we have reported on acceptable reduction of a subacute medial tibial subluxation with use of a HEF for 6 weeks after arthroscopic débridement of a deformed subacute bucket-handle lateral meniscus tear. Our case report is unique in that it describes use of a HEF alone for the reduction of a subacute tibial subluxation in any plane without the need for more extensive ligament reconstruction.

The injury here was primarily a lateral ligamentous injury. In the nonanatomical repair that was performed, the LCL and the iliotibial band were reattached to the proximal-lateral tibia. Had we started treating this injury from the time of the patient’s accident, then, depending on repair integrity, we might have considered acute augmentation of the anatomical repair of LCL with Larson-type reconstruction of the LCL and the popliteofibular ligament. Alternatively, acute reconstruction of the LCL and popliteus would be considered if the lateral structures were either irreparable or of very poor quality. In addition, had we initially seen the coronal instability/translation, we might have acutely considered either a staged procedure of a multiplanar external fixator or a HEF.

Given the narrowed lateral joint space, the débridement of the lateral meniscus, and the risk of developing posttraumatic arthritis, our patient will probably need total knee arthroplasty (TKA) at some point. We informed her that she had advanced lateral compartment joint space narrowing and arthritic progression and that she would eventually need TKA based on pain or dysfunction. We think the longevity of that TKA will be predictable and good, as she now had improved tibiofemoral alignment and stability of the collateral ligamentous structures. If she had been allowed to maintain the coronally subluxed position, it would have led to medial ligamentous attenuation and would have compromised the success and longevity of the TKA. In essence, a crucial part of the utility of the HEF was improved coronal tibiofemoral alignment and, therefore, decreased abnormal forces on both the repaired lateral ligaments and the native medial ligamentous structures. Although temporary external fixation issues related to infection risk and patient discomfort are recognized,^21-23 use of HEF alone can be part of the treatment considerations for fixed tibial subluxations in any plane when they present after treatment for multiligamentous injury.

Am J Orthop. 2016;45(7):E497-E502. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Fat embolism syndrome (FES) occurs in long-bone fractures and classically presents with the triad of hypoxia, petechia, and altered mental status, or the criteria of Gurd and Wilson.¹ The Lindeque criteria (femur fracture, pH <7.3, increased work of breathing) are also used.^1,2 FES is a potentially fatal complication, with mortality rates ranging from 10% to 36%.^1,3 FES typically occurs within 24 to 72 hours after initial insult, with one study finding an average of 48.5 hours after injury and an incidence of 0.15% to 2.4%.⁴ The overall FES rate is <1% in retrospective reviews and 11% to 29% in prospective studies.⁵ FES may present without one or all of the Gurd and Wilson criteria,⁶ and cerebral fat embolism (CFE) can be even more difficult to diagnose. Patients with CFE typically present with a wide array of postoperative neurologic deficits, commonly in the 24- to 72-hour window in which FES typically occurs. Correct diagnosis and management of CFE require a high index of suspicion and knowledge of the diagnostic work-up. In the postoperative setting, it can be difficult to distinguish CFE-related neurologic deficits from the normal sequelae of anesthesia, pain medications, and other factors.

In this article, we report the case of a 42-year-old woman who developed CFE after reamed intramedullary nail fixation of femoral and tibial shaft fractures. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 42-year-old woman with no past medical history was injured when a horse reared and fell on her. Initial emergent computed tomography (CT) was negative for intracranial hemorrhage, and injury radiographs were obtained (Figures 1A, 1B).

About 9 hours after surgery and 36 hours after injury, the patient was unresponsive. Vital signs, including oxygen saturation, were within normal limits, but she was unable to verbalize. Physical examination revealed symmetric facial musculature but also generalized weakness and diffuse hypertonicity and hyperreflexia. Initial laboratory results, including complete blood cell count, electrolyte panel, and troponin levels, were unremarkable. Naloxone was administered to rule out opioid overdose. An immediate code stroke and neurology consultation was requested. An emergent CT scan of the brain was negative; an urgent magnetic resonance imaging (MRI) scan showed multiple punctate T2/FLAIR (fluid attenuated inversion recovery) hyperintensities with restricted diffusion, predominantly in a parasagittal white matter distribution (Figure 2).

Discussion

Postoperative Acute Mental Status Change

There are many causes of postoperative mental status change after intramedullary nailing. Change may be cardiogenic, infectious, pharmacologic, or neurologic in origin. Age should be considered in the work-up of postoperative mental status change, as common complications differ between older and younger patients, with geriatric patients at particularly high risk for delirium.

Next to be evaluated are vital signs—particularly hypoxia, as isolated tachycardia may simply be a manifestation of pain. The cardiac system is then assessed with EKG and cardiac-specific laboratory tests, including a troponin level test if there is suspicion of myocardial infarction. PE and FES are complications with a higher prevalence in intramedullary nailing, and pulmonary involvement can be ruled out with the CT with PE protocol. Skin examination is important as well, as FES presents with petechial rash in 60% of patients⁸ (rash was absent in our patient’s case). Narcotic overdose is easily ruled out with administration of naloxone. Infection and sepsis can cause mental changes, though more commonly in the elderly and seldom so soon after surgery. Evaluation for infection and sepsis involves urinalysis and culturing of blood, urine, and other bodily fluids. If there is concern about surgical site infection, the postoperative dressing should be immediately removed and the wound examined. Last, neurologic and embolic phenomena can be initially investigated with CT to rule out hemorrhagic stroke. If CT of the brain is negative, MRI should be performed. MRI is the gold standard for diagnosing ischemic stroke and CFE caused by FES.⁹

Prevalence of Fat Embolism Syndrome

Development of intramedullary fat release in patients with long-bone injuries is common. A prospective study found circulating fat globules in 95% of 43 patients with femur fractures.¹⁰ In another study, transesophageal EKG showed cardiac embolism in 62% of patients who had undergone intramedullary nail fixation.¹¹ Despite this high rate, only 0.9% to 2.2% of patients developed symptomatic FES. Risk factors for FES include younger age, multiple fractures, closed fractures, and nonoperative or delayed management of long-bone fractures.² As already mentioned, average time to FES presentation after long-bone fracture is about 48 hours. One study found that FES typically occurs within 24 to 72 hours after initial insult (average, 48.5 hours) and that the incidence of FES is 0.15% in tibia fractures, 0.78% in femur fractures, and 2.4% in multiple long-bone fractures.⁴ The timeline is consistent with the present case—our patient developed symptoms about 36 hours after injury. In addition, other studies have found a higher mortality rate (5%-15%) for patients with bilateral femur fractures than for patients with only one fracture.^7,12,13 Patients with a floating knee injury (ipsilateral tibia and femur fractures) are at higher risk for FES and have higher overall morbidity and mortality rates in comparison with patients with an isolated femur or tibia fracture, though the increased risk has not been quantified.

Review of Case Literature: FES With CFE

Few cases of FES with symptomatic CFE in the setting of long-bone fracture or long-bone surgery have been reported in the literature. There is wide variation in the development of FES with respect to preoperative or postoperative status and mechanism of injury. Duran and colleagues¹⁴ described a 20-year-old man with ipsilateral tibia and femur fractures caused by gunshots. Twenty-four hours after presentation, he developed tonic-clonic seizures and the classic triad of rash, hypoxia, and altered mental status. MRI confirmed CFE secondary to FES. The patient was optimized neurologically before definitive fixation and was discharged with minimal neurologic deficits on POD-27. Chang and colleagues¹⁵ and Yeo and colleagues¹⁶ described CFE in patients who underwent bilateral total knee arthroplasty. Symptoms developed 9 hours and 2 days after surgery, respectively. Both patients had fat emboli in the lungs and brain, underwent intensive care treatment, and recovered from the initial insult. After discharge at 44 days and 2 weeks, respectively, they fully recovered.

Other patients with CFE have had less favorable outcomes. Chen and colleagues⁶ reported the case of a 31-year-old man who sustained closed femur and tibia fractures in an automobile collision and experienced an acute decline in neurologic status 1 hour after arrival in the emergency department. The patient was intubated, CFE was diagnosed on the basis of MRI findings, and the orthopedic injuries were treated with external fixation. After 2 weeks, the patient was discharged with persistent neurologic deficits and the need for long-term tube feeding. Walshe and colleagues¹⁷ reported the case of a 19-year-old woman who sustained multiple long-bone injuries and traumatic brain injury and showed fat emboli on MRI. The patient experienced brain herniation while in the intensive care unit and later was declared brain-dead. According to the literature, it is important to maintain high suspicion for FES and possible CFE in the setting of high-energy fracture but also to be aware that FES may develop even with nondisplaced fracture or with reaming of the intramedullary canal in elective total joint arthroplasty.¹⁸

Pathophysiology of Fat Embolism Syndrome

The pathophysiology of FES and specifically of CFE is not widely understood. Two main theories on the development of FES have been advanced.

The mechanical theory suggests that exposing intramedullary long-bone contents allows fat to mobilize into the bloodstream.¹⁹ This occurs in the setting of long-bone fracture and in canal preparation during joint replacement surgery. More fat extravasates into the venous system after femur fracture than after tibia fracture, which accounts for the higher risk for FES in femoral shaft fractures and the even higher risk in concomitant femur and tibia fractures.⁴ In addition to there being a risk of fat embolism from the fracture itself, placing the patient in traction or reaming the intramedullary canal may exacerbate this effect by increased extravasation of fat from the medullary canal. With extravasation of fatty bone marrow into the venous system, fat emboli are free to travel back to the lungs, where they can cause infarcts within the lung parenchyma.

In the mechanical theory, presence of PFO may allow fat globules to pass into the systemic circulation and cause end-organ emboli. In the event of cerebral emboli, neurologic symptoms may vary widely and may include diffuse encephalopathy and global deficits.²⁰ Dog studies have found a possible mechanism for CFE in the absence of PFO. One such study, which used femoral pressurization to replicate cemented femoral arthroplasty, found that many fat globules had traversed the lungs after release into bone marrow,²¹ supporting the theory that fat droplets can traverse the pulmonary system without sequestration in the lung parenchyma. Riding and colleagues²² reported finding pulmonary arteriovenous shunts, which are thought to allow CFE to occur in the absence of PFO. More studies are needed to determine the prevalence of shunts and their overall contribution to CFE development in patients with long-bone fracture.

The biochemical theory holds that bodily trauma induces the release of free fatty acids (FFAs) from the capillaries into the bloodstream.²³ This stress response is mediated by catecholamines, which activate the adenyl cyclase pathway, which activates lipase, which hydrolyzes stored triglycerides to FFAs and glycerol. The concentration of circulating FFA was increased in 9 of 10 patients in one study.²³ Increased FFAs in the bloodstream can accelerate local and end-organ clotting, leading to thrombocytopenia and endothelial injury. In addition, patients with hypercoagulable diseases are at higher risk for postoperative thromboembolism.²⁴ However, with a negative hypercoagulable work-up and with negative chest helical CT and EKG, which did not demonstrate PFO, the explanation for CFE in our patient may more likely reside with the arteriovenous shunt theory proposed by Riding and colleagues.²²

Diagnosis and Treatment

Proper care of orthopedic patients who potentially have FES/CFE involves prompt diagnosis, immediate symptomatic care, and early coordination with neurology and medical services to rule out other causes of symptoms. Obtaining advanced imaging to rule out other potential causes and to confirm the diagnosis is crucial. The patient in this case report did not exhibit any focal neurologic deficits, but emergent CT of the brain was indicated to rule out a hemorrhagic event. If a stroke secondary to FES is clinically suspected, MRI should be obtained as soon as possible. Multiple studies have found that the “starfield” pattern, which is best seen as multiple punctate hyperintensities on T2 imaging, is the typical radiographic manifestation of CFE.⁹ This applies to patients who are in the 24- to 72-hour window after long-bone fracture or fixation and who fit Gurd and Wilson¹ criteria or Lindeque^1,2criteria, or who exhibit a change in mental status but have a negative CT scan of the brain, as was the case with our patient. Once the diagnosis is made, treatment involves addressing the symptoms (Figure 4).

Fat Embolism Syndrome in Reamed and Unreamed Nailing

Over the past several decades, the number of long bones fixed with intramedullary nails has increased significantly.²⁶ There is debate regarding whether use of reamed intramedullary nails increases the risk of fat emboli relative to use of unreamed nails, but multiple studies have found no significant difference.^26,27 Pulmonary shunting occurs in both reamed and unreamed nailing; neither technique has an advantage in terms of cardiopulmonary complications. In multiple studies, reamed nails have the advantage of improved healing rates.²⁷ A sheep study compared reamed and unreamed femoral nailing.²⁸ After nailing, sheep lungs were examined histologically for the presence of bone marrow fat embolism. The embolism rate was higher with unreamed nailing (10.25%) than with reamed nailing (6.66%). One large study of the adverse effects of reamed and unreamed nailing in 1226 patients with tibial shaft fracture found that those with open fractures had higher rates of a negative event (nonunion, infection, fasciotomy, hardware failure, need for dynamization) after reamed nailing.²⁹ Patients with closed fractures had fewer events after reamed nailing. The authors concluded there is a potential benefit in outcome with reamed intramedullary nailing in patients with closed tibial shaft fractures, but they did not comment on development of FES. In a study of the effect of subject position on intramedullary pressure and fat embolism release, dogs were positioned either supine or lateral for tibial and femoral reaming.³⁰ The authors measured various physiologic parameters, including cardiac output, pulmonary arterial wedge pressure, arterial and venous blood gas, and blood cell counts. There were no statistically significant differences in values between the 2 groups in any variable, indicating that position does not affect FES development in the orthopedic trauma setting.

Conclusion

FES and CFE are potential devastating sequelae of both long-bone fracture and long-bone instrumentation. It is important to recognize these entities in the acute setting and to consider them in the differential diagnosis of a trauma or postoperative patient who experiences sudden onset of altered mental status with or without dyspnea or a petechial rash. If CFE is suspected, early advanced imaging (including urgent MRI) should be obtained with rapid involvement of a multidisciplinary team that can optimize the chance for successful recovery of both neurologic and physical function. The best treatment, early prevention and diagnosis, maximizes care of symptoms. As is evidenced in this case report, rapid diagnosis and treatment often result in recovery from a majority of the symptoms of FES and CFE.

Am J Orthop. 2016;45(7):E515-E521. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Fat embolism syndrome (FES) occurs in long-bone fractures and classically presents with the triad of hypoxia, petechia, and altered mental status, or the criteria of Gurd and Wilson.¹ The Lindeque criteria (femur fracture, pH <7.3, increased work of breathing) are also used.^1,2 FES is a potentially fatal complication, with mortality rates ranging from 10% to 36%.^1,3 FES typically occurs within 24 to 72 hours after initial insult, with one study finding an average of 48.5 hours after injury and an incidence of 0.15% to 2.4%.⁴ The overall FES rate is <1% in retrospective reviews and 11% to 29% in prospective studies.⁵ FES may present without one or all of the Gurd and Wilson criteria,⁶ and cerebral fat embolism (CFE) can be even more difficult to diagnose. Patients with CFE typically present with a wide array of postoperative neurologic deficits, commonly in the 24- to 72-hour window in which FES typically occurs. Correct diagnosis and management of CFE require a high index of suspicion and knowledge of the diagnostic work-up. In the postoperative setting, it can be difficult to distinguish CFE-related neurologic deficits from the normal sequelae of anesthesia, pain medications, and other factors.

In this article, we report the case of a 42-year-old woman who developed CFE after reamed intramedullary nail fixation of femoral and tibial shaft fractures. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 42-year-old woman with no past medical history was injured when a horse reared and fell on her. Initial emergent computed tomography (CT) was negative for intracranial hemorrhage, and injury radiographs were obtained (Figures 1A, 1B).

About 9 hours after surgery and 36 hours after injury, the patient was unresponsive. Vital signs, including oxygen saturation, were within normal limits, but she was unable to verbalize. Physical examination revealed symmetric facial musculature but also generalized weakness and diffuse hypertonicity and hyperreflexia. Initial laboratory results, including complete blood cell count, electrolyte panel, and troponin levels, were unremarkable. Naloxone was administered to rule out opioid overdose. An immediate code stroke and neurology consultation was requested. An emergent CT scan of the brain was negative; an urgent magnetic resonance imaging (MRI) scan showed multiple punctate T2/FLAIR (fluid attenuated inversion recovery) hyperintensities with restricted diffusion, predominantly in a parasagittal white matter distribution (Figure 2).

Discussion

Postoperative Acute Mental Status Change

There are many causes of postoperative mental status change after intramedullary nailing. Change may be cardiogenic, infectious, pharmacologic, or neurologic in origin. Age should be considered in the work-up of postoperative mental status change, as common complications differ between older and younger patients, with geriatric patients at particularly high risk for delirium.

Next to be evaluated are vital signs—particularly hypoxia, as isolated tachycardia may simply be a manifestation of pain. The cardiac system is then assessed with EKG and cardiac-specific laboratory tests, including a troponin level test if there is suspicion of myocardial infarction. PE and FES are complications with a higher prevalence in intramedullary nailing, and pulmonary involvement can be ruled out with the CT with PE protocol. Skin examination is important as well, as FES presents with petechial rash in 60% of patients⁸ (rash was absent in our patient’s case). Narcotic overdose is easily ruled out with administration of naloxone. Infection and sepsis can cause mental changes, though more commonly in the elderly and seldom so soon after surgery. Evaluation for infection and sepsis involves urinalysis and culturing of blood, urine, and other bodily fluids. If there is concern about surgical site infection, the postoperative dressing should be immediately removed and the wound examined. Last, neurologic and embolic phenomena can be initially investigated with CT to rule out hemorrhagic stroke. If CT of the brain is negative, MRI should be performed. MRI is the gold standard for diagnosing ischemic stroke and CFE caused by FES.⁹

Prevalence of Fat Embolism Syndrome

Development of intramedullary fat release in patients with long-bone injuries is common. A prospective study found circulating fat globules in 95% of 43 patients with femur fractures.¹⁰ In another study, transesophageal EKG showed cardiac embolism in 62% of patients who had undergone intramedullary nail fixation.¹¹ Despite this high rate, only 0.9% to 2.2% of patients developed symptomatic FES. Risk factors for FES include younger age, multiple fractures, closed fractures, and nonoperative or delayed management of long-bone fractures.² As already mentioned, average time to FES presentation after long-bone fracture is about 48 hours. One study found that FES typically occurs within 24 to 72 hours after initial insult (average, 48.5 hours) and that the incidence of FES is 0.15% in tibia fractures, 0.78% in femur fractures, and 2.4% in multiple long-bone fractures.⁴ The timeline is consistent with the present case—our patient developed symptoms about 36 hours after injury. In addition, other studies have found a higher mortality rate (5%-15%) for patients with bilateral femur fractures than for patients with only one fracture.^7,12,13 Patients with a floating knee injury (ipsilateral tibia and femur fractures) are at higher risk for FES and have higher overall morbidity and mortality rates in comparison with patients with an isolated femur or tibia fracture, though the increased risk has not been quantified.

Review of Case Literature: FES With CFE

Few cases of FES with symptomatic CFE in the setting of long-bone fracture or long-bone surgery have been reported in the literature. There is wide variation in the development of FES with respect to preoperative or postoperative status and mechanism of injury. Duran and colleagues¹⁴ described a 20-year-old man with ipsilateral tibia and femur fractures caused by gunshots. Twenty-four hours after presentation, he developed tonic-clonic seizures and the classic triad of rash, hypoxia, and altered mental status. MRI confirmed CFE secondary to FES. The patient was optimized neurologically before definitive fixation and was discharged with minimal neurologic deficits on POD-27. Chang and colleagues¹⁵ and Yeo and colleagues¹⁶ described CFE in patients who underwent bilateral total knee arthroplasty. Symptoms developed 9 hours and 2 days after surgery, respectively. Both patients had fat emboli in the lungs and brain, underwent intensive care treatment, and recovered from the initial insult. After discharge at 44 days and 2 weeks, respectively, they fully recovered.

Other patients with CFE have had less favorable outcomes. Chen and colleagues⁶ reported the case of a 31-year-old man who sustained closed femur and tibia fractures in an automobile collision and experienced an acute decline in neurologic status 1 hour after arrival in the emergency department. The patient was intubated, CFE was diagnosed on the basis of MRI findings, and the orthopedic injuries were treated with external fixation. After 2 weeks, the patient was discharged with persistent neurologic deficits and the need for long-term tube feeding. Walshe and colleagues¹⁷ reported the case of a 19-year-old woman who sustained multiple long-bone injuries and traumatic brain injury and showed fat emboli on MRI. The patient experienced brain herniation while in the intensive care unit and later was declared brain-dead. According to the literature, it is important to maintain high suspicion for FES and possible CFE in the setting of high-energy fracture but also to be aware that FES may develop even with nondisplaced fracture or with reaming of the intramedullary canal in elective total joint arthroplasty.¹⁸

Pathophysiology of Fat Embolism Syndrome

The pathophysiology of FES and specifically of CFE is not widely understood. Two main theories on the development of FES have been advanced.

The mechanical theory suggests that exposing intramedullary long-bone contents allows fat to mobilize into the bloodstream.¹⁹ This occurs in the setting of long-bone fracture and in canal preparation during joint replacement surgery. More fat extravasates into the venous system after femur fracture than after tibia fracture, which accounts for the higher risk for FES in femoral shaft fractures and the even higher risk in concomitant femur and tibia fractures.⁴ In addition to there being a risk of fat embolism from the fracture itself, placing the patient in traction or reaming the intramedullary canal may exacerbate this effect by increased extravasation of fat from the medullary canal. With extravasation of fatty bone marrow into the venous system, fat emboli are free to travel back to the lungs, where they can cause infarcts within the lung parenchyma.

In the mechanical theory, presence of PFO may allow fat globules to pass into the systemic circulation and cause end-organ emboli. In the event of cerebral emboli, neurologic symptoms may vary widely and may include diffuse encephalopathy and global deficits.²⁰ Dog studies have found a possible mechanism for CFE in the absence of PFO. One such study, which used femoral pressurization to replicate cemented femoral arthroplasty, found that many fat globules had traversed the lungs after release into bone marrow,²¹ supporting the theory that fat droplets can traverse the pulmonary system without sequestration in the lung parenchyma. Riding and colleagues²² reported finding pulmonary arteriovenous shunts, which are thought to allow CFE to occur in the absence of PFO. More studies are needed to determine the prevalence of shunts and their overall contribution to CFE development in patients with long-bone fracture.

The biochemical theory holds that bodily trauma induces the release of free fatty acids (FFAs) from the capillaries into the bloodstream.²³ This stress response is mediated by catecholamines, which activate the adenyl cyclase pathway, which activates lipase, which hydrolyzes stored triglycerides to FFAs and glycerol. The concentration of circulating FFA was increased in 9 of 10 patients in one study.²³ Increased FFAs in the bloodstream can accelerate local and end-organ clotting, leading to thrombocytopenia and endothelial injury. In addition, patients with hypercoagulable diseases are at higher risk for postoperative thromboembolism.²⁴ However, with a negative hypercoagulable work-up and with negative chest helical CT and EKG, which did not demonstrate PFO, the explanation for CFE in our patient may more likely reside with the arteriovenous shunt theory proposed by Riding and colleagues.²²

Diagnosis and Treatment

Proper care of orthopedic patients who potentially have FES/CFE involves prompt diagnosis, immediate symptomatic care, and early coordination with neurology and medical services to rule out other causes of symptoms. Obtaining advanced imaging to rule out other potential causes and to confirm the diagnosis is crucial. The patient in this case report did not exhibit any focal neurologic deficits, but emergent CT of the brain was indicated to rule out a hemorrhagic event. If a stroke secondary to FES is clinically suspected, MRI should be obtained as soon as possible. Multiple studies have found that the “starfield” pattern, which is best seen as multiple punctate hyperintensities on T2 imaging, is the typical radiographic manifestation of CFE.⁹ This applies to patients who are in the 24- to 72-hour window after long-bone fracture or fixation and who fit Gurd and Wilson¹ criteria or Lindeque^1,2criteria, or who exhibit a change in mental status but have a negative CT scan of the brain, as was the case with our patient. Once the diagnosis is made, treatment involves addressing the symptoms (Figure 4).

Fat Embolism Syndrome in Reamed and Unreamed Nailing

Over the past several decades, the number of long bones fixed with intramedullary nails has increased significantly.²⁶ There is debate regarding whether use of reamed intramedullary nails increases the risk of fat emboli relative to use of unreamed nails, but multiple studies have found no significant difference.^26,27 Pulmonary shunting occurs in both reamed and unreamed nailing; neither technique has an advantage in terms of cardiopulmonary complications. In multiple studies, reamed nails have the advantage of improved healing rates.²⁷ A sheep study compared reamed and unreamed femoral nailing.²⁸ After nailing, sheep lungs were examined histologically for the presence of bone marrow fat embolism. The embolism rate was higher with unreamed nailing (10.25%) than with reamed nailing (6.66%). One large study of the adverse effects of reamed and unreamed nailing in 1226 patients with tibial shaft fracture found that those with open fractures had higher rates of a negative event (nonunion, infection, fasciotomy, hardware failure, need for dynamization) after reamed nailing.²⁹ Patients with closed fractures had fewer events after reamed nailing. The authors concluded there is a potential benefit in outcome with reamed intramedullary nailing in patients with closed tibial shaft fractures, but they did not comment on development of FES. In a study of the effect of subject position on intramedullary pressure and fat embolism release, dogs were positioned either supine or lateral for tibial and femoral reaming.³⁰ The authors measured various physiologic parameters, including cardiac output, pulmonary arterial wedge pressure, arterial and venous blood gas, and blood cell counts. There were no statistically significant differences in values between the 2 groups in any variable, indicating that position does not affect FES development in the orthopedic trauma setting.

Conclusion

FES and CFE are potential devastating sequelae of both long-bone fracture and long-bone instrumentation. It is important to recognize these entities in the acute setting and to consider them in the differential diagnosis of a trauma or postoperative patient who experiences sudden onset of altered mental status with or without dyspnea or a petechial rash. If CFE is suspected, early advanced imaging (including urgent MRI) should be obtained with rapid involvement of a multidisciplinary team that can optimize the chance for successful recovery of both neurologic and physical function. The best treatment, early prevention and diagnosis, maximizes care of symptoms. As is evidenced in this case report, rapid diagnosis and treatment often result in recovery from a majority of the symptoms of FES and CFE.

Am J Orthop. 2016;45(7):E515-E521. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Fat embolism syndrome (FES) occurs in long-bone fractures and classically presents with the triad of hypoxia, petechia, and altered mental status, or the criteria of Gurd and Wilson.¹ The Lindeque criteria (femur fracture, pH <7.3, increased work of breathing) are also used.^1,2 FES is a potentially fatal complication, with mortality rates ranging from 10% to 36%.^1,3 FES typically occurs within 24 to 72 hours after initial insult, with one study finding an average of 48.5 hours after injury and an incidence of 0.15% to 2.4%.⁴ The overall FES rate is <1% in retrospective reviews and 11% to 29% in prospective studies.⁵ FES may present without one or all of the Gurd and Wilson criteria,⁶ and cerebral fat embolism (CFE) can be even more difficult to diagnose. Patients with CFE typically present with a wide array of postoperative neurologic deficits, commonly in the 24- to 72-hour window in which FES typically occurs. Correct diagnosis and management of CFE require a high index of suspicion and knowledge of the diagnostic work-up. In the postoperative setting, it can be difficult to distinguish CFE-related neurologic deficits from the normal sequelae of anesthesia, pain medications, and other factors.

In this article, we report the case of a 42-year-old woman who developed CFE after reamed intramedullary nail fixation of femoral and tibial shaft fractures. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 42-year-old woman with no past medical history was injured when a horse reared and fell on her. Initial emergent computed tomography (CT) was negative for intracranial hemorrhage, and injury radiographs were obtained (Figures 1A, 1B).

About 9 hours after surgery and 36 hours after injury, the patient was unresponsive. Vital signs, including oxygen saturation, were within normal limits, but she was unable to verbalize. Physical examination revealed symmetric facial musculature but also generalized weakness and diffuse hypertonicity and hyperreflexia. Initial laboratory results, including complete blood cell count, electrolyte panel, and troponin levels, were unremarkable. Naloxone was administered to rule out opioid overdose. An immediate code stroke and neurology consultation was requested. An emergent CT scan of the brain was negative; an urgent magnetic resonance imaging (MRI) scan showed multiple punctate T2/FLAIR (fluid attenuated inversion recovery) hyperintensities with restricted diffusion, predominantly in a parasagittal white matter distribution (Figure 2).

Discussion

Postoperative Acute Mental Status Change

There are many causes of postoperative mental status change after intramedullary nailing. Change may be cardiogenic, infectious, pharmacologic, or neurologic in origin. Age should be considered in the work-up of postoperative mental status change, as common complications differ between older and younger patients, with geriatric patients at particularly high risk for delirium.

Next to be evaluated are vital signs—particularly hypoxia, as isolated tachycardia may simply be a manifestation of pain. The cardiac system is then assessed with EKG and cardiac-specific laboratory tests, including a troponin level test if there is suspicion of myocardial infarction. PE and FES are complications with a higher prevalence in intramedullary nailing, and pulmonary involvement can be ruled out with the CT with PE protocol. Skin examination is important as well, as FES presents with petechial rash in 60% of patients⁸ (rash was absent in our patient’s case). Narcotic overdose is easily ruled out with administration of naloxone. Infection and sepsis can cause mental changes, though more commonly in the elderly and seldom so soon after surgery. Evaluation for infection and sepsis involves urinalysis and culturing of blood, urine, and other bodily fluids. If there is concern about surgical site infection, the postoperative dressing should be immediately removed and the wound examined. Last, neurologic and embolic phenomena can be initially investigated with CT to rule out hemorrhagic stroke. If CT of the brain is negative, MRI should be performed. MRI is the gold standard for diagnosing ischemic stroke and CFE caused by FES.⁹

Prevalence of Fat Embolism Syndrome

Development of intramedullary fat release in patients with long-bone injuries is common. A prospective study found circulating fat globules in 95% of 43 patients with femur fractures.¹⁰ In another study, transesophageal EKG showed cardiac embolism in 62% of patients who had undergone intramedullary nail fixation.¹¹ Despite this high rate, only 0.9% to 2.2% of patients developed symptomatic FES. Risk factors for FES include younger age, multiple fractures, closed fractures, and nonoperative or delayed management of long-bone fractures.² As already mentioned, average time to FES presentation after long-bone fracture is about 48 hours. One study found that FES typically occurs within 24 to 72 hours after initial insult (average, 48.5 hours) and that the incidence of FES is 0.15% in tibia fractures, 0.78% in femur fractures, and 2.4% in multiple long-bone fractures.⁴ The timeline is consistent with the present case—our patient developed symptoms about 36 hours after injury. In addition, other studies have found a higher mortality rate (5%-15%) for patients with bilateral femur fractures than for patients with only one fracture.^7,12,13 Patients with a floating knee injury (ipsilateral tibia and femur fractures) are at higher risk for FES and have higher overall morbidity and mortality rates in comparison with patients with an isolated femur or tibia fracture, though the increased risk has not been quantified.

Review of Case Literature: FES With CFE

Few cases of FES with symptomatic CFE in the setting of long-bone fracture or long-bone surgery have been reported in the literature. There is wide variation in the development of FES with respect to preoperative or postoperative status and mechanism of injury. Duran and colleagues¹⁴ described a 20-year-old man with ipsilateral tibia and femur fractures caused by gunshots. Twenty-four hours after presentation, he developed tonic-clonic seizures and the classic triad of rash, hypoxia, and altered mental status. MRI confirmed CFE secondary to FES. The patient was optimized neurologically before definitive fixation and was discharged with minimal neurologic deficits on POD-27. Chang and colleagues¹⁵ and Yeo and colleagues¹⁶ described CFE in patients who underwent bilateral total knee arthroplasty. Symptoms developed 9 hours and 2 days after surgery, respectively. Both patients had fat emboli in the lungs and brain, underwent intensive care treatment, and recovered from the initial insult. After discharge at 44 days and 2 weeks, respectively, they fully recovered.

Other patients with CFE have had less favorable outcomes. Chen and colleagues⁶ reported the case of a 31-year-old man who sustained closed femur and tibia fractures in an automobile collision and experienced an acute decline in neurologic status 1 hour after arrival in the emergency department. The patient was intubated, CFE was diagnosed on the basis of MRI findings, and the orthopedic injuries were treated with external fixation. After 2 weeks, the patient was discharged with persistent neurologic deficits and the need for long-term tube feeding. Walshe and colleagues¹⁷ reported the case of a 19-year-old woman who sustained multiple long-bone injuries and traumatic brain injury and showed fat emboli on MRI. The patient experienced brain herniation while in the intensive care unit and later was declared brain-dead. According to the literature, it is important to maintain high suspicion for FES and possible CFE in the setting of high-energy fracture but also to be aware that FES may develop even with nondisplaced fracture or with reaming of the intramedullary canal in elective total joint arthroplasty.¹⁸

Pathophysiology of Fat Embolism Syndrome

The pathophysiology of FES and specifically of CFE is not widely understood. Two main theories on the development of FES have been advanced.

The mechanical theory suggests that exposing intramedullary long-bone contents allows fat to mobilize into the bloodstream.¹⁹ This occurs in the setting of long-bone fracture and in canal preparation during joint replacement surgery. More fat extravasates into the venous system after femur fracture than after tibia fracture, which accounts for the higher risk for FES in femoral shaft fractures and the even higher risk in concomitant femur and tibia fractures.⁴ In addition to there being a risk of fat embolism from the fracture itself, placing the patient in traction or reaming the intramedullary canal may exacerbate this effect by increased extravasation of fat from the medullary canal. With extravasation of fatty bone marrow into the venous system, fat emboli are free to travel back to the lungs, where they can cause infarcts within the lung parenchyma.

In the mechanical theory, presence of PFO may allow fat globules to pass into the systemic circulation and cause end-organ emboli. In the event of cerebral emboli, neurologic symptoms may vary widely and may include diffuse encephalopathy and global deficits.²⁰ Dog studies have found a possible mechanism for CFE in the absence of PFO. One such study, which used femoral pressurization to replicate cemented femoral arthroplasty, found that many fat globules had traversed the lungs after release into bone marrow,²¹ supporting the theory that fat droplets can traverse the pulmonary system without sequestration in the lung parenchyma. Riding and colleagues²² reported finding pulmonary arteriovenous shunts, which are thought to allow CFE to occur in the absence of PFO. More studies are needed to determine the prevalence of shunts and their overall contribution to CFE development in patients with long-bone fracture.

The biochemical theory holds that bodily trauma induces the release of free fatty acids (FFAs) from the capillaries into the bloodstream.²³ This stress response is mediated by catecholamines, which activate the adenyl cyclase pathway, which activates lipase, which hydrolyzes stored triglycerides to FFAs and glycerol. The concentration of circulating FFA was increased in 9 of 10 patients in one study.²³ Increased FFAs in the bloodstream can accelerate local and end-organ clotting, leading to thrombocytopenia and endothelial injury. In addition, patients with hypercoagulable diseases are at higher risk for postoperative thromboembolism.²⁴ However, with a negative hypercoagulable work-up and with negative chest helical CT and EKG, which did not demonstrate PFO, the explanation for CFE in our patient may more likely reside with the arteriovenous shunt theory proposed by Riding and colleagues.²²

Diagnosis and Treatment

Proper care of orthopedic patients who potentially have FES/CFE involves prompt diagnosis, immediate symptomatic care, and early coordination with neurology and medical services to rule out other causes of symptoms. Obtaining advanced imaging to rule out other potential causes and to confirm the diagnosis is crucial. The patient in this case report did not exhibit any focal neurologic deficits, but emergent CT of the brain was indicated to rule out a hemorrhagic event. If a stroke secondary to FES is clinically suspected, MRI should be obtained as soon as possible. Multiple studies have found that the “starfield” pattern, which is best seen as multiple punctate hyperintensities on T2 imaging, is the typical radiographic manifestation of CFE.⁹ This applies to patients who are in the 24- to 72-hour window after long-bone fracture or fixation and who fit Gurd and Wilson¹ criteria or Lindeque^1,2criteria, or who exhibit a change in mental status but have a negative CT scan of the brain, as was the case with our patient. Once the diagnosis is made, treatment involves addressing the symptoms (Figure 4).

Fat Embolism Syndrome in Reamed and Unreamed Nailing

Over the past several decades, the number of long bones fixed with intramedullary nails has increased significantly.²⁶ There is debate regarding whether use of reamed intramedullary nails increases the risk of fat emboli relative to use of unreamed nails, but multiple studies have found no significant difference.^26,27 Pulmonary shunting occurs in both reamed and unreamed nailing; neither technique has an advantage in terms of cardiopulmonary complications. In multiple studies, reamed nails have the advantage of improved healing rates.²⁷ A sheep study compared reamed and unreamed femoral nailing.²⁸ After nailing, sheep lungs were examined histologically for the presence of bone marrow fat embolism. The embolism rate was higher with unreamed nailing (10.25%) than with reamed nailing (6.66%). One large study of the adverse effects of reamed and unreamed nailing in 1226 patients with tibial shaft fracture found that those with open fractures had higher rates of a negative event (nonunion, infection, fasciotomy, hardware failure, need for dynamization) after reamed nailing.²⁹ Patients with closed fractures had fewer events after reamed nailing. The authors concluded there is a potential benefit in outcome with reamed intramedullary nailing in patients with closed tibial shaft fractures, but they did not comment on development of FES. In a study of the effect of subject position on intramedullary pressure and fat embolism release, dogs were positioned either supine or lateral for tibial and femoral reaming.³⁰ The authors measured various physiologic parameters, including cardiac output, pulmonary arterial wedge pressure, arterial and venous blood gas, and blood cell counts. There were no statistically significant differences in values between the 2 groups in any variable, indicating that position does not affect FES development in the orthopedic trauma setting.

Conclusion

FES and CFE are potential devastating sequelae of both long-bone fracture and long-bone instrumentation. It is important to recognize these entities in the acute setting and to consider them in the differential diagnosis of a trauma or postoperative patient who experiences sudden onset of altered mental status with or without dyspnea or a petechial rash. If CFE is suspected, early advanced imaging (including urgent MRI) should be obtained with rapid involvement of a multidisciplinary team that can optimize the chance for successful recovery of both neurologic and physical function. The best treatment, early prevention and diagnosis, maximizes care of symptoms. As is evidenced in this case report, rapid diagnosis and treatment often result in recovery from a majority of the symptoms of FES and CFE.

Am J Orthop. 2016;45(7):E515-E521. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Septic arthritis is a common orthopedic emergency. The most common causative organism is Staphylococcus aureus. Mycotic infections, such as those involving Candida organisms, are much less common but just as debilitating. Delayed diagnosis of septic arthritis caused by Candida infection may result in increased morbidity, making treatment more challenging. Here we report a case of Candida albicans septic arthritis of the ankle and subtalar joint in a patient with diabetes mellitus (DM) and rheumatoid arthritis (RA). The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 52-year-old woman with type 2 DM (requiring subcutaneous insulin analogue therapy) and RA presented to a local emergency department with a 3-day history of right ankle pain after having the subtalar joint injected with steroid by a rheumatologist 4 weeks earlier. For about 2 weeks, there was purulent discharge from the peroneal sheath. The patient’s RA was being treated with prednisolone (maintenance therapy). Physical examination revealed low-grade pyrexia (37.8°C) and difficulty bearing full weight on the ankle. Clinically, the joint was not erythematous, but active and passive movements were painful. Blood tests revealed a C-reactive protein level of 98 mg/dL and a white blood cell (WBC) count of 11.3 × 10⁹/L. Erythrocyte sedimentation rate (ESR) was not checked. The ankle underwent magnetic resonance imaging (Figures A-D).

Mycotic screening of the fluid was positive for C albicans. The patient was referred to the orthopedic team, which performed urgent arthroscopic surgical débridement, biopsy, and washout of the subtalar joint. After surgery, a 6-week course of antifungal therapy with anidulafungin was started, per specialist microbiology advice.

The septic ankle was successfully managed with arthroscopic surgical débridement followed by treatment with anidulafungin. The patient continued to make good progress and was weight-bearing when discharged home from the orthopedic unit.

Discussion

Worldwide, about 1 in 6 people has arthritis, which affects daily lifestyle and reduces quality of life. Degenerative, inflammatory, and septic arthritis each has its management challenges.¹

Septic arthritis is an acute infection of the joint, usually of bacterial etiology. It can present as a polyarticular arthropathy (~15% of cases),^2,3 but a monoarthropathy of the hip, knee, or ankle is more common.⁴The Kocher criteria are often applied to cases of suspected septic arthritis of joints, even though they were initially used to distinguish septic arthritis from transient synovitis in pediatric hip joints.⁵ Kocher and colleagues⁵ reported 4 key clinical criteria: inability to bear weight, WBC count over 12 × 10⁹/L, ESR over 40 mm/h, and temperature over 38.5°C. When all 4 criteria are met, the predictive value is 99.6%. These criteria are now widely applied to adult joints, and not only the hips.

In septic arthritis, the most common causative pathogen is S aureus.^3,6Streptococcus, Neisseria, and Pseudomonas also are common.⁷ Although much rarer, Candida variants and other mycotic pathogens have been implicated as well.⁸C albicans is a well-known fungus that colonizes mucosal surfaces. Research indicates increased oral C albicans colonization in rheumatoid patients.⁹ Although most Candida septic arthritis cases are caused by C albicans, there is no large body of data showing the true incidence of fungal pathogens in septic arthritis.

Our literature search yielded 2 case reports on Candida septic arthritis involving the ankle, but the causative organisms were Candida parapsilosis and Candida glabrata.^9,10 Cases of Candida septic arthritis involving the knee or shoulder have also been reported.^11-15 Case reports demonstrate that Candida fungal arthritis is extremely rare.⁹ Etiology reportedly includes direct intra-articular inoculation by surgery or secondary to hematogenous seeding, particularly in immunocompromised patients.¹⁰ Risk factors include immunosuppression and joint suppression. DM and RA are common comorbidities in patients with septic arthritis.^6,16 The pathophysiology of RA is inflammatory pannus formation of the periarticular surface with subsequent articular cartilage destruction and erosion, as well as progressive deformity and functional debilitation.¹Patients with DM are at increased risk for developing fungal and other infections. Factors increasing this risk include disruption of skin-barrier integrity; reduced peripheral oxygen and blood supply, which also disrupts antibiotic delivery; and hyperglycemia-induced reduction in antibody function and disruption of phagocytosis and chemotaxis.¹⁷Fungi are eukaryotic, and infections caused by these organisms are difficult to treat.¹⁸ As fungal infections are more prevalent among immunosuppressed patients, they often result in prolonged treatment without guarantee of eradication, as spores may persist subclinically.

Literature on C albicans septic arthritis is lacking in general but especially in rheumatoid patients. Delayed diagnosis and suboptimal treatment may result in fungal osteomyelitis. There is little evidence on treating this rare fungal complication, and outcomes historically have been poor.¹⁹In an animal model, Marijnissen and colleagues²⁰ found that C albicans infection can increase destruction in an arthritic joint by cytokine environment modification. The result was advanced destruction of the joint and debilitation. For disease management, the authors considered these essential: early diagnosis, prompt treatment, and, as indicated, surgical débridement.

Treatment of Candida septic arthritis largely involves use of antifungal medication, either with surgical débridement, as in our patient’s case, or without. Which antifungal medication to use should be based on sensitivities, identified from wound aspirate, and microbiology advice about treatment duration. The antibiotic should be a broad-spectrum antifungal cover, in keeping with local antibiotic prescribing guidelines, which can be refined once definitive organism culture and sensitivity results are known. However, early aggressive treatment is essential. Periprosthetic fungal infection is rarely resolved without implant removal.²¹

Conclusion

This case reflects the complexities of septic arthritis caused by atypical pathogens and highlights the need for clinical vigilance in the setting of comorbidities, such as DM and RA. Failure to consider the diagnosis early on might result in delayed and inadequate treatment, increased joint destruction, and, potentially, osteomyelitis with subsequent increased morbidity. Early diagnosis (based on joint aspirate findings), surgical débridement, and prolonged aggressive treatment with antifungal medication are the mainstays of treatment.

Am J Orthop. 2016;45(7):E478-E480. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Septic arthritis is a common orthopedic emergency. The most common causative organism is Staphylococcus aureus. Mycotic infections, such as those involving Candida organisms, are much less common but just as debilitating. Delayed diagnosis of septic arthritis caused by Candida infection may result in increased morbidity, making treatment more challenging. Here we report a case of Candida albicans septic arthritis of the ankle and subtalar joint in a patient with diabetes mellitus (DM) and rheumatoid arthritis (RA). The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 52-year-old woman with type 2 DM (requiring subcutaneous insulin analogue therapy) and RA presented to a local emergency department with a 3-day history of right ankle pain after having the subtalar joint injected with steroid by a rheumatologist 4 weeks earlier. For about 2 weeks, there was purulent discharge from the peroneal sheath. The patient’s RA was being treated with prednisolone (maintenance therapy). Physical examination revealed low-grade pyrexia (37.8°C) and difficulty bearing full weight on the ankle. Clinically, the joint was not erythematous, but active and passive movements were painful. Blood tests revealed a C-reactive protein level of 98 mg/dL and a white blood cell (WBC) count of 11.3 × 10⁹/L. Erythrocyte sedimentation rate (ESR) was not checked. The ankle underwent magnetic resonance imaging (Figures A-D).

Mycotic screening of the fluid was positive for C albicans. The patient was referred to the orthopedic team, which performed urgent arthroscopic surgical débridement, biopsy, and washout of the subtalar joint. After surgery, a 6-week course of antifungal therapy with anidulafungin was started, per specialist microbiology advice.

The septic ankle was successfully managed with arthroscopic surgical débridement followed by treatment with anidulafungin. The patient continued to make good progress and was weight-bearing when discharged home from the orthopedic unit.

Discussion

Worldwide, about 1 in 6 people has arthritis, which affects daily lifestyle and reduces quality of life. Degenerative, inflammatory, and septic arthritis each has its management challenges.¹

Septic arthritis is an acute infection of the joint, usually of bacterial etiology. It can present as a polyarticular arthropathy (~15% of cases),^2,3 but a monoarthropathy of the hip, knee, or ankle is more common.⁴The Kocher criteria are often applied to cases of suspected septic arthritis of joints, even though they were initially used to distinguish septic arthritis from transient synovitis in pediatric hip joints.⁵ Kocher and colleagues⁵ reported 4 key clinical criteria: inability to bear weight, WBC count over 12 × 10⁹/L, ESR over 40 mm/h, and temperature over 38.5°C. When all 4 criteria are met, the predictive value is 99.6%. These criteria are now widely applied to adult joints, and not only the hips.

In septic arthritis, the most common causative pathogen is S aureus.^3,6Streptococcus, Neisseria, and Pseudomonas also are common.⁷ Although much rarer, Candida variants and other mycotic pathogens have been implicated as well.⁸C albicans is a well-known fungus that colonizes mucosal surfaces. Research indicates increased oral C albicans colonization in rheumatoid patients.⁹ Although most Candida septic arthritis cases are caused by C albicans, there is no large body of data showing the true incidence of fungal pathogens in septic arthritis.

Our literature search yielded 2 case reports on Candida septic arthritis involving the ankle, but the causative organisms were Candida parapsilosis and Candida glabrata.^9,10 Cases of Candida septic arthritis involving the knee or shoulder have also been reported.^11-15 Case reports demonstrate that Candida fungal arthritis is extremely rare.⁹ Etiology reportedly includes direct intra-articular inoculation by surgery or secondary to hematogenous seeding, particularly in immunocompromised patients.¹⁰ Risk factors include immunosuppression and joint suppression. DM and RA are common comorbidities in patients with septic arthritis.^6,16 The pathophysiology of RA is inflammatory pannus formation of the periarticular surface with subsequent articular cartilage destruction and erosion, as well as progressive deformity and functional debilitation.¹Patients with DM are at increased risk for developing fungal and other infections. Factors increasing this risk include disruption of skin-barrier integrity; reduced peripheral oxygen and blood supply, which also disrupts antibiotic delivery; and hyperglycemia-induced reduction in antibody function and disruption of phagocytosis and chemotaxis.¹⁷Fungi are eukaryotic, and infections caused by these organisms are difficult to treat.¹⁸ As fungal infections are more prevalent among immunosuppressed patients, they often result in prolonged treatment without guarantee of eradication, as spores may persist subclinically.

Literature on C albicans septic arthritis is lacking in general but especially in rheumatoid patients. Delayed diagnosis and suboptimal treatment may result in fungal osteomyelitis. There is little evidence on treating this rare fungal complication, and outcomes historically have been poor.¹⁹In an animal model, Marijnissen and colleagues²⁰ found that C albicans infection can increase destruction in an arthritic joint by cytokine environment modification. The result was advanced destruction of the joint and debilitation. For disease management, the authors considered these essential: early diagnosis, prompt treatment, and, as indicated, surgical débridement.

Treatment of Candida septic arthritis largely involves use of antifungal medication, either with surgical débridement, as in our patient’s case, or without. Which antifungal medication to use should be based on sensitivities, identified from wound aspirate, and microbiology advice about treatment duration. The antibiotic should be a broad-spectrum antifungal cover, in keeping with local antibiotic prescribing guidelines, which can be refined once definitive organism culture and sensitivity results are known. However, early aggressive treatment is essential. Periprosthetic fungal infection is rarely resolved without implant removal.²¹

Conclusion

This case reflects the complexities of septic arthritis caused by atypical pathogens and highlights the need for clinical vigilance in the setting of comorbidities, such as DM and RA. Failure to consider the diagnosis early on might result in delayed and inadequate treatment, increased joint destruction, and, potentially, osteomyelitis with subsequent increased morbidity. Early diagnosis (based on joint aspirate findings), surgical débridement, and prolonged aggressive treatment with antifungal medication are the mainstays of treatment.

Am J Orthop. 2016;45(7):E478-E480. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Septic arthritis is a common orthopedic emergency. The most common causative organism is Staphylococcus aureus. Mycotic infections, such as those involving Candida organisms, are much less common but just as debilitating. Delayed diagnosis of septic arthritis caused by Candida infection may result in increased morbidity, making treatment more challenging. Here we report a case of Candida albicans septic arthritis of the ankle and subtalar joint in a patient with diabetes mellitus (DM) and rheumatoid arthritis (RA). The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 52-year-old woman with type 2 DM (requiring subcutaneous insulin analogue therapy) and RA presented to a local emergency department with a 3-day history of right ankle pain after having the subtalar joint injected with steroid by a rheumatologist 4 weeks earlier. For about 2 weeks, there was purulent discharge from the peroneal sheath. The patient’s RA was being treated with prednisolone (maintenance therapy). Physical examination revealed low-grade pyrexia (37.8°C) and difficulty bearing full weight on the ankle. Clinically, the joint was not erythematous, but active and passive movements were painful. Blood tests revealed a C-reactive protein level of 98 mg/dL and a white blood cell (WBC) count of 11.3 × 10⁹/L. Erythrocyte sedimentation rate (ESR) was not checked. The ankle underwent magnetic resonance imaging (Figures A-D).

Mycotic screening of the fluid was positive for C albicans. The patient was referred to the orthopedic team, which performed urgent arthroscopic surgical débridement, biopsy, and washout of the subtalar joint. After surgery, a 6-week course of antifungal therapy with anidulafungin was started, per specialist microbiology advice.

The septic ankle was successfully managed with arthroscopic surgical débridement followed by treatment with anidulafungin. The patient continued to make good progress and was weight-bearing when discharged home from the orthopedic unit.

Discussion

Worldwide, about 1 in 6 people has arthritis, which affects daily lifestyle and reduces quality of life. Degenerative, inflammatory, and septic arthritis each has its management challenges.¹

Septic arthritis is an acute infection of the joint, usually of bacterial etiology. It can present as a polyarticular arthropathy (~15% of cases),^2,3 but a monoarthropathy of the hip, knee, or ankle is more common.⁴The Kocher criteria are often applied to cases of suspected septic arthritis of joints, even though they were initially used to distinguish septic arthritis from transient synovitis in pediatric hip joints.⁵ Kocher and colleagues⁵ reported 4 key clinical criteria: inability to bear weight, WBC count over 12 × 10⁹/L, ESR over 40 mm/h, and temperature over 38.5°C. When all 4 criteria are met, the predictive value is 99.6%. These criteria are now widely applied to adult joints, and not only the hips.

In septic arthritis, the most common causative pathogen is S aureus.^3,6Streptococcus, Neisseria, and Pseudomonas also are common.⁷ Although much rarer, Candida variants and other mycotic pathogens have been implicated as well.⁸C albicans is a well-known fungus that colonizes mucosal surfaces. Research indicates increased oral C albicans colonization in rheumatoid patients.⁹ Although most Candida septic arthritis cases are caused by C albicans, there is no large body of data showing the true incidence of fungal pathogens in septic arthritis.

Our literature search yielded 2 case reports on Candida septic arthritis involving the ankle, but the causative organisms were Candida parapsilosis and Candida glabrata.^9,10 Cases of Candida septic arthritis involving the knee or shoulder have also been reported.^11-15 Case reports demonstrate that Candida fungal arthritis is extremely rare.⁹ Etiology reportedly includes direct intra-articular inoculation by surgery or secondary to hematogenous seeding, particularly in immunocompromised patients.¹⁰ Risk factors include immunosuppression and joint suppression. DM and RA are common comorbidities in patients with septic arthritis.^6,16 The pathophysiology of RA is inflammatory pannus formation of the periarticular surface with subsequent articular cartilage destruction and erosion, as well as progressive deformity and functional debilitation.¹Patients with DM are at increased risk for developing fungal and other infections. Factors increasing this risk include disruption of skin-barrier integrity; reduced peripheral oxygen and blood supply, which also disrupts antibiotic delivery; and hyperglycemia-induced reduction in antibody function and disruption of phagocytosis and chemotaxis.¹⁷Fungi are eukaryotic, and infections caused by these organisms are difficult to treat.¹⁸ As fungal infections are more prevalent among immunosuppressed patients, they often result in prolonged treatment without guarantee of eradication, as spores may persist subclinically.

Literature on C albicans septic arthritis is lacking in general but especially in rheumatoid patients. Delayed diagnosis and suboptimal treatment may result in fungal osteomyelitis. There is little evidence on treating this rare fungal complication, and outcomes historically have been poor.¹⁹In an animal model, Marijnissen and colleagues²⁰ found that C albicans infection can increase destruction in an arthritic joint by cytokine environment modification. The result was advanced destruction of the joint and debilitation. For disease management, the authors considered these essential: early diagnosis, prompt treatment, and, as indicated, surgical débridement.

Treatment of Candida septic arthritis largely involves use of antifungal medication, either with surgical débridement, as in our patient’s case, or without. Which antifungal medication to use should be based on sensitivities, identified from wound aspirate, and microbiology advice about treatment duration. The antibiotic should be a broad-spectrum antifungal cover, in keeping with local antibiotic prescribing guidelines, which can be refined once definitive organism culture and sensitivity results are known. However, early aggressive treatment is essential. Periprosthetic fungal infection is rarely resolved without implant removal.²¹

Conclusion

This case reflects the complexities of septic arthritis caused by atypical pathogens and highlights the need for clinical vigilance in the setting of comorbidities, such as DM and RA. Failure to consider the diagnosis early on might result in delayed and inadequate treatment, increased joint destruction, and, potentially, osteomyelitis with subsequent increased morbidity. Early diagnosis (based on joint aspirate findings), surgical débridement, and prolonged aggressive treatment with antifungal medication are the mainstays of treatment.

Am J Orthop. 2016;45(7):E478-E480. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

An 89-year-old man presented to the ED with facial trauma due to a mechanical fall after losing his balance on uneven pavement and hitting the right side of his face. Physical examination revealed an ecchymosis inferior to the right eye and tenderness to palpation at the right maxilla and bilateral nasolabial folds. Maxillofacial computed tomography (CT) was ordered for further evaluation; representative images are presented above (Figure 1a and 1b).

What is the diagnosis?

Answer

A noncontrast CT of the maxillofacial bones demonstrated acute fractures through the bilateral pterygoid plates (white arrows, Figure 2a). The fractures extended through the medial and lateral walls of the bilateral maxillary sinuses (red arrows, Figure 2a), and propagated to the frontal processes of the maxilla (red arrows, Figure 2b), extending toward the alveolar process, indicating involvement of the anterolateral margin of the nasal fossa. The full extent of the fracture is best seen on a 3D-reconstructed image (red arrows, Figure 3). Additional images (not presented here) confirmed no fracture involvement of the orbital floors, nasal bones, or zygomatic arches. Expected posttraumatic hemorrhage was appreciated within the maxillary sinuses (white asterisks, Figure 2a).

Le Fort Fractures

The findings described above are characteristic of a Le Fort I fracture pattern. Initially described in 1901 by René Le Fort, a French surgeon, the Le Fort classification system details somewhat predictable midface fracture patterns resulting in various degrees of craniofacial disassociation.¹ Using weights that were dropped on cadaveric heads, Le Fort discovered that the pterygoid plates must be disrupted in order for the midface facial bones to separate from the skull base. As such, when diagnosing a Le Fort fracture, fracture of the pterygoid plate must be present, regardless of the fracture type (Le Fort I, II, and III).²

Le Fort I Fracture. This fracture pattern (red line, Figure 4) is referred to as a “floating palate” and involves separation of the hard palate from the skull base via fracture extension from the pterygoid plates into the maxillary sinus walls, as demonstrated in this case. The key distinguisher of the Le Fort I pattern is involvement of the anterolateral margin of the nasal fossa.²

Le Fort II Fracture. This fracture pattern (blue line, Figure 4) describes a “floating maxilla” wherein the pterygoid plate fractures are met with a pyramidal-type fracture pattern of the midface. The maxillary teeth form the base of the pyramid, and the fracture extends superiorly through the infraorbital rims bilaterally and toward the nasofrontal suture.^2,3 Le Fort II fractures result in the maxilla floating freely from the rest of the midface and skull base.

Le Fort III Fracture. This fracture pattern (green lines, Figure 4) describes a “floating face” with complete craniofacial disjunction resulting from fracture of the pterygoid plates, nasofrontal suture, maxillofrontal suture, orbital wall, and zygomatic arch/zygomaticofrontal suture.^2,3

It is important to note that midface trauma represents a complex spectrum of injuries, and Le Fort fractures only account for a small percentage of facial bone fractures that present through Level 1 trauma centers.² Le Fort fracture patterns can coexist with other fracture patterns and also can be seen in combination with each other. For example, one side of the face may demonstrate a Le Fort II pattern while the other side concurrently demonstrates a Le Fort III pattern. Though not robust enough for complete description of and surgical planning for facial fractures, this classification system is a succinct and well-accepted means of describing major fracture planes.

An 89-year-old man presented to the ED with facial trauma due to a mechanical fall after losing his balance on uneven pavement and hitting the right side of his face. Physical examination revealed an ecchymosis inferior to the right eye and tenderness to palpation at the right maxilla and bilateral nasolabial folds. Maxillofacial computed tomography (CT) was ordered for further evaluation; representative images are presented above (Figure 1a and 1b).

What is the diagnosis?

Answer

A noncontrast CT of the maxillofacial bones demonstrated acute fractures through the bilateral pterygoid plates (white arrows, Figure 2a). The fractures extended through the medial and lateral walls of the bilateral maxillary sinuses (red arrows, Figure 2a), and propagated to the frontal processes of the maxilla (red arrows, Figure 2b), extending toward the alveolar process, indicating involvement of the anterolateral margin of the nasal fossa. The full extent of the fracture is best seen on a 3D-reconstructed image (red arrows, Figure 3). Additional images (not presented here) confirmed no fracture involvement of the orbital floors, nasal bones, or zygomatic arches. Expected posttraumatic hemorrhage was appreciated within the maxillary sinuses (white asterisks, Figure 2a).

Le Fort Fractures

The findings described above are characteristic of a Le Fort I fracture pattern. Initially described in 1901 by René Le Fort, a French surgeon, the Le Fort classification system details somewhat predictable midface fracture patterns resulting in various degrees of craniofacial disassociation.¹ Using weights that were dropped on cadaveric heads, Le Fort discovered that the pterygoid plates must be disrupted in order for the midface facial bones to separate from the skull base. As such, when diagnosing a Le Fort fracture, fracture of the pterygoid plate must be present, regardless of the fracture type (Le Fort I, II, and III).²

Le Fort I Fracture. This fracture pattern (red line, Figure 4) is referred to as a “floating palate” and involves separation of the hard palate from the skull base via fracture extension from the pterygoid plates into the maxillary sinus walls, as demonstrated in this case. The key distinguisher of the Le Fort I pattern is involvement of the anterolateral margin of the nasal fossa.²

Le Fort II Fracture. This fracture pattern (blue line, Figure 4) describes a “floating maxilla” wherein the pterygoid plate fractures are met with a pyramidal-type fracture pattern of the midface. The maxillary teeth form the base of the pyramid, and the fracture extends superiorly through the infraorbital rims bilaterally and toward the nasofrontal suture.^2,3 Le Fort II fractures result in the maxilla floating freely from the rest of the midface and skull base.

Le Fort III Fracture. This fracture pattern (green lines, Figure 4) describes a “floating face” with complete craniofacial disjunction resulting from fracture of the pterygoid plates, nasofrontal suture, maxillofrontal suture, orbital wall, and zygomatic arch/zygomaticofrontal suture.^2,3

It is important to note that midface trauma represents a complex spectrum of injuries, and Le Fort fractures only account for a small percentage of facial bone fractures that present through Level 1 trauma centers.² Le Fort fracture patterns can coexist with other fracture patterns and also can be seen in combination with each other. For example, one side of the face may demonstrate a Le Fort II pattern while the other side concurrently demonstrates a Le Fort III pattern. Though not robust enough for complete description of and surgical planning for facial fractures, this classification system is a succinct and well-accepted means of describing major fracture planes.

An 89-year-old man presented to the ED with facial trauma due to a mechanical fall after losing his balance on uneven pavement and hitting the right side of his face. Physical examination revealed an ecchymosis inferior to the right eye and tenderness to palpation at the right maxilla and bilateral nasolabial folds. Maxillofacial computed tomography (CT) was ordered for further evaluation; representative images are presented above (Figure 1a and 1b).

What is the diagnosis?

Answer

A noncontrast CT of the maxillofacial bones demonstrated acute fractures through the bilateral pterygoid plates (white arrows, Figure 2a). The fractures extended through the medial and lateral walls of the bilateral maxillary sinuses (red arrows, Figure 2a), and propagated to the frontal processes of the maxilla (red arrows, Figure 2b), extending toward the alveolar process, indicating involvement of the anterolateral margin of the nasal fossa. The full extent of the fracture is best seen on a 3D-reconstructed image (red arrows, Figure 3). Additional images (not presented here) confirmed no fracture involvement of the orbital floors, nasal bones, or zygomatic arches. Expected posttraumatic hemorrhage was appreciated within the maxillary sinuses (white asterisks, Figure 2a).

Le Fort Fractures

The findings described above are characteristic of a Le Fort I fracture pattern. Initially described in 1901 by René Le Fort, a French surgeon, the Le Fort classification system details somewhat predictable midface fracture patterns resulting in various degrees of craniofacial disassociation.¹ Using weights that were dropped on cadaveric heads, Le Fort discovered that the pterygoid plates must be disrupted in order for the midface facial bones to separate from the skull base. As such, when diagnosing a Le Fort fracture, fracture of the pterygoid plate must be present, regardless of the fracture type (Le Fort I, II, and III).²

Le Fort I Fracture. This fracture pattern (red line, Figure 4) is referred to as a “floating palate” and involves separation of the hard palate from the skull base via fracture extension from the pterygoid plates into the maxillary sinus walls, as demonstrated in this case. The key distinguisher of the Le Fort I pattern is involvement of the anterolateral margin of the nasal fossa.²

Le Fort II Fracture. This fracture pattern (blue line, Figure 4) describes a “floating maxilla” wherein the pterygoid plate fractures are met with a pyramidal-type fracture pattern of the midface. The maxillary teeth form the base of the pyramid, and the fracture extends superiorly through the infraorbital rims bilaterally and toward the nasofrontal suture.^2,3 Le Fort II fractures result in the maxilla floating freely from the rest of the midface and skull base.

Le Fort III Fracture. This fracture pattern (green lines, Figure 4) describes a “floating face” with complete craniofacial disjunction resulting from fracture of the pterygoid plates, nasofrontal suture, maxillofrontal suture, orbital wall, and zygomatic arch/zygomaticofrontal suture.^2,3

It is important to note that midface trauma represents a complex spectrum of injuries, and Le Fort fractures only account for a small percentage of facial bone fractures that present through Level 1 trauma centers.² Le Fort fracture patterns can coexist with other fracture patterns and also can be seen in combination with each other. For example, one side of the face may demonstrate a Le Fort II pattern while the other side concurrently demonstrates a Le Fort III pattern. Though not robust enough for complete description of and surgical planning for facial fractures, this classification system is a succinct and well-accepted means of describing major fracture planes.

Case

A 68-year-old woman presented to the ED 5 days after receiving onabotulinumtoxinA cosmetic injections for wrinkles of the face and neck. She stated that she was unable to raise her head while in a supine position and that her head felt heavy when standing. She also experienced spasms and strain of the posterior cervical neck muscles. In addition, the patient described a constant need to swallow forcefully throughout the day, and felt an intermittent heavy sensation over her larynx that was associated with stridor. She noted these symptoms began 5 days after the onabotulinumtoxinA injections and had peaked 2 days prior to presentation. She also complained of dysphagia without odynophagia, but denied any changes in her voice.

The patient first began onabotulinumtoxinA injections 12 years earlier for aesthetic treatment of glabellar and peri-orbital wrinkles. She initially received the injections at a regular interval of 90 to 100 days. During the course of the first 2 years of treatment, the patient was under the care of a plastic surgeon; thereafter, she sought treatment at a physician-owned medical spa because it offered onabotulinumtoxinA at a lower price. The injections at the medical spa were administered by a physician assistant (PA). The patient stated that although the PA had steadily increased the dose of onabotulinumtoxinA to maintain the desired aesthetic effect, this was the first time she had experienced any side effects from the treatment.

The ED staff contacted the medical spa provider, who reviewed the patient’s medical record over the telephone. The PA stated that he had been the only practitioner at the facility to administer the onabotulinumtoxinA injections to the patient over her past 10 years there as a client. He further informed the emergency physician (EP) that 12 days prior to presentation, he had given the patient a total of 50 IU of onabotulinumtoxinA, in five separate injections, into the mid frontalis muscle; a total of 35 IU, in seven separate injections, into the glabellar region (procerus and corrugator muscles bilaterally); 20 IU into the lateral and inferior-lateral orbicularis oculi bilaterally, in four separate injections per side, (40 IU total); and a total of 100 IU in the anterior platysma, in 20 separate injections, for a total 1-day onabotulinumtoxinA dose of 225 IU.

The PA explained to the EP that he mixed the onabotulinumtoxinA in the patient’s room and had shown her the vials and dilution standard as recommended by the manufacturer because she had been requiring increased dosages and had previously questioned whether the onabotulinumtoxinA was diluted. The PA denied any other patients experiencing similar adverse events as those of the patient’s.

Over the last 10 years, the patient had received onabotulinumtoxinA in the nasolabial folds, upper and lower lip wrinkles, mentalis, depressor angular oris, buccal, nasalis, lateral brow, masseter, and calf muscles. The dosage of onabotulinumtoxinA at this most recent injection cycle was unchanged from her previous visit 3 months prior. According to the PA, the practice did not use abobotulinumtoxinA or incobotulinumtoxinA.

Regarding the patient’s medical history, she had no health issues suggestive of myasthenia gravis, multiple sclerosis, or Guillain-Barré syndrome. Examination of the face revealed decreased muscle excursion of the frontalis muscle from mid-brow to mid-brow, and stair-step wrinkle formation bilaterally. The procerus muscle was very weak, and the corrugator muscles were moderately diminished in strength. The lateral orbicularis oculi were very weak at each canthus. The extra-ocular muscles were intact. She had full mandibular excursion, and powerful movement of the tongue. The oropharynx and floor of the mouth were normal. She was noted to purposefully swallow and extend her neck every 90 to 120 seconds to “clear her throat,” though she did not drool and was able to handle her secretions and swallow fluids without aspiration. Her voice was normal and she was able to recite the letters “KKKKK,” “OOOOO,” and “EEEEE” in rapid fashion without breathiness or stridor. The rest of her facial muscles were normal.

While supine, the patient strained to lift her head and complained of a suffocating sensation over the larynx. She had no rashes or edema, and the remainder of the physical examination, vital signs, and pulse oximetry were normal. Laboratory evaluation, which included a complete blood count and serum electrolytes, was also normal.

An otolaryngologist consultation for laryngoscopy was obtained. After reviewing the patient’s case, the otolaryngologist concluded that given the patient’s history, intermittent stridor, and an absence of signs or symptoms suggestive of an impending upper airway obstruction (UAO), laryngoscopy was not warranted.

A plastic surgery consultation was then obtained. The patient’s examination was as noted above, and her vital signs and pulse oximetry remained normal throughout her ED stay. Although botulinum and botulinum antibody titers were ordered, the patient refused testing due to cost concerns. She was discharged home by plastic surgery services with a diagnosis of floppy neck and dysphagia secondary to aesthetic botulinum toxin paralysis of the bilateral sternocleidomastoid muscles and platysma. She was given a prescription for metoclopramide hydrochloride to stimulate motility of the upper gastrointestinal tract and to potentially improve swallowing.¹⁰

The patient was scheduled for a follow-up evaluation with the plastic surgeon 2 days after discharge. She was instructed to call 911 if she experienced stridor, shortness of breath, drooling, or if any airway issues arose. The patient did not return for her follow-up appointment with the plastic surgeon.

Discussion

Clostridium Botulinum Toxins

Clostridium botulinum is a gram-positive spore-forming anaerobic bacterium that produces extremely potent neuro-exotoxins. C botulinum is found in soil, contaminated foods, and in illicit injectable drugs (eg, heroin). Seven distinct antigenic botulinum toxins (A, B, C1, D, E, F, and G) are produced by several strains of C botulinum. Systemically, each neurotoxin is able to produce severe morbidity and mortality by causing generalized muscle paralysis and death by respiratory failure. The lethal dose of these agents is approximating 10(-9) g/kg body weight. Botulinum toxin type A is the most potent.^1,2

Nonetheless, botulinum toxin has been used clinically since the early 1970s. Currently, there are three FDA-approved botulinum toxin type A agents and one type B formulation (rimabotulinumtoxinB) (Table). Each formulation is unique, proprietary, and differs in molecular weight, toxin-complex size, protein content, and inactive ingredients. The effectiveness and adverse event profile for these four botulinum toxins is individually dependent upon the different dilutions and potency, onset of action, duration of effect, diffusion, and migration potential. Hence, the effective dose of one botulinum toxin does not equate to any other, resulting in a lack of interchangeability between botulinum toxins (eg, 5 IU of incobotulinumtoxinA does not equal 5 IU of onabotulinumtoxinA).

Aesthetic Indications

Historically, the use of botulinum toxin for aesthetic treatment of wrinkles and platysmal bands was first reported by Blitzer³ in 1993.Subsequently, the use of botulinum toxin for the aesthetic treatment of facial wrinkles, hypertrophic platysmal bands and horizontal neck lines gained popularity within the public and medical community.^3-5

Anatomically, the platysma is a thin sheet-like muscle that originates in the superior fascia of the pectoralis and deltoid fascia, and extends over the full length of the neck up past the mandible and continuing into the submuscular aponeurotic system. The platysma is innervated by the seventh cranial nerve and functions to pull the jaw downward. The platysma muscle is attached directly to the skin. With normal aging, the anterior neck skin becomes flaccid, the central platysmal bands thicken and contract—forming bands, horizontal wrinkles, and loss of definition of the neck noticed at rest and with contraction of the platysma muscle. These vertical bands are known as platysmal bands. The platysmal bands are benign consequences of aging and as such are targets of correction through surgery or botulinum toxin injection.^6,7

Mechanism of Action

Platysmal band and horizontal line injection techniques with botulinum toxin have been reported in the literature with dosages ranging from 15 IU to 200 IU used to block the Soluble N-ethylmaleimide-sensitive factor activating protein receptors. Typical onset of action begins at 3 days, with full paralytic effect at 7 days. Repeat injections every 3 to 4 months are required with prolonged effects seen with each subsequent injection due to chemodenervation-induced muscle atrophy.^4,7,8

Adverse Effects

Commercial botulinum toxin type A has been associated with minor and transient side effects. Moderate complications seen in the neck region include transient soft-tissue edema, dermal ecchymoses, intramuscular hematoma, diffuse muscle soreness, neck flexor weakness, and headaches.^4,8,9

The use of botulinum toxin for chemodenervation of the platysma can produce significant weakness of other neck muscles, including the sternocleidomastoid, cricothyroid, sternothyroid, and sternohyoid. Floppy neck and dysphagia may be due to diffusion of the toxin into the muscles of deglutition of the larynx; injection directly into the sternocleidomastoid muscle; or a result of the systemic effects of large dosages. Hoarseness, breathiness, and dysphagia may occur 3 to 4 days after injection, especially with doses over 75 IU.¹⁰

The recommended concentration of botulinum toxin type A causes a diffusion average of 1 cm in all directions from the injection sites. However, as the dilution increases, so does the zone of diffusion. Typical discharge instructions for platysma treatment include the overuse of the neck muscles for 2 to 4 hours after injection to encourage the botulinum toxin uptake for optimal result. Site manipulation (rubbing or massaging) also increases diffusion. For botulinum toxin type B, the zone of diffusion is greater because its molecular weight is less than the type A toxins, thus making it an undesirable agent for aesthetic facial chemodenervation.^4,11

Toxin Resistance

Botulinum toxin resistance is a known complication that occurs normally as a result of the body recognizing the neurotoxin as a foreign substance and producing neutralizing antibodies (NAb). Primary botulinum toxin failure is known in patients who require high doses of the neurotoxin for treatment of neuromuscular disorders.¹² Complete secondary therapy failure is known to occur in cosmetic patients after a single dose and those who have been receiving low-dose botulinum toxin regularly. The risk of NAb development increases with long-term treatment and high doses.^12-18

Floppy Neck and Dysphagia

As previously noted, floppy neck and dysphagia are adverse clinical findings of botulinum toxin effect on the platysma, sternocleidomastoid, or the paralaryngeal muscles. In this case, the patient was fortunate to have only sustained weakness of the platysma and sternocleidomastoid muscles despite both a large neck and total body dose. Paralaryngeal muscle paralysis is not life-threatening, but the distress may precipitate paradoxical vocal cord motion and stridor.

Stridor

Stridor is typically a symptom of an upper airway obstruction (UAO) process. Typical UAO conditions encountered in the ED are infections (eg, epiglottitis, croup), foreign body, allergy, and laryngeal trauma. The age of the patient, onset of stridor, course of the stridor (ie, intermittent, continuous, worsening), associated symptoms (eg, fever, rash, swelling of oral soft tissues), and bruising must be ascertained.

In differentiating the etiology of stridor, the EP should observe the patient for any associated change in voice, inability to handle secretions, and position of comfort. Patients with stridor require admission and evaluation by an otolaryngologist as expeditiously as possible because impending UAO may quickly progress to complete UAO necessitating emergent intubation.

An atypical presentation of stridor to the ED is sporadic stridor. Sporadic attacks of stridor during activity have been associated with the entity of paradoxical vocal cord motion. Patients usually describe a choking sensation with inability to breathe resulting in an audible inspiratory and/or expiratory sound—ie, stridor. Wheezing may or may not be present. Patients may also describe tightness in the neck and sometimes in the chest. The attacks are usually seconds to minutes in duration. More often, there is a precipitating or an inducing factor such as hyperventilation, cough, panting, phonatory tasks, or the inhalation of irritants or perfume, or an oropharyngeal or laryngeal manipulation prior or postextubation. The feeling of stress alone is commonly reported prior to the attacks. When evaluating patients presenting with floppy neck, dysphagia, and stridor, it is imperative that the clinician conduct a thorough history and physical examination to determine if the symptoms are secondary to a systemic or local effect, and whether the patient will progress to an acute UAO (vocal cord paralysis) necessitating intubation in the ED and subsequent tracheostomy.^19,20

Conclusion

The ready availability of botulinum toxins and their low-cost-benefit ratio continue to promote over-utilization for treatment of facial wrinkles, platysmal bands, and horizontal lines; migraine headache; and hyperhidrosis. Complications associated with overuse of botulinum toxins are due to either administration of a large single dose or from regional diffusion. With the increasing number of patients receiving botulinum injections, EPs should be aware of the four available toxin types onset of action, adverse events, and potential life-threatening complications of regional neck injections.

Case

A 68-year-old woman presented to the ED 5 days after receiving onabotulinumtoxinA cosmetic injections for wrinkles of the face and neck. She stated that she was unable to raise her head while in a supine position and that her head felt heavy when standing. She also experienced spasms and strain of the posterior cervical neck muscles. In addition, the patient described a constant need to swallow forcefully throughout the day, and felt an intermittent heavy sensation over her larynx that was associated with stridor. She noted these symptoms began 5 days after the onabotulinumtoxinA injections and had peaked 2 days prior to presentation. She also complained of dysphagia without odynophagia, but denied any changes in her voice.

The patient first began onabotulinumtoxinA injections 12 years earlier for aesthetic treatment of glabellar and peri-orbital wrinkles. She initially received the injections at a regular interval of 90 to 100 days. During the course of the first 2 years of treatment, the patient was under the care of a plastic surgeon; thereafter, she sought treatment at a physician-owned medical spa because it offered onabotulinumtoxinA at a lower price. The injections at the medical spa were administered by a physician assistant (PA). The patient stated that although the PA had steadily increased the dose of onabotulinumtoxinA to maintain the desired aesthetic effect, this was the first time she had experienced any side effects from the treatment.

The ED staff contacted the medical spa provider, who reviewed the patient’s medical record over the telephone. The PA stated that he had been the only practitioner at the facility to administer the onabotulinumtoxinA injections to the patient over her past 10 years there as a client. He further informed the emergency physician (EP) that 12 days prior to presentation, he had given the patient a total of 50 IU of onabotulinumtoxinA, in five separate injections, into the mid frontalis muscle; a total of 35 IU, in seven separate injections, into the glabellar region (procerus and corrugator muscles bilaterally); 20 IU into the lateral and inferior-lateral orbicularis oculi bilaterally, in four separate injections per side, (40 IU total); and a total of 100 IU in the anterior platysma, in 20 separate injections, for a total 1-day onabotulinumtoxinA dose of 225 IU.

The PA explained to the EP that he mixed the onabotulinumtoxinA in the patient’s room and had shown her the vials and dilution standard as recommended by the manufacturer because she had been requiring increased dosages and had previously questioned whether the onabotulinumtoxinA was diluted. The PA denied any other patients experiencing similar adverse events as those of the patient’s.

Over the last 10 years, the patient had received onabotulinumtoxinA in the nasolabial folds, upper and lower lip wrinkles, mentalis, depressor angular oris, buccal, nasalis, lateral brow, masseter, and calf muscles. The dosage of onabotulinumtoxinA at this most recent injection cycle was unchanged from her previous visit 3 months prior. According to the PA, the practice did not use abobotulinumtoxinA or incobotulinumtoxinA.

Regarding the patient’s medical history, she had no health issues suggestive of myasthenia gravis, multiple sclerosis, or Guillain-Barré syndrome. Examination of the face revealed decreased muscle excursion of the frontalis muscle from mid-brow to mid-brow, and stair-step wrinkle formation bilaterally. The procerus muscle was very weak, and the corrugator muscles were moderately diminished in strength. The lateral orbicularis oculi were very weak at each canthus. The extra-ocular muscles were intact. She had full mandibular excursion, and powerful movement of the tongue. The oropharynx and floor of the mouth were normal. She was noted to purposefully swallow and extend her neck every 90 to 120 seconds to “clear her throat,” though she did not drool and was able to handle her secretions and swallow fluids without aspiration. Her voice was normal and she was able to recite the letters “KKKKK,” “OOOOO,” and “EEEEE” in rapid fashion without breathiness or stridor. The rest of her facial muscles were normal.

While supine, the patient strained to lift her head and complained of a suffocating sensation over the larynx. She had no rashes or edema, and the remainder of the physical examination, vital signs, and pulse oximetry were normal. Laboratory evaluation, which included a complete blood count and serum electrolytes, was also normal.

An otolaryngologist consultation for laryngoscopy was obtained. After reviewing the patient’s case, the otolaryngologist concluded that given the patient’s history, intermittent stridor, and an absence of signs or symptoms suggestive of an impending upper airway obstruction (UAO), laryngoscopy was not warranted.

A plastic surgery consultation was then obtained. The patient’s examination was as noted above, and her vital signs and pulse oximetry remained normal throughout her ED stay. Although botulinum and botulinum antibody titers were ordered, the patient refused testing due to cost concerns. She was discharged home by plastic surgery services with a diagnosis of floppy neck and dysphagia secondary to aesthetic botulinum toxin paralysis of the bilateral sternocleidomastoid muscles and platysma. She was given a prescription for metoclopramide hydrochloride to stimulate motility of the upper gastrointestinal tract and to potentially improve swallowing.¹⁰

The patient was scheduled for a follow-up evaluation with the plastic surgeon 2 days after discharge. She was instructed to call 911 if she experienced stridor, shortness of breath, drooling, or if any airway issues arose. The patient did not return for her follow-up appointment with the plastic surgeon.

Discussion

Clostridium Botulinum Toxins

Clostridium botulinum is a gram-positive spore-forming anaerobic bacterium that produces extremely potent neuro-exotoxins. C botulinum is found in soil, contaminated foods, and in illicit injectable drugs (eg, heroin). Seven distinct antigenic botulinum toxins (A, B, C1, D, E, F, and G) are produced by several strains of C botulinum. Systemically, each neurotoxin is able to produce severe morbidity and mortality by causing generalized muscle paralysis and death by respiratory failure. The lethal dose of these agents is approximating 10(-9) g/kg body weight. Botulinum toxin type A is the most potent.^1,2

Nonetheless, botulinum toxin has been used clinically since the early 1970s. Currently, there are three FDA-approved botulinum toxin type A agents and one type B formulation (rimabotulinumtoxinB) (Table). Each formulation is unique, proprietary, and differs in molecular weight, toxin-complex size, protein content, and inactive ingredients. The effectiveness and adverse event profile for these four botulinum toxins is individually dependent upon the different dilutions and potency, onset of action, duration of effect, diffusion, and migration potential. Hence, the effective dose of one botulinum toxin does not equate to any other, resulting in a lack of interchangeability between botulinum toxins (eg, 5 IU of incobotulinumtoxinA does not equal 5 IU of onabotulinumtoxinA).

Aesthetic Indications

Historically, the use of botulinum toxin for aesthetic treatment of wrinkles and platysmal bands was first reported by Blitzer³ in 1993.Subsequently, the use of botulinum toxin for the aesthetic treatment of facial wrinkles, hypertrophic platysmal bands and horizontal neck lines gained popularity within the public and medical community.^3-5

Anatomically, the platysma is a thin sheet-like muscle that originates in the superior fascia of the pectoralis and deltoid fascia, and extends over the full length of the neck up past the mandible and continuing into the submuscular aponeurotic system. The platysma is innervated by the seventh cranial nerve and functions to pull the jaw downward. The platysma muscle is attached directly to the skin. With normal aging, the anterior neck skin becomes flaccid, the central platysmal bands thicken and contract—forming bands, horizontal wrinkles, and loss of definition of the neck noticed at rest and with contraction of the platysma muscle. These vertical bands are known as platysmal bands. The platysmal bands are benign consequences of aging and as such are targets of correction through surgery or botulinum toxin injection.^6,7

Mechanism of Action

Platysmal band and horizontal line injection techniques with botulinum toxin have been reported in the literature with dosages ranging from 15 IU to 200 IU used to block the Soluble N-ethylmaleimide-sensitive factor activating protein receptors. Typical onset of action begins at 3 days, with full paralytic effect at 7 days. Repeat injections every 3 to 4 months are required with prolonged effects seen with each subsequent injection due to chemodenervation-induced muscle atrophy.^4,7,8

Adverse Effects

Commercial botulinum toxin type A has been associated with minor and transient side effects. Moderate complications seen in the neck region include transient soft-tissue edema, dermal ecchymoses, intramuscular hematoma, diffuse muscle soreness, neck flexor weakness, and headaches.^4,8,9

The use of botulinum toxin for chemodenervation of the platysma can produce significant weakness of other neck muscles, including the sternocleidomastoid, cricothyroid, sternothyroid, and sternohyoid. Floppy neck and dysphagia may be due to diffusion of the toxin into the muscles of deglutition of the larynx; injection directly into the sternocleidomastoid muscle; or a result of the systemic effects of large dosages. Hoarseness, breathiness, and dysphagia may occur 3 to 4 days after injection, especially with doses over 75 IU.¹⁰

The recommended concentration of botulinum toxin type A causes a diffusion average of 1 cm in all directions from the injection sites. However, as the dilution increases, so does the zone of diffusion. Typical discharge instructions for platysma treatment include the overuse of the neck muscles for 2 to 4 hours after injection to encourage the botulinum toxin uptake for optimal result. Site manipulation (rubbing or massaging) also increases diffusion. For botulinum toxin type B, the zone of diffusion is greater because its molecular weight is less than the type A toxins, thus making it an undesirable agent for aesthetic facial chemodenervation.^4,11

Toxin Resistance

Botulinum toxin resistance is a known complication that occurs normally as a result of the body recognizing the neurotoxin as a foreign substance and producing neutralizing antibodies (NAb). Primary botulinum toxin failure is known in patients who require high doses of the neurotoxin for treatment of neuromuscular disorders.¹² Complete secondary therapy failure is known to occur in cosmetic patients after a single dose and those who have been receiving low-dose botulinum toxin regularly. The risk of NAb development increases with long-term treatment and high doses.^12-18

Floppy Neck and Dysphagia

As previously noted, floppy neck and dysphagia are adverse clinical findings of botulinum toxin effect on the platysma, sternocleidomastoid, or the paralaryngeal muscles. In this case, the patient was fortunate to have only sustained weakness of the platysma and sternocleidomastoid muscles despite both a large neck and total body dose. Paralaryngeal muscle paralysis is not life-threatening, but the distress may precipitate paradoxical vocal cord motion and stridor.

Stridor

Stridor is typically a symptom of an upper airway obstruction (UAO) process. Typical UAO conditions encountered in the ED are infections (eg, epiglottitis, croup), foreign body, allergy, and laryngeal trauma. The age of the patient, onset of stridor, course of the stridor (ie, intermittent, continuous, worsening), associated symptoms (eg, fever, rash, swelling of oral soft tissues), and bruising must be ascertained.

In differentiating the etiology of stridor, the EP should observe the patient for any associated change in voice, inability to handle secretions, and position of comfort. Patients with stridor require admission and evaluation by an otolaryngologist as expeditiously as possible because impending UAO may quickly progress to complete UAO necessitating emergent intubation.

An atypical presentation of stridor to the ED is sporadic stridor. Sporadic attacks of stridor during activity have been associated with the entity of paradoxical vocal cord motion. Patients usually describe a choking sensation with inability to breathe resulting in an audible inspiratory and/or expiratory sound—ie, stridor. Wheezing may or may not be present. Patients may also describe tightness in the neck and sometimes in the chest. The attacks are usually seconds to minutes in duration. More often, there is a precipitating or an inducing factor such as hyperventilation, cough, panting, phonatory tasks, or the inhalation of irritants or perfume, or an oropharyngeal or laryngeal manipulation prior or postextubation. The feeling of stress alone is commonly reported prior to the attacks. When evaluating patients presenting with floppy neck, dysphagia, and stridor, it is imperative that the clinician conduct a thorough history and physical examination to determine if the symptoms are secondary to a systemic or local effect, and whether the patient will progress to an acute UAO (vocal cord paralysis) necessitating intubation in the ED and subsequent tracheostomy.^19,20

Conclusion

The ready availability of botulinum toxins and their low-cost-benefit ratio continue to promote over-utilization for treatment of facial wrinkles, platysmal bands, and horizontal lines; migraine headache; and hyperhidrosis. Complications associated with overuse of botulinum toxins are due to either administration of a large single dose or from regional diffusion. With the increasing number of patients receiving botulinum injections, EPs should be aware of the four available toxin types onset of action, adverse events, and potential life-threatening complications of regional neck injections.

Case

A 68-year-old woman presented to the ED 5 days after receiving onabotulinumtoxinA cosmetic injections for wrinkles of the face and neck. She stated that she was unable to raise her head while in a supine position and that her head felt heavy when standing. She also experienced spasms and strain of the posterior cervical neck muscles. In addition, the patient described a constant need to swallow forcefully throughout the day, and felt an intermittent heavy sensation over her larynx that was associated with stridor. She noted these symptoms began 5 days after the onabotulinumtoxinA injections and had peaked 2 days prior to presentation. She also complained of dysphagia without odynophagia, but denied any changes in her voice.

The patient first began onabotulinumtoxinA injections 12 years earlier for aesthetic treatment of glabellar and peri-orbital wrinkles. She initially received the injections at a regular interval of 90 to 100 days. During the course of the first 2 years of treatment, the patient was under the care of a plastic surgeon; thereafter, she sought treatment at a physician-owned medical spa because it offered onabotulinumtoxinA at a lower price. The injections at the medical spa were administered by a physician assistant (PA). The patient stated that although the PA had steadily increased the dose of onabotulinumtoxinA to maintain the desired aesthetic effect, this was the first time she had experienced any side effects from the treatment.

The ED staff contacted the medical spa provider, who reviewed the patient’s medical record over the telephone. The PA stated that he had been the only practitioner at the facility to administer the onabotulinumtoxinA injections to the patient over her past 10 years there as a client. He further informed the emergency physician (EP) that 12 days prior to presentation, he had given the patient a total of 50 IU of onabotulinumtoxinA, in five separate injections, into the mid frontalis muscle; a total of 35 IU, in seven separate injections, into the glabellar region (procerus and corrugator muscles bilaterally); 20 IU into the lateral and inferior-lateral orbicularis oculi bilaterally, in four separate injections per side, (40 IU total); and a total of 100 IU in the anterior platysma, in 20 separate injections, for a total 1-day onabotulinumtoxinA dose of 225 IU.

The PA explained to the EP that he mixed the onabotulinumtoxinA in the patient’s room and had shown her the vials and dilution standard as recommended by the manufacturer because she had been requiring increased dosages and had previously questioned whether the onabotulinumtoxinA was diluted. The PA denied any other patients experiencing similar adverse events as those of the patient’s.

Over the last 10 years, the patient had received onabotulinumtoxinA in the nasolabial folds, upper and lower lip wrinkles, mentalis, depressor angular oris, buccal, nasalis, lateral brow, masseter, and calf muscles. The dosage of onabotulinumtoxinA at this most recent injection cycle was unchanged from her previous visit 3 months prior. According to the PA, the practice did not use abobotulinumtoxinA or incobotulinumtoxinA.

Regarding the patient’s medical history, she had no health issues suggestive of myasthenia gravis, multiple sclerosis, or Guillain-Barré syndrome. Examination of the face revealed decreased muscle excursion of the frontalis muscle from mid-brow to mid-brow, and stair-step wrinkle formation bilaterally. The procerus muscle was very weak, and the corrugator muscles were moderately diminished in strength. The lateral orbicularis oculi were very weak at each canthus. The extra-ocular muscles were intact. She had full mandibular excursion, and powerful movement of the tongue. The oropharynx and floor of the mouth were normal. She was noted to purposefully swallow and extend her neck every 90 to 120 seconds to “clear her throat,” though she did not drool and was able to handle her secretions and swallow fluids without aspiration. Her voice was normal and she was able to recite the letters “KKKKK,” “OOOOO,” and “EEEEE” in rapid fashion without breathiness or stridor. The rest of her facial muscles were normal.

While supine, the patient strained to lift her head and complained of a suffocating sensation over the larynx. She had no rashes or edema, and the remainder of the physical examination, vital signs, and pulse oximetry were normal. Laboratory evaluation, which included a complete blood count and serum electrolytes, was also normal.

An otolaryngologist consultation for laryngoscopy was obtained. After reviewing the patient’s case, the otolaryngologist concluded that given the patient’s history, intermittent stridor, and an absence of signs or symptoms suggestive of an impending upper airway obstruction (UAO), laryngoscopy was not warranted.

A plastic surgery consultation was then obtained. The patient’s examination was as noted above, and her vital signs and pulse oximetry remained normal throughout her ED stay. Although botulinum and botulinum antibody titers were ordered, the patient refused testing due to cost concerns. She was discharged home by plastic surgery services with a diagnosis of floppy neck and dysphagia secondary to aesthetic botulinum toxin paralysis of the bilateral sternocleidomastoid muscles and platysma. She was given a prescription for metoclopramide hydrochloride to stimulate motility of the upper gastrointestinal tract and to potentially improve swallowing.¹⁰

The patient was scheduled for a follow-up evaluation with the plastic surgeon 2 days after discharge. She was instructed to call 911 if she experienced stridor, shortness of breath, drooling, or if any airway issues arose. The patient did not return for her follow-up appointment with the plastic surgeon.

Discussion

Clostridium Botulinum Toxins

Clostridium botulinum is a gram-positive spore-forming anaerobic bacterium that produces extremely potent neuro-exotoxins. C botulinum is found in soil, contaminated foods, and in illicit injectable drugs (eg, heroin). Seven distinct antigenic botulinum toxins (A, B, C1, D, E, F, and G) are produced by several strains of C botulinum. Systemically, each neurotoxin is able to produce severe morbidity and mortality by causing generalized muscle paralysis and death by respiratory failure. The lethal dose of these agents is approximating 10(-9) g/kg body weight. Botulinum toxin type A is the most potent.^1,2

Nonetheless, botulinum toxin has been used clinically since the early 1970s. Currently, there are three FDA-approved botulinum toxin type A agents and one type B formulation (rimabotulinumtoxinB) (Table). Each formulation is unique, proprietary, and differs in molecular weight, toxin-complex size, protein content, and inactive ingredients. The effectiveness and adverse event profile for these four botulinum toxins is individually dependent upon the different dilutions and potency, onset of action, duration of effect, diffusion, and migration potential. Hence, the effective dose of one botulinum toxin does not equate to any other, resulting in a lack of interchangeability between botulinum toxins (eg, 5 IU of incobotulinumtoxinA does not equal 5 IU of onabotulinumtoxinA).

Aesthetic Indications

Historically, the use of botulinum toxin for aesthetic treatment of wrinkles and platysmal bands was first reported by Blitzer³ in 1993.Subsequently, the use of botulinum toxin for the aesthetic treatment of facial wrinkles, hypertrophic platysmal bands and horizontal neck lines gained popularity within the public and medical community.^3-5

Anatomically, the platysma is a thin sheet-like muscle that originates in the superior fascia of the pectoralis and deltoid fascia, and extends over the full length of the neck up past the mandible and continuing into the submuscular aponeurotic system. The platysma is innervated by the seventh cranial nerve and functions to pull the jaw downward. The platysma muscle is attached directly to the skin. With normal aging, the anterior neck skin becomes flaccid, the central platysmal bands thicken and contract—forming bands, horizontal wrinkles, and loss of definition of the neck noticed at rest and with contraction of the platysma muscle. These vertical bands are known as platysmal bands. The platysmal bands are benign consequences of aging and as such are targets of correction through surgery or botulinum toxin injection.^6,7

Mechanism of Action

Platysmal band and horizontal line injection techniques with botulinum toxin have been reported in the literature with dosages ranging from 15 IU to 200 IU used to block the Soluble N-ethylmaleimide-sensitive factor activating protein receptors. Typical onset of action begins at 3 days, with full paralytic effect at 7 days. Repeat injections every 3 to 4 months are required with prolonged effects seen with each subsequent injection due to chemodenervation-induced muscle atrophy.^4,7,8

Adverse Effects

Commercial botulinum toxin type A has been associated with minor and transient side effects. Moderate complications seen in the neck region include transient soft-tissue edema, dermal ecchymoses, intramuscular hematoma, diffuse muscle soreness, neck flexor weakness, and headaches.^4,8,9

The use of botulinum toxin for chemodenervation of the platysma can produce significant weakness of other neck muscles, including the sternocleidomastoid, cricothyroid, sternothyroid, and sternohyoid. Floppy neck and dysphagia may be due to diffusion of the toxin into the muscles of deglutition of the larynx; injection directly into the sternocleidomastoid muscle; or a result of the systemic effects of large dosages. Hoarseness, breathiness, and dysphagia may occur 3 to 4 days after injection, especially with doses over 75 IU.¹⁰

The recommended concentration of botulinum toxin type A causes a diffusion average of 1 cm in all directions from the injection sites. However, as the dilution increases, so does the zone of diffusion. Typical discharge instructions for platysma treatment include the overuse of the neck muscles for 2 to 4 hours after injection to encourage the botulinum toxin uptake for optimal result. Site manipulation (rubbing or massaging) also increases diffusion. For botulinum toxin type B, the zone of diffusion is greater because its molecular weight is less than the type A toxins, thus making it an undesirable agent for aesthetic facial chemodenervation.^4,11

Toxin Resistance

Botulinum toxin resistance is a known complication that occurs normally as a result of the body recognizing the neurotoxin as a foreign substance and producing neutralizing antibodies (NAb). Primary botulinum toxin failure is known in patients who require high doses of the neurotoxin for treatment of neuromuscular disorders.¹² Complete secondary therapy failure is known to occur in cosmetic patients after a single dose and those who have been receiving low-dose botulinum toxin regularly. The risk of NAb development increases with long-term treatment and high doses.^12-18

Floppy Neck and Dysphagia

As previously noted, floppy neck and dysphagia are adverse clinical findings of botulinum toxin effect on the platysma, sternocleidomastoid, or the paralaryngeal muscles. In this case, the patient was fortunate to have only sustained weakness of the platysma and sternocleidomastoid muscles despite both a large neck and total body dose. Paralaryngeal muscle paralysis is not life-threatening, but the distress may precipitate paradoxical vocal cord motion and stridor.

Stridor

Stridor is typically a symptom of an upper airway obstruction (UAO) process. Typical UAO conditions encountered in the ED are infections (eg, epiglottitis, croup), foreign body, allergy, and laryngeal trauma. The age of the patient, onset of stridor, course of the stridor (ie, intermittent, continuous, worsening), associated symptoms (eg, fever, rash, swelling of oral soft tissues), and bruising must be ascertained.

In differentiating the etiology of stridor, the EP should observe the patient for any associated change in voice, inability to handle secretions, and position of comfort. Patients with stridor require admission and evaluation by an otolaryngologist as expeditiously as possible because impending UAO may quickly progress to complete UAO necessitating emergent intubation.

An atypical presentation of stridor to the ED is sporadic stridor. Sporadic attacks of stridor during activity have been associated with the entity of paradoxical vocal cord motion. Patients usually describe a choking sensation with inability to breathe resulting in an audible inspiratory and/or expiratory sound—ie, stridor. Wheezing may or may not be present. Patients may also describe tightness in the neck and sometimes in the chest. The attacks are usually seconds to minutes in duration. More often, there is a precipitating or an inducing factor such as hyperventilation, cough, panting, phonatory tasks, or the inhalation of irritants or perfume, or an oropharyngeal or laryngeal manipulation prior or postextubation. The feeling of stress alone is commonly reported prior to the attacks. When evaluating patients presenting with floppy neck, dysphagia, and stridor, it is imperative that the clinician conduct a thorough history and physical examination to determine if the symptoms are secondary to a systemic or local effect, and whether the patient will progress to an acute UAO (vocal cord paralysis) necessitating intubation in the ED and subsequent tracheostomy.^19,20

Conclusion

The ready availability of botulinum toxins and their low-cost-benefit ratio continue to promote over-utilization for treatment of facial wrinkles, platysmal bands, and horizontal lines; migraine headache; and hyperhidrosis. Complications associated with overuse of botulinum toxins are due to either administration of a large single dose or from regional diffusion. With the increasing number of patients receiving botulinum injections, EPs should be aware of the four available toxin types onset of action, adverse events, and potential life-threatening complications of regional neck injections.

Case

A 30-year-old man without prior respiratory illness presented with coughing, wheezing, dyspnea on exertion, and decreased exercise tolerance after a 7-hour overnight exposure to yak-dung smoke. This episode took place at 4,240 m elevation in Pheriche village, along the Everest Base Camp trekking route within the Khumbu region of the Nepali Himalayas. Prior to going to bed that evening, the group of five cohabitants had a difficult time igniting the potbelly heating stove filled with yak-dung biomass fuel in the common room. Each time they tried to light it, the fire would smolder and go out within a few minutes, despite the group’s attempts at adjusting the flue and air intake. Eventually, they abandoned further attempts and retired to bed at approximately 9:30 pm. The patient woke up 7 hours later coughing and gasping for air. His room, which was adjacent to the common room, was clouded with smoke that had entered from the open doorway. The stove’s chimney was later found to be clogged; the yak-dung fuel had reignited after everyone had gone to bed and smoldered all night long, producing copious amounts of smoke directly into the common room—and consequently into the patient’s room. The patient’s cohabitants slept in rooms with closed doors farther away from the common room, and did not experience significant respiratory symptoms. After awakening that morning, the patient embarked on a 2-day backpacking trip and began having spastic coughing fits, wheezing with deep inspiration, dyspnea on exertion, fatigue, and decreased exercise tolerance.

The differential diagnosis included altitude illness, airway mucociliary dysfunction (commonly known as Khumbu cough),¹ carbon monoxide (CO) poisoning, acute inhalation injury (AII) resulting in reactive airway disease syndrome (RADS), and high-altitude pulmonary edema (HAPE). Although the group hiked to Kongma La Pass (elevation, 5,545 m), and slept at 5,200 m (960 m higher than their starting point), the patient had not exhibited any symptoms of altitude illness (eg, headache, dizziness, fatigue, sleep disturbances, anorexia, nausea). Auscultation of the patient by the two physicians who accompanied him on the hike noted mild expiratory wheezing without rales or rhonchi, making HAPE unlikely in the differential diagnosis.

Although it is likely the patient had significant CO exposure, he did not display profound symptoms of CO toxicity (eg, light-headedness, headache, vertigo, nausea, or confusion). It is unclear whether the symptoms of decreased exercise tolerance and fatigue were due to CO poisoning as no co-oximeter was available to assess the patient’s CO levels.^2,3 Upon return from the trip, pulse oximetry showed the patient to have an oxygen (O₂) saturation of 89% on room air, which was within appropriate range for their altitude.

One of the physicians offered the patient an albuterol metered-dose inhaler, which provided profound and immediate relief of his coughing and wheezing. The patient continued to use the albuterol inhaler every 2 to 4 hours over the next 2 days. The dyspnea on exertion and decreased exercise tolerance improved after 24 hours of treatment; the rest of his respiratory symptoms resolved after approximately 5 days at the starting elevation, and he returned to his usual baseline state of health. No follow-up chest X-rays were obtained, and the patient has had no subsequent recurrence of these symptoms despite return to higher altitude in the subsequent year.

Discussion

Nearly one-third to one-half of the world’s population relies on biomass fuels for domestic heating or cooking, with developing countries accounting for 99% of its use.⁴ These fuels consist of dried dung cakes or patties, agricultural products, coal, and firewood. In the Khumbu region of Nepal above timberline, yak-dung patties are used exclusively for heating and frequently for cooking. Most guesthouses in this region have potbelly-style stoves in the common dining areas, which are fueled by yak dung and ventilated with a chimney.

Pulmonary Pathophysiology of Inhaled Irritants

Biomass fuels are responsible for numerous air pollutants due to incomplete combustion. These fuels suspend particulate matter, CO, nitrogen dioxide, polycyclic aromatic hydrocarbons, and volatile organic compounds, including acetone, methyl ethyl ketone, benzene, formaldehyde, and toluene.⁵ Compared to other biomass fuel sources, dung-cake combustion results in higher emissions of relatively very small particulate matter with peak concentrations ranging from 0.23 to 0.3 μm in size, which penetrate and affect the distal airway. ⁶ Their combustion also releases volatile organic compounds and CO.^7,8 Aside from indoor air pollution, yak-dung combustion in the Nepali Himalayan valley contributes significantly to the ambient airborne concentrations of lead, copper, aluminum, magnesium, and elemental and organic carbon.⁹

Emergency physicians (EPs) are often the first-line treating physician for patients exposed not only to biomass fuels, but also home, forest, or occupational fires resulting in smoke inhalation or AII.¹⁰ These terms refer to the wide number of substances that may be present in the smoke and collectively affect the patient. Inhaled substances classified as irritants, such as smoke and particulate matter, can harm the epithelium of the respiratory tract, with highly water-soluble or larger particles (>10 μm) mostly affecting the upper airways. These irritants cause symptoms of progressive coughing, and wheezing; or stridor resulting in tracheitis, bronchitis, bronchiolitis, alveolitis, pulmonary edema, and/or airway obstruction. Smaller particles (<2.5 μm) can penetrate further into the lung and affect the distal airway to a greater degree. These particles are able to infiltrate the terminal bronchioles and alveoli, leading to localized inflammatory reaction and bronchospasm.¹¹Smoke may also contain chemical asphyxiants such as CO or hydrogen cyanide, which can be absorbed, leading to systemic toxicity and interfering with O₂ delivery or utilization. Importantly, high concentrations of any gas can act as an asphyxiant due to displacement of O₂.¹² Thermal injuries are also possible from fire and smoke exposure, typically affecting the upper airways. Steam inhalation can even cause irritation and burns below the vocal cords.¹³

Reactive Airway Disease Syndrome

Reactive airway disease syndrome is a constellation of symptoms presenting similar to asthma with persistent airway reactivity after an AII, and is the most common sequelae of exposure to biomass fuel combustion. This syndrome is not specifically caused by one type of particulate, irritant, or chemical component of the smoke.

Symptoms

Symptoms such as cough, dyspnea, and wheezing may begin minutes after exposure, and can persist for years due to bronchial hyperresponsiveness.¹⁴ These chronic symptoms of RADS have been well highlighted by New York Fire Department rescue workers from the World Trade Center collapse, of whom 16% continued to show symptoms of RADS 1 year later.¹⁵

Treatment

Bronchodilator therapy is the mainstay of treatment for RADS. Patients who have RADS often respond well to treatment, and show improvement in symptoms and spirometry testing.

Sequelae Associated With Biomass Fuel Exposure

A cross-sectional study showed significant reductions (P < .001) in all pulmonary function testing parameters for cow-dung fuel users compared to those who use modern energy sources: forced expiratory volume in the first second (FEV₁), forced vital capacity (FVC), FEV₁/FVC ratio, and mid-flow rate between the first 25% and 75% of forced expiratory flow. Linear regression showed a 12.4% reduction in FVC of cow-dung users, and 36% (compared to 20% in modern energy-source users) were noted to have pulmonary infections.¹⁶

Due to these emissions, biomass fuel exposure causes high levels of morbidity and mortality in developing countries, with nearly 2 million attributable deaths annually.¹ Chronic exposure to biomass fuel emissions can lead to increased risk of diseases, including respiratory problems (eg, pneumonia, tuberculosis and chronic obstructive pulmonary disease, lung cancer, asthma), low birthweight, cataracts, and cardiovascular events.^2,17 Women are at higher risk compared to other family members, as they typically spend approximately 3 to 4 hours longer daily in tents,⁵ and perform the majoring of the cooking duties. For pregnant women, the developing fetus may also be exposed, which can lead to increased rates of fetal demise.¹⁸

Conclusion

Our report represents the first reported case of “dung lung” or RADS from yak-dung biomass fuel combustion exposure. In the medical literature, there has been one previous case report of dung lung by Osbern and Crapo¹⁹ in 1981 in which the authors described three patients who died from aspiration of liquid manure in a storage facility.Our case highlights the prevalence of biomass fuel combustion in the third world, the dangerous air pollutants from their emissions, and the morbidity associated with improper ventilation of biomass fuel combustion.

Case

A 30-year-old man without prior respiratory illness presented with coughing, wheezing, dyspnea on exertion, and decreased exercise tolerance after a 7-hour overnight exposure to yak-dung smoke. This episode took place at 4,240 m elevation in Pheriche village, along the Everest Base Camp trekking route within the Khumbu region of the Nepali Himalayas. Prior to going to bed that evening, the group of five cohabitants had a difficult time igniting the potbelly heating stove filled with yak-dung biomass fuel in the common room. Each time they tried to light it, the fire would smolder and go out within a few minutes, despite the group’s attempts at adjusting the flue and air intake. Eventually, they abandoned further attempts and retired to bed at approximately 9:30 pm. The patient woke up 7 hours later coughing and gasping for air. His room, which was adjacent to the common room, was clouded with smoke that had entered from the open doorway. The stove’s chimney was later found to be clogged; the yak-dung fuel had reignited after everyone had gone to bed and smoldered all night long, producing copious amounts of smoke directly into the common room—and consequently into the patient’s room. The patient’s cohabitants slept in rooms with closed doors farther away from the common room, and did not experience significant respiratory symptoms. After awakening that morning, the patient embarked on a 2-day backpacking trip and began having spastic coughing fits, wheezing with deep inspiration, dyspnea on exertion, fatigue, and decreased exercise tolerance.

The differential diagnosis included altitude illness, airway mucociliary dysfunction (commonly known as Khumbu cough),¹ carbon monoxide (CO) poisoning, acute inhalation injury (AII) resulting in reactive airway disease syndrome (RADS), and high-altitude pulmonary edema (HAPE). Although the group hiked to Kongma La Pass (elevation, 5,545 m), and slept at 5,200 m (960 m higher than their starting point), the patient had not exhibited any symptoms of altitude illness (eg, headache, dizziness, fatigue, sleep disturbances, anorexia, nausea). Auscultation of the patient by the two physicians who accompanied him on the hike noted mild expiratory wheezing without rales or rhonchi, making HAPE unlikely in the differential diagnosis.

Although it is likely the patient had significant CO exposure, he did not display profound symptoms of CO toxicity (eg, light-headedness, headache, vertigo, nausea, or confusion). It is unclear whether the symptoms of decreased exercise tolerance and fatigue were due to CO poisoning as no co-oximeter was available to assess the patient’s CO levels.^2,3 Upon return from the trip, pulse oximetry showed the patient to have an oxygen (O₂) saturation of 89% on room air, which was within appropriate range for their altitude.

One of the physicians offered the patient an albuterol metered-dose inhaler, which provided profound and immediate relief of his coughing and wheezing. The patient continued to use the albuterol inhaler every 2 to 4 hours over the next 2 days. The dyspnea on exertion and decreased exercise tolerance improved after 24 hours of treatment; the rest of his respiratory symptoms resolved after approximately 5 days at the starting elevation, and he returned to his usual baseline state of health. No follow-up chest X-rays were obtained, and the patient has had no subsequent recurrence of these symptoms despite return to higher altitude in the subsequent year.

Discussion

Nearly one-third to one-half of the world’s population relies on biomass fuels for domestic heating or cooking, with developing countries accounting for 99% of its use.⁴ These fuels consist of dried dung cakes or patties, agricultural products, coal, and firewood. In the Khumbu region of Nepal above timberline, yak-dung patties are used exclusively for heating and frequently for cooking. Most guesthouses in this region have potbelly-style stoves in the common dining areas, which are fueled by yak dung and ventilated with a chimney.

Pulmonary Pathophysiology of Inhaled Irritants

Biomass fuels are responsible for numerous air pollutants due to incomplete combustion. These fuels suspend particulate matter, CO, nitrogen dioxide, polycyclic aromatic hydrocarbons, and volatile organic compounds, including acetone, methyl ethyl ketone, benzene, formaldehyde, and toluene.⁵ Compared to other biomass fuel sources, dung-cake combustion results in higher emissions of relatively very small particulate matter with peak concentrations ranging from 0.23 to 0.3 μm in size, which penetrate and affect the distal airway. ⁶ Their combustion also releases volatile organic compounds and CO.^7,8 Aside from indoor air pollution, yak-dung combustion in the Nepali Himalayan valley contributes significantly to the ambient airborne concentrations of lead, copper, aluminum, magnesium, and elemental and organic carbon.⁹

Emergency physicians (EPs) are often the first-line treating physician for patients exposed not only to biomass fuels, but also home, forest, or occupational fires resulting in smoke inhalation or AII.¹⁰ These terms refer to the wide number of substances that may be present in the smoke and collectively affect the patient. Inhaled substances classified as irritants, such as smoke and particulate matter, can harm the epithelium of the respiratory tract, with highly water-soluble or larger particles (>10 μm) mostly affecting the upper airways. These irritants cause symptoms of progressive coughing, and wheezing; or stridor resulting in tracheitis, bronchitis, bronchiolitis, alveolitis, pulmonary edema, and/or airway obstruction. Smaller particles (<2.5 μm) can penetrate further into the lung and affect the distal airway to a greater degree. These particles are able to infiltrate the terminal bronchioles and alveoli, leading to localized inflammatory reaction and bronchospasm.¹¹Smoke may also contain chemical asphyxiants such as CO or hydrogen cyanide, which can be absorbed, leading to systemic toxicity and interfering with O₂ delivery or utilization. Importantly, high concentrations of any gas can act as an asphyxiant due to displacement of O₂.¹² Thermal injuries are also possible from fire and smoke exposure, typically affecting the upper airways. Steam inhalation can even cause irritation and burns below the vocal cords.¹³

Reactive Airway Disease Syndrome

Reactive airway disease syndrome is a constellation of symptoms presenting similar to asthma with persistent airway reactivity after an AII, and is the most common sequelae of exposure to biomass fuel combustion. This syndrome is not specifically caused by one type of particulate, irritant, or chemical component of the smoke.

Symptoms

Symptoms such as cough, dyspnea, and wheezing may begin minutes after exposure, and can persist for years due to bronchial hyperresponsiveness.¹⁴ These chronic symptoms of RADS have been well highlighted by New York Fire Department rescue workers from the World Trade Center collapse, of whom 16% continued to show symptoms of RADS 1 year later.¹⁵

Treatment

Bronchodilator therapy is the mainstay of treatment for RADS. Patients who have RADS often respond well to treatment, and show improvement in symptoms and spirometry testing.

Sequelae Associated With Biomass Fuel Exposure

A cross-sectional study showed significant reductions (P < .001) in all pulmonary function testing parameters for cow-dung fuel users compared to those who use modern energy sources: forced expiratory volume in the first second (FEV₁), forced vital capacity (FVC), FEV₁/FVC ratio, and mid-flow rate between the first 25% and 75% of forced expiratory flow. Linear regression showed a 12.4% reduction in FVC of cow-dung users, and 36% (compared to 20% in modern energy-source users) were noted to have pulmonary infections.¹⁶

Due to these emissions, biomass fuel exposure causes high levels of morbidity and mortality in developing countries, with nearly 2 million attributable deaths annually.¹ Chronic exposure to biomass fuel emissions can lead to increased risk of diseases, including respiratory problems (eg, pneumonia, tuberculosis and chronic obstructive pulmonary disease, lung cancer, asthma), low birthweight, cataracts, and cardiovascular events.^2,17 Women are at higher risk compared to other family members, as they typically spend approximately 3 to 4 hours longer daily in tents,⁵ and perform the majoring of the cooking duties. For pregnant women, the developing fetus may also be exposed, which can lead to increased rates of fetal demise.¹⁸

Conclusion

Our report represents the first reported case of “dung lung” or RADS from yak-dung biomass fuel combustion exposure. In the medical literature, there has been one previous case report of dung lung by Osbern and Crapo¹⁹ in 1981 in which the authors described three patients who died from aspiration of liquid manure in a storage facility.Our case highlights the prevalence of biomass fuel combustion in the third world, the dangerous air pollutants from their emissions, and the morbidity associated with improper ventilation of biomass fuel combustion.

Case

A 30-year-old man without prior respiratory illness presented with coughing, wheezing, dyspnea on exertion, and decreased exercise tolerance after a 7-hour overnight exposure to yak-dung smoke. This episode took place at 4,240 m elevation in Pheriche village, along the Everest Base Camp trekking route within the Khumbu region of the Nepali Himalayas. Prior to going to bed that evening, the group of five cohabitants had a difficult time igniting the potbelly heating stove filled with yak-dung biomass fuel in the common room. Each time they tried to light it, the fire would smolder and go out within a few minutes, despite the group’s attempts at adjusting the flue and air intake. Eventually, they abandoned further attempts and retired to bed at approximately 9:30 pm. The patient woke up 7 hours later coughing and gasping for air. His room, which was adjacent to the common room, was clouded with smoke that had entered from the open doorway. The stove’s chimney was later found to be clogged; the yak-dung fuel had reignited after everyone had gone to bed and smoldered all night long, producing copious amounts of smoke directly into the common room—and consequently into the patient’s room. The patient’s cohabitants slept in rooms with closed doors farther away from the common room, and did not experience significant respiratory symptoms. After awakening that morning, the patient embarked on a 2-day backpacking trip and began having spastic coughing fits, wheezing with deep inspiration, dyspnea on exertion, fatigue, and decreased exercise tolerance.

The differential diagnosis included altitude illness, airway mucociliary dysfunction (commonly known as Khumbu cough),¹ carbon monoxide (CO) poisoning, acute inhalation injury (AII) resulting in reactive airway disease syndrome (RADS), and high-altitude pulmonary edema (HAPE). Although the group hiked to Kongma La Pass (elevation, 5,545 m), and slept at 5,200 m (960 m higher than their starting point), the patient had not exhibited any symptoms of altitude illness (eg, headache, dizziness, fatigue, sleep disturbances, anorexia, nausea). Auscultation of the patient by the two physicians who accompanied him on the hike noted mild expiratory wheezing without rales or rhonchi, making HAPE unlikely in the differential diagnosis.

Although it is likely the patient had significant CO exposure, he did not display profound symptoms of CO toxicity (eg, light-headedness, headache, vertigo, nausea, or confusion). It is unclear whether the symptoms of decreased exercise tolerance and fatigue were due to CO poisoning as no co-oximeter was available to assess the patient’s CO levels.^2,3 Upon return from the trip, pulse oximetry showed the patient to have an oxygen (O₂) saturation of 89% on room air, which was within appropriate range for their altitude.

One of the physicians offered the patient an albuterol metered-dose inhaler, which provided profound and immediate relief of his coughing and wheezing. The patient continued to use the albuterol inhaler every 2 to 4 hours over the next 2 days. The dyspnea on exertion and decreased exercise tolerance improved after 24 hours of treatment; the rest of his respiratory symptoms resolved after approximately 5 days at the starting elevation, and he returned to his usual baseline state of health. No follow-up chest X-rays were obtained, and the patient has had no subsequent recurrence of these symptoms despite return to higher altitude in the subsequent year.

Discussion

Nearly one-third to one-half of the world’s population relies on biomass fuels for domestic heating or cooking, with developing countries accounting for 99% of its use.⁴ These fuels consist of dried dung cakes or patties, agricultural products, coal, and firewood. In the Khumbu region of Nepal above timberline, yak-dung patties are used exclusively for heating and frequently for cooking. Most guesthouses in this region have potbelly-style stoves in the common dining areas, which are fueled by yak dung and ventilated with a chimney.

Pulmonary Pathophysiology of Inhaled Irritants

Biomass fuels are responsible for numerous air pollutants due to incomplete combustion. These fuels suspend particulate matter, CO, nitrogen dioxide, polycyclic aromatic hydrocarbons, and volatile organic compounds, including acetone, methyl ethyl ketone, benzene, formaldehyde, and toluene.⁵ Compared to other biomass fuel sources, dung-cake combustion results in higher emissions of relatively very small particulate matter with peak concentrations ranging from 0.23 to 0.3 μm in size, which penetrate and affect the distal airway. ⁶ Their combustion also releases volatile organic compounds and CO.^7,8 Aside from indoor air pollution, yak-dung combustion in the Nepali Himalayan valley contributes significantly to the ambient airborne concentrations of lead, copper, aluminum, magnesium, and elemental and organic carbon.⁹

Emergency physicians (EPs) are often the first-line treating physician for patients exposed not only to biomass fuels, but also home, forest, or occupational fires resulting in smoke inhalation or AII.¹⁰ These terms refer to the wide number of substances that may be present in the smoke and collectively affect the patient. Inhaled substances classified as irritants, such as smoke and particulate matter, can harm the epithelium of the respiratory tract, with highly water-soluble or larger particles (>10 μm) mostly affecting the upper airways. These irritants cause symptoms of progressive coughing, and wheezing; or stridor resulting in tracheitis, bronchitis, bronchiolitis, alveolitis, pulmonary edema, and/or airway obstruction. Smaller particles (<2.5 μm) can penetrate further into the lung and affect the distal airway to a greater degree. These particles are able to infiltrate the terminal bronchioles and alveoli, leading to localized inflammatory reaction and bronchospasm.¹¹Smoke may also contain chemical asphyxiants such as CO or hydrogen cyanide, which can be absorbed, leading to systemic toxicity and interfering with O₂ delivery or utilization. Importantly, high concentrations of any gas can act as an asphyxiant due to displacement of O₂.¹² Thermal injuries are also possible from fire and smoke exposure, typically affecting the upper airways. Steam inhalation can even cause irritation and burns below the vocal cords.¹³

Reactive Airway Disease Syndrome

Reactive airway disease syndrome is a constellation of symptoms presenting similar to asthma with persistent airway reactivity after an AII, and is the most common sequelae of exposure to biomass fuel combustion. This syndrome is not specifically caused by one type of particulate, irritant, or chemical component of the smoke.

Symptoms

Symptoms such as cough, dyspnea, and wheezing may begin minutes after exposure, and can persist for years due to bronchial hyperresponsiveness.¹⁴ These chronic symptoms of RADS have been well highlighted by New York Fire Department rescue workers from the World Trade Center collapse, of whom 16% continued to show symptoms of RADS 1 year later.¹⁵

Treatment

Bronchodilator therapy is the mainstay of treatment for RADS. Patients who have RADS often respond well to treatment, and show improvement in symptoms and spirometry testing.

Sequelae Associated With Biomass Fuel Exposure

A cross-sectional study showed significant reductions (P < .001) in all pulmonary function testing parameters for cow-dung fuel users compared to those who use modern energy sources: forced expiratory volume in the first second (FEV₁), forced vital capacity (FVC), FEV₁/FVC ratio, and mid-flow rate between the first 25% and 75% of forced expiratory flow. Linear regression showed a 12.4% reduction in FVC of cow-dung users, and 36% (compared to 20% in modern energy-source users) were noted to have pulmonary infections.¹⁶

Due to these emissions, biomass fuel exposure causes high levels of morbidity and mortality in developing countries, with nearly 2 million attributable deaths annually.¹ Chronic exposure to biomass fuel emissions can lead to increased risk of diseases, including respiratory problems (eg, pneumonia, tuberculosis and chronic obstructive pulmonary disease, lung cancer, asthma), low birthweight, cataracts, and cardiovascular events.^2,17 Women are at higher risk compared to other family members, as they typically spend approximately 3 to 4 hours longer daily in tents,⁵ and perform the majoring of the cooking duties. For pregnant women, the developing fetus may also be exposed, which can lead to increased rates of fetal demise.¹⁸

Conclusion

Our report represents the first reported case of “dung lung” or RADS from yak-dung biomass fuel combustion exposure. In the medical literature, there has been one previous case report of dung lung by Osbern and Crapo¹⁹ in 1981 in which the authors described three patients who died from aspiration of liquid manure in a storage facility.Our case highlights the prevalence of biomass fuel combustion in the third world, the dangerous air pollutants from their emissions, and the morbidity associated with improper ventilation of biomass fuel combustion.

THE CASE

A 59-year-old woman from the Democratic Republic of the Congo presented to our family medicine clinic with acute worsening of longstanding headaches. Using a Swahili interpreter, the patient reported a 15-year history of recurrent, intermittent headaches that had been previously diagnosed as migraines. Over the prior 2 months, the headaches had intensified with new symptoms of dizziness, ocular pain, and blurred vision with red flashes. She had no hemiplegia, dysarthria, respiratory symptoms, night sweats, or weight loss. A neurologic exam was negative.

Before immigrating to the United States 14 years earlier, the patient lived for 6 months in a refugee camp in the Congo. At the time of her immigration, she was negative for human immunodeficiency virus (HIV), and a tuberculosis (TB) skin test was positive. A chest x-ray was normal and she had no respiratory symptoms. Shortly after her immigration, she completed 6 months of isoniazid treatment for latent TB.

THE DIAGNOSIS

A computed tomography (CT) scan of the patient’s head demonstrated a large right frontal mass. The differential diagnosis included neoplasm, sarcoidosis, or, less likely, an infectious etiology. A contrast-enhanced magnetic resonance image (MRI) of the brain showed multiple heterogeneous enhancing lesions, with the largest measuring 4.4 cm x 4.6 cm x 3 cm (FIGURE 1). Significant surrounding edema caused a 1.6-cm midline shift, subfalcine herniation, and impending uncal herniation. A CT of the abdomen and chest showed no pulmonary masses or metastatic disease, but did reveal a single 1-cm lymph node in the mediastinum and a 1.2-cm right axillary node.

A craniotomy was performed, which confirmed a large mass adhered to the dura. Surgeons removed the mass en bloc; pathology was consistent with a necrotizing granuloma. Acid-fast bacilli (AFB) staining of 3 specimens was negative. Because the tissue was preserved in formalin, mycobacterial cultures could not be obtained. A cerebrospinal fluid analysis showed lymphocytosis and elevated protein, consistent with neurotuberculosis. Blood testing for Mycobacterium tuberculosis with interferon gamma release assay (IGRA) was negative, as was testing for HIV 1 and 2. In addition, induced sputum was AFB-smear negative, as was an M tuberculosis polymerase chain reaction test.

Despite the negative AFB stain and negative IGRA, the patient’s findings were suspicious for TB, so we began to treat her empirically for neurotuberculosis with a 4-drug regimen (isoniazid, rifampin, pyrazinamide, and ethambutol).

In an attempt to confirm the diagnosis of TB and determine sensitivities, we performed a right axillary lymph node biopsy and sent it to the Centers for Disease Control and Prevention (CDC), along with the preserved neural tissue. Using a newly developed technique, the CDC amplified and sequenced mycobacterial DNA from both the central nervous system (CNS) mass and the axillary node, confirming M tuberculosis complex species. Cultures from the axillary node grew pan-sensitive M tuberculosis.

DISCUSSION

The imaging studies of central nervous system TB are often indistinguishable from those of patients with metastatic disease.About one-third of the world’s population has either active or latent TB.¹ In areas where TB is endemic, tuberculomas have accounted for up to 20% of intracranial masses.² In non-endemic regions, however, they are relatively uncommon. The 3 manifestations of active CNS TB are meningitis, tuberculoma, and abscess.³ The clinical presentation and imaging studies of CNS TB are often indistinguishable from those of patients with malignant neoplasms or metastatic disease. Biopsies may be necessary to distinguish tuberculomas from other intracranial lesions such as pyogenic abscesses or necrotic tumors.⁴ Mycobacterial cultures were not done on the brain biopsies of our patient because of the high clinical suspicion for neoplasm. Axillary lymph node tissue ultimately confirmed the diagnosis and provided sensitivities.

A diagnosis of CNS tuberculoma without meningitis can be challenging because the clinical presentation is often vague, mild, or even asymptomatic. Constitutional symptoms may include headache, fever, and anorexia.⁵

In our patient, IGRA testing was also negative. For latent TB, IGRAs are considered to be at least as sensitive as, and considerably more specific than TB skin testing, but their use in CNS TB is less well understood. Studies evaluating IGRA sensitivity for TB meningitis show variable results. In one study, IGRAs were positive in only 50% of culture-confirmed cases of TB meningitis in an HIV-negative population.⁶

Obtain sputum samples for all patients with extrapulmonary TB

The CDC recommends sputum sampling for all patients with extrapulmonary TB, even in the absence of pulmonary symptoms or radiographic findings, to determine the level of infectivity and potential need for a contact investigation.⁷

Due to low sensitivity of currently available rapid diagnostic tests and high mortality associated with delayed treatment, initiation of empiric treatment is recommended when the probability of CNS TB is high.⁵

Initiation of empiric treatment is advisable when the probability of CNS TB is high.

Treatment duration for CNS tuberculomas is based on one randomized controlled trial,⁸ a small number of observational studies, a prospective cohort study looking at radiographic resolution,⁹ and expert opinion. Treatment recommendations often do not distinguish CNS tuberculomas from TB meningitis.¹⁰ CNS tuberculomas are commonly treated with a minimum of 12 months of therapy, generally using the same medications and dosages used in the treatment of pulmonary TB, starting with 4 first-line agents: isoniazid, rifampin, pyrazinamide, and ethambutol. Modification of the treatment regimen may be made once sensitivities are available.¹⁰

Our patient. After cultures were determined to be pan-sensitive, our patient’s treatment regimen was simplified to rifampin and isoniazid, which she continued for the remainder of her treatment course. Her treatment was discontinued after 18 months when quarterly MRIs showed stabilization of the tuberculomas (FIGURE 2).

Following her surgery, she was started on levetiractam for seizure prophylaxis. She subsequently had a seizure on 2 occasions when the medication was discontinued or decreased, so we chose to continue it. The patient is asymptomatic from her disease with no residual deficits.

THE TAKEAWAY

A change in headache patterns in a patient over the age of 50 is a red flag that warrants imaging. In patients from countries where TB is endemic,¹¹ consider neurotuberculosis in the differential diagnosis of worsening headaches and progressive neurologic symptoms.

A diagnosis of CNS TB can be difficult and requires a high level of clinical suspicion, but early diagnosis and treatment of neurotuberculosis can minimize the high risk of morbidity and mortality. Treatment for TB shouldn’t be withheld in cases in which there’s a strong clinical suspicion for TB, but for which a definitive diagnosis is still pending.

THE CASE

A 59-year-old woman from the Democratic Republic of the Congo presented to our family medicine clinic with acute worsening of longstanding headaches. Using a Swahili interpreter, the patient reported a 15-year history of recurrent, intermittent headaches that had been previously diagnosed as migraines. Over the prior 2 months, the headaches had intensified with new symptoms of dizziness, ocular pain, and blurred vision with red flashes. She had no hemiplegia, dysarthria, respiratory symptoms, night sweats, or weight loss. A neurologic exam was negative.

Before immigrating to the United States 14 years earlier, the patient lived for 6 months in a refugee camp in the Congo. At the time of her immigration, she was negative for human immunodeficiency virus (HIV), and a tuberculosis (TB) skin test was positive. A chest x-ray was normal and she had no respiratory symptoms. Shortly after her immigration, she completed 6 months of isoniazid treatment for latent TB.

THE DIAGNOSIS

A computed tomography (CT) scan of the patient’s head demonstrated a large right frontal mass. The differential diagnosis included neoplasm, sarcoidosis, or, less likely, an infectious etiology. A contrast-enhanced magnetic resonance image (MRI) of the brain showed multiple heterogeneous enhancing lesions, with the largest measuring 4.4 cm x 4.6 cm x 3 cm (FIGURE 1). Significant surrounding edema caused a 1.6-cm midline shift, subfalcine herniation, and impending uncal herniation. A CT of the abdomen and chest showed no pulmonary masses or metastatic disease, but did reveal a single 1-cm lymph node in the mediastinum and a 1.2-cm right axillary node.

A craniotomy was performed, which confirmed a large mass adhered to the dura. Surgeons removed the mass en bloc; pathology was consistent with a necrotizing granuloma. Acid-fast bacilli (AFB) staining of 3 specimens was negative. Because the tissue was preserved in formalin, mycobacterial cultures could not be obtained. A cerebrospinal fluid analysis showed lymphocytosis and elevated protein, consistent with neurotuberculosis. Blood testing for Mycobacterium tuberculosis with interferon gamma release assay (IGRA) was negative, as was testing for HIV 1 and 2. In addition, induced sputum was AFB-smear negative, as was an M tuberculosis polymerase chain reaction test.

Despite the negative AFB stain and negative IGRA, the patient’s findings were suspicious for TB, so we began to treat her empirically for neurotuberculosis with a 4-drug regimen (isoniazid, rifampin, pyrazinamide, and ethambutol).

In an attempt to confirm the diagnosis of TB and determine sensitivities, we performed a right axillary lymph node biopsy and sent it to the Centers for Disease Control and Prevention (CDC), along with the preserved neural tissue. Using a newly developed technique, the CDC amplified and sequenced mycobacterial DNA from both the central nervous system (CNS) mass and the axillary node, confirming M tuberculosis complex species. Cultures from the axillary node grew pan-sensitive M tuberculosis.

DISCUSSION

The imaging studies of central nervous system TB are often indistinguishable from those of patients with metastatic disease.About one-third of the world’s population has either active or latent TB.¹ In areas where TB is endemic, tuberculomas have accounted for up to 20% of intracranial masses.² In non-endemic regions, however, they are relatively uncommon. The 3 manifestations of active CNS TB are meningitis, tuberculoma, and abscess.³ The clinical presentation and imaging studies of CNS TB are often indistinguishable from those of patients with malignant neoplasms or metastatic disease. Biopsies may be necessary to distinguish tuberculomas from other intracranial lesions such as pyogenic abscesses or necrotic tumors.⁴ Mycobacterial cultures were not done on the brain biopsies of our patient because of the high clinical suspicion for neoplasm. Axillary lymph node tissue ultimately confirmed the diagnosis and provided sensitivities.

A diagnosis of CNS tuberculoma without meningitis can be challenging because the clinical presentation is often vague, mild, or even asymptomatic. Constitutional symptoms may include headache, fever, and anorexia.⁵

In our patient, IGRA testing was also negative. For latent TB, IGRAs are considered to be at least as sensitive as, and considerably more specific than TB skin testing, but their use in CNS TB is less well understood. Studies evaluating IGRA sensitivity for TB meningitis show variable results. In one study, IGRAs were positive in only 50% of culture-confirmed cases of TB meningitis in an HIV-negative population.⁶

Obtain sputum samples for all patients with extrapulmonary TB

The CDC recommends sputum sampling for all patients with extrapulmonary TB, even in the absence of pulmonary symptoms or radiographic findings, to determine the level of infectivity and potential need for a contact investigation.⁷

Due to low sensitivity of currently available rapid diagnostic tests and high mortality associated with delayed treatment, initiation of empiric treatment is recommended when the probability of CNS TB is high.⁵

Initiation of empiric treatment is advisable when the probability of CNS TB is high.

Treatment duration for CNS tuberculomas is based on one randomized controlled trial,⁸ a small number of observational studies, a prospective cohort study looking at radiographic resolution,⁹ and expert opinion. Treatment recommendations often do not distinguish CNS tuberculomas from TB meningitis.¹⁰ CNS tuberculomas are commonly treated with a minimum of 12 months of therapy, generally using the same medications and dosages used in the treatment of pulmonary TB, starting with 4 first-line agents: isoniazid, rifampin, pyrazinamide, and ethambutol. Modification of the treatment regimen may be made once sensitivities are available.¹⁰

Our patient. After cultures were determined to be pan-sensitive, our patient’s treatment regimen was simplified to rifampin and isoniazid, which she continued for the remainder of her treatment course. Her treatment was discontinued after 18 months when quarterly MRIs showed stabilization of the tuberculomas (FIGURE 2).

Following her surgery, she was started on levetiractam for seizure prophylaxis. She subsequently had a seizure on 2 occasions when the medication was discontinued or decreased, so we chose to continue it. The patient is asymptomatic from her disease with no residual deficits.

THE TAKEAWAY

A change in headache patterns in a patient over the age of 50 is a red flag that warrants imaging. In patients from countries where TB is endemic,¹¹ consider neurotuberculosis in the differential diagnosis of worsening headaches and progressive neurologic symptoms.

A diagnosis of CNS TB can be difficult and requires a high level of clinical suspicion, but early diagnosis and treatment of neurotuberculosis can minimize the high risk of morbidity and mortality. Treatment for TB shouldn’t be withheld in cases in which there’s a strong clinical suspicion for TB, but for which a definitive diagnosis is still pending.

THE CASE

A 59-year-old woman from the Democratic Republic of the Congo presented to our family medicine clinic with acute worsening of longstanding headaches. Using a Swahili interpreter, the patient reported a 15-year history of recurrent, intermittent headaches that had been previously diagnosed as migraines. Over the prior 2 months, the headaches had intensified with new symptoms of dizziness, ocular pain, and blurred vision with red flashes. She had no hemiplegia, dysarthria, respiratory symptoms, night sweats, or weight loss. A neurologic exam was negative.

Before immigrating to the United States 14 years earlier, the patient lived for 6 months in a refugee camp in the Congo. At the time of her immigration, she was negative for human immunodeficiency virus (HIV), and a tuberculosis (TB) skin test was positive. A chest x-ray was normal and she had no respiratory symptoms. Shortly after her immigration, she completed 6 months of isoniazid treatment for latent TB.

THE DIAGNOSIS

A computed tomography (CT) scan of the patient’s head demonstrated a large right frontal mass. The differential diagnosis included neoplasm, sarcoidosis, or, less likely, an infectious etiology. A contrast-enhanced magnetic resonance image (MRI) of the brain showed multiple heterogeneous enhancing lesions, with the largest measuring 4.4 cm x 4.6 cm x 3 cm (FIGURE 1). Significant surrounding edema caused a 1.6-cm midline shift, subfalcine herniation, and impending uncal herniation. A CT of the abdomen and chest showed no pulmonary masses or metastatic disease, but did reveal a single 1-cm lymph node in the mediastinum and a 1.2-cm right axillary node.

A craniotomy was performed, which confirmed a large mass adhered to the dura. Surgeons removed the mass en bloc; pathology was consistent with a necrotizing granuloma. Acid-fast bacilli (AFB) staining of 3 specimens was negative. Because the tissue was preserved in formalin, mycobacterial cultures could not be obtained. A cerebrospinal fluid analysis showed lymphocytosis and elevated protein, consistent with neurotuberculosis. Blood testing for Mycobacterium tuberculosis with interferon gamma release assay (IGRA) was negative, as was testing for HIV 1 and 2. In addition, induced sputum was AFB-smear negative, as was an M tuberculosis polymerase chain reaction test.

Despite the negative AFB stain and negative IGRA, the patient’s findings were suspicious for TB, so we began to treat her empirically for neurotuberculosis with a 4-drug regimen (isoniazid, rifampin, pyrazinamide, and ethambutol).

In an attempt to confirm the diagnosis of TB and determine sensitivities, we performed a right axillary lymph node biopsy and sent it to the Centers for Disease Control and Prevention (CDC), along with the preserved neural tissue. Using a newly developed technique, the CDC amplified and sequenced mycobacterial DNA from both the central nervous system (CNS) mass and the axillary node, confirming M tuberculosis complex species. Cultures from the axillary node grew pan-sensitive M tuberculosis.

DISCUSSION

The imaging studies of central nervous system TB are often indistinguishable from those of patients with metastatic disease.About one-third of the world’s population has either active or latent TB.¹ In areas where TB is endemic, tuberculomas have accounted for up to 20% of intracranial masses.² In non-endemic regions, however, they are relatively uncommon. The 3 manifestations of active CNS TB are meningitis, tuberculoma, and abscess.³ The clinical presentation and imaging studies of CNS TB are often indistinguishable from those of patients with malignant neoplasms or metastatic disease. Biopsies may be necessary to distinguish tuberculomas from other intracranial lesions such as pyogenic abscesses or necrotic tumors.⁴ Mycobacterial cultures were not done on the brain biopsies of our patient because of the high clinical suspicion for neoplasm. Axillary lymph node tissue ultimately confirmed the diagnosis and provided sensitivities.

A diagnosis of CNS tuberculoma without meningitis can be challenging because the clinical presentation is often vague, mild, or even asymptomatic. Constitutional symptoms may include headache, fever, and anorexia.⁵

In our patient, IGRA testing was also negative. For latent TB, IGRAs are considered to be at least as sensitive as, and considerably more specific than TB skin testing, but their use in CNS TB is less well understood. Studies evaluating IGRA sensitivity for TB meningitis show variable results. In one study, IGRAs were positive in only 50% of culture-confirmed cases of TB meningitis in an HIV-negative population.⁶

Obtain sputum samples for all patients with extrapulmonary TB

The CDC recommends sputum sampling for all patients with extrapulmonary TB, even in the absence of pulmonary symptoms or radiographic findings, to determine the level of infectivity and potential need for a contact investigation.⁷

Due to low sensitivity of currently available rapid diagnostic tests and high mortality associated with delayed treatment, initiation of empiric treatment is recommended when the probability of CNS TB is high.⁵

Initiation of empiric treatment is advisable when the probability of CNS TB is high.

Treatment duration for CNS tuberculomas is based on one randomized controlled trial,⁸ a small number of observational studies, a prospective cohort study looking at radiographic resolution,⁹ and expert opinion. Treatment recommendations often do not distinguish CNS tuberculomas from TB meningitis.¹⁰ CNS tuberculomas are commonly treated with a minimum of 12 months of therapy, generally using the same medications and dosages used in the treatment of pulmonary TB, starting with 4 first-line agents: isoniazid, rifampin, pyrazinamide, and ethambutol. Modification of the treatment regimen may be made once sensitivities are available.¹⁰

Our patient. After cultures were determined to be pan-sensitive, our patient’s treatment regimen was simplified to rifampin and isoniazid, which she continued for the remainder of her treatment course. Her treatment was discontinued after 18 months when quarterly MRIs showed stabilization of the tuberculomas (FIGURE 2).

Following her surgery, she was started on levetiractam for seizure prophylaxis. She subsequently had a seizure on 2 occasions when the medication was discontinued or decreased, so we chose to continue it. The patient is asymptomatic from her disease with no residual deficits.

THE TAKEAWAY

A change in headache patterns in a patient over the age of 50 is a red flag that warrants imaging. In patients from countries where TB is endemic,¹¹ consider neurotuberculosis in the differential diagnosis of worsening headaches and progressive neurologic symptoms.

A diagnosis of CNS TB can be difficult and requires a high level of clinical suspicion, but early diagnosis and treatment of neurotuberculosis can minimize the high risk of morbidity and mortality. Treatment for TB shouldn’t be withheld in cases in which there’s a strong clinical suspicion for TB, but for which a definitive diagnosis is still pending.

CASE 1

A 50-year-old man sought care for progressive dyspnea on exertion, abdominal bloating, and bilateral leg edema. He had hypertension that was being treated with atenolol, nifedipine, and enalapril. On examination, his blood pressure was 157/80 mm Hg and his heart rate was 50 beats/min. Jugular venous pressure was grossly elevated with occasional cannon A waves. The patient also had decreased breath sounds in both lower lung zones and moderate pitting edema up to the knees. A chest x-ray showed a small bilateral pleural effusion and no cardiomegaly. An electrocardiogram revealed complete atrioventricular (AV) block with a ventricular response of 50 beats/min. Computed tomography (CT) angiography revealed no evidence of a pulmonary embolus, but did show several enlarged (up to 3.5 cm in diameter) lymph nodes in the upper and middle mediastinum (FIGURE 1). We performed an echocardiogram.

CASE 2

A 79-year-old man with hypertension and diabetes presented to our medical center with acute dyspnea. During the physical examination, we noted bilateral diminished breath sounds with expiratory wheezes and an irregular pulse. Chest x-ray showed mild pulmonary congestion. A chest CT demonstrated bilateral small pleural effusions and multiple enlarged mediastinal lymph nodes with a maximal diameter of 2.4 cm (FIGURE 2A). One week later, the patient’s shortness of breath increased and he was hospitalized. A chest x-ray at that time showed moderate pulmonary congestion, so we performed an echocardiogram.

THE DIAGNOSIS

The echocardiogram for the 50-year-old patient in Case 1 revealed a mildly dilated left ventricle with normal systolic function, diastolic left ventricular (LV) dysfunction, moderate tricuspid regurgitation, and mild pulmonary hypertension. Extensive testing for malignancy and tuberculosis was negative.

For the 79-year-old patient in Case 2, echocardiography demonstrated concentric LV hypertrophy, mild dilatation of the left ventricle, normal LV systolic function, LV diastolic dysfunction with elevated LV diastolic filling pressure, and mild-to-moderate pulmonary hypertension.

Based on these results, we diagnosed both patients with diastolic heart failure. The patient in the second case had features of cardiac asthma, as well. Both patients had also developed reversible mediastinal lymphadenopathy (MLN), of which the diastolic heart failure was the only apparent cause. In both cases, radiologists did not note any suspicious findings for malignancy beyond the MLN.

DISCUSSION

Systolic heart failure has been previously recognized as a cause of MLN.^1,2 Other causes of MLN include sarcoidosis, various malignancies, pulmonary infections, and occupational lung diseases. There are, however, no reports of MLN in patients with diastolic heart failure.

Heart failure and MLN. Slanetz et al reported one series of 46 patients who had undergone CT of the chest during periods of congestive heart failure (CHF).¹ There was mediastinal lymph node enlargement in 55% of these patients. In a subset of 17 patients who had elevated capillary wedge pressure, 82% had some degree of lymphadenopathy.

Erly et al² retrospectively studied 44 patients who had a thoracic CT performed before cardiac transplantation. Twenty-nine (66%) had at least one enlarged mediastinal lymph node (>1 cm). Eighty-one percent of patients with an ejection fraction <35% had lymphadenopathy, while none of the patients with an ejection fraction >35% had lymphadenopathy. Most enlarged lymph nodes were pretracheal, with a mean short axis diameter of 1.3 cm.

However, Storto et al reported that an association between CHF and MLN was not found in 7 patients undergoing high-resolution CT imaging.³ There are also cases of MLN in patients with pulmonary hypertension without systolic dysfunction.⁴

Chabbert et al studied 31 consecutive patients with subacute left heart failure (mean ejection fraction, 39%).⁵ Enlarged mediastinal lymph nodes were present in 13 patients (42%). Other radiographic features included blurred contour of the lymph nodes in 5 patients (16%) and hazy mediastinal fat in one patient (3%). Follow-up CT showed a significant decrease in the size of the lymph nodes in 8 of 13 patients (62%) following initiation of treatment.

Heart failure and malignancy. A PubMed search with the keywords “diastolic dysfunction” and “lymphoma” found 7 references in the English language. There is a report of 125 survivors of childhood lymphomas treated with mediastinal radiotherapy and anthracyclines,⁶ another of 44 children treated for acute lymphoblastic leukemia and Hodgkin’s lymphoma⁷, a report of 294 patients who had received mediastinal irradiation for the treatment of Hodgkin’s disease,⁸ and another of 106 survivors of non-Hodgkin’s and Hodgkin’s lymphomas.⁹ None of these reports, however, made any mention of mediastinal lymphadenopathy.

What caused the lymphadenopathy in our patients?

Our 2 patients had volume overload due to diastolic dysfunction with elevated LV end diastolic pressure. Our first patient also had a loss of AV synchronization—which was reversible upon pacemaker insertion—that probably exacerbated the heart failure.

The mechanism for the lymphadenopathy is not clear, but may be due to cardiogenic pulmonary edema causing distension of the pulmonary lymphatic vessels and pulmonary hypertension. In a study of patients with severe systolic dysfunction undergoing evaluation for cardiac transplant, there was a relationship (albeit weak), between MLN and mitral regurgitation, tricuspid regurgitation, elevated mean pulmonary artery pressure, elevated pulmonary capillary wedge pressure, and elevated right atrial pressure.¹⁰

How to accurately detect and treat MLN

MLN may be detected by chest x-ray, CT, magnetic resonance imaging, or endoscopic ultrasound examinations. The clinical situation will dictate the imaging modality used. Keep in mind that it is difficult to make a comparison between a finding of lymphadenopathy on one modality and another, especially if one is looking for a change in size.

Up until now, we were not aware of any other cases of MLN linked to diastolic heart failure.

If clinically appropriate, a trial of diuretics, such as intravenous (IV) furosemide 80 mg, should be considered before embarking on invasive procedures such as mediastinal lymph node biopsy.

Our patients. The 50-year-old man in Case 1 responded well to 80 mg of IV furosemide after one hour and improved further upon receipt of a pacemaker the next day. A repeat thoracic CT one month later showed complete resolution of the MLN.

The 79-year-old man in Case 2 also received 80 mg of IV furosemide and improved within 3 hours. A month later, a repeat thoracic CT showed a significant reduction in the size of all the enlarged lymph nodes (FIGURE 2B).

THE TAKEAWAY

The importance of these 2 cases is that they show that heart failure—even diastolic alone—can produce enlarged mediastinal lymph nodes. In patients with heart failure in whom unexpected MLN is detected, consideration should be given to performing a repeat imaging examination after the administration of diuretics.

CASE 1

A 50-year-old man sought care for progressive dyspnea on exertion, abdominal bloating, and bilateral leg edema. He had hypertension that was being treated with atenolol, nifedipine, and enalapril. On examination, his blood pressure was 157/80 mm Hg and his heart rate was 50 beats/min. Jugular venous pressure was grossly elevated with occasional cannon A waves. The patient also had decreased breath sounds in both lower lung zones and moderate pitting edema up to the knees. A chest x-ray showed a small bilateral pleural effusion and no cardiomegaly. An electrocardiogram revealed complete atrioventricular (AV) block with a ventricular response of 50 beats/min. Computed tomography (CT) angiography revealed no evidence of a pulmonary embolus, but did show several enlarged (up to 3.5 cm in diameter) lymph nodes in the upper and middle mediastinum (FIGURE 1). We performed an echocardiogram.

CASE 2

A 79-year-old man with hypertension and diabetes presented to our medical center with acute dyspnea. During the physical examination, we noted bilateral diminished breath sounds with expiratory wheezes and an irregular pulse. Chest x-ray showed mild pulmonary congestion. A chest CT demonstrated bilateral small pleural effusions and multiple enlarged mediastinal lymph nodes with a maximal diameter of 2.4 cm (FIGURE 2A). One week later, the patient’s shortness of breath increased and he was hospitalized. A chest x-ray at that time showed moderate pulmonary congestion, so we performed an echocardiogram.

THE DIAGNOSIS

The echocardiogram for the 50-year-old patient in Case 1 revealed a mildly dilated left ventricle with normal systolic function, diastolic left ventricular (LV) dysfunction, moderate tricuspid regurgitation, and mild pulmonary hypertension. Extensive testing for malignancy and tuberculosis was negative.

For the 79-year-old patient in Case 2, echocardiography demonstrated concentric LV hypertrophy, mild dilatation of the left ventricle, normal LV systolic function, LV diastolic dysfunction with elevated LV diastolic filling pressure, and mild-to-moderate pulmonary hypertension.

Based on these results, we diagnosed both patients with diastolic heart failure. The patient in the second case had features of cardiac asthma, as well. Both patients had also developed reversible mediastinal lymphadenopathy (MLN), of which the diastolic heart failure was the only apparent cause. In both cases, radiologists did not note any suspicious findings for malignancy beyond the MLN.

DISCUSSION

Systolic heart failure has been previously recognized as a cause of MLN.^1,2 Other causes of MLN include sarcoidosis, various malignancies, pulmonary infections, and occupational lung diseases. There are, however, no reports of MLN in patients with diastolic heart failure.

Heart failure and MLN. Slanetz et al reported one series of 46 patients who had undergone CT of the chest during periods of congestive heart failure (CHF).¹ There was mediastinal lymph node enlargement in 55% of these patients. In a subset of 17 patients who had elevated capillary wedge pressure, 82% had some degree of lymphadenopathy.

Erly et al² retrospectively studied 44 patients who had a thoracic CT performed before cardiac transplantation. Twenty-nine (66%) had at least one enlarged mediastinal lymph node (>1 cm). Eighty-one percent of patients with an ejection fraction <35% had lymphadenopathy, while none of the patients with an ejection fraction >35% had lymphadenopathy. Most enlarged lymph nodes were pretracheal, with a mean short axis diameter of 1.3 cm.

However, Storto et al reported that an association between CHF and MLN was not found in 7 patients undergoing high-resolution CT imaging.³ There are also cases of MLN in patients with pulmonary hypertension without systolic dysfunction.⁴

Chabbert et al studied 31 consecutive patients with subacute left heart failure (mean ejection fraction, 39%).⁵ Enlarged mediastinal lymph nodes were present in 13 patients (42%). Other radiographic features included blurred contour of the lymph nodes in 5 patients (16%) and hazy mediastinal fat in one patient (3%). Follow-up CT showed a significant decrease in the size of the lymph nodes in 8 of 13 patients (62%) following initiation of treatment.

Heart failure and malignancy. A PubMed search with the keywords “diastolic dysfunction” and “lymphoma” found 7 references in the English language. There is a report of 125 survivors of childhood lymphomas treated with mediastinal radiotherapy and anthracyclines,⁶ another of 44 children treated for acute lymphoblastic leukemia and Hodgkin’s lymphoma⁷, a report of 294 patients who had received mediastinal irradiation for the treatment of Hodgkin’s disease,⁸ and another of 106 survivors of non-Hodgkin’s and Hodgkin’s lymphomas.⁹ None of these reports, however, made any mention of mediastinal lymphadenopathy.

What caused the lymphadenopathy in our patients?

Our 2 patients had volume overload due to diastolic dysfunction with elevated LV end diastolic pressure. Our first patient also had a loss of AV synchronization—which was reversible upon pacemaker insertion—that probably exacerbated the heart failure.

The mechanism for the lymphadenopathy is not clear, but may be due to cardiogenic pulmonary edema causing distension of the pulmonary lymphatic vessels and pulmonary hypertension. In a study of patients with severe systolic dysfunction undergoing evaluation for cardiac transplant, there was a relationship (albeit weak), between MLN and mitral regurgitation, tricuspid regurgitation, elevated mean pulmonary artery pressure, elevated pulmonary capillary wedge pressure, and elevated right atrial pressure.¹⁰

How to accurately detect and treat MLN

MLN may be detected by chest x-ray, CT, magnetic resonance imaging, or endoscopic ultrasound examinations. The clinical situation will dictate the imaging modality used. Keep in mind that it is difficult to make a comparison between a finding of lymphadenopathy on one modality and another, especially if one is looking for a change in size.

Up until now, we were not aware of any other cases of MLN linked to diastolic heart failure.

If clinically appropriate, a trial of diuretics, such as intravenous (IV) furosemide 80 mg, should be considered before embarking on invasive procedures such as mediastinal lymph node biopsy.

Our patients. The 50-year-old man in Case 1 responded well to 80 mg of IV furosemide after one hour and improved further upon receipt of a pacemaker the next day. A repeat thoracic CT one month later showed complete resolution of the MLN.

The 79-year-old man in Case 2 also received 80 mg of IV furosemide and improved within 3 hours. A month later, a repeat thoracic CT showed a significant reduction in the size of all the enlarged lymph nodes (FIGURE 2B).

THE TAKEAWAY

The importance of these 2 cases is that they show that heart failure—even diastolic alone—can produce enlarged mediastinal lymph nodes. In patients with heart failure in whom unexpected MLN is detected, consideration should be given to performing a repeat imaging examination after the administration of diuretics.

CASE 1

A 50-year-old man sought care for progressive dyspnea on exertion, abdominal bloating, and bilateral leg edema. He had hypertension that was being treated with atenolol, nifedipine, and enalapril. On examination, his blood pressure was 157/80 mm Hg and his heart rate was 50 beats/min. Jugular venous pressure was grossly elevated with occasional cannon A waves. The patient also had decreased breath sounds in both lower lung zones and moderate pitting edema up to the knees. A chest x-ray showed a small bilateral pleural effusion and no cardiomegaly. An electrocardiogram revealed complete atrioventricular (AV) block with a ventricular response of 50 beats/min. Computed tomography (CT) angiography revealed no evidence of a pulmonary embolus, but did show several enlarged (up to 3.5 cm in diameter) lymph nodes in the upper and middle mediastinum (FIGURE 1). We performed an echocardiogram.

CASE 2

A 79-year-old man with hypertension and diabetes presented to our medical center with acute dyspnea. During the physical examination, we noted bilateral diminished breath sounds with expiratory wheezes and an irregular pulse. Chest x-ray showed mild pulmonary congestion. A chest CT demonstrated bilateral small pleural effusions and multiple enlarged mediastinal lymph nodes with a maximal diameter of 2.4 cm (FIGURE 2A). One week later, the patient’s shortness of breath increased and he was hospitalized. A chest x-ray at that time showed moderate pulmonary congestion, so we performed an echocardiogram.

THE DIAGNOSIS

The echocardiogram for the 50-year-old patient in Case 1 revealed a mildly dilated left ventricle with normal systolic function, diastolic left ventricular (LV) dysfunction, moderate tricuspid regurgitation, and mild pulmonary hypertension. Extensive testing for malignancy and tuberculosis was negative.

For the 79-year-old patient in Case 2, echocardiography demonstrated concentric LV hypertrophy, mild dilatation of the left ventricle, normal LV systolic function, LV diastolic dysfunction with elevated LV diastolic filling pressure, and mild-to-moderate pulmonary hypertension.

Based on these results, we diagnosed both patients with diastolic heart failure. The patient in the second case had features of cardiac asthma, as well. Both patients had also developed reversible mediastinal lymphadenopathy (MLN), of which the diastolic heart failure was the only apparent cause. In both cases, radiologists did not note any suspicious findings for malignancy beyond the MLN.

DISCUSSION

Systolic heart failure has been previously recognized as a cause of MLN.^1,2 Other causes of MLN include sarcoidosis, various malignancies, pulmonary infections, and occupational lung diseases. There are, however, no reports of MLN in patients with diastolic heart failure.

Heart failure and MLN. Slanetz et al reported one series of 46 patients who had undergone CT of the chest during periods of congestive heart failure (CHF).¹ There was mediastinal lymph node enlargement in 55% of these patients. In a subset of 17 patients who had elevated capillary wedge pressure, 82% had some degree of lymphadenopathy.

Erly et al² retrospectively studied 44 patients who had a thoracic CT performed before cardiac transplantation. Twenty-nine (66%) had at least one enlarged mediastinal lymph node (>1 cm). Eighty-one percent of patients with an ejection fraction <35% had lymphadenopathy, while none of the patients with an ejection fraction >35% had lymphadenopathy. Most enlarged lymph nodes were pretracheal, with a mean short axis diameter of 1.3 cm.

However, Storto et al reported that an association between CHF and MLN was not found in 7 patients undergoing high-resolution CT imaging.³ There are also cases of MLN in patients with pulmonary hypertension without systolic dysfunction.⁴

Chabbert et al studied 31 consecutive patients with subacute left heart failure (mean ejection fraction, 39%).⁵ Enlarged mediastinal lymph nodes were present in 13 patients (42%). Other radiographic features included blurred contour of the lymph nodes in 5 patients (16%) and hazy mediastinal fat in one patient (3%). Follow-up CT showed a significant decrease in the size of the lymph nodes in 8 of 13 patients (62%) following initiation of treatment.

Heart failure and malignancy. A PubMed search with the keywords “diastolic dysfunction” and “lymphoma” found 7 references in the English language. There is a report of 125 survivors of childhood lymphomas treated with mediastinal radiotherapy and anthracyclines,⁶ another of 44 children treated for acute lymphoblastic leukemia and Hodgkin’s lymphoma⁷, a report of 294 patients who had received mediastinal irradiation for the treatment of Hodgkin’s disease,⁸ and another of 106 survivors of non-Hodgkin’s and Hodgkin’s lymphomas.⁹ None of these reports, however, made any mention of mediastinal lymphadenopathy.

What caused the lymphadenopathy in our patients?

Our 2 patients had volume overload due to diastolic dysfunction with elevated LV end diastolic pressure. Our first patient also had a loss of AV synchronization—which was reversible upon pacemaker insertion—that probably exacerbated the heart failure.

The mechanism for the lymphadenopathy is not clear, but may be due to cardiogenic pulmonary edema causing distension of the pulmonary lymphatic vessels and pulmonary hypertension. In a study of patients with severe systolic dysfunction undergoing evaluation for cardiac transplant, there was a relationship (albeit weak), between MLN and mitral regurgitation, tricuspid regurgitation, elevated mean pulmonary artery pressure, elevated pulmonary capillary wedge pressure, and elevated right atrial pressure.¹⁰

How to accurately detect and treat MLN

MLN may be detected by chest x-ray, CT, magnetic resonance imaging, or endoscopic ultrasound examinations. The clinical situation will dictate the imaging modality used. Keep in mind that it is difficult to make a comparison between a finding of lymphadenopathy on one modality and another, especially if one is looking for a change in size.

Up until now, we were not aware of any other cases of MLN linked to diastolic heart failure.

If clinically appropriate, a trial of diuretics, such as intravenous (IV) furosemide 80 mg, should be considered before embarking on invasive procedures such as mediastinal lymph node biopsy.

Our patients. The 50-year-old man in Case 1 responded well to 80 mg of IV furosemide after one hour and improved further upon receipt of a pacemaker the next day. A repeat thoracic CT one month later showed complete resolution of the MLN.

The 79-year-old man in Case 2 also received 80 mg of IV furosemide and improved within 3 hours. A month later, a repeat thoracic CT showed a significant reduction in the size of all the enlarged lymph nodes (FIGURE 2B).

THE TAKEAWAY

The importance of these 2 cases is that they show that heart failure—even diastolic alone—can produce enlarged mediastinal lymph nodes. In patients with heart failure in whom unexpected MLN is detected, consideration should be given to performing a repeat imaging examination after the administration of diuretics.

Sarcoidosis is a multisystem granulomatous disease of unknown etiology that most commonly affects the lungs, eyes, and skin. Cutaneous involvement is reported in 25% to 35% of patients with sarcoidosis and may occur in a variety of forms including macules, papules, plaques, and lupus pernio.^1,2 Dermatologists commonly are confronted with the diagnosis and management of sarcoidosis because of its high incidence of cutaneous involvement. Due to the protean nature of the disease, skin biopsy plays a key role in confirming the diagnosis. Histological evidence of noncaseating granulomas in combination with an appropriate clinical and radiographic picture is necessary for the diagnosis of sarcoidosis.^1,2 Brincker and Wilbek³ first described the link between pulmonary sarcoidosis and an increased incidence of malignancy in 1974. Since then, a number of studies have suggested that sarcoidosis may be associated with an increased risk for hematologic malignancy as well as an increased risk for cancers of the lungs, stomach, colon, liver, and skin.^4,5 To date, few studies exist that examine the relationship between cutaneous sarcoidosis and malignancy.⁶

We describe 3 patients with sarcoidosis who developed squamous cell carcinoma (SCC) of the skin, including 2 black patients, which highlights the potential for SCC development.

Case Reports

Patient 1

A black woman in her 60s with a history of sarcoidosis affecting the lungs and skin that was well controlled with biweekly adalimumab 40 mg subcutaneous injections presented with a new dark painful lesion on the right third finger. She reported the lesion had been present for 1 to 2 years prior to the current presentation and was increasing in size. She had no history of prior skin cancers.

Physical examination revealed a waxy, brown-pigmented papule with overlying scale on the ulnar aspect of the right third digit near the web space (Figure 1A). A shave biopsy revealed atypical keratinocytes involving all layers of the epidermis along with associated parakeratotic scale consistent with a diagnosis of SCC in situ (Figure 1B). Human papillomavirus staining was negative. Due to the location of the lesion, the patient underwent Mohs micrographic surgery and the lesion was completely excised.

Patient 2

A black woman in her 60s with a history of cutaneous sarcoidosis that was maintained on minocycline 100 mg twice daily, chloroquine 250 mg daily, tacrolimus ointment 0.1%, tretinoin cream 0.025%, and intermittent intralesional triamcinolone acetonide injections to the nose, as well as quiescent pulmonary sarcoidosis, developed a new, growing, asymptomatic, hyperpigmented lesion on the left side of the submandibular neck over a period of a few months. A biopsy was performed and the lesion was found to be an SCC, which subsequently was completely excised.

Patient 3

A white man in his 60s with a history of prior quiescent pulmonary sarcoidosis, remote melanoma, and multiple nonmelanoma skin cancers developed scaly papules on the scalp for months, one that was interpreted by an outside pathologist as an invasive SCC (Figure 2A). He was referred to our institution for Mohs micrographic surgery. On presentation when his scalp was shaved for surgery, he was noted to have several violaceous, annular, thin plaques on the scalp (Figure 2B). A biopsy of an annular plaque demonstrated several areas of granulomatous dermatitis consistent with a diagnosis of cutaneous sarcoidosis (Figure 2C). The patient had clinical lymphadenopathy of the neck and supraclavicular region. Given the patient’s history, the differential diagnosis for these lesions included metastatic SCC, lymphoma, and sarcoidosis. The patient underwent a positron emission tomography scan, which demonstrated fluorodeoxyglucose-positive regions in both lungs and the right side of the neck. After evaluation by the pulmonary and otorhinolaryngology departments, including a lymph node biopsy, the positron emission tomography–enhancing lesions were ultimately determined to be consistent with sarcoidosis.

The patient underwent Mohs micrographic surgery for treatment of the scalp SCC and was started on triamcinolone cream 0.1% for the body, clobetasol propionate foam 0.05% for the scalp, and hydroxychloroquine sulfate 400 mg daily for the cutaneous sarcoidosis. His annular scalp lesions resolved, but over the following 12 months the patient had numerous clinically suspicious skin lesions that were biopsied and were consistent with multiple basal cell carcinomas, actinic keratoses, and SCC in situ. They were treated with surgery, cryosurgical destruction with liquid nitrogen, and 5-fluorouracil cream.

Comment

The potential increased risk for malignancy in patients with sarcoidosis has been well documented.^3-6 Brincker and Wilbek³ first reported this association after studying 2544 patients with pulmonary sarcoidosis from 1962 to 1971. In particular, they noted a difference between the expected and observed number of cases of malignancy, particularly lung cancer and lymphoma, in the sarcoidosis population.³ In a study of 10,037 hospitalized sarcoidosis patients from 1964 to 2004, Ji et al⁵ noted a 40% overall increase in the incidence of cancer and found that the risk for malignancy was highest in the year following hospitalization. Interestingly, they found that the risk for developing cutaneous SCC was elevated in sarcoidosis patients even after the first year following hospitalization.⁵ In a retrospective cohort study examining more than 9000 patients, Askling et al⁴ also confirmed the increased incidence of malignancy in sarcoidosis patients. Specifically, the authors found a higher than expected occurrence of skin cancer, both melanoma (standardized incidence ratio, 1.6; 95% confidence interval, 1.1-2.3) and nonmelanoma skin cancer (standardized incidence ratio, 2.8; 95% confidence interval, 2.0-3.8) in patients with sarcoidosis.⁴ Reich et al⁷ cross-matched 30,000 cases from the Kaiser Permanente Northwest Region Tumor Registry against a sarcoidosis registry of 243 cases to evaluate for evidence of linkage between sarcoidosis and malignancy. They concluded that there may be an etiologic relationship between sarcoidosis and malignancy in at least one-quarter of cases in which both are present and hypothesized that granulomas may be the result of a cell-mediated reaction to tumor antigens.⁷

Few published studies specifically address the incidence of malignancy in patients with primarily cutaneous sarcoidosis. Cutaneous sarcoidosis includes nonspecific lesions, such as erythema nodosum, as well as specific lesions, such as papules, plaques, nodules, and lupus pernio.⁸ Alexandrescu et al⁶ evaluated 110 patients with a diagnosis of both sarcoidosis (cutaneous and noncutaneous) and malignancy. Through their analysis, they found that cutaneous sarcoidosis is seen more commonly in patients presenting with sarcoidosis and malignancy (56.4%) than in the total sarcoidosis population (20%–25%). From these findings, the authors concluded that cutaneous sarcoidosis appears to be a subtype of sarcoidosis associated with cancer.⁶

We report 3 cases that specifically illustrate a link between cutaneous sarcoidosis and an increased risk for cutaneous SCC. Because sarcoidosis commonly affects the skin, patients often present to dermatologists for care. Once the initial diagnosis of cutaneous sarcoidosis is made via biopsy, it is natural to be tempted to attribute any new skin lesions to worsening or active disease; however, as cutaneous sarcoidosis may take on a variety of nonspecific forms, it is important to biopsy any unusual lesions. In our case series, patient 3 presented at several different points with scaly scalp lesions. Upon biopsy, several of these lesions were found to be SCCs, while others demonstrated regions of granulomatous inflammation consistent with a diagnosis of cutaneous sarcoidosis. On further review of pathology during the preparation of this manuscript after the initial diagnoses were made, it was further noted that it is challenging to distinguish granulomatous inflammation with reactive pseudoepitheliomatous hyperplasia from SCC. The fact that these lesions were clinically indistinguishable illustrates the critical importance of appropriate-depth biopsy in this situation, and the histopathologic challenges highlighted herein are important for pathologists to remember.

Patients 1 and 2 were both black women, and the fact that these patients both presented with cutaneous SCCs—one of whom was immunosuppressed due to treatment with adalimumab, the other without systemic immunosuppression—exemplifies the need for comprehensive skin examinations in sarcoidosis patients as well as for biopsies of new or unusual lesions.

The mechanism for the development of malignancy in patients with sarcoidosis is unknown and likely is multifactorial. Multiple theories have been proposed.^1,2,5,6,8 Sarcoidosis is marked by the development of granulomas secondary to the interaction between CD4⁺ T cells and antigen-presenting cells, which is mediated by various cytokines and chemokines, including IL-2 and IFN-γ. Patients with sarcoidosis have been found to have oligoclonal T-cell lineages with a limited receptor repertoire, suggestive of selective immune system activation, as well as a deficiency of certain types of regulatory cells, namely natural killer cells.^1,2 This immune dysregulation has been postulated to play an etiologic role in the development of malignancy in sarcoidosis patients.^1,2,5 Furthermore, the chronic inflammation found in the organs commonly affected by both sarcoidosis and malignancy is another possible mechanism.^6,8 Finally, immunosuppression and mutagenesis secondary to the treatment modalities used in sarcoidosis may be another contributing factor.⁶

Conclusion

An association between sarcoidosis and malignancy has been suggested for several decades. We specifically report 3 cases of patients with cutaneous sarcoidosis who presented with concurrent cutaneous SCCs. Given the varied and often nonspecific nature of cutaneous sarcoidosis, these cases highlight the importance of biopsy when sarcoidosis patients present with new and unusual skin lesions. Additionally, they illustrate the importance of thorough skin examinations in sarcoidosis patients as well as some of the challenges these patients pose for dermatologists.

Sarcoidosis is a multisystem granulomatous disease of unknown etiology that most commonly affects the lungs, eyes, and skin. Cutaneous involvement is reported in 25% to 35% of patients with sarcoidosis and may occur in a variety of forms including macules, papules, plaques, and lupus pernio.^1,2 Dermatologists commonly are confronted with the diagnosis and management of sarcoidosis because of its high incidence of cutaneous involvement. Due to the protean nature of the disease, skin biopsy plays a key role in confirming the diagnosis. Histological evidence of noncaseating granulomas in combination with an appropriate clinical and radiographic picture is necessary for the diagnosis of sarcoidosis.^1,2 Brincker and Wilbek³ first described the link between pulmonary sarcoidosis and an increased incidence of malignancy in 1974. Since then, a number of studies have suggested that sarcoidosis may be associated with an increased risk for hematologic malignancy as well as an increased risk for cancers of the lungs, stomach, colon, liver, and skin.^4,5 To date, few studies exist that examine the relationship between cutaneous sarcoidosis and malignancy.⁶

We describe 3 patients with sarcoidosis who developed squamous cell carcinoma (SCC) of the skin, including 2 black patients, which highlights the potential for SCC development.

Case Reports

Patient 1

A black woman in her 60s with a history of sarcoidosis affecting the lungs and skin that was well controlled with biweekly adalimumab 40 mg subcutaneous injections presented with a new dark painful lesion on the right third finger. She reported the lesion had been present for 1 to 2 years prior to the current presentation and was increasing in size. She had no history of prior skin cancers.

Physical examination revealed a waxy, brown-pigmented papule with overlying scale on the ulnar aspect of the right third digit near the web space (Figure 1A). A shave biopsy revealed atypical keratinocytes involving all layers of the epidermis along with associated parakeratotic scale consistent with a diagnosis of SCC in situ (Figure 1B). Human papillomavirus staining was negative. Due to the location of the lesion, the patient underwent Mohs micrographic surgery and the lesion was completely excised.

Patient 2

A black woman in her 60s with a history of cutaneous sarcoidosis that was maintained on minocycline 100 mg twice daily, chloroquine 250 mg daily, tacrolimus ointment 0.1%, tretinoin cream 0.025%, and intermittent intralesional triamcinolone acetonide injections to the nose, as well as quiescent pulmonary sarcoidosis, developed a new, growing, asymptomatic, hyperpigmented lesion on the left side of the submandibular neck over a period of a few months. A biopsy was performed and the lesion was found to be an SCC, which subsequently was completely excised.

Patient 3

A white man in his 60s with a history of prior quiescent pulmonary sarcoidosis, remote melanoma, and multiple nonmelanoma skin cancers developed scaly papules on the scalp for months, one that was interpreted by an outside pathologist as an invasive SCC (Figure 2A). He was referred to our institution for Mohs micrographic surgery. On presentation when his scalp was shaved for surgery, he was noted to have several violaceous, annular, thin plaques on the scalp (Figure 2B). A biopsy of an annular plaque demonstrated several areas of granulomatous dermatitis consistent with a diagnosis of cutaneous sarcoidosis (Figure 2C). The patient had clinical lymphadenopathy of the neck and supraclavicular region. Given the patient’s history, the differential diagnosis for these lesions included metastatic SCC, lymphoma, and sarcoidosis. The patient underwent a positron emission tomography scan, which demonstrated fluorodeoxyglucose-positive regions in both lungs and the right side of the neck. After evaluation by the pulmonary and otorhinolaryngology departments, including a lymph node biopsy, the positron emission tomography–enhancing lesions were ultimately determined to be consistent with sarcoidosis.

The patient underwent Mohs micrographic surgery for treatment of the scalp SCC and was started on triamcinolone cream 0.1% for the body, clobetasol propionate foam 0.05% for the scalp, and hydroxychloroquine sulfate 400 mg daily for the cutaneous sarcoidosis. His annular scalp lesions resolved, but over the following 12 months the patient had numerous clinically suspicious skin lesions that were biopsied and were consistent with multiple basal cell carcinomas, actinic keratoses, and SCC in situ. They were treated with surgery, cryosurgical destruction with liquid nitrogen, and 5-fluorouracil cream.

Comment

The potential increased risk for malignancy in patients with sarcoidosis has been well documented.^3-6 Brincker and Wilbek³ first reported this association after studying 2544 patients with pulmonary sarcoidosis from 1962 to 1971. In particular, they noted a difference between the expected and observed number of cases of malignancy, particularly lung cancer and lymphoma, in the sarcoidosis population.³ In a study of 10,037 hospitalized sarcoidosis patients from 1964 to 2004, Ji et al⁵ noted a 40% overall increase in the incidence of cancer and found that the risk for malignancy was highest in the year following hospitalization. Interestingly, they found that the risk for developing cutaneous SCC was elevated in sarcoidosis patients even after the first year following hospitalization.⁵ In a retrospective cohort study examining more than 9000 patients, Askling et al⁴ also confirmed the increased incidence of malignancy in sarcoidosis patients. Specifically, the authors found a higher than expected occurrence of skin cancer, both melanoma (standardized incidence ratio, 1.6; 95% confidence interval, 1.1-2.3) and nonmelanoma skin cancer (standardized incidence ratio, 2.8; 95% confidence interval, 2.0-3.8) in patients with sarcoidosis.⁴ Reich et al⁷ cross-matched 30,000 cases from the Kaiser Permanente Northwest Region Tumor Registry against a sarcoidosis registry of 243 cases to evaluate for evidence of linkage between sarcoidosis and malignancy. They concluded that there may be an etiologic relationship between sarcoidosis and malignancy in at least one-quarter of cases in which both are present and hypothesized that granulomas may be the result of a cell-mediated reaction to tumor antigens.⁷

Few published studies specifically address the incidence of malignancy in patients with primarily cutaneous sarcoidosis. Cutaneous sarcoidosis includes nonspecific lesions, such as erythema nodosum, as well as specific lesions, such as papules, plaques, nodules, and lupus pernio.⁸ Alexandrescu et al⁶ evaluated 110 patients with a diagnosis of both sarcoidosis (cutaneous and noncutaneous) and malignancy. Through their analysis, they found that cutaneous sarcoidosis is seen more commonly in patients presenting with sarcoidosis and malignancy (56.4%) than in the total sarcoidosis population (20%–25%). From these findings, the authors concluded that cutaneous sarcoidosis appears to be a subtype of sarcoidosis associated with cancer.⁶

We report 3 cases that specifically illustrate a link between cutaneous sarcoidosis and an increased risk for cutaneous SCC. Because sarcoidosis commonly affects the skin, patients often present to dermatologists for care. Once the initial diagnosis of cutaneous sarcoidosis is made via biopsy, it is natural to be tempted to attribute any new skin lesions to worsening or active disease; however, as cutaneous sarcoidosis may take on a variety of nonspecific forms, it is important to biopsy any unusual lesions. In our case series, patient 3 presented at several different points with scaly scalp lesions. Upon biopsy, several of these lesions were found to be SCCs, while others demonstrated regions of granulomatous inflammation consistent with a diagnosis of cutaneous sarcoidosis. On further review of pathology during the preparation of this manuscript after the initial diagnoses were made, it was further noted that it is challenging to distinguish granulomatous inflammation with reactive pseudoepitheliomatous hyperplasia from SCC. The fact that these lesions were clinically indistinguishable illustrates the critical importance of appropriate-depth biopsy in this situation, and the histopathologic challenges highlighted herein are important for pathologists to remember.

Patients 1 and 2 were both black women, and the fact that these patients both presented with cutaneous SCCs—one of whom was immunosuppressed due to treatment with adalimumab, the other without systemic immunosuppression—exemplifies the need for comprehensive skin examinations in sarcoidosis patients as well as for biopsies of new or unusual lesions.

The mechanism for the development of malignancy in patients with sarcoidosis is unknown and likely is multifactorial. Multiple theories have been proposed.^1,2,5,6,8 Sarcoidosis is marked by the development of granulomas secondary to the interaction between CD4⁺ T cells and antigen-presenting cells, which is mediated by various cytokines and chemokines, including IL-2 and IFN-γ. Patients with sarcoidosis have been found to have oligoclonal T-cell lineages with a limited receptor repertoire, suggestive of selective immune system activation, as well as a deficiency of certain types of regulatory cells, namely natural killer cells.^1,2 This immune dysregulation has been postulated to play an etiologic role in the development of malignancy in sarcoidosis patients.^1,2,5 Furthermore, the chronic inflammation found in the organs commonly affected by both sarcoidosis and malignancy is another possible mechanism.^6,8 Finally, immunosuppression and mutagenesis secondary to the treatment modalities used in sarcoidosis may be another contributing factor.⁶

Conclusion

An association between sarcoidosis and malignancy has been suggested for several decades. We specifically report 3 cases of patients with cutaneous sarcoidosis who presented with concurrent cutaneous SCCs. Given the varied and often nonspecific nature of cutaneous sarcoidosis, these cases highlight the importance of biopsy when sarcoidosis patients present with new and unusual skin lesions. Additionally, they illustrate the importance of thorough skin examinations in sarcoidosis patients as well as some of the challenges these patients pose for dermatologists.

Sarcoidosis is a multisystem granulomatous disease of unknown etiology that most commonly affects the lungs, eyes, and skin. Cutaneous involvement is reported in 25% to 35% of patients with sarcoidosis and may occur in a variety of forms including macules, papules, plaques, and lupus pernio.^1,2 Dermatologists commonly are confronted with the diagnosis and management of sarcoidosis because of its high incidence of cutaneous involvement. Due to the protean nature of the disease, skin biopsy plays a key role in confirming the diagnosis. Histological evidence of noncaseating granulomas in combination with an appropriate clinical and radiographic picture is necessary for the diagnosis of sarcoidosis.^1,2 Brincker and Wilbek³ first described the link between pulmonary sarcoidosis and an increased incidence of malignancy in 1974. Since then, a number of studies have suggested that sarcoidosis may be associated with an increased risk for hematologic malignancy as well as an increased risk for cancers of the lungs, stomach, colon, liver, and skin.^4,5 To date, few studies exist that examine the relationship between cutaneous sarcoidosis and malignancy.⁶

We describe 3 patients with sarcoidosis who developed squamous cell carcinoma (SCC) of the skin, including 2 black patients, which highlights the potential for SCC development.

Case Reports

Patient 1

A black woman in her 60s with a history of sarcoidosis affecting the lungs and skin that was well controlled with biweekly adalimumab 40 mg subcutaneous injections presented with a new dark painful lesion on the right third finger. She reported the lesion had been present for 1 to 2 years prior to the current presentation and was increasing in size. She had no history of prior skin cancers.

Physical examination revealed a waxy, brown-pigmented papule with overlying scale on the ulnar aspect of the right third digit near the web space (Figure 1A). A shave biopsy revealed atypical keratinocytes involving all layers of the epidermis along with associated parakeratotic scale consistent with a diagnosis of SCC in situ (Figure 1B). Human papillomavirus staining was negative. Due to the location of the lesion, the patient underwent Mohs micrographic surgery and the lesion was completely excised.

Patient 2

A black woman in her 60s with a history of cutaneous sarcoidosis that was maintained on minocycline 100 mg twice daily, chloroquine 250 mg daily, tacrolimus ointment 0.1%, tretinoin cream 0.025%, and intermittent intralesional triamcinolone acetonide injections to the nose, as well as quiescent pulmonary sarcoidosis, developed a new, growing, asymptomatic, hyperpigmented lesion on the left side of the submandibular neck over a period of a few months. A biopsy was performed and the lesion was found to be an SCC, which subsequently was completely excised.

Patient 3

A white man in his 60s with a history of prior quiescent pulmonary sarcoidosis, remote melanoma, and multiple nonmelanoma skin cancers developed scaly papules on the scalp for months, one that was interpreted by an outside pathologist as an invasive SCC (Figure 2A). He was referred to our institution for Mohs micrographic surgery. On presentation when his scalp was shaved for surgery, he was noted to have several violaceous, annular, thin plaques on the scalp (Figure 2B). A biopsy of an annular plaque demonstrated several areas of granulomatous dermatitis consistent with a diagnosis of cutaneous sarcoidosis (Figure 2C). The patient had clinical lymphadenopathy of the neck and supraclavicular region. Given the patient’s history, the differential diagnosis for these lesions included metastatic SCC, lymphoma, and sarcoidosis. The patient underwent a positron emission tomography scan, which demonstrated fluorodeoxyglucose-positive regions in both lungs and the right side of the neck. After evaluation by the pulmonary and otorhinolaryngology departments, including a lymph node biopsy, the positron emission tomography–enhancing lesions were ultimately determined to be consistent with sarcoidosis.

The patient underwent Mohs micrographic surgery for treatment of the scalp SCC and was started on triamcinolone cream 0.1% for the body, clobetasol propionate foam 0.05% for the scalp, and hydroxychloroquine sulfate 400 mg daily for the cutaneous sarcoidosis. His annular scalp lesions resolved, but over the following 12 months the patient had numerous clinically suspicious skin lesions that were biopsied and were consistent with multiple basal cell carcinomas, actinic keratoses, and SCC in situ. They were treated with surgery, cryosurgical destruction with liquid nitrogen, and 5-fluorouracil cream.

Comment

The potential increased risk for malignancy in patients with sarcoidosis has been well documented.^3-6 Brincker and Wilbek³ first reported this association after studying 2544 patients with pulmonary sarcoidosis from 1962 to 1971. In particular, they noted a difference between the expected and observed number of cases of malignancy, particularly lung cancer and lymphoma, in the sarcoidosis population.³ In a study of 10,037 hospitalized sarcoidosis patients from 1964 to 2004, Ji et al⁵ noted a 40% overall increase in the incidence of cancer and found that the risk for malignancy was highest in the year following hospitalization. Interestingly, they found that the risk for developing cutaneous SCC was elevated in sarcoidosis patients even after the first year following hospitalization.⁵ In a retrospective cohort study examining more than 9000 patients, Askling et al⁴ also confirmed the increased incidence of malignancy in sarcoidosis patients. Specifically, the authors found a higher than expected occurrence of skin cancer, both melanoma (standardized incidence ratio, 1.6; 95% confidence interval, 1.1-2.3) and nonmelanoma skin cancer (standardized incidence ratio, 2.8; 95% confidence interval, 2.0-3.8) in patients with sarcoidosis.⁴ Reich et al⁷ cross-matched 30,000 cases from the Kaiser Permanente Northwest Region Tumor Registry against a sarcoidosis registry of 243 cases to evaluate for evidence of linkage between sarcoidosis and malignancy. They concluded that there may be an etiologic relationship between sarcoidosis and malignancy in at least one-quarter of cases in which both are present and hypothesized that granulomas may be the result of a cell-mediated reaction to tumor antigens.⁷

Few published studies specifically address the incidence of malignancy in patients with primarily cutaneous sarcoidosis. Cutaneous sarcoidosis includes nonspecific lesions, such as erythema nodosum, as well as specific lesions, such as papules, plaques, nodules, and lupus pernio.⁸ Alexandrescu et al⁶ evaluated 110 patients with a diagnosis of both sarcoidosis (cutaneous and noncutaneous) and malignancy. Through their analysis, they found that cutaneous sarcoidosis is seen more commonly in patients presenting with sarcoidosis and malignancy (56.4%) than in the total sarcoidosis population (20%–25%). From these findings, the authors concluded that cutaneous sarcoidosis appears to be a subtype of sarcoidosis associated with cancer.⁶

We report 3 cases that specifically illustrate a link between cutaneous sarcoidosis and an increased risk for cutaneous SCC. Because sarcoidosis commonly affects the skin, patients often present to dermatologists for care. Once the initial diagnosis of cutaneous sarcoidosis is made via biopsy, it is natural to be tempted to attribute any new skin lesions to worsening or active disease; however, as cutaneous sarcoidosis may take on a variety of nonspecific forms, it is important to biopsy any unusual lesions. In our case series, patient 3 presented at several different points with scaly scalp lesions. Upon biopsy, several of these lesions were found to be SCCs, while others demonstrated regions of granulomatous inflammation consistent with a diagnosis of cutaneous sarcoidosis. On further review of pathology during the preparation of this manuscript after the initial diagnoses were made, it was further noted that it is challenging to distinguish granulomatous inflammation with reactive pseudoepitheliomatous hyperplasia from SCC. The fact that these lesions were clinically indistinguishable illustrates the critical importance of appropriate-depth biopsy in this situation, and the histopathologic challenges highlighted herein are important for pathologists to remember.

Patients 1 and 2 were both black women, and the fact that these patients both presented with cutaneous SCCs—one of whom was immunosuppressed due to treatment with adalimumab, the other without systemic immunosuppression—exemplifies the need for comprehensive skin examinations in sarcoidosis patients as well as for biopsies of new or unusual lesions.

The mechanism for the development of malignancy in patients with sarcoidosis is unknown and likely is multifactorial. Multiple theories have been proposed.^1,2,5,6,8 Sarcoidosis is marked by the development of granulomas secondary to the interaction between CD4⁺ T cells and antigen-presenting cells, which is mediated by various cytokines and chemokines, including IL-2 and IFN-γ. Patients with sarcoidosis have been found to have oligoclonal T-cell lineages with a limited receptor repertoire, suggestive of selective immune system activation, as well as a deficiency of certain types of regulatory cells, namely natural killer cells.^1,2 This immune dysregulation has been postulated to play an etiologic role in the development of malignancy in sarcoidosis patients.^1,2,5 Furthermore, the chronic inflammation found in the organs commonly affected by both sarcoidosis and malignancy is another possible mechanism.^6,8 Finally, immunosuppression and mutagenesis secondary to the treatment modalities used in sarcoidosis may be another contributing factor.⁶

Conclusion

An association between sarcoidosis and malignancy has been suggested for several decades. We specifically report 3 cases of patients with cutaneous sarcoidosis who presented with concurrent cutaneous SCCs. Given the varied and often nonspecific nature of cutaneous sarcoidosis, these cases highlight the importance of biopsy when sarcoidosis patients present with new and unusual skin lesions. Additionally, they illustrate the importance of thorough skin examinations in sarcoidosis patients as well as some of the challenges these patients pose for dermatologists.

In 1909, Sabouraud¹ published a report delineating the clinical subsets of a chronic fungal infection of the scalp known as favus. The rarest subset was termed favus papyroide and consisted of a thin, dry, gray, parchmentlike crust up to 5 cm in diameter. Hair shafts were described as piercing the crust, with the underlying skin exhibiting erythema, moisture, and erosions. Children were reported to be affected more often than adults.¹ Subsequent descriptions of patients with similar presentations have not appeared in the medical literature. In this case, an elderly woman with tinea capitis (TC) due to Trichophyton rubrum exhibited features of favus papyroide.

Case Report

An 87-year-old woman with a long history of actinic keratoses and nonmelanoma skin cancers presented to our dermatology clinic with numerous growths on the head, neck, and arms. The patient resided in a nursing home and had a history of hypertension, osteoarthritis, and mild to moderate dementia. Physical examination revealed a frail elderly woman in a wheelchair. Numerous actinic keratoses were noted on the arms and face. Examination of the scalp revealed a large, white-gray, palm-sized plaque on the crown (Figure 1) with 2 yellow, quarter-sized, hyperkeratotic nodules on the left temple and left parietal scalp. The differential diagnosis for the nodules on the temple and scalp included squamous cell carcinoma and hyperkeratotic actinic keratosis, and both lesions were biopsied. Histologically, they demonstrated pronounced hyperkeratosis and parakeratosis with numerous infiltrating neutrophils. The stratum malpighii exhibited focal atypia consistent with an actinic keratosis with areas of spongiosis and pustular folliculitis but no evidence of an invasive cutaneous malignancy. Periodic acid–Schiff stains were performed on both specimens and revealed numerous fungal hyphae within the stratum corneum (Figure 2) as well as evidence of a fungal folliculitis.

At a follow-up visit 2 weeks later, a portion of the hyperkeratotic material on the crown of the scalp was lifted free from the skin surface, removed with scissors, and submitted for histologic analysis and culture. The underlying skin exhibited substantial erythema and diffuse alopecia. The specimen consisted entirely of masses of hyperkeratotic and parakeratotic stratum corneum with numerous infiltrating neutrophils, cellular debris, and focal secondary bacterial colonization (Figure 3). Fungal hyphae and spores were readily demonstrated on Gomori methenamine-silver stain (Figure 4). A fungal culture from this material failed to demonstrate growth at 28 days. The organism was molecularly identified as T rubrum using the Sanger sequencing assay. The patient was treated with fluconazole 150 mg once daily for 3 weeks with eventual resolution of the plaque. The patient died approximately 3 months later (unrelated to her scalp infection).

Comment

Favus, or tinea favosa, is a chronic inflammatory dermatophyte infection of the scalp, less commonly involving the skin and nails.² The classic lesion is termed a scutulum or godet consisting of concave, cup-shaped, yellow crusts typically pierced by a single hair shaft.¹ With an increase in size, the scutula may become confluent. Alopecia commonly results and infected patients may exude a “cheesy” or “mousy” odor from the lesions.³ Sabouraud¹ delineated 3 clinical presentations of favus: (1) favus pityroide, the most common type consisting of a seborrheic dermatitis–like picture and scutula; (2) favus impetigoide, exhibiting honey-colored crusts reminiscent of impetigo but without appreciable scutula; and (3) favus papyroide, the rarest variant, demonstrating a dry, gray, parchmentlike crust pierced by hair shafts overlying an eroded erythematous scalp.

Favus usually is acquired in childhood or adolescence and often persists into adulthood.³ It is transmitted directly by hairs, infected keratinocytes, and fomites. Child-to-child transmission is much less common than other forms of TC.⁴ The responsible organism is almost always Trichophyton schoenleinii, with rare cases of Trichophyton violaceum, Trichophyton verrucosum, Trichophyton mentagrophytes var quinckeanum, Microsporum canis, and Microsporum gypseum having been reported.^2,5,6 This anthropophilic dermatophyte infects only humans, is capable of surviving in the same dwelling space for generations, and is believed to require prolonged exposure for transmission. Trichophyton schoenleinii was the predominant infectious cause of TC in eastern Europe in the 19th and early 20th centuries, but its incidence has dramatically declined in the last 50 years.⁷ A survey conducted in 1997 and published in 2001 of TC that was culture-positive for T schoenleinii in 19 European countries found only 3 cases among 3671 isolates (0.08%).⁸ Between 1980 and 2005, no cases were reported in the British Isles.⁹ Currently, favus generally is found in impoverished geographic regions with poor hygiene, malnutrition, and limited access to health care; however, endemic foci in Kentucky, Quebec, and Montreal have been reported in North America.¹⁰ Although favus rarely resolves spontaneously, T schoenleinii was eradicated in most of the world with the introduction of griseofulvin in 1958.⁷ Terbinafine and itraconazole are currently the drugs of choice for therapy.¹⁰

Tinea capitis is the most common fungal infection in children, with 1 in 20 US children displaying evidence of overt infection.¹¹ Infection in adults is rare and most affected patients typically display serious illnesses with concomitant immune compromise.¹² Only 3% to 5% of cases arise in patients older than 20 years.¹³ Adult hair appears to be relatively resistant to dermatophyte infection, probably from the fungistatic properties of long-chain fatty acids found in sebum.¹³ Tinea capitis in adults usually occurs in postmenopausal women, presumably from involution of sebaceous glands associated with declining estrogen levels. Patients typically exhibit erythematous scaly patches with central clearing, alopecia, varying degrees of inflammation, and few pustules, though exudative and heavily inflammatory lesions also have been described.¹⁴

In the current case, TC was not raised in the differential diagnosis. Regardless, given that scaly red patches and papules of the scalp may represent a dermatophyte infection in this patient population, clinicians are encouraged to consider this possibility. Transmission is by direct human-to-human contact and contact with objects containing fomites including brushes, combs, bedding, clothing, toys, furniture, and telephones.¹⁵ It is frequently spread among family members and classmates.¹⁶

Prior to World War II, most cases of TC in the United States were due to M canis, with Microsporum audouinii becoming more prevalent until the 1960s and 1970s when Trichophyton tonsurans began surging in incidence.^12,17 Currently, the latter organism is responsible for more than 95% of TC cases in the United States.¹⁸Microsporum canis is the main causative species in Europe but varies widely by country. In the Middle East and Africa, T violaceum is responsible for many infections.

Trichophyton rubrum–associated TC appears to be a rare occurrence. A global study in 1995 noted that less than 1% of TC cases were due to T rubrum infection, most having been described in emerging nations.¹² A meta-analysis of 9 studies from developed countries found only 9 of 10,145 cases of TC with a culture positive for T rubrum.¹⁴ In adults, infected patients typically exhibit either evidence of a concomitant fungal infection of the skin and/or nails or health conditions with impaired immunity, whereas in children, interfamilial spread appears more common.¹¹

In 1909, Sabouraud¹ published a report delineating the clinical subsets of a chronic fungal infection of the scalp known as favus. The rarest subset was termed favus papyroide and consisted of a thin, dry, gray, parchmentlike crust up to 5 cm in diameter. Hair shafts were described as piercing the crust, with the underlying skin exhibiting erythema, moisture, and erosions. Children were reported to be affected more often than adults.¹ Subsequent descriptions of patients with similar presentations have not appeared in the medical literature. In this case, an elderly woman with tinea capitis (TC) due to Trichophyton rubrum exhibited features of favus papyroide.

Case Report

An 87-year-old woman with a long history of actinic keratoses and nonmelanoma skin cancers presented to our dermatology clinic with numerous growths on the head, neck, and arms. The patient resided in a nursing home and had a history of hypertension, osteoarthritis, and mild to moderate dementia. Physical examination revealed a frail elderly woman in a wheelchair. Numerous actinic keratoses were noted on the arms and face. Examination of the scalp revealed a large, white-gray, palm-sized plaque on the crown (Figure 1) with 2 yellow, quarter-sized, hyperkeratotic nodules on the left temple and left parietal scalp. The differential diagnosis for the nodules on the temple and scalp included squamous cell carcinoma and hyperkeratotic actinic keratosis, and both lesions were biopsied. Histologically, they demonstrated pronounced hyperkeratosis and parakeratosis with numerous infiltrating neutrophils. The stratum malpighii exhibited focal atypia consistent with an actinic keratosis with areas of spongiosis and pustular folliculitis but no evidence of an invasive cutaneous malignancy. Periodic acid–Schiff stains were performed on both specimens and revealed numerous fungal hyphae within the stratum corneum (Figure 2) as well as evidence of a fungal folliculitis.

At a follow-up visit 2 weeks later, a portion of the hyperkeratotic material on the crown of the scalp was lifted free from the skin surface, removed with scissors, and submitted for histologic analysis and culture. The underlying skin exhibited substantial erythema and diffuse alopecia. The specimen consisted entirely of masses of hyperkeratotic and parakeratotic stratum corneum with numerous infiltrating neutrophils, cellular debris, and focal secondary bacterial colonization (Figure 3). Fungal hyphae and spores were readily demonstrated on Gomori methenamine-silver stain (Figure 4). A fungal culture from this material failed to demonstrate growth at 28 days. The organism was molecularly identified as T rubrum using the Sanger sequencing assay. The patient was treated with fluconazole 150 mg once daily for 3 weeks with eventual resolution of the plaque. The patient died approximately 3 months later (unrelated to her scalp infection).

Comment

Favus, or tinea favosa, is a chronic inflammatory dermatophyte infection of the scalp, less commonly involving the skin and nails.² The classic lesion is termed a scutulum or godet consisting of concave, cup-shaped, yellow crusts typically pierced by a single hair shaft.¹ With an increase in size, the scutula may become confluent. Alopecia commonly results and infected patients may exude a “cheesy” or “mousy” odor from the lesions.³ Sabouraud¹ delineated 3 clinical presentations of favus: (1) favus pityroide, the most common type consisting of a seborrheic dermatitis–like picture and scutula; (2) favus impetigoide, exhibiting honey-colored crusts reminiscent of impetigo but without appreciable scutula; and (3) favus papyroide, the rarest variant, demonstrating a dry, gray, parchmentlike crust pierced by hair shafts overlying an eroded erythematous scalp.

Favus usually is acquired in childhood or adolescence and often persists into adulthood.³ It is transmitted directly by hairs, infected keratinocytes, and fomites. Child-to-child transmission is much less common than other forms of TC.⁴ The responsible organism is almost always Trichophyton schoenleinii, with rare cases of Trichophyton violaceum, Trichophyton verrucosum, Trichophyton mentagrophytes var quinckeanum, Microsporum canis, and Microsporum gypseum having been reported.^2,5,6 This anthropophilic dermatophyte infects only humans, is capable of surviving in the same dwelling space for generations, and is believed to require prolonged exposure for transmission. Trichophyton schoenleinii was the predominant infectious cause of TC in eastern Europe in the 19th and early 20th centuries, but its incidence has dramatically declined in the last 50 years.⁷ A survey conducted in 1997 and published in 2001 of TC that was culture-positive for T schoenleinii in 19 European countries found only 3 cases among 3671 isolates (0.08%).⁸ Between 1980 and 2005, no cases were reported in the British Isles.⁹ Currently, favus generally is found in impoverished geographic regions with poor hygiene, malnutrition, and limited access to health care; however, endemic foci in Kentucky, Quebec, and Montreal have been reported in North America.¹⁰ Although favus rarely resolves spontaneously, T schoenleinii was eradicated in most of the world with the introduction of griseofulvin in 1958.⁷ Terbinafine and itraconazole are currently the drugs of choice for therapy.¹⁰

Tinea capitis is the most common fungal infection in children, with 1 in 20 US children displaying evidence of overt infection.¹¹ Infection in adults is rare and most affected patients typically display serious illnesses with concomitant immune compromise.¹² Only 3% to 5% of cases arise in patients older than 20 years.¹³ Adult hair appears to be relatively resistant to dermatophyte infection, probably from the fungistatic properties of long-chain fatty acids found in sebum.¹³ Tinea capitis in adults usually occurs in postmenopausal women, presumably from involution of sebaceous glands associated with declining estrogen levels. Patients typically exhibit erythematous scaly patches with central clearing, alopecia, varying degrees of inflammation, and few pustules, though exudative and heavily inflammatory lesions also have been described.¹⁴

In the current case, TC was not raised in the differential diagnosis. Regardless, given that scaly red patches and papules of the scalp may represent a dermatophyte infection in this patient population, clinicians are encouraged to consider this possibility. Transmission is by direct human-to-human contact and contact with objects containing fomites including brushes, combs, bedding, clothing, toys, furniture, and telephones.¹⁵ It is frequently spread among family members and classmates.¹⁶

Prior to World War II, most cases of TC in the United States were due to M canis, with Microsporum audouinii becoming more prevalent until the 1960s and 1970s when Trichophyton tonsurans began surging in incidence.^12,17 Currently, the latter organism is responsible for more than 95% of TC cases in the United States.¹⁸Microsporum canis is the main causative species in Europe but varies widely by country. In the Middle East and Africa, T violaceum is responsible for many infections.

Trichophyton rubrum–associated TC appears to be a rare occurrence. A global study in 1995 noted that less than 1% of TC cases were due to T rubrum infection, most having been described in emerging nations.¹² A meta-analysis of 9 studies from developed countries found only 9 of 10,145 cases of TC with a culture positive for T rubrum.¹⁴ In adults, infected patients typically exhibit either evidence of a concomitant fungal infection of the skin and/or nails or health conditions with impaired immunity, whereas in children, interfamilial spread appears more common.¹¹

In 1909, Sabouraud¹ published a report delineating the clinical subsets of a chronic fungal infection of the scalp known as favus. The rarest subset was termed favus papyroide and consisted of a thin, dry, gray, parchmentlike crust up to 5 cm in diameter. Hair shafts were described as piercing the crust, with the underlying skin exhibiting erythema, moisture, and erosions. Children were reported to be affected more often than adults.¹ Subsequent descriptions of patients with similar presentations have not appeared in the medical literature. In this case, an elderly woman with tinea capitis (TC) due to Trichophyton rubrum exhibited features of favus papyroide.

Case Report

An 87-year-old woman with a long history of actinic keratoses and nonmelanoma skin cancers presented to our dermatology clinic with numerous growths on the head, neck, and arms. The patient resided in a nursing home and had a history of hypertension, osteoarthritis, and mild to moderate dementia. Physical examination revealed a frail elderly woman in a wheelchair. Numerous actinic keratoses were noted on the arms and face. Examination of the scalp revealed a large, white-gray, palm-sized plaque on the crown (Figure 1) with 2 yellow, quarter-sized, hyperkeratotic nodules on the left temple and left parietal scalp. The differential diagnosis for the nodules on the temple and scalp included squamous cell carcinoma and hyperkeratotic actinic keratosis, and both lesions were biopsied. Histologically, they demonstrated pronounced hyperkeratosis and parakeratosis with numerous infiltrating neutrophils. The stratum malpighii exhibited focal atypia consistent with an actinic keratosis with areas of spongiosis and pustular folliculitis but no evidence of an invasive cutaneous malignancy. Periodic acid–Schiff stains were performed on both specimens and revealed numerous fungal hyphae within the stratum corneum (Figure 2) as well as evidence of a fungal folliculitis.

At a follow-up visit 2 weeks later, a portion of the hyperkeratotic material on the crown of the scalp was lifted free from the skin surface, removed with scissors, and submitted for histologic analysis and culture. The underlying skin exhibited substantial erythema and diffuse alopecia. The specimen consisted entirely of masses of hyperkeratotic and parakeratotic stratum corneum with numerous infiltrating neutrophils, cellular debris, and focal secondary bacterial colonization (Figure 3). Fungal hyphae and spores were readily demonstrated on Gomori methenamine-silver stain (Figure 4). A fungal culture from this material failed to demonstrate growth at 28 days. The organism was molecularly identified as T rubrum using the Sanger sequencing assay. The patient was treated with fluconazole 150 mg once daily for 3 weeks with eventual resolution of the plaque. The patient died approximately 3 months later (unrelated to her scalp infection).

Comment

Favus, or tinea favosa, is a chronic inflammatory dermatophyte infection of the scalp, less commonly involving the skin and nails.² The classic lesion is termed a scutulum or godet consisting of concave, cup-shaped, yellow crusts typically pierced by a single hair shaft.¹ With an increase in size, the scutula may become confluent. Alopecia commonly results and infected patients may exude a “cheesy” or “mousy” odor from the lesions.³ Sabouraud¹ delineated 3 clinical presentations of favus: (1) favus pityroide, the most common type consisting of a seborrheic dermatitis–like picture and scutula; (2) favus impetigoide, exhibiting honey-colored crusts reminiscent of impetigo but without appreciable scutula; and (3) favus papyroide, the rarest variant, demonstrating a dry, gray, parchmentlike crust pierced by hair shafts overlying an eroded erythematous scalp.

Favus usually is acquired in childhood or adolescence and often persists into adulthood.³ It is transmitted directly by hairs, infected keratinocytes, and fomites. Child-to-child transmission is much less common than other forms of TC.⁴ The responsible organism is almost always Trichophyton schoenleinii, with rare cases of Trichophyton violaceum, Trichophyton verrucosum, Trichophyton mentagrophytes var quinckeanum, Microsporum canis, and Microsporum gypseum having been reported.^2,5,6 This anthropophilic dermatophyte infects only humans, is capable of surviving in the same dwelling space for generations, and is believed to require prolonged exposure for transmission. Trichophyton schoenleinii was the predominant infectious cause of TC in eastern Europe in the 19th and early 20th centuries, but its incidence has dramatically declined in the last 50 years.⁷ A survey conducted in 1997 and published in 2001 of TC that was culture-positive for T schoenleinii in 19 European countries found only 3 cases among 3671 isolates (0.08%).⁸ Between 1980 and 2005, no cases were reported in the British Isles.⁹ Currently, favus generally is found in impoverished geographic regions with poor hygiene, malnutrition, and limited access to health care; however, endemic foci in Kentucky, Quebec, and Montreal have been reported in North America.¹⁰ Although favus rarely resolves spontaneously, T schoenleinii was eradicated in most of the world with the introduction of griseofulvin in 1958.⁷ Terbinafine and itraconazole are currently the drugs of choice for therapy.¹⁰

Tinea capitis is the most common fungal infection in children, with 1 in 20 US children displaying evidence of overt infection.¹¹ Infection in adults is rare and most affected patients typically display serious illnesses with concomitant immune compromise.¹² Only 3% to 5% of cases arise in patients older than 20 years.¹³ Adult hair appears to be relatively resistant to dermatophyte infection, probably from the fungistatic properties of long-chain fatty acids found in sebum.¹³ Tinea capitis in adults usually occurs in postmenopausal women, presumably from involution of sebaceous glands associated with declining estrogen levels. Patients typically exhibit erythematous scaly patches with central clearing, alopecia, varying degrees of inflammation, and few pustules, though exudative and heavily inflammatory lesions also have been described.¹⁴

In the current case, TC was not raised in the differential diagnosis. Regardless, given that scaly red patches and papules of the scalp may represent a dermatophyte infection in this patient population, clinicians are encouraged to consider this possibility. Transmission is by direct human-to-human contact and contact with objects containing fomites including brushes, combs, bedding, clothing, toys, furniture, and telephones.¹⁵ It is frequently spread among family members and classmates.¹⁶

Prior to World War II, most cases of TC in the United States were due to M canis, with Microsporum audouinii becoming more prevalent until the 1960s and 1970s when Trichophyton tonsurans began surging in incidence.^12,17 Currently, the latter organism is responsible for more than 95% of TC cases in the United States.¹⁸Microsporum canis is the main causative species in Europe but varies widely by country. In the Middle East and Africa, T violaceum is responsible for many infections.

Trichophyton rubrum–associated TC appears to be a rare occurrence. A global study in 1995 noted that less than 1% of TC cases were due to T rubrum infection, most having been described in emerging nations.¹² A meta-analysis of 9 studies from developed countries found only 9 of 10,145 cases of TC with a culture positive for T rubrum.¹⁴ In adults, infected patients typically exhibit either evidence of a concomitant fungal infection of the skin and/or nails or health conditions with impaired immunity, whereas in children, interfamilial spread appears more common.¹¹