Case Reports

Rheumatologic conditions and infections may imitate each other, often making diagnosis challenging. Therefore, it is imperative to obtain adequate histories and have a keen eye for these potentially confounding differential diagnoses. Immunosuppressants used in managing rheumatologic etiologies have detrimental consequences in undiagnosed underlying infections. Consequently, worsening symptoms with standard therapy should raise awareness to a different diagnosis.

Nontuberculous mycobacteria (NTM) are slow-growing organisms difficult to yield in culture. Initial negative synovial fluid stains and cultures when suspecting NTM infectious arthritis or tenosynovitis should not exclude the diagnosis if there is a strong clinical scenario. The identification of Mycobacterium marinum (M marinum) infection in the hand is of utmost importance given that delayed treatment may cause significant and even permanent disability.

We present the case of a 73-year-old male patient with progressively worsening right-hand tenosynovitis who was evaluated for crystal-induced and sarcoid arthropathies in the setting of negative synovial biopsy cultures but was subsequently diagnosed with M marinum infectious tenosynovitis after a second surgical debridement.

Case Presentation

A 73-year-old male patient with history of type 2 diabetes mellitus, hypertension, hyperlipidemia, hypothyroidism, bilateral knee osteoarthritis, obstructive sleep apnea, and posttraumatic stress disorder presented to the emergency department (ED) with right wrist swelling and pain for 4 days. The patient reported that he was working in his garden when symptoms started. He did not recall any skin abrasions or wounds, insect bites, thorn punctures, trauma, or exposure to swimming pools or fish tanks. Patient was afebrile, and vital signs were within normal range. On physical examination, there was erythema, swelling, and tenderness in the dorsum of the right hand and over the dorsal aspect of the fourth metacarpophalangeal joint (Figure 1). The skin was intact.

Symptoms had not responded to 7 days of cefalexin nor to a short course of oral steroids. Leukocytosis of 14.35 × 10⁹/L (reference range, 3.90-9.90 × 10⁹/L) with neutrophilia at 11.10 × 10^9/L (reference range, 1.73-6.37 × 10⁹/L) was noted. Sedimentation rate and C-reactive protein levels were normal. Right-hand X-ray was remarkable for chondrocalcinosis in the triangular fibrocartilage. Right upper extremity magnetic resonance imaging (MRI) revealed diffuse inflammation in the right wrist and hand (Figure 2). There was no evidence of septic arthritis or osteomyelitis. Consequently, orthopedic service recommended no surgical intervention. Additionally, the patient had preserved range of motion that further indicated tenosynovitis, which could be medically managed with antibiotics, rather than a septic joint.

One dose of IV piperacillin/tazobactam was given at the ED, and he was admitted to the internal medicine ward with right hand and wrist cellulitis and indolent suppurative tenosynovitis. Empiric IV ceftriaxone and vancomycin were started as per infectious disease (ID) service with adequate response defined as a reduction of the swelling, erythema, and tenderness of the right hand and wrist. Differential diagnosis included sporotrichosis, nocardia vs NTM infection.

Interventional radiology was consulted for right wrist drainage. However, only 1 mL of fluid was obtained. Synovial fluid was sent for cell count and differential, crystal analysis, bacterial cultures, fungal cultures, and acid-fast bacilli (AFB) stains and culture. Neutrophils were 43% and lymphocytes were 57%. Crystal analysis was negative. Bacterial culture and mycology were negative. AFB stain and culture results were negative after 6 weeks. Based on gardening history and risk of thorn exposure and low suspicion for common bacterial pathogens, ID service switched antibiotics to moxifloxacin, minocycline, and linezolid for broad coverage to complete 3 weeks as outpatient. The patient reported significantly improved pain and handgrip with notable decrease in swelling. Nonetheless, 3 weeks after completing antibiotics, the right-hand pain recurred, raising concern for complex regional syndrome vs crystalline arthropathy.

Discussion

M marinum is an NTM found in bodies of water and marine settings. Infection arises after direct contact of lacerated skin with contaminated water. In a review article of 5 cases of M marinum tenosynovitis, they found that all individuals had wounds with exposure to fish or shrimp while in the water or while handling seafood.¹ The incidence of this infection is infrequent, estimated to be 0.04 cases per 100,000, with only about 25% of these cases presenting as tenosynovitis.² The incubation period ranges from 2 to 4 weeks.³ Late identification of this organism is common because of its slow development. For example, presentation from first exposure to symptom onset may take as long as 32 days.¹ In addition, in the same review, surgical intervention occurred in 63 days.¹ It has been reported that AFB stains are positive in just 9% of cases, which confounds diagnosis even more.⁴ After synovial tissue culture is obtained, it takes approximately 6 weeks for the organism to grow. Moreover, diagnosis may take longer if it is not suspected.⁵

Four types of M marinum infections have been described.⁵ The status of the immune system plays a role in how the manifestations present. The first type is limited, which is seen in immunocompetent persons, characterized by skin involvement, such as erythematous nodular lesions, that may improve on their own in months or years.⁴ Conversely, in immunosuppressed patients, the second type of infection may cause sporotrichoid spreading described as following lymphangitic pattern. The third type presents with musculoskeletal findings, such as arthritis, tenosynovitis, bursitis, or osteomyelitis, as seen in our patient. The fourth type consists of systemic manifestations.⁵ Medications that lower the immune system, such as corticosteroids, chemotherapy, and biologic disease modifying agents, may increase the risk for developing this entity.⁴ Specifically, antitumor necrosis factor inhibitors have been historically associated with mycobacterium infections.⁶

Patients are frequently diagnosed with soft tissue infection, such as abscesses or cellulitis, as in our case. They may at times be found to have other musculoskeletal conditions such as trigger finger.¹ Other similar presenting entities are psoriatic arthritis, rheumatoid arthritis, and remitting seronegative arthritis.⁴ These clinical resemblances complicate the scenario, especially when initial cultures are negative, as the treatment for these rheumatic diseases is immunosuppression, which adversely impact the fastidious infection. In our case, the improved swelling and range of motion after the 3-week course of empiric antibiotics for suppurative tenosynovitis was initially reassuring that the previous infection had been successfully treated. Subsequently, the presence of chondrocalcinosis in the triangular fibrocartilage in the right-hand X-rays, persistent pain, and the tophi-like appearance of the right third proximal interphalangeal nodule raised concerns for crystalline arthropathies, such as calcium pyrophosphate deposition vs gout. Nonetheless, given the lack of response to low-dose steroids, an ongoing infectious process was strongly considered.

Sarcoidosis was a concern after the first synovial biopsy revealed noncaseating granulomas and negative stains and cultures. Sarcoid tenosynovitis is rare with only 22 cases described as per a 2015 report.⁷ Musculoskeletal involvement in sarcoidosis has been reported in 1 to 13% of sarcoid patients.⁷ Once again, unresponsiveness to steroids led to another synovial biopsy for culture due to potential infection. Akin to other cases, more than one surgical debridement was required to diagnose our patient.

Conclusions

Our case reinforces the vital role of history gathering in establishing diagnoses. It underscores the value of clinical suspicion especially in patients unresponsive to standard treatment for inflammatory arthritis, namely corticosteroids. Tissue biopsy with culture for AFB is crucial for accurate diagnosis in NTM infection, which may imitate rheumatic inflammatory arthritis. Clinicians should be keenly aware of this fastidious, indolent organism in the setting of persistent localized tenosynovitis.

Rheumatologic conditions and infections may imitate each other, often making diagnosis challenging. Therefore, it is imperative to obtain adequate histories and have a keen eye for these potentially confounding differential diagnoses. Immunosuppressants used in managing rheumatologic etiologies have detrimental consequences in undiagnosed underlying infections. Consequently, worsening symptoms with standard therapy should raise awareness to a different diagnosis.

Nontuberculous mycobacteria (NTM) are slow-growing organisms difficult to yield in culture. Initial negative synovial fluid stains and cultures when suspecting NTM infectious arthritis or tenosynovitis should not exclude the diagnosis if there is a strong clinical scenario. The identification of Mycobacterium marinum (M marinum) infection in the hand is of utmost importance given that delayed treatment may cause significant and even permanent disability.

We present the case of a 73-year-old male patient with progressively worsening right-hand tenosynovitis who was evaluated for crystal-induced and sarcoid arthropathies in the setting of negative synovial biopsy cultures but was subsequently diagnosed with M marinum infectious tenosynovitis after a second surgical debridement.

Case Presentation

A 73-year-old male patient with history of type 2 diabetes mellitus, hypertension, hyperlipidemia, hypothyroidism, bilateral knee osteoarthritis, obstructive sleep apnea, and posttraumatic stress disorder presented to the emergency department (ED) with right wrist swelling and pain for 4 days. The patient reported that he was working in his garden when symptoms started. He did not recall any skin abrasions or wounds, insect bites, thorn punctures, trauma, or exposure to swimming pools or fish tanks. Patient was afebrile, and vital signs were within normal range. On physical examination, there was erythema, swelling, and tenderness in the dorsum of the right hand and over the dorsal aspect of the fourth metacarpophalangeal joint (Figure 1). The skin was intact.

Symptoms had not responded to 7 days of cefalexin nor to a short course of oral steroids. Leukocytosis of 14.35 × 10⁹/L (reference range, 3.90-9.90 × 10⁹/L) with neutrophilia at 11.10 × 10^9/L (reference range, 1.73-6.37 × 10⁹/L) was noted. Sedimentation rate and C-reactive protein levels were normal. Right-hand X-ray was remarkable for chondrocalcinosis in the triangular fibrocartilage. Right upper extremity magnetic resonance imaging (MRI) revealed diffuse inflammation in the right wrist and hand (Figure 2). There was no evidence of septic arthritis or osteomyelitis. Consequently, orthopedic service recommended no surgical intervention. Additionally, the patient had preserved range of motion that further indicated tenosynovitis, which could be medically managed with antibiotics, rather than a septic joint.

One dose of IV piperacillin/tazobactam was given at the ED, and he was admitted to the internal medicine ward with right hand and wrist cellulitis and indolent suppurative tenosynovitis. Empiric IV ceftriaxone and vancomycin were started as per infectious disease (ID) service with adequate response defined as a reduction of the swelling, erythema, and tenderness of the right hand and wrist. Differential diagnosis included sporotrichosis, nocardia vs NTM infection.

Interventional radiology was consulted for right wrist drainage. However, only 1 mL of fluid was obtained. Synovial fluid was sent for cell count and differential, crystal analysis, bacterial cultures, fungal cultures, and acid-fast bacilli (AFB) stains and culture. Neutrophils were 43% and lymphocytes were 57%. Crystal analysis was negative. Bacterial culture and mycology were negative. AFB stain and culture results were negative after 6 weeks. Based on gardening history and risk of thorn exposure and low suspicion for common bacterial pathogens, ID service switched antibiotics to moxifloxacin, minocycline, and linezolid for broad coverage to complete 3 weeks as outpatient. The patient reported significantly improved pain and handgrip with notable decrease in swelling. Nonetheless, 3 weeks after completing antibiotics, the right-hand pain recurred, raising concern for complex regional syndrome vs crystalline arthropathy.

Discussion

M marinum is an NTM found in bodies of water and marine settings. Infection arises after direct contact of lacerated skin with contaminated water. In a review article of 5 cases of M marinum tenosynovitis, they found that all individuals had wounds with exposure to fish or shrimp while in the water or while handling seafood.¹ The incidence of this infection is infrequent, estimated to be 0.04 cases per 100,000, with only about 25% of these cases presenting as tenosynovitis.² The incubation period ranges from 2 to 4 weeks.³ Late identification of this organism is common because of its slow development. For example, presentation from first exposure to symptom onset may take as long as 32 days.¹ In addition, in the same review, surgical intervention occurred in 63 days.¹ It has been reported that AFB stains are positive in just 9% of cases, which confounds diagnosis even more.⁴ After synovial tissue culture is obtained, it takes approximately 6 weeks for the organism to grow. Moreover, diagnosis may take longer if it is not suspected.⁵

Four types of M marinum infections have been described.⁵ The status of the immune system plays a role in how the manifestations present. The first type is limited, which is seen in immunocompetent persons, characterized by skin involvement, such as erythematous nodular lesions, that may improve on their own in months or years.⁴ Conversely, in immunosuppressed patients, the second type of infection may cause sporotrichoid spreading described as following lymphangitic pattern. The third type presents with musculoskeletal findings, such as arthritis, tenosynovitis, bursitis, or osteomyelitis, as seen in our patient. The fourth type consists of systemic manifestations.⁵ Medications that lower the immune system, such as corticosteroids, chemotherapy, and biologic disease modifying agents, may increase the risk for developing this entity.⁴ Specifically, antitumor necrosis factor inhibitors have been historically associated with mycobacterium infections.⁶

Patients are frequently diagnosed with soft tissue infection, such as abscesses or cellulitis, as in our case. They may at times be found to have other musculoskeletal conditions such as trigger finger.¹ Other similar presenting entities are psoriatic arthritis, rheumatoid arthritis, and remitting seronegative arthritis.⁴ These clinical resemblances complicate the scenario, especially when initial cultures are negative, as the treatment for these rheumatic diseases is immunosuppression, which adversely impact the fastidious infection. In our case, the improved swelling and range of motion after the 3-week course of empiric antibiotics for suppurative tenosynovitis was initially reassuring that the previous infection had been successfully treated. Subsequently, the presence of chondrocalcinosis in the triangular fibrocartilage in the right-hand X-rays, persistent pain, and the tophi-like appearance of the right third proximal interphalangeal nodule raised concerns for crystalline arthropathies, such as calcium pyrophosphate deposition vs gout. Nonetheless, given the lack of response to low-dose steroids, an ongoing infectious process was strongly considered.

Sarcoidosis was a concern after the first synovial biopsy revealed noncaseating granulomas and negative stains and cultures. Sarcoid tenosynovitis is rare with only 22 cases described as per a 2015 report.⁷ Musculoskeletal involvement in sarcoidosis has been reported in 1 to 13% of sarcoid patients.⁷ Once again, unresponsiveness to steroids led to another synovial biopsy for culture due to potential infection. Akin to other cases, more than one surgical debridement was required to diagnose our patient.

Conclusions

Our case reinforces the vital role of history gathering in establishing diagnoses. It underscores the value of clinical suspicion especially in patients unresponsive to standard treatment for inflammatory arthritis, namely corticosteroids. Tissue biopsy with culture for AFB is crucial for accurate diagnosis in NTM infection, which may imitate rheumatic inflammatory arthritis. Clinicians should be keenly aware of this fastidious, indolent organism in the setting of persistent localized tenosynovitis.

Rheumatologic conditions and infections may imitate each other, often making diagnosis challenging. Therefore, it is imperative to obtain adequate histories and have a keen eye for these potentially confounding differential diagnoses. Immunosuppressants used in managing rheumatologic etiologies have detrimental consequences in undiagnosed underlying infections. Consequently, worsening symptoms with standard therapy should raise awareness to a different diagnosis.

Nontuberculous mycobacteria (NTM) are slow-growing organisms difficult to yield in culture. Initial negative synovial fluid stains and cultures when suspecting NTM infectious arthritis or tenosynovitis should not exclude the diagnosis if there is a strong clinical scenario. The identification of Mycobacterium marinum (M marinum) infection in the hand is of utmost importance given that delayed treatment may cause significant and even permanent disability.

We present the case of a 73-year-old male patient with progressively worsening right-hand tenosynovitis who was evaluated for crystal-induced and sarcoid arthropathies in the setting of negative synovial biopsy cultures but was subsequently diagnosed with M marinum infectious tenosynovitis after a second surgical debridement.

Case Presentation

A 73-year-old male patient with history of type 2 diabetes mellitus, hypertension, hyperlipidemia, hypothyroidism, bilateral knee osteoarthritis, obstructive sleep apnea, and posttraumatic stress disorder presented to the emergency department (ED) with right wrist swelling and pain for 4 days. The patient reported that he was working in his garden when symptoms started. He did not recall any skin abrasions or wounds, insect bites, thorn punctures, trauma, or exposure to swimming pools or fish tanks. Patient was afebrile, and vital signs were within normal range. On physical examination, there was erythema, swelling, and tenderness in the dorsum of the right hand and over the dorsal aspect of the fourth metacarpophalangeal joint (Figure 1). The skin was intact.

Symptoms had not responded to 7 days of cefalexin nor to a short course of oral steroids. Leukocytosis of 14.35 × 10⁹/L (reference range, 3.90-9.90 × 10⁹/L) with neutrophilia at 11.10 × 10^9/L (reference range, 1.73-6.37 × 10⁹/L) was noted. Sedimentation rate and C-reactive protein levels were normal. Right-hand X-ray was remarkable for chondrocalcinosis in the triangular fibrocartilage. Right upper extremity magnetic resonance imaging (MRI) revealed diffuse inflammation in the right wrist and hand (Figure 2). There was no evidence of septic arthritis or osteomyelitis. Consequently, orthopedic service recommended no surgical intervention. Additionally, the patient had preserved range of motion that further indicated tenosynovitis, which could be medically managed with antibiotics, rather than a septic joint.

One dose of IV piperacillin/tazobactam was given at the ED, and he was admitted to the internal medicine ward with right hand and wrist cellulitis and indolent suppurative tenosynovitis. Empiric IV ceftriaxone and vancomycin were started as per infectious disease (ID) service with adequate response defined as a reduction of the swelling, erythema, and tenderness of the right hand and wrist. Differential diagnosis included sporotrichosis, nocardia vs NTM infection.

Interventional radiology was consulted for right wrist drainage. However, only 1 mL of fluid was obtained. Synovial fluid was sent for cell count and differential, crystal analysis, bacterial cultures, fungal cultures, and acid-fast bacilli (AFB) stains and culture. Neutrophils were 43% and lymphocytes were 57%. Crystal analysis was negative. Bacterial culture and mycology were negative. AFB stain and culture results were negative after 6 weeks. Based on gardening history and risk of thorn exposure and low suspicion for common bacterial pathogens, ID service switched antibiotics to moxifloxacin, minocycline, and linezolid for broad coverage to complete 3 weeks as outpatient. The patient reported significantly improved pain and handgrip with notable decrease in swelling. Nonetheless, 3 weeks after completing antibiotics, the right-hand pain recurred, raising concern for complex regional syndrome vs crystalline arthropathy.

Discussion

M marinum is an NTM found in bodies of water and marine settings. Infection arises after direct contact of lacerated skin with contaminated water. In a review article of 5 cases of M marinum tenosynovitis, they found that all individuals had wounds with exposure to fish or shrimp while in the water or while handling seafood.¹ The incidence of this infection is infrequent, estimated to be 0.04 cases per 100,000, with only about 25% of these cases presenting as tenosynovitis.² The incubation period ranges from 2 to 4 weeks.³ Late identification of this organism is common because of its slow development. For example, presentation from first exposure to symptom onset may take as long as 32 days.¹ In addition, in the same review, surgical intervention occurred in 63 days.¹ It has been reported that AFB stains are positive in just 9% of cases, which confounds diagnosis even more.⁴ After synovial tissue culture is obtained, it takes approximately 6 weeks for the organism to grow. Moreover, diagnosis may take longer if it is not suspected.⁵

Four types of M marinum infections have been described.⁵ The status of the immune system plays a role in how the manifestations present. The first type is limited, which is seen in immunocompetent persons, characterized by skin involvement, such as erythematous nodular lesions, that may improve on their own in months or years.⁴ Conversely, in immunosuppressed patients, the second type of infection may cause sporotrichoid spreading described as following lymphangitic pattern. The third type presents with musculoskeletal findings, such as arthritis, tenosynovitis, bursitis, or osteomyelitis, as seen in our patient. The fourth type consists of systemic manifestations.⁵ Medications that lower the immune system, such as corticosteroids, chemotherapy, and biologic disease modifying agents, may increase the risk for developing this entity.⁴ Specifically, antitumor necrosis factor inhibitors have been historically associated with mycobacterium infections.⁶

Patients are frequently diagnosed with soft tissue infection, such as abscesses or cellulitis, as in our case. They may at times be found to have other musculoskeletal conditions such as trigger finger.¹ Other similar presenting entities are psoriatic arthritis, rheumatoid arthritis, and remitting seronegative arthritis.⁴ These clinical resemblances complicate the scenario, especially when initial cultures are negative, as the treatment for these rheumatic diseases is immunosuppression, which adversely impact the fastidious infection. In our case, the improved swelling and range of motion after the 3-week course of empiric antibiotics for suppurative tenosynovitis was initially reassuring that the previous infection had been successfully treated. Subsequently, the presence of chondrocalcinosis in the triangular fibrocartilage in the right-hand X-rays, persistent pain, and the tophi-like appearance of the right third proximal interphalangeal nodule raised concerns for crystalline arthropathies, such as calcium pyrophosphate deposition vs gout. Nonetheless, given the lack of response to low-dose steroids, an ongoing infectious process was strongly considered.

Sarcoidosis was a concern after the first synovial biopsy revealed noncaseating granulomas and negative stains and cultures. Sarcoid tenosynovitis is rare with only 22 cases described as per a 2015 report.⁷ Musculoskeletal involvement in sarcoidosis has been reported in 1 to 13% of sarcoid patients.⁷ Once again, unresponsiveness to steroids led to another synovial biopsy for culture due to potential infection. Akin to other cases, more than one surgical debridement was required to diagnose our patient.

Conclusions

Our case reinforces the vital role of history gathering in establishing diagnoses. It underscores the value of clinical suspicion especially in patients unresponsive to standard treatment for inflammatory arthritis, namely corticosteroids. Tissue biopsy with culture for AFB is crucial for accurate diagnosis in NTM infection, which may imitate rheumatic inflammatory arthritis. Clinicians should be keenly aware of this fastidious, indolent organism in the setting of persistent localized tenosynovitis.

The brachial plexus is a group of interwoven nerves arising from the cervical spinal cord and coursing through the neck, shoulder, and axilla with terminal branches extending to the distal arm.¹ Disorders of the brachial plexus are more rare than other isolated peripheral nerve disorders, trauma being the most common etiology.¹ Traction, neoplasms, radiation exposure, external compression, and inflammatory processes, such as Parsonage-Turner syndrome, have also been described as less common etiologies.²

Rhabdomyolysis, a condition in which muscle breakdown occurs, is an uncommon and perhaps underrecognized cause of brachial plexopathy. Rhabdomyolysis is often caused by muscle overuse, trauma, prolonged immobilization, drugs, or toxins. Substances indicated as precipitating factors include alcohol, opioids, cocaine, and amphetamines.^3,4 As rhabdomyolysis progresses, swelling and edema can compress surrounding structures. Therefore, in cases of rhabdomyolysis involving the muscles of the neck and shoulder girdle, external compression of the brachial plexus can potentially cause brachial plexopathy. Rare cases of this phenomenon occurring as a sequela of substance use have been described.^1,5-9 Few cases have been reported in the literature.

The following case report describes a patient who experienced rhabdomyolysis following use of crack cocaine contaminated with fentanyl, which subsequently caused bilateral brachial plexopathy. 

Case Presentation

A 68-year-old male patient with a history of polysubstance use disorder presented to the emergency department with complete loss of sensory and motor function of both arms. He had fallen asleep on his couch the previous evening with his arms crossed over his chest in the prone position. He reported using crack cocaine earlier that day that was later discovered to be contaminated with fentanyl. The patient reported using no other substances, including alcohol. When he woke about 7 hours later, the patient’s arms were completely paralyzed.

On admission, the patient presented with an agitated mental status. The patient presented with 0/5 strength bilaterally in the upper extremities (UEs) accompanied by numbness and tingling. Radial pulses were palpable in both arms. All UE reflexes were absent, but patellar reflex was intact bilaterally. On hospital day 2, the patient was awake, alert, and oriented to person, place, and time and could provide a full history. The patient’s cranial nerves were intact with shoulder shrug testing mildly weak at 4/5 strength. The patient had 0/5 strength bilaterally and bilateral absent reflexes in the UEs. Sensation was markedly decreased, as he was unable to feel temperature, pinprick sensation, or general touch in both UEs. Coordination of the UEs could not be tested due to weakness. No response could be elicited from the median or ulnar nerve bilaterally on somatosensory evoked potential study. The lower extremities were intact to movement, sensation, coordination, and reflexes.

Serum electrolytes and glucose levels were normal. The creatine phosphokinase (CPK) level was elevated at 21,292 IU/L. Creatinine and blood urea nitrogen levels were elevated at 1.7 mg/dL and 32 mg/dL, respectively. Serum B12, thyroid-stimulating hormone, and hemoglobin A_1c levels were normal. Urine drug screen was positive for cocaine metabolite and fentanyl but negative for other substances, including alcohol. The patient stated emphatically he had only used crack cocaine, so it was presumed that the crack cocaine had been contaminated with fentanyl.

Computed tomography (CT) of the head was normal and revealed no acute intracranial process. Further imaging studies included magnetic resonance imaging (MRI) of the brain and spinal cord and subsequently of the brachial plexus. There was no evidence of a spinal cord or intracranial lesion. However, there was abnormal signal in the lower neck greater on the right side suggesting an edematous inflammatory process involving part of the shoulder girdle musculature. This included the trapezius, levator scapula, rhomboid, and serratus anterior muscles, as well as prominent fluid signal in the right supraclavicular fossa. The abnormal signal was less prominent on the left and involved the serratus anterior muscle. To a lesser extent, there also was involvement of the distal attachment site of the anterior and middle scalene muscles on the right greater than the left. It is presumed that muscular edema resulted in partial narrowing of the thoracic outlet bilaterally with corresponding mass effect on the traversing brachial plexus, resulting in the patient’s symptoms (Figure).

Discussion

Rhabdomyolysis is a condition defined by myocyte necrosis that results in release of cellular contents and local edema. Inciting events may be traumatic, metabolic, ischemic, or substance induced. Common substances indicated include cocaine, amphetamines, acetaminophen, opioids, and alcohol.¹⁰ It classically presents with muscle pain and a marked elevation in serum CPK level, but other metabolic disturbances, acute kidney injury, or toxic hepatitis may also occur. A more uncommon sequela of rhabdomyolysis is plexopathy caused by edematous swelling and compression of the surrounding structures.

Rare cases of brachial plexopathy caused by rhabdomyolysis following substance use have been described. In many of these cases, rhabdomyolysis occurred after alcohol use with or without concurrent use of prescription opioids or heroin.^7-9 One case following use of 3,4-methylenedioxy-N-methylamptamine (MDMA) and marijuana use was reported.¹ Another case of concurrent brachial plexopathy and Horner syndrome in a 29-year-old male patient following ingestion of alcohol and opioids has also been described.⁵ The rate of occurrence of this phenomenon in the general population is unknown.

In the case of our patient, cocaine metabolite and fentanyl were the only substances found on urine drug screen. The patient had used crack cocaine that had presumably been contaminated with fentanyl, a high potency synthetic opioid. The rate of fentanyl contamination of street drugs is variable. It is a subject of high concern, considering the increasing rates of synthetic opioid overdose-related deaths. According to the US Centers for Disease Control and Prevention, synthetic opioids have played a role in the increasing rates of cocaine-related overdose deaths. Conversely, in more than half of all overdose deaths involving fentanyl derivatives, patients also tested positive for cocaine, methamphetamine, or heroin. In recent studies conducted in various cities in the northeastern US, rates of fentanyl metabolite detection were much higher than rates of reported fentanyl use.¹¹ Cases of crack cocaine contamination with fentanyl derivatives have been reported in Canada and Washington.¹²

The pathophysiology of rhabdomyolysis caused by substance use has not been definitively identified, but it is hypothesized that the cause is 2-fold. The first insult is the direct toxicity of the substances to myocytes.^8,9 The second factor is prolonged immobilization in a position that compresses the affected musculature and blood supply, causing both mechanical stress and ischemia to the muscles and brachial plexus. This prolonged immobilization can frequently follow use of substances, such as alcohol or opioids.⁹ Cases have been reported wherein rhabdomyolysis causing brachial plexopathy occurred despite relatively normal positioning of the arms and shoulders during sleep.⁹ In our case, the patient had fallen asleep with his arms crossed over his chest in the prone position with his head turned, though he could not recall to which side. Although he stated that he had slept in this position regularly, the effects of fentanyl may have prevented the patient from waking to adjust his posture. This position had potential to compress the musculature of the neck and shoulders and restrict blood flow, resulting in the focal rhabdomyolysis seen in this patient. In theory, the position could also cause a stretch injury of the brachial plexus, although a pure stretch injury would more likely present unilaterally and without evidence of rhabdomyolysis.

Chronic ethanol use may have been a major contributor by both sensitizing the muscles to toxicity of other substances and induction of CYP450 enzymes that are normally responsible for metabolizing other drugs.⁸ Alcohol also inhibits gluconeogenesis and leads to hyperpolarization of myocytes, further contributing to their susceptibility to damage.⁹ Our patient had a prior history of alcohol use years before this event, but not at the time of this event.

Our patient had other known risk factors for rhabdomyolysis, including his long-term statin therapy, but it is unclear whether these were contributing factors in his case.¹⁰ Of the medications that are known to cause rhabdomyolysis, statins are among the most commonly described, although the mechanism through which this process occurs is not clear. A case of rhabdomyolysis following use of cocaine and heroin in a patient on long-standing statin therapy has been described.¹³ Our review of the literature found no cases of statin-induced rhabdomyolysis associated with brachial plexopathy. It is possible that concurrent statin therapy has an additive effect to other substances in inducing rhabdomyolysis.

Parsonage-Turner syndrome, also known as neuralgic amyotrophy, should also be included in the differential diagnosis. While there have been multiple etiologies proposed for Parsonage-Turner syndrome, it is generally thought to begin as a primary inflammatory process targeting the brachial plexus. One case report describes Parsonage-Turner syndrome progressing to secondary rhabdomyolysis.⁶ In this case, no primary etiology was identified, so the Parsonage-Turner syndrome diagnosis was made with secondary rhabdomyolysis.⁶ We believe it is possible that this case and others may have been misdiagnosed as Parsonage-Turner syndrome.

Conclusions

This case report adds to the literature describing focal rhabdomyolysis causing secondary bilateral brachial plexopathy after substance use. Further research is needed to establish a definitive pathophysiology as well as treatment guidelines. Evidence-based treatment could mean better outcomes and quicker recoveries for future patients with this condition.

The brachial plexus is a group of interwoven nerves arising from the cervical spinal cord and coursing through the neck, shoulder, and axilla with terminal branches extending to the distal arm.¹ Disorders of the brachial plexus are more rare than other isolated peripheral nerve disorders, trauma being the most common etiology.¹ Traction, neoplasms, radiation exposure, external compression, and inflammatory processes, such as Parsonage-Turner syndrome, have also been described as less common etiologies.²

Rhabdomyolysis, a condition in which muscle breakdown occurs, is an uncommon and perhaps underrecognized cause of brachial plexopathy. Rhabdomyolysis is often caused by muscle overuse, trauma, prolonged immobilization, drugs, or toxins. Substances indicated as precipitating factors include alcohol, opioids, cocaine, and amphetamines.^3,4 As rhabdomyolysis progresses, swelling and edema can compress surrounding structures. Therefore, in cases of rhabdomyolysis involving the muscles of the neck and shoulder girdle, external compression of the brachial plexus can potentially cause brachial plexopathy. Rare cases of this phenomenon occurring as a sequela of substance use have been described.^1,5-9 Few cases have been reported in the literature.

The following case report describes a patient who experienced rhabdomyolysis following use of crack cocaine contaminated with fentanyl, which subsequently caused bilateral brachial plexopathy. 

Case Presentation

A 68-year-old male patient with a history of polysubstance use disorder presented to the emergency department with complete loss of sensory and motor function of both arms. He had fallen asleep on his couch the previous evening with his arms crossed over his chest in the prone position. He reported using crack cocaine earlier that day that was later discovered to be contaminated with fentanyl. The patient reported using no other substances, including alcohol. When he woke about 7 hours later, the patient’s arms were completely paralyzed.

On admission, the patient presented with an agitated mental status. The patient presented with 0/5 strength bilaterally in the upper extremities (UEs) accompanied by numbness and tingling. Radial pulses were palpable in both arms. All UE reflexes were absent, but patellar reflex was intact bilaterally. On hospital day 2, the patient was awake, alert, and oriented to person, place, and time and could provide a full history. The patient’s cranial nerves were intact with shoulder shrug testing mildly weak at 4/5 strength. The patient had 0/5 strength bilaterally and bilateral absent reflexes in the UEs. Sensation was markedly decreased, as he was unable to feel temperature, pinprick sensation, or general touch in both UEs. Coordination of the UEs could not be tested due to weakness. No response could be elicited from the median or ulnar nerve bilaterally on somatosensory evoked potential study. The lower extremities were intact to movement, sensation, coordination, and reflexes.

Serum electrolytes and glucose levels were normal. The creatine phosphokinase (CPK) level was elevated at 21,292 IU/L. Creatinine and blood urea nitrogen levels were elevated at 1.7 mg/dL and 32 mg/dL, respectively. Serum B12, thyroid-stimulating hormone, and hemoglobin A_1c levels were normal. Urine drug screen was positive for cocaine metabolite and fentanyl but negative for other substances, including alcohol. The patient stated emphatically he had only used crack cocaine, so it was presumed that the crack cocaine had been contaminated with fentanyl.

Computed tomography (CT) of the head was normal and revealed no acute intracranial process. Further imaging studies included magnetic resonance imaging (MRI) of the brain and spinal cord and subsequently of the brachial plexus. There was no evidence of a spinal cord or intracranial lesion. However, there was abnormal signal in the lower neck greater on the right side suggesting an edematous inflammatory process involving part of the shoulder girdle musculature. This included the trapezius, levator scapula, rhomboid, and serratus anterior muscles, as well as prominent fluid signal in the right supraclavicular fossa. The abnormal signal was less prominent on the left and involved the serratus anterior muscle. To a lesser extent, there also was involvement of the distal attachment site of the anterior and middle scalene muscles on the right greater than the left. It is presumed that muscular edema resulted in partial narrowing of the thoracic outlet bilaterally with corresponding mass effect on the traversing brachial plexus, resulting in the patient’s symptoms (Figure).

Discussion

Rhabdomyolysis is a condition defined by myocyte necrosis that results in release of cellular contents and local edema. Inciting events may be traumatic, metabolic, ischemic, or substance induced. Common substances indicated include cocaine, amphetamines, acetaminophen, opioids, and alcohol.¹⁰ It classically presents with muscle pain and a marked elevation in serum CPK level, but other metabolic disturbances, acute kidney injury, or toxic hepatitis may also occur. A more uncommon sequela of rhabdomyolysis is plexopathy caused by edematous swelling and compression of the surrounding structures.

Rare cases of brachial plexopathy caused by rhabdomyolysis following substance use have been described. In many of these cases, rhabdomyolysis occurred after alcohol use with or without concurrent use of prescription opioids or heroin.^7-9 One case following use of 3,4-methylenedioxy-N-methylamptamine (MDMA) and marijuana use was reported.¹ Another case of concurrent brachial plexopathy and Horner syndrome in a 29-year-old male patient following ingestion of alcohol and opioids has also been described.⁵ The rate of occurrence of this phenomenon in the general population is unknown.

In the case of our patient, cocaine metabolite and fentanyl were the only substances found on urine drug screen. The patient had used crack cocaine that had presumably been contaminated with fentanyl, a high potency synthetic opioid. The rate of fentanyl contamination of street drugs is variable. It is a subject of high concern, considering the increasing rates of synthetic opioid overdose-related deaths. According to the US Centers for Disease Control and Prevention, synthetic opioids have played a role in the increasing rates of cocaine-related overdose deaths. Conversely, in more than half of all overdose deaths involving fentanyl derivatives, patients also tested positive for cocaine, methamphetamine, or heroin. In recent studies conducted in various cities in the northeastern US, rates of fentanyl metabolite detection were much higher than rates of reported fentanyl use.¹¹ Cases of crack cocaine contamination with fentanyl derivatives have been reported in Canada and Washington.¹²

The pathophysiology of rhabdomyolysis caused by substance use has not been definitively identified, but it is hypothesized that the cause is 2-fold. The first insult is the direct toxicity of the substances to myocytes.^8,9 The second factor is prolonged immobilization in a position that compresses the affected musculature and blood supply, causing both mechanical stress and ischemia to the muscles and brachial plexus. This prolonged immobilization can frequently follow use of substances, such as alcohol or opioids.⁹ Cases have been reported wherein rhabdomyolysis causing brachial plexopathy occurred despite relatively normal positioning of the arms and shoulders during sleep.⁹ In our case, the patient had fallen asleep with his arms crossed over his chest in the prone position with his head turned, though he could not recall to which side. Although he stated that he had slept in this position regularly, the effects of fentanyl may have prevented the patient from waking to adjust his posture. This position had potential to compress the musculature of the neck and shoulders and restrict blood flow, resulting in the focal rhabdomyolysis seen in this patient. In theory, the position could also cause a stretch injury of the brachial plexus, although a pure stretch injury would more likely present unilaterally and without evidence of rhabdomyolysis.

Chronic ethanol use may have been a major contributor by both sensitizing the muscles to toxicity of other substances and induction of CYP450 enzymes that are normally responsible for metabolizing other drugs.⁸ Alcohol also inhibits gluconeogenesis and leads to hyperpolarization of myocytes, further contributing to their susceptibility to damage.⁹ Our patient had a prior history of alcohol use years before this event, but not at the time of this event.

Our patient had other known risk factors for rhabdomyolysis, including his long-term statin therapy, but it is unclear whether these were contributing factors in his case.¹⁰ Of the medications that are known to cause rhabdomyolysis, statins are among the most commonly described, although the mechanism through which this process occurs is not clear. A case of rhabdomyolysis following use of cocaine and heroin in a patient on long-standing statin therapy has been described.¹³ Our review of the literature found no cases of statin-induced rhabdomyolysis associated with brachial plexopathy. It is possible that concurrent statin therapy has an additive effect to other substances in inducing rhabdomyolysis.

Parsonage-Turner syndrome, also known as neuralgic amyotrophy, should also be included in the differential diagnosis. While there have been multiple etiologies proposed for Parsonage-Turner syndrome, it is generally thought to begin as a primary inflammatory process targeting the brachial plexus. One case report describes Parsonage-Turner syndrome progressing to secondary rhabdomyolysis.⁶ In this case, no primary etiology was identified, so the Parsonage-Turner syndrome diagnosis was made with secondary rhabdomyolysis.⁶ We believe it is possible that this case and others may have been misdiagnosed as Parsonage-Turner syndrome.

Conclusions

This case report adds to the literature describing focal rhabdomyolysis causing secondary bilateral brachial plexopathy after substance use. Further research is needed to establish a definitive pathophysiology as well as treatment guidelines. Evidence-based treatment could mean better outcomes and quicker recoveries for future patients with this condition.

The brachial plexus is a group of interwoven nerves arising from the cervical spinal cord and coursing through the neck, shoulder, and axilla with terminal branches extending to the distal arm.¹ Disorders of the brachial plexus are more rare than other isolated peripheral nerve disorders, trauma being the most common etiology.¹ Traction, neoplasms, radiation exposure, external compression, and inflammatory processes, such as Parsonage-Turner syndrome, have also been described as less common etiologies.²

Rhabdomyolysis, a condition in which muscle breakdown occurs, is an uncommon and perhaps underrecognized cause of brachial plexopathy. Rhabdomyolysis is often caused by muscle overuse, trauma, prolonged immobilization, drugs, or toxins. Substances indicated as precipitating factors include alcohol, opioids, cocaine, and amphetamines.^3,4 As rhabdomyolysis progresses, swelling and edema can compress surrounding structures. Therefore, in cases of rhabdomyolysis involving the muscles of the neck and shoulder girdle, external compression of the brachial plexus can potentially cause brachial plexopathy. Rare cases of this phenomenon occurring as a sequela of substance use have been described.^1,5-9 Few cases have been reported in the literature.

The following case report describes a patient who experienced rhabdomyolysis following use of crack cocaine contaminated with fentanyl, which subsequently caused bilateral brachial plexopathy. 

Case Presentation

A 68-year-old male patient with a history of polysubstance use disorder presented to the emergency department with complete loss of sensory and motor function of both arms. He had fallen asleep on his couch the previous evening with his arms crossed over his chest in the prone position. He reported using crack cocaine earlier that day that was later discovered to be contaminated with fentanyl. The patient reported using no other substances, including alcohol. When he woke about 7 hours later, the patient’s arms were completely paralyzed.

On admission, the patient presented with an agitated mental status. The patient presented with 0/5 strength bilaterally in the upper extremities (UEs) accompanied by numbness and tingling. Radial pulses were palpable in both arms. All UE reflexes were absent, but patellar reflex was intact bilaterally. On hospital day 2, the patient was awake, alert, and oriented to person, place, and time and could provide a full history. The patient’s cranial nerves were intact with shoulder shrug testing mildly weak at 4/5 strength. The patient had 0/5 strength bilaterally and bilateral absent reflexes in the UEs. Sensation was markedly decreased, as he was unable to feel temperature, pinprick sensation, or general touch in both UEs. Coordination of the UEs could not be tested due to weakness. No response could be elicited from the median or ulnar nerve bilaterally on somatosensory evoked potential study. The lower extremities were intact to movement, sensation, coordination, and reflexes.

Serum electrolytes and glucose levels were normal. The creatine phosphokinase (CPK) level was elevated at 21,292 IU/L. Creatinine and blood urea nitrogen levels were elevated at 1.7 mg/dL and 32 mg/dL, respectively. Serum B12, thyroid-stimulating hormone, and hemoglobin A_1c levels were normal. Urine drug screen was positive for cocaine metabolite and fentanyl but negative for other substances, including alcohol. The patient stated emphatically he had only used crack cocaine, so it was presumed that the crack cocaine had been contaminated with fentanyl.

Computed tomography (CT) of the head was normal and revealed no acute intracranial process. Further imaging studies included magnetic resonance imaging (MRI) of the brain and spinal cord and subsequently of the brachial plexus. There was no evidence of a spinal cord or intracranial lesion. However, there was abnormal signal in the lower neck greater on the right side suggesting an edematous inflammatory process involving part of the shoulder girdle musculature. This included the trapezius, levator scapula, rhomboid, and serratus anterior muscles, as well as prominent fluid signal in the right supraclavicular fossa. The abnormal signal was less prominent on the left and involved the serratus anterior muscle. To a lesser extent, there also was involvement of the distal attachment site of the anterior and middle scalene muscles on the right greater than the left. It is presumed that muscular edema resulted in partial narrowing of the thoracic outlet bilaterally with corresponding mass effect on the traversing brachial plexus, resulting in the patient’s symptoms (Figure).

Discussion

Rhabdomyolysis is a condition defined by myocyte necrosis that results in release of cellular contents and local edema. Inciting events may be traumatic, metabolic, ischemic, or substance induced. Common substances indicated include cocaine, amphetamines, acetaminophen, opioids, and alcohol.¹⁰ It classically presents with muscle pain and a marked elevation in serum CPK level, but other metabolic disturbances, acute kidney injury, or toxic hepatitis may also occur. A more uncommon sequela of rhabdomyolysis is plexopathy caused by edematous swelling and compression of the surrounding structures.

Rare cases of brachial plexopathy caused by rhabdomyolysis following substance use have been described. In many of these cases, rhabdomyolysis occurred after alcohol use with or without concurrent use of prescription opioids or heroin.^7-9 One case following use of 3,4-methylenedioxy-N-methylamptamine (MDMA) and marijuana use was reported.¹ Another case of concurrent brachial plexopathy and Horner syndrome in a 29-year-old male patient following ingestion of alcohol and opioids has also been described.⁵ The rate of occurrence of this phenomenon in the general population is unknown.

In the case of our patient, cocaine metabolite and fentanyl were the only substances found on urine drug screen. The patient had used crack cocaine that had presumably been contaminated with fentanyl, a high potency synthetic opioid. The rate of fentanyl contamination of street drugs is variable. It is a subject of high concern, considering the increasing rates of synthetic opioid overdose-related deaths. According to the US Centers for Disease Control and Prevention, synthetic opioids have played a role in the increasing rates of cocaine-related overdose deaths. Conversely, in more than half of all overdose deaths involving fentanyl derivatives, patients also tested positive for cocaine, methamphetamine, or heroin. In recent studies conducted in various cities in the northeastern US, rates of fentanyl metabolite detection were much higher than rates of reported fentanyl use.¹¹ Cases of crack cocaine contamination with fentanyl derivatives have been reported in Canada and Washington.¹²

The pathophysiology of rhabdomyolysis caused by substance use has not been definitively identified, but it is hypothesized that the cause is 2-fold. The first insult is the direct toxicity of the substances to myocytes.^8,9 The second factor is prolonged immobilization in a position that compresses the affected musculature and blood supply, causing both mechanical stress and ischemia to the muscles and brachial plexus. This prolonged immobilization can frequently follow use of substances, such as alcohol or opioids.⁹ Cases have been reported wherein rhabdomyolysis causing brachial plexopathy occurred despite relatively normal positioning of the arms and shoulders during sleep.⁹ In our case, the patient had fallen asleep with his arms crossed over his chest in the prone position with his head turned, though he could not recall to which side. Although he stated that he had slept in this position regularly, the effects of fentanyl may have prevented the patient from waking to adjust his posture. This position had potential to compress the musculature of the neck and shoulders and restrict blood flow, resulting in the focal rhabdomyolysis seen in this patient. In theory, the position could also cause a stretch injury of the brachial plexus, although a pure stretch injury would more likely present unilaterally and without evidence of rhabdomyolysis.

Chronic ethanol use may have been a major contributor by both sensitizing the muscles to toxicity of other substances and induction of CYP450 enzymes that are normally responsible for metabolizing other drugs.⁸ Alcohol also inhibits gluconeogenesis and leads to hyperpolarization of myocytes, further contributing to their susceptibility to damage.⁹ Our patient had a prior history of alcohol use years before this event, but not at the time of this event.

Our patient had other known risk factors for rhabdomyolysis, including his long-term statin therapy, but it is unclear whether these were contributing factors in his case.¹⁰ Of the medications that are known to cause rhabdomyolysis, statins are among the most commonly described, although the mechanism through which this process occurs is not clear. A case of rhabdomyolysis following use of cocaine and heroin in a patient on long-standing statin therapy has been described.¹³ Our review of the literature found no cases of statin-induced rhabdomyolysis associated with brachial plexopathy. It is possible that concurrent statin therapy has an additive effect to other substances in inducing rhabdomyolysis.

Parsonage-Turner syndrome, also known as neuralgic amyotrophy, should also be included in the differential diagnosis. While there have been multiple etiologies proposed for Parsonage-Turner syndrome, it is generally thought to begin as a primary inflammatory process targeting the brachial plexus. One case report describes Parsonage-Turner syndrome progressing to secondary rhabdomyolysis.⁶ In this case, no primary etiology was identified, so the Parsonage-Turner syndrome diagnosis was made with secondary rhabdomyolysis.⁶ We believe it is possible that this case and others may have been misdiagnosed as Parsonage-Turner syndrome.

Conclusions

This case report adds to the literature describing focal rhabdomyolysis causing secondary bilateral brachial plexopathy after substance use. Further research is needed to establish a definitive pathophysiology as well as treatment guidelines. Evidence-based treatment could mean better outcomes and quicker recoveries for future patients with this condition.

Pneumatosis intestinalis (PI) is the finding of gas within the walls of the intestine on imaging. It is most commonly detected via radiograph or computed tomography (CT). The diseases leading to the accumulation of gas within the submucosal space of the gastrointestinal (GI) tract are heterogenous, and the finding of PI itself has a wide range of clinical implications from impending clinical deterioration to an incidental finding of minimal consequence.

We present the case of a veteran who had sustained a remote anoxic brain injury resulting in chronic dependence on a gastrostomy tube for enteral nutrition, found incidentally to have PI without signs of intra-abdominal catastrophe. An exclusion of other, more lifethreatening causes of PI led to a diagnosis of benign PI secondary to the presence of his gastrostomy tube. This case highlights the importance of interpreting the finding of PI in the clinical context of the specific patient and how conservative management may be appropriate in some cases.

Case Presentation

A 61-year-old male patient was admitted for fever. The patient had a remote history of cardiac arrest complicated by anoxic brain injury requiring tracheostomy, gastrostomy tube, and a suprapubic catheter with recurrent catheter-associated urinary tract infections (CAUTI), secondary seizure disorder, atrial fibrillation off anticoagulation due to recurrent GI bleeding, and treatment naive chronic hepatitis C virus. His ability to provide a clinical history was limited by his nonverbal status. He had no prior surgical history but had presented a month earlier for a high-grade small bowel obstruction (SBO) with pneumobilia that was managed conservatively as the surgical team deemed him a poor candidate for surgical intervention with his extensive comorbidities. A bioethics consultation at the time supported minimizing potential surgical risk in favor of conservative medical management; this was discussed with the patient’s surrogate decision maker, who also wished to avoid surgery. The SBO resolved with conservative management. He had been residing in a nursing home and doing well until 24 hours prior to admission when he developed fevers.

Vital signs on admission showed a temperature of 100.8 °F, heart rate 100 beats per minute, blood pressure 116/85, respiratory rate 22 per minute, and oxygen saturation of 100% on 6 L of oxygen via tracheostomy collar. His initial examination was notable for clear lung sounds, a nondistended nonrigid abdomen with an indwelling percutaneous gastrostomy tube, and absence of areas of skin breakdown or erythema. Notable laboratory studies showed a leukocytosis and urinalysis suggestive of CAUTI (Table). His urinary catheter was exchanged, he was fluid resuscitated and started on empiric vancomycin and piperacillin-tazobactam for management of sepsis due to CAUTI.

For the first 3 days of his hospitalization, he demonstrated clinical improvement on vancomycin and piperacillin-tazobactam while awaiting results from his urine bacterial culture. On hospital day 3, hedeveloped recurrent nonbloody, nonbilious emesis despite no change in the rate or formulation of his enteral nutrition. He also had 3 watery brown bowel movements. His vital signs remained within normal limits. His abdominal examination at this point showed mild distention and was hypertympanic to percussion, but there was no rigidity or involuntary guarding. On hospital day 4, he continued to have emesis with an unchanged abdominal examination. The differential diagnosis included recurrence of prior SBO, ileus, intestinal ischemia, enteral nutrition intolerance, Clostridioides difficile (C difficile) colitis, and GI dysmotility because of his anoxic brain injury.

Testing for C difficile was negative. An abdominal radiograph was obtained and revealed no bowel obstruction but, alarmingly, showed extensive intramural bowel gas, suggestive of PI (Figure 1). His leukocyte count, serum bicarbonate, and serum lactate levels remained within normal limits. A CT with contrast of the abdomen and pelvis demonstrated no vascular obstruction but confirmed the presence of diffuse intramural gas in his stomach and proximal small bowel, as well as the presence of mesenteric and portal venous gas (Figures 2 and 3). Although his abdominal examination had not changed and did not suggest peritonitis, general surgery was consulted to discuss the need for surgical intervention. Given his overall clinical stability and high surgical risk due to his many comorbidities, surgery recommended a conservative approach.

Through the following hospital days, his enteral nutrition was held and serial abdominal examinations were performed without change. Serial laboratory studies, including serum lactate and leukocyte count, remained reassuringly within normal limits. His urine culture eventually revealed multidrugresistant Pseudomonas aeruginosa. Antimicrobial therapy was narrowed to piperacillintazobactam for a complete course. Enteral nutrition was gradually reintroduced at a low rate, ultimately reaching goal rate with return of bowel function by hospital day 9. Despite extensive workup, the etiology of his transient enteral nutrition intolerance remained uncertain, though an adverse effect of antibiotic therapy was thought possible. Follow-up abdominal radiographs demonstrated interval improvement of PI. He was discharged back to his skilled nursing facility on hospital day 11 without incident.

Discussion

PI is an incompletely understood condition seen in multiple diseases. Patients may present with highly variable symptoms, often more attributable to the underlying disease causing the PI than the presence of PI, as patients may be entirely asymptomatic. When symptoms are attributed to PI, those most reported are abdominal pain, bloody stools, and diarrhea.¹ It is often detected on abdominal plain films. Alternative methods of diagnosis include ultrasonography, barium enema, and endoscopy although the last method has been known to occasionally lead to bowel perforation.^2-6 The most sensitive method of detection is CT, which also provides additional information about abdominal pathology and may identify the underlying process responsible for the PI.⁷

While not fully understood, much information about PI and its pathogenesis is known. Understanding the mechanisms of PI is vital to direct the clinician’s evaluation of the patient for reversible conditions that may cause PI. Early descriptions of PI in the literature documented an association with pyloric stenosis, leading to the theory that gas from the intestinal lumen is driven into the submucosal space during episodes of forceful vomiting with increased intraluminal pressure.⁸ As PI was subsequently described in multiple other disease states not typically associated with increased intraluminal pressure such as inflammatory bowel disease, GI malignancy, cryptosporidiosis and CMV infection, additional theories about the pathogenesis of PI have arisen.^9-24 There is now experimental data to support multiple mechanisms of intramural gas accumulation. It has become accepted that PI represents a common pathway shared across various pathologic states and results from multifactorial mechanisms of gas entry into the intestinal wall.^25-29

Factors leading to the development of PI include bacterial production of gas, intraluminal GI gas compositions, increased intraluminal pressure, pulmonary gas tracking through vessels communicating with the thorax, and mucosal disruption. PI has been linked to bacterial infections of the GI tract in humans including C difficile, Klebsiella, and Whipple disease.^14-18 In animal models, C difficile within the walls of rat intestine results in the appearance of pneumocysts, or discrete collections of submucosal gas, which are the hallmark feature of PI.³⁰ It is thought that direct invasion of bacteria into intramural spaces can cause PI in humans, although bacteria have yet to be directly isolated from the pneumocysts. Translocation of luminal gas into pneumocysts found in PI is theorized to be driven by differences in partial pressures.³¹ The concentration of hydrogen within the intestinal lumen is high due to bacterial production. Hydrogen, diffusing along its partial pressure gradient between the lumen and blood, accumulates within the intestinal wall and causes the formation of pneumocysts. This phenomenon has been hypothesized to explain the tendency for pneumocysts to form around the mesenteric vasculature.

Gas from the lumen can also be forced into the intestinal wall during an abrupt increase in intra-abdominal pressure, such as that seen with forceful vomiting. The final possible origin of the gas is the lungs, as PI has been associated with lung disease. It was previously thought that gas from ruptured alveoli tracks along mediastinal vessels, below the diaphragm, and into the mesentery.³⁰ Newer theories argue that increased intra-abdominal pressure, typical of patients with obstructive lung disease and frequent coughing, is the driver of PI by the mechanism previously described.^32-34 Additionally, mucosal disruption leads to increased permeability and allows accumulation of gas within the intestinal walls. Mucosal abnormalities have been described in histopathologic studies of patients with PI and associated with conditions known to compromise mucosal integrity, such as immunodeficiencies, inflammatory bowel disease, and the receipt of cytotoxic chemotherapy.^10,12,19-23

Our patient likely had mucosal disruption due to his gastrostomy tube as well as increased intraluminal pressure from recurrent vomiting, contributing to translocation of otherwise normal intraluminal gas. The presence of portal venous gas, as seen in this case, has historically portended a worse prognosis, with 37% mortality in one series.^7,35,36 However, portal venous gas as well as pneumoperitoneum occur in benign etiologies of PI as well. It is thought that this occurs due to rupture of the submucosal pneumocysts through the wall opposite the intestinal lumen and thus does not result in a direct communication between the intestinal lumen and the peritoneal cavity.¹²

PI is not a diagnosis but a manifestation of an underlying disease. As such, the treatment of PI is targeted toward the underlying condition. Of note, the pattern and extent of PI seen on imaging has not been shown to correlate with the severity of the underlying pathologic process.^35,37 Instead, assessment of the patient and their clinical trajectory should determine the appropriate treatment. The decision facing the clinician when PI is discovered is whether urgent surgery is indicated, as is the case in mesenteric ischemia, bowel necrosis, or intestinal perforation, conditions known to be associated with PI. Otherwise, there is no definitive treatment for PI. Bowel rest is almost universally pursued. There are reports of treating with supranormal levels of supplemental oxygen, maintaining arterial partial pressure of oxygen above 300 mm Hg, with a face mask and 8 L/min flow rate.^38,39 The proposed mechanisms of benefit include establishing a favorable diffusion gradient for intramural gas to exit the pneumocysts as well as creating an inhospitable, aerobic environment for hydrogenproducing anaerobic enteric bacteria. A prudent approach for most cases of PI is conservative management with bowel rest and supplemental oxygen unless there is a definitive indication for urgent surgical intervention, such as peritonitis, abdominal sepsis, or perforation.^40,41 Management recommendations suggest that up to 50% of cases can be successfully managed nonoperatively.⁴²

Conclusions

PI is the radiographic finding of gas within the walls of the intestinal tract and has variable clinical significance. It can represent a benign incidental finding or a sequela of intraabdominal emergencies such as mesenteric ischemia or bowel necrosis. Because PI is seen in a variety of disorders, several proposed mechanisms are supported in the medical literature. These include bacterial production of gas, gas pressure gradients between the intestinal lumen and the blood, increased intraluminal pressure, pulmonary gas tracking from intrathoracic vessels, and mucosal disruption. The evaluation of a patient with PI must begin with an assessment for the need for urgent surgical intervention. Additional management measures include bowel rest, IV hydration, and supplemental oxygen administration. Because of its wide variety of etiologies of varying clinical urgency, placing the finding of PI in the context of the patient is paramount to selecting an appropriate management strategy.

Pneumatosis intestinalis (PI) is the finding of gas within the walls of the intestine on imaging. It is most commonly detected via radiograph or computed tomography (CT). The diseases leading to the accumulation of gas within the submucosal space of the gastrointestinal (GI) tract are heterogenous, and the finding of PI itself has a wide range of clinical implications from impending clinical deterioration to an incidental finding of minimal consequence.

We present the case of a veteran who had sustained a remote anoxic brain injury resulting in chronic dependence on a gastrostomy tube for enteral nutrition, found incidentally to have PI without signs of intra-abdominal catastrophe. An exclusion of other, more lifethreatening causes of PI led to a diagnosis of benign PI secondary to the presence of his gastrostomy tube. This case highlights the importance of interpreting the finding of PI in the clinical context of the specific patient and how conservative management may be appropriate in some cases.

Case Presentation

A 61-year-old male patient was admitted for fever. The patient had a remote history of cardiac arrest complicated by anoxic brain injury requiring tracheostomy, gastrostomy tube, and a suprapubic catheter with recurrent catheter-associated urinary tract infections (CAUTI), secondary seizure disorder, atrial fibrillation off anticoagulation due to recurrent GI bleeding, and treatment naive chronic hepatitis C virus. His ability to provide a clinical history was limited by his nonverbal status. He had no prior surgical history but had presented a month earlier for a high-grade small bowel obstruction (SBO) with pneumobilia that was managed conservatively as the surgical team deemed him a poor candidate for surgical intervention with his extensive comorbidities. A bioethics consultation at the time supported minimizing potential surgical risk in favor of conservative medical management; this was discussed with the patient’s surrogate decision maker, who also wished to avoid surgery. The SBO resolved with conservative management. He had been residing in a nursing home and doing well until 24 hours prior to admission when he developed fevers.

Vital signs on admission showed a temperature of 100.8 °F, heart rate 100 beats per minute, blood pressure 116/85, respiratory rate 22 per minute, and oxygen saturation of 100% on 6 L of oxygen via tracheostomy collar. His initial examination was notable for clear lung sounds, a nondistended nonrigid abdomen with an indwelling percutaneous gastrostomy tube, and absence of areas of skin breakdown or erythema. Notable laboratory studies showed a leukocytosis and urinalysis suggestive of CAUTI (Table). His urinary catheter was exchanged, he was fluid resuscitated and started on empiric vancomycin and piperacillin-tazobactam for management of sepsis due to CAUTI.

For the first 3 days of his hospitalization, he demonstrated clinical improvement on vancomycin and piperacillin-tazobactam while awaiting results from his urine bacterial culture. On hospital day 3, hedeveloped recurrent nonbloody, nonbilious emesis despite no change in the rate or formulation of his enteral nutrition. He also had 3 watery brown bowel movements. His vital signs remained within normal limits. His abdominal examination at this point showed mild distention and was hypertympanic to percussion, but there was no rigidity or involuntary guarding. On hospital day 4, he continued to have emesis with an unchanged abdominal examination. The differential diagnosis included recurrence of prior SBO, ileus, intestinal ischemia, enteral nutrition intolerance, Clostridioides difficile (C difficile) colitis, and GI dysmotility because of his anoxic brain injury.

Testing for C difficile was negative. An abdominal radiograph was obtained and revealed no bowel obstruction but, alarmingly, showed extensive intramural bowel gas, suggestive of PI (Figure 1). His leukocyte count, serum bicarbonate, and serum lactate levels remained within normal limits. A CT with contrast of the abdomen and pelvis demonstrated no vascular obstruction but confirmed the presence of diffuse intramural gas in his stomach and proximal small bowel, as well as the presence of mesenteric and portal venous gas (Figures 2 and 3). Although his abdominal examination had not changed and did not suggest peritonitis, general surgery was consulted to discuss the need for surgical intervention. Given his overall clinical stability and high surgical risk due to his many comorbidities, surgery recommended a conservative approach.

Through the following hospital days, his enteral nutrition was held and serial abdominal examinations were performed without change. Serial laboratory studies, including serum lactate and leukocyte count, remained reassuringly within normal limits. His urine culture eventually revealed multidrugresistant Pseudomonas aeruginosa. Antimicrobial therapy was narrowed to piperacillintazobactam for a complete course. Enteral nutrition was gradually reintroduced at a low rate, ultimately reaching goal rate with return of bowel function by hospital day 9. Despite extensive workup, the etiology of his transient enteral nutrition intolerance remained uncertain, though an adverse effect of antibiotic therapy was thought possible. Follow-up abdominal radiographs demonstrated interval improvement of PI. He was discharged back to his skilled nursing facility on hospital day 11 without incident.

Discussion

PI is an incompletely understood condition seen in multiple diseases. Patients may present with highly variable symptoms, often more attributable to the underlying disease causing the PI than the presence of PI, as patients may be entirely asymptomatic. When symptoms are attributed to PI, those most reported are abdominal pain, bloody stools, and diarrhea.¹ It is often detected on abdominal plain films. Alternative methods of diagnosis include ultrasonography, barium enema, and endoscopy although the last method has been known to occasionally lead to bowel perforation.^2-6 The most sensitive method of detection is CT, which also provides additional information about abdominal pathology and may identify the underlying process responsible for the PI.⁷

While not fully understood, much information about PI and its pathogenesis is known. Understanding the mechanisms of PI is vital to direct the clinician’s evaluation of the patient for reversible conditions that may cause PI. Early descriptions of PI in the literature documented an association with pyloric stenosis, leading to the theory that gas from the intestinal lumen is driven into the submucosal space during episodes of forceful vomiting with increased intraluminal pressure.⁸ As PI was subsequently described in multiple other disease states not typically associated with increased intraluminal pressure such as inflammatory bowel disease, GI malignancy, cryptosporidiosis and CMV infection, additional theories about the pathogenesis of PI have arisen.^9-24 There is now experimental data to support multiple mechanisms of intramural gas accumulation. It has become accepted that PI represents a common pathway shared across various pathologic states and results from multifactorial mechanisms of gas entry into the intestinal wall.^25-29

Factors leading to the development of PI include bacterial production of gas, intraluminal GI gas compositions, increased intraluminal pressure, pulmonary gas tracking through vessels communicating with the thorax, and mucosal disruption. PI has been linked to bacterial infections of the GI tract in humans including C difficile, Klebsiella, and Whipple disease.^14-18 In animal models, C difficile within the walls of rat intestine results in the appearance of pneumocysts, or discrete collections of submucosal gas, which are the hallmark feature of PI.³⁰ It is thought that direct invasion of bacteria into intramural spaces can cause PI in humans, although bacteria have yet to be directly isolated from the pneumocysts. Translocation of luminal gas into pneumocysts found in PI is theorized to be driven by differences in partial pressures.³¹ The concentration of hydrogen within the intestinal lumen is high due to bacterial production. Hydrogen, diffusing along its partial pressure gradient between the lumen and blood, accumulates within the intestinal wall and causes the formation of pneumocysts. This phenomenon has been hypothesized to explain the tendency for pneumocysts to form around the mesenteric vasculature.

Gas from the lumen can also be forced into the intestinal wall during an abrupt increase in intra-abdominal pressure, such as that seen with forceful vomiting. The final possible origin of the gas is the lungs, as PI has been associated with lung disease. It was previously thought that gas from ruptured alveoli tracks along mediastinal vessels, below the diaphragm, and into the mesentery.³⁰ Newer theories argue that increased intra-abdominal pressure, typical of patients with obstructive lung disease and frequent coughing, is the driver of PI by the mechanism previously described.^32-34 Additionally, mucosal disruption leads to increased permeability and allows accumulation of gas within the intestinal walls. Mucosal abnormalities have been described in histopathologic studies of patients with PI and associated with conditions known to compromise mucosal integrity, such as immunodeficiencies, inflammatory bowel disease, and the receipt of cytotoxic chemotherapy.^10,12,19-23

Our patient likely had mucosal disruption due to his gastrostomy tube as well as increased intraluminal pressure from recurrent vomiting, contributing to translocation of otherwise normal intraluminal gas. The presence of portal venous gas, as seen in this case, has historically portended a worse prognosis, with 37% mortality in one series.^7,35,36 However, portal venous gas as well as pneumoperitoneum occur in benign etiologies of PI as well. It is thought that this occurs due to rupture of the submucosal pneumocysts through the wall opposite the intestinal lumen and thus does not result in a direct communication between the intestinal lumen and the peritoneal cavity.¹²

PI is not a diagnosis but a manifestation of an underlying disease. As such, the treatment of PI is targeted toward the underlying condition. Of note, the pattern and extent of PI seen on imaging has not been shown to correlate with the severity of the underlying pathologic process.^35,37 Instead, assessment of the patient and their clinical trajectory should determine the appropriate treatment. The decision facing the clinician when PI is discovered is whether urgent surgery is indicated, as is the case in mesenteric ischemia, bowel necrosis, or intestinal perforation, conditions known to be associated with PI. Otherwise, there is no definitive treatment for PI. Bowel rest is almost universally pursued. There are reports of treating with supranormal levels of supplemental oxygen, maintaining arterial partial pressure of oxygen above 300 mm Hg, with a face mask and 8 L/min flow rate.^38,39 The proposed mechanisms of benefit include establishing a favorable diffusion gradient for intramural gas to exit the pneumocysts as well as creating an inhospitable, aerobic environment for hydrogenproducing anaerobic enteric bacteria. A prudent approach for most cases of PI is conservative management with bowel rest and supplemental oxygen unless there is a definitive indication for urgent surgical intervention, such as peritonitis, abdominal sepsis, or perforation.^40,41 Management recommendations suggest that up to 50% of cases can be successfully managed nonoperatively.⁴²

Conclusions

PI is the radiographic finding of gas within the walls of the intestinal tract and has variable clinical significance. It can represent a benign incidental finding or a sequela of intraabdominal emergencies such as mesenteric ischemia or bowel necrosis. Because PI is seen in a variety of disorders, several proposed mechanisms are supported in the medical literature. These include bacterial production of gas, gas pressure gradients between the intestinal lumen and the blood, increased intraluminal pressure, pulmonary gas tracking from intrathoracic vessels, and mucosal disruption. The evaluation of a patient with PI must begin with an assessment for the need for urgent surgical intervention. Additional management measures include bowel rest, IV hydration, and supplemental oxygen administration. Because of its wide variety of etiologies of varying clinical urgency, placing the finding of PI in the context of the patient is paramount to selecting an appropriate management strategy.

Pneumatosis intestinalis (PI) is the finding of gas within the walls of the intestine on imaging. It is most commonly detected via radiograph or computed tomography (CT). The diseases leading to the accumulation of gas within the submucosal space of the gastrointestinal (GI) tract are heterogenous, and the finding of PI itself has a wide range of clinical implications from impending clinical deterioration to an incidental finding of minimal consequence.

We present the case of a veteran who had sustained a remote anoxic brain injury resulting in chronic dependence on a gastrostomy tube for enteral nutrition, found incidentally to have PI without signs of intra-abdominal catastrophe. An exclusion of other, more lifethreatening causes of PI led to a diagnosis of benign PI secondary to the presence of his gastrostomy tube. This case highlights the importance of interpreting the finding of PI in the clinical context of the specific patient and how conservative management may be appropriate in some cases.

Case Presentation

A 61-year-old male patient was admitted for fever. The patient had a remote history of cardiac arrest complicated by anoxic brain injury requiring tracheostomy, gastrostomy tube, and a suprapubic catheter with recurrent catheter-associated urinary tract infections (CAUTI), secondary seizure disorder, atrial fibrillation off anticoagulation due to recurrent GI bleeding, and treatment naive chronic hepatitis C virus. His ability to provide a clinical history was limited by his nonverbal status. He had no prior surgical history but had presented a month earlier for a high-grade small bowel obstruction (SBO) with pneumobilia that was managed conservatively as the surgical team deemed him a poor candidate for surgical intervention with his extensive comorbidities. A bioethics consultation at the time supported minimizing potential surgical risk in favor of conservative medical management; this was discussed with the patient’s surrogate decision maker, who also wished to avoid surgery. The SBO resolved with conservative management. He had been residing in a nursing home and doing well until 24 hours prior to admission when he developed fevers.

Vital signs on admission showed a temperature of 100.8 °F, heart rate 100 beats per minute, blood pressure 116/85, respiratory rate 22 per minute, and oxygen saturation of 100% on 6 L of oxygen via tracheostomy collar. His initial examination was notable for clear lung sounds, a nondistended nonrigid abdomen with an indwelling percutaneous gastrostomy tube, and absence of areas of skin breakdown or erythema. Notable laboratory studies showed a leukocytosis and urinalysis suggestive of CAUTI (Table). His urinary catheter was exchanged, he was fluid resuscitated and started on empiric vancomycin and piperacillin-tazobactam for management of sepsis due to CAUTI.

For the first 3 days of his hospitalization, he demonstrated clinical improvement on vancomycin and piperacillin-tazobactam while awaiting results from his urine bacterial culture. On hospital day 3, hedeveloped recurrent nonbloody, nonbilious emesis despite no change in the rate or formulation of his enteral nutrition. He also had 3 watery brown bowel movements. His vital signs remained within normal limits. His abdominal examination at this point showed mild distention and was hypertympanic to percussion, but there was no rigidity or involuntary guarding. On hospital day 4, he continued to have emesis with an unchanged abdominal examination. The differential diagnosis included recurrence of prior SBO, ileus, intestinal ischemia, enteral nutrition intolerance, Clostridioides difficile (C difficile) colitis, and GI dysmotility because of his anoxic brain injury.

Testing for C difficile was negative. An abdominal radiograph was obtained and revealed no bowel obstruction but, alarmingly, showed extensive intramural bowel gas, suggestive of PI (Figure 1). His leukocyte count, serum bicarbonate, and serum lactate levels remained within normal limits. A CT with contrast of the abdomen and pelvis demonstrated no vascular obstruction but confirmed the presence of diffuse intramural gas in his stomach and proximal small bowel, as well as the presence of mesenteric and portal venous gas (Figures 2 and 3). Although his abdominal examination had not changed and did not suggest peritonitis, general surgery was consulted to discuss the need for surgical intervention. Given his overall clinical stability and high surgical risk due to his many comorbidities, surgery recommended a conservative approach.

Through the following hospital days, his enteral nutrition was held and serial abdominal examinations were performed without change. Serial laboratory studies, including serum lactate and leukocyte count, remained reassuringly within normal limits. His urine culture eventually revealed multidrugresistant Pseudomonas aeruginosa. Antimicrobial therapy was narrowed to piperacillintazobactam for a complete course. Enteral nutrition was gradually reintroduced at a low rate, ultimately reaching goal rate with return of bowel function by hospital day 9. Despite extensive workup, the etiology of his transient enteral nutrition intolerance remained uncertain, though an adverse effect of antibiotic therapy was thought possible. Follow-up abdominal radiographs demonstrated interval improvement of PI. He was discharged back to his skilled nursing facility on hospital day 11 without incident.

Discussion

PI is an incompletely understood condition seen in multiple diseases. Patients may present with highly variable symptoms, often more attributable to the underlying disease causing the PI than the presence of PI, as patients may be entirely asymptomatic. When symptoms are attributed to PI, those most reported are abdominal pain, bloody stools, and diarrhea.¹ It is often detected on abdominal plain films. Alternative methods of diagnosis include ultrasonography, barium enema, and endoscopy although the last method has been known to occasionally lead to bowel perforation.^2-6 The most sensitive method of detection is CT, which also provides additional information about abdominal pathology and may identify the underlying process responsible for the PI.⁷

While not fully understood, much information about PI and its pathogenesis is known. Understanding the mechanisms of PI is vital to direct the clinician’s evaluation of the patient for reversible conditions that may cause PI. Early descriptions of PI in the literature documented an association with pyloric stenosis, leading to the theory that gas from the intestinal lumen is driven into the submucosal space during episodes of forceful vomiting with increased intraluminal pressure.⁸ As PI was subsequently described in multiple other disease states not typically associated with increased intraluminal pressure such as inflammatory bowel disease, GI malignancy, cryptosporidiosis and CMV infection, additional theories about the pathogenesis of PI have arisen.^9-24 There is now experimental data to support multiple mechanisms of intramural gas accumulation. It has become accepted that PI represents a common pathway shared across various pathologic states and results from multifactorial mechanisms of gas entry into the intestinal wall.^25-29

Factors leading to the development of PI include bacterial production of gas, intraluminal GI gas compositions, increased intraluminal pressure, pulmonary gas tracking through vessels communicating with the thorax, and mucosal disruption. PI has been linked to bacterial infections of the GI tract in humans including C difficile, Klebsiella, and Whipple disease.^14-18 In animal models, C difficile within the walls of rat intestine results in the appearance of pneumocysts, or discrete collections of submucosal gas, which are the hallmark feature of PI.³⁰ It is thought that direct invasion of bacteria into intramural spaces can cause PI in humans, although bacteria have yet to be directly isolated from the pneumocysts. Translocation of luminal gas into pneumocysts found in PI is theorized to be driven by differences in partial pressures.³¹ The concentration of hydrogen within the intestinal lumen is high due to bacterial production. Hydrogen, diffusing along its partial pressure gradient between the lumen and blood, accumulates within the intestinal wall and causes the formation of pneumocysts. This phenomenon has been hypothesized to explain the tendency for pneumocysts to form around the mesenteric vasculature.

Gas from the lumen can also be forced into the intestinal wall during an abrupt increase in intra-abdominal pressure, such as that seen with forceful vomiting. The final possible origin of the gas is the lungs, as PI has been associated with lung disease. It was previously thought that gas from ruptured alveoli tracks along mediastinal vessels, below the diaphragm, and into the mesentery.³⁰ Newer theories argue that increased intra-abdominal pressure, typical of patients with obstructive lung disease and frequent coughing, is the driver of PI by the mechanism previously described.^32-34 Additionally, mucosal disruption leads to increased permeability and allows accumulation of gas within the intestinal walls. Mucosal abnormalities have been described in histopathologic studies of patients with PI and associated with conditions known to compromise mucosal integrity, such as immunodeficiencies, inflammatory bowel disease, and the receipt of cytotoxic chemotherapy.^10,12,19-23

Our patient likely had mucosal disruption due to his gastrostomy tube as well as increased intraluminal pressure from recurrent vomiting, contributing to translocation of otherwise normal intraluminal gas. The presence of portal venous gas, as seen in this case, has historically portended a worse prognosis, with 37% mortality in one series.^7,35,36 However, portal venous gas as well as pneumoperitoneum occur in benign etiologies of PI as well. It is thought that this occurs due to rupture of the submucosal pneumocysts through the wall opposite the intestinal lumen and thus does not result in a direct communication between the intestinal lumen and the peritoneal cavity.¹²

PI is not a diagnosis but a manifestation of an underlying disease. As such, the treatment of PI is targeted toward the underlying condition. Of note, the pattern and extent of PI seen on imaging has not been shown to correlate with the severity of the underlying pathologic process.^35,37 Instead, assessment of the patient and their clinical trajectory should determine the appropriate treatment. The decision facing the clinician when PI is discovered is whether urgent surgery is indicated, as is the case in mesenteric ischemia, bowel necrosis, or intestinal perforation, conditions known to be associated with PI. Otherwise, there is no definitive treatment for PI. Bowel rest is almost universally pursued. There are reports of treating with supranormal levels of supplemental oxygen, maintaining arterial partial pressure of oxygen above 300 mm Hg, with a face mask and 8 L/min flow rate.^38,39 The proposed mechanisms of benefit include establishing a favorable diffusion gradient for intramural gas to exit the pneumocysts as well as creating an inhospitable, aerobic environment for hydrogenproducing anaerobic enteric bacteria. A prudent approach for most cases of PI is conservative management with bowel rest and supplemental oxygen unless there is a definitive indication for urgent surgical intervention, such as peritonitis, abdominal sepsis, or perforation.^40,41 Management recommendations suggest that up to 50% of cases can be successfully managed nonoperatively.⁴²

Conclusions

PI is the radiographic finding of gas within the walls of the intestinal tract and has variable clinical significance. It can represent a benign incidental finding or a sequela of intraabdominal emergencies such as mesenteric ischemia or bowel necrosis. Because PI is seen in a variety of disorders, several proposed mechanisms are supported in the medical literature. These include bacterial production of gas, gas pressure gradients between the intestinal lumen and the blood, increased intraluminal pressure, pulmonary gas tracking from intrathoracic vessels, and mucosal disruption. The evaluation of a patient with PI must begin with an assessment for the need for urgent surgical intervention. Additional management measures include bowel rest, IV hydration, and supplemental oxygen administration. Because of its wide variety of etiologies of varying clinical urgency, placing the finding of PI in the context of the patient is paramount to selecting an appropriate management strategy.

THE CASE

A 62-year-old postmenopausal woman presented to the clinic as a new patient for her annual physical examination. She reported a 9-year history of symptoms including dysuria, post-void dribbling, dyspareunia, and urinary incontinence on review of systems. Her physical examination revealed an anterior vaginal wall bulge (FIGURE). Results of a urinalysis were negative. The patient was referred to Urology for further evaluation.

THE DIAGNOSIS

A pelvic magnetic resonance imaging (MRI) scan revealed a large periurethral diverticulum with a horseshoe shape.

DISCUSSION

Urethral diverticulum is a permanent sac-like cavity projecting into the periurethral fascia arising from the posterior urethral lumen.¹ It is a rare condition that affects fewer than 20 per 1 million women per year.² Urethral diverticulum can range from 1 cm to 8 cm in diameter and is located in the mid or distal urethra.^1,3

Women are more likely than men to develop urethral diverticulum, and it can manifest at any age, usually in the third through seventh decade.^4,5 It was once thought to be more common in Black women, although the literature does not support this.⁶ Black women are 3 times more likely to be operated on than White women to treat urethral diverticula.⁷

Unknown origin. Most cases of urethral diverticulum are acquired; the etiology is uncertain.^8,9 The assumption is that urethral diverticulum occurs as a result of repeated infection of the periurethral glands with subsequent obstruction, abscess formation, and chronic inflammation.^1,2,4 Childbirth trauma, iatrogenic causes, and urethral instrumentation have also been implicated.^3,4 In rare cases of congenital urethral diverticula, the diverticula are thought to be remnants of Gartner duct cysts, and yet, incidence in the pediatric population is low.⁸

Diagnosis is confirmed through physical exam and imaging

The urethral diverticulum manifests anteriorly and palpation of the anterior vaginal wall may reveal a painful mass.¹⁰ A split-speculum is used for careful inspection and palpation of the anterior vaginal wall.⁹ If the diverticulum is found to be firm on palpation, or there is bloody urethral drainage, malignancy (although rare) must be ruled out.^4,5 Refer such patients to a urologist or urogynecologist.

The MRI, with or without endoluminal coil, is considered the gold standard in diagnosing urethral diverticulum.

Radiologic imaging (eg, ultrasound, voiding cystourethrography [VCUG], and MRI) is useful in detecting the size, location, and extent of the diverticulum, revealing the relationship to surrounding tissues, and providing insights for appropriate surgical management.^3,4,9 Ultrasound, which is usually readily available, noninvasive, and less expensive, can be considered for initial screening of suspected urethral diverticulum.^3,11 A postvoid MRI is recommended when a urethral diverticulum is highly suspected.^11,12 The MRI, with or without endoluminal coil, is considered the gold standard; it is a favorable complement to the work-up and offers the most diagnostic value.^3,4 According to a single-institution study, the MRI was 100% sensitive and specific in diagnosing urethral diverticulum.¹² However, the limitation of the MRI lies in its cost and lack of availability in some countries.¹³

Continue to: Nonspecific symptoms may lead to misdiagnosis

Nonspecific symptoms may lead to misdiagnosis. The symptoms associated with urethral diverticulum are diverse and linked to several differential diagnoses (TABLE).^3,4,12 The most common signs and symptoms are pelvic pain, urethral mass, dyspareunia, dysuria, urinary incontinence, and post-void dribbling—all of which are considered nonspecific.^3,10,11 These nonspecific symptoms (or even an absence of symptoms), along with a physician’s lack of familiarity with urethral diverticulum, can result in a misdiagnosis or even a delayed diagnosis (up to 5.2 years).^3,10

Managing symptoms vs preventing recurrence

Conservative management with antibiotics, anticholinergics, and/or observation is acceptable for patients with mild symptoms and those who are pregnant or who have a current infection or serious comorbidities that preclude surgery.^3,9 Complete excision of the urethral diverticulum with reconstruction is considered the most effective surgical management for symptom relief and recurrence prevention.^3,4,11,14

Our patient underwent a successful transvaginal suburethral diverticulectomy.

THE TAKEAWAY

The diagnosis of female urethral diverticulum is often delayed or misdiagnosed because symptoms are diverse and nonspecific. One should have a high degree of suspicion for urethral diverticulum in patients with dysuria, dyspareunia, pelvic pain, urinary incontinence, and irritative voiding symptoms who are not responding to conservative management. Ultrasound is an appropriate first-line imaging modality. However, a pelvic MRI is the most sensitive and specific in diagnosing urethral diverticulum.¹²

CORRESPONDENCE
Folashade Omole, MD, FAAFP, 720 Westview Drive, Atlanta, GA 30310; [email protected]

THE CASE

A 62-year-old postmenopausal woman presented to the clinic as a new patient for her annual physical examination. She reported a 9-year history of symptoms including dysuria, post-void dribbling, dyspareunia, and urinary incontinence on review of systems. Her physical examination revealed an anterior vaginal wall bulge (FIGURE). Results of a urinalysis were negative. The patient was referred to Urology for further evaluation.

THE DIAGNOSIS

A pelvic magnetic resonance imaging (MRI) scan revealed a large periurethral diverticulum with a horseshoe shape.

DISCUSSION

Urethral diverticulum is a permanent sac-like cavity projecting into the periurethral fascia arising from the posterior urethral lumen.¹ It is a rare condition that affects fewer than 20 per 1 million women per year.² Urethral diverticulum can range from 1 cm to 8 cm in diameter and is located in the mid or distal urethra.^1,3

Women are more likely than men to develop urethral diverticulum, and it can manifest at any age, usually in the third through seventh decade.^4,5 It was once thought to be more common in Black women, although the literature does not support this.⁶ Black women are 3 times more likely to be operated on than White women to treat urethral diverticula.⁷

Unknown origin. Most cases of urethral diverticulum are acquired; the etiology is uncertain.^8,9 The assumption is that urethral diverticulum occurs as a result of repeated infection of the periurethral glands with subsequent obstruction, abscess formation, and chronic inflammation.^1,2,4 Childbirth trauma, iatrogenic causes, and urethral instrumentation have also been implicated.^3,4 In rare cases of congenital urethral diverticula, the diverticula are thought to be remnants of Gartner duct cysts, and yet, incidence in the pediatric population is low.⁸

Diagnosis is confirmed through physical exam and imaging

The urethral diverticulum manifests anteriorly and palpation of the anterior vaginal wall may reveal a painful mass.¹⁰ A split-speculum is used for careful inspection and palpation of the anterior vaginal wall.⁹ If the diverticulum is found to be firm on palpation, or there is bloody urethral drainage, malignancy (although rare) must be ruled out.^4,5 Refer such patients to a urologist or urogynecologist.

The MRI, with or without endoluminal coil, is considered the gold standard in diagnosing urethral diverticulum.

Radiologic imaging (eg, ultrasound, voiding cystourethrography [VCUG], and MRI) is useful in detecting the size, location, and extent of the diverticulum, revealing the relationship to surrounding tissues, and providing insights for appropriate surgical management.^3,4,9 Ultrasound, which is usually readily available, noninvasive, and less expensive, can be considered for initial screening of suspected urethral diverticulum.^3,11 A postvoid MRI is recommended when a urethral diverticulum is highly suspected.^11,12 The MRI, with or without endoluminal coil, is considered the gold standard; it is a favorable complement to the work-up and offers the most diagnostic value.^3,4 According to a single-institution study, the MRI was 100% sensitive and specific in diagnosing urethral diverticulum.¹² However, the limitation of the MRI lies in its cost and lack of availability in some countries.¹³

Continue to: Nonspecific symptoms may lead to misdiagnosis

Nonspecific symptoms may lead to misdiagnosis. The symptoms associated with urethral diverticulum are diverse and linked to several differential diagnoses (TABLE).^3,4,12 The most common signs and symptoms are pelvic pain, urethral mass, dyspareunia, dysuria, urinary incontinence, and post-void dribbling—all of which are considered nonspecific.^3,10,11 These nonspecific symptoms (or even an absence of symptoms), along with a physician’s lack of familiarity with urethral diverticulum, can result in a misdiagnosis or even a delayed diagnosis (up to 5.2 years).^3,10

Managing symptoms vs preventing recurrence

Conservative management with antibiotics, anticholinergics, and/or observation is acceptable for patients with mild symptoms and those who are pregnant or who have a current infection or serious comorbidities that preclude surgery.^3,9 Complete excision of the urethral diverticulum with reconstruction is considered the most effective surgical management for symptom relief and recurrence prevention.^3,4,11,14

Our patient underwent a successful transvaginal suburethral diverticulectomy.

THE TAKEAWAY

The diagnosis of female urethral diverticulum is often delayed or misdiagnosed because symptoms are diverse and nonspecific. One should have a high degree of suspicion for urethral diverticulum in patients with dysuria, dyspareunia, pelvic pain, urinary incontinence, and irritative voiding symptoms who are not responding to conservative management. Ultrasound is an appropriate first-line imaging modality. However, a pelvic MRI is the most sensitive and specific in diagnosing urethral diverticulum.¹²

CORRESPONDENCE
Folashade Omole, MD, FAAFP, 720 Westview Drive, Atlanta, GA 30310; [email protected]

THE CASE

A 62-year-old postmenopausal woman presented to the clinic as a new patient for her annual physical examination. She reported a 9-year history of symptoms including dysuria, post-void dribbling, dyspareunia, and urinary incontinence on review of systems. Her physical examination revealed an anterior vaginal wall bulge (FIGURE). Results of a urinalysis were negative. The patient was referred to Urology for further evaluation.

THE DIAGNOSIS

A pelvic magnetic resonance imaging (MRI) scan revealed a large periurethral diverticulum with a horseshoe shape.

DISCUSSION

Urethral diverticulum is a permanent sac-like cavity projecting into the periurethral fascia arising from the posterior urethral lumen.¹ It is a rare condition that affects fewer than 20 per 1 million women per year.² Urethral diverticulum can range from 1 cm to 8 cm in diameter and is located in the mid or distal urethra.^1,3

Women are more likely than men to develop urethral diverticulum, and it can manifest at any age, usually in the third through seventh decade.^4,5 It was once thought to be more common in Black women, although the literature does not support this.⁶ Black women are 3 times more likely to be operated on than White women to treat urethral diverticula.⁷

Unknown origin. Most cases of urethral diverticulum are acquired; the etiology is uncertain.^8,9 The assumption is that urethral diverticulum occurs as a result of repeated infection of the periurethral glands with subsequent obstruction, abscess formation, and chronic inflammation.^1,2,4 Childbirth trauma, iatrogenic causes, and urethral instrumentation have also been implicated.^3,4 In rare cases of congenital urethral diverticula, the diverticula are thought to be remnants of Gartner duct cysts, and yet, incidence in the pediatric population is low.⁸

Diagnosis is confirmed through physical exam and imaging

The urethral diverticulum manifests anteriorly and palpation of the anterior vaginal wall may reveal a painful mass.¹⁰ A split-speculum is used for careful inspection and palpation of the anterior vaginal wall.⁹ If the diverticulum is found to be firm on palpation, or there is bloody urethral drainage, malignancy (although rare) must be ruled out.^4,5 Refer such patients to a urologist or urogynecologist.

The MRI, with or without endoluminal coil, is considered the gold standard in diagnosing urethral diverticulum.

Radiologic imaging (eg, ultrasound, voiding cystourethrography [VCUG], and MRI) is useful in detecting the size, location, and extent of the diverticulum, revealing the relationship to surrounding tissues, and providing insights for appropriate surgical management.^3,4,9 Ultrasound, which is usually readily available, noninvasive, and less expensive, can be considered for initial screening of suspected urethral diverticulum.^3,11 A postvoid MRI is recommended when a urethral diverticulum is highly suspected.^11,12 The MRI, with or without endoluminal coil, is considered the gold standard; it is a favorable complement to the work-up and offers the most diagnostic value.^3,4 According to a single-institution study, the MRI was 100% sensitive and specific in diagnosing urethral diverticulum.¹² However, the limitation of the MRI lies in its cost and lack of availability in some countries.¹³

Continue to: Nonspecific symptoms may lead to misdiagnosis

Nonspecific symptoms may lead to misdiagnosis. The symptoms associated with urethral diverticulum are diverse and linked to several differential diagnoses (TABLE).^3,4,12 The most common signs and symptoms are pelvic pain, urethral mass, dyspareunia, dysuria, urinary incontinence, and post-void dribbling—all of which are considered nonspecific.^3,10,11 These nonspecific symptoms (or even an absence of symptoms), along with a physician’s lack of familiarity with urethral diverticulum, can result in a misdiagnosis or even a delayed diagnosis (up to 5.2 years).^3,10

Managing symptoms vs preventing recurrence

Conservative management with antibiotics, anticholinergics, and/or observation is acceptable for patients with mild symptoms and those who are pregnant or who have a current infection or serious comorbidities that preclude surgery.^3,9 Complete excision of the urethral diverticulum with reconstruction is considered the most effective surgical management for symptom relief and recurrence prevention.^3,4,11,14

Our patient underwent a successful transvaginal suburethral diverticulectomy.

THE TAKEAWAY

The diagnosis of female urethral diverticulum is often delayed or misdiagnosed because symptoms are diverse and nonspecific. One should have a high degree of suspicion for urethral diverticulum in patients with dysuria, dyspareunia, pelvic pain, urinary incontinence, and irritative voiding symptoms who are not responding to conservative management. Ultrasound is an appropriate first-line imaging modality. However, a pelvic MRI is the most sensitive and specific in diagnosing urethral diverticulum.¹²

CORRESPONDENCE
Folashade Omole, MD, FAAFP, 720 Westview Drive, Atlanta, GA 30310; [email protected]

Airbags are lifesaving during motor vehicle accidents (MVAs), but their deployment has been associated with skin issues such as irritant dermatitis¹; lacerations²; abrasions³; and thermal, friction, and chemical burns.^4-6 Ocular issues such as alkaline chemical keratitis⁷ and ocular alkali injuries⁸ also have been described.

Airbag deployment is triggered by rapid deceleration and impact, which ignite a sodium azide cartridge, causing the woven nylon bag to inflate with hydrocarbon gases.⁸ This leads to release of sodium hydroxide, sodium bicarbonate, and metallic oxides in an aerosolized form. If a tear in the meshwork of the airbag occurs, exposure to an even larger amount of powder containing caustic alkali chemicals can occur.⁸

We describe a patient who developed a bullous reaction to airbag contents after he was involved in an MVA in which the airbag deployed.

Case Report

A 35-year-old man with a history of type 2 diabetes mellitus and chronic hepatitis B presented to the dermatology clinic for an evaluation of new-onset blisters. The rash occurred 1 day after the patient was involved in an MVA in which he was exposed to the airbag’s contents after it burst. He had been evaluated twice in the emergency department for the skin eruption before being referred to dermatology. He noted the lesions were pruritic and painful. Prior treatments included silver sulfadiazine cream 1% and clobetasol cream 0.05%, though he discontinued using the latter because of burning with application. Physical examination revealed tense vesicles and bullae on an erythematous base on the right lower flank, forearms, and legs, with the exception of the lower right leg where a cast had been from a prior injury (Figure 1).

Two punch biopsies of the left arm were performed and sent for hematoxylin and eosin staining and direct immunofluorescence to rule out bullous diseases, such as bullous pemphigoid, linear IgA, and bullous lupus. Hematoxylin and eosin staining revealed extensive spongiosis with blister formation and a dense perivascular infiltrate in the superficial and mid dermis composed of lymphocytes with numerous scattered eosinophils (Figures 2 and 3). Direct immunofluorescence studies were negative. Treatment with oral prednisone and oral antihistamines was initiated.

At 10-day follow-up, the patient had a few residual bullae; most lesions were demonstrating various stages of healing (Figure 4). The patient’s cast had been removed, and there were no lesions in this previously covered area. At 6-week follow-up he had continued healing of the bullae and erosions as well as postinflammatory hyperpigmentation (Figure 5).

Comment

With the advent of airbags for safety purposes, these potentially lifesaving devices also have been known to cause injury.⁹ In 1998, the most commonly reported airbag injuries were ocular injuries.¹⁰ Cutaneous manifestations of airbag injury are less well known.¹¹

Two cases of airbag deployment with skin blistering have been reported in the literature based on a PubMed search of articles indexed for MEDLINE using the terms airbag blistering or airbag bullae^12,13; however, the blistering was described in the context of a burn. One case of the effects of airbag deployment residue highlights a patient arriving to the emergency department with erythema and blisters on the hands within 48 hours of airbag deployment in an MVA, and the treatment was standard burn therapy.¹² Another case report described a patient with a second-degree burn with a 12-cm blister occurring on the radial side of the hand and distal forearm following an MVA and airbag deployment, which was treated conservatively.¹³ Cases of thermal burns, chemical burns, and irritant contact dermatitis after airbag deployment have been described in the literature.^{4-6,11,12,14,15} Our patient’s distal right lower leg was covered with a cast for osteomyelitis, and no blisters had developed in this area. It is likely that the transfer of airbag contents occurred during the process of unbuckling his seatbelt, which could explain the bullae that developed on the right flank. Per the Centers for Disease Control and Prevention, individuals should quickly remove clothing and wash their body with large amounts of soap and water following exposure to sodium azide.¹⁶

In 1989, the Federal Motor Vehicle Safety Standard No. 208 (occupant crash protection) became effective, stating all cars must have vehicle crash protection.¹² Prior to 1993, it was reported that there had been no associated chemical injuries with airbag deployment. Subsequently, a 6-month retrospective study in 1993 showed that dermal injuries were found in connection with the presence of sodium hydroxide in automobile airbags.¹² By 2004, it was known that airbags could cause chemical and thermal burns in addition to traumatic injuries from deployment.¹ Since 2007, all motor vehicles have been required to have advanced airbags, which are engineered to sense the presence of passengers and determine if the airbag will deploy, and if so, how much to deploy to minimize airbag-related injury.³

The brand of car that our patient drove during the MVA is one with known airbag recalls due to safety defects; however, the year and actual model of the vehicle are not known, so specific information about the airbag in question is not available. It has been noted that some defective airbag inflators that were exposed to excess moisture during the manufacturing process could explode during deployment, causing shrapnel and airbag rupture, which has been linked to nearly 300 injuries worldwide.¹⁷

Conclusion

It is evident that the use of airbag devices reduces morbidity and mortality due to MVAs.⁹ It also had been reported that up to 96% of airbag-related injuries are relatively minor, which many would argue justifies their use.¹⁸ Furthermore, it has been reported that 99.8% of skin injuries following airbag deployment are minor.¹⁹ In the United States, it is mandated that every vehicle have functional airbags installed.⁸

This case highlights the potential for substantial airbag-induced skin reactions, specifically a bullous reaction, following airbag deployment. The persistent pruritus and lasting postinflammatory hyperpigmentation seen in this case were certainly worrisome for our patient. We also present this case to remind dermatology providers of possible treatment approaches to these skin reactions. Immediate cleansing of the affected areas of skin may help avoid such reactions.

Airbags are lifesaving during motor vehicle accidents (MVAs), but their deployment has been associated with skin issues such as irritant dermatitis¹; lacerations²; abrasions³; and thermal, friction, and chemical burns.^4-6 Ocular issues such as alkaline chemical keratitis⁷ and ocular alkali injuries⁸ also have been described.

Airbag deployment is triggered by rapid deceleration and impact, which ignite a sodium azide cartridge, causing the woven nylon bag to inflate with hydrocarbon gases.⁸ This leads to release of sodium hydroxide, sodium bicarbonate, and metallic oxides in an aerosolized form. If a tear in the meshwork of the airbag occurs, exposure to an even larger amount of powder containing caustic alkali chemicals can occur.⁸

We describe a patient who developed a bullous reaction to airbag contents after he was involved in an MVA in which the airbag deployed.

Case Report

A 35-year-old man with a history of type 2 diabetes mellitus and chronic hepatitis B presented to the dermatology clinic for an evaluation of new-onset blisters. The rash occurred 1 day after the patient was involved in an MVA in which he was exposed to the airbag’s contents after it burst. He had been evaluated twice in the emergency department for the skin eruption before being referred to dermatology. He noted the lesions were pruritic and painful. Prior treatments included silver sulfadiazine cream 1% and clobetasol cream 0.05%, though he discontinued using the latter because of burning with application. Physical examination revealed tense vesicles and bullae on an erythematous base on the right lower flank, forearms, and legs, with the exception of the lower right leg where a cast had been from a prior injury (Figure 1).

Two punch biopsies of the left arm were performed and sent for hematoxylin and eosin staining and direct immunofluorescence to rule out bullous diseases, such as bullous pemphigoid, linear IgA, and bullous lupus. Hematoxylin and eosin staining revealed extensive spongiosis with blister formation and a dense perivascular infiltrate in the superficial and mid dermis composed of lymphocytes with numerous scattered eosinophils (Figures 2 and 3). Direct immunofluorescence studies were negative. Treatment with oral prednisone and oral antihistamines was initiated.

At 10-day follow-up, the patient had a few residual bullae; most lesions were demonstrating various stages of healing (Figure 4). The patient’s cast had been removed, and there were no lesions in this previously covered area. At 6-week follow-up he had continued healing of the bullae and erosions as well as postinflammatory hyperpigmentation (Figure 5).

Comment

With the advent of airbags for safety purposes, these potentially lifesaving devices also have been known to cause injury.⁹ In 1998, the most commonly reported airbag injuries were ocular injuries.¹⁰ Cutaneous manifestations of airbag injury are less well known.¹¹

Two cases of airbag deployment with skin blistering have been reported in the literature based on a PubMed search of articles indexed for MEDLINE using the terms airbag blistering or airbag bullae^12,13; however, the blistering was described in the context of a burn. One case of the effects of airbag deployment residue highlights a patient arriving to the emergency department with erythema and blisters on the hands within 48 hours of airbag deployment in an MVA, and the treatment was standard burn therapy.¹² Another case report described a patient with a second-degree burn with a 12-cm blister occurring on the radial side of the hand and distal forearm following an MVA and airbag deployment, which was treated conservatively.¹³ Cases of thermal burns, chemical burns, and irritant contact dermatitis after airbag deployment have been described in the literature.^{4-6,11,12,14,15} Our patient’s distal right lower leg was covered with a cast for osteomyelitis, and no blisters had developed in this area. It is likely that the transfer of airbag contents occurred during the process of unbuckling his seatbelt, which could explain the bullae that developed on the right flank. Per the Centers for Disease Control and Prevention, individuals should quickly remove clothing and wash their body with large amounts of soap and water following exposure to sodium azide.¹⁶

In 1989, the Federal Motor Vehicle Safety Standard No. 208 (occupant crash protection) became effective, stating all cars must have vehicle crash protection.¹² Prior to 1993, it was reported that there had been no associated chemical injuries with airbag deployment. Subsequently, a 6-month retrospective study in 1993 showed that dermal injuries were found in connection with the presence of sodium hydroxide in automobile airbags.¹² By 2004, it was known that airbags could cause chemical and thermal burns in addition to traumatic injuries from deployment.¹ Since 2007, all motor vehicles have been required to have advanced airbags, which are engineered to sense the presence of passengers and determine if the airbag will deploy, and if so, how much to deploy to minimize airbag-related injury.³

The brand of car that our patient drove during the MVA is one with known airbag recalls due to safety defects; however, the year and actual model of the vehicle are not known, so specific information about the airbag in question is not available. It has been noted that some defective airbag inflators that were exposed to excess moisture during the manufacturing process could explode during deployment, causing shrapnel and airbag rupture, which has been linked to nearly 300 injuries worldwide.¹⁷

Conclusion

It is evident that the use of airbag devices reduces morbidity and mortality due to MVAs.⁹ It also had been reported that up to 96% of airbag-related injuries are relatively minor, which many would argue justifies their use.¹⁸ Furthermore, it has been reported that 99.8% of skin injuries following airbag deployment are minor.¹⁹ In the United States, it is mandated that every vehicle have functional airbags installed.⁸

This case highlights the potential for substantial airbag-induced skin reactions, specifically a bullous reaction, following airbag deployment. The persistent pruritus and lasting postinflammatory hyperpigmentation seen in this case were certainly worrisome for our patient. We also present this case to remind dermatology providers of possible treatment approaches to these skin reactions. Immediate cleansing of the affected areas of skin may help avoid such reactions.

Airbags are lifesaving during motor vehicle accidents (MVAs), but their deployment has been associated with skin issues such as irritant dermatitis¹; lacerations²; abrasions³; and thermal, friction, and chemical burns.^4-6 Ocular issues such as alkaline chemical keratitis⁷ and ocular alkali injuries⁸ also have been described.

Airbag deployment is triggered by rapid deceleration and impact, which ignite a sodium azide cartridge, causing the woven nylon bag to inflate with hydrocarbon gases.⁸ This leads to release of sodium hydroxide, sodium bicarbonate, and metallic oxides in an aerosolized form. If a tear in the meshwork of the airbag occurs, exposure to an even larger amount of powder containing caustic alkali chemicals can occur.⁸

We describe a patient who developed a bullous reaction to airbag contents after he was involved in an MVA in which the airbag deployed.

Case Report

A 35-year-old man with a history of type 2 diabetes mellitus and chronic hepatitis B presented to the dermatology clinic for an evaluation of new-onset blisters. The rash occurred 1 day after the patient was involved in an MVA in which he was exposed to the airbag’s contents after it burst. He had been evaluated twice in the emergency department for the skin eruption before being referred to dermatology. He noted the lesions were pruritic and painful. Prior treatments included silver sulfadiazine cream 1% and clobetasol cream 0.05%, though he discontinued using the latter because of burning with application. Physical examination revealed tense vesicles and bullae on an erythematous base on the right lower flank, forearms, and legs, with the exception of the lower right leg where a cast had been from a prior injury (Figure 1).

Two punch biopsies of the left arm were performed and sent for hematoxylin and eosin staining and direct immunofluorescence to rule out bullous diseases, such as bullous pemphigoid, linear IgA, and bullous lupus. Hematoxylin and eosin staining revealed extensive spongiosis with blister formation and a dense perivascular infiltrate in the superficial and mid dermis composed of lymphocytes with numerous scattered eosinophils (Figures 2 and 3). Direct immunofluorescence studies were negative. Treatment with oral prednisone and oral antihistamines was initiated.

At 10-day follow-up, the patient had a few residual bullae; most lesions were demonstrating various stages of healing (Figure 4). The patient’s cast had been removed, and there were no lesions in this previously covered area. At 6-week follow-up he had continued healing of the bullae and erosions as well as postinflammatory hyperpigmentation (Figure 5).

Comment

With the advent of airbags for safety purposes, these potentially lifesaving devices also have been known to cause injury.⁹ In 1998, the most commonly reported airbag injuries were ocular injuries.¹⁰ Cutaneous manifestations of airbag injury are less well known.¹¹

Two cases of airbag deployment with skin blistering have been reported in the literature based on a PubMed search of articles indexed for MEDLINE using the terms airbag blistering or airbag bullae^12,13; however, the blistering was described in the context of a burn. One case of the effects of airbag deployment residue highlights a patient arriving to the emergency department with erythema and blisters on the hands within 48 hours of airbag deployment in an MVA, and the treatment was standard burn therapy.¹² Another case report described a patient with a second-degree burn with a 12-cm blister occurring on the radial side of the hand and distal forearm following an MVA and airbag deployment, which was treated conservatively.¹³ Cases of thermal burns, chemical burns, and irritant contact dermatitis after airbag deployment have been described in the literature.^{4-6,11,12,14,15} Our patient’s distal right lower leg was covered with a cast for osteomyelitis, and no blisters had developed in this area. It is likely that the transfer of airbag contents occurred during the process of unbuckling his seatbelt, which could explain the bullae that developed on the right flank. Per the Centers for Disease Control and Prevention, individuals should quickly remove clothing and wash their body with large amounts of soap and water following exposure to sodium azide.¹⁶

In 1989, the Federal Motor Vehicle Safety Standard No. 208 (occupant crash protection) became effective, stating all cars must have vehicle crash protection.¹² Prior to 1993, it was reported that there had been no associated chemical injuries with airbag deployment. Subsequently, a 6-month retrospective study in 1993 showed that dermal injuries were found in connection with the presence of sodium hydroxide in automobile airbags.¹² By 2004, it was known that airbags could cause chemical and thermal burns in addition to traumatic injuries from deployment.¹ Since 2007, all motor vehicles have been required to have advanced airbags, which are engineered to sense the presence of passengers and determine if the airbag will deploy, and if so, how much to deploy to minimize airbag-related injury.³

The brand of car that our patient drove during the MVA is one with known airbag recalls due to safety defects; however, the year and actual model of the vehicle are not known, so specific information about the airbag in question is not available. It has been noted that some defective airbag inflators that were exposed to excess moisture during the manufacturing process could explode during deployment, causing shrapnel and airbag rupture, which has been linked to nearly 300 injuries worldwide.¹⁷

Conclusion

It is evident that the use of airbag devices reduces morbidity and mortality due to MVAs.⁹ It also had been reported that up to 96% of airbag-related injuries are relatively minor, which many would argue justifies their use.¹⁸ Furthermore, it has been reported that 99.8% of skin injuries following airbag deployment are minor.¹⁹ In the United States, it is mandated that every vehicle have functional airbags installed.⁸

This case highlights the potential for substantial airbag-induced skin reactions, specifically a bullous reaction, following airbag deployment. The persistent pruritus and lasting postinflammatory hyperpigmentation seen in this case were certainly worrisome for our patient. We also present this case to remind dermatology providers of possible treatment approaches to these skin reactions. Immediate cleansing of the affected areas of skin may help avoid such reactions.

Case Report

A 60-year-old man presented with eroded areas in the mouth and blistering eruptions on the scalp, face, trunk, arms, and legs. He initially presented to an outside hospital 4 years prior and was treated with oral prednisone 50 mg daily, to which the eruptions responded rapidly; however, following a nearly 5-mg reduction of the dose per week by the patient and irregular oral administration, he experienced several episodes of recurrence, but he could not remember the exact dosage of prednisone he had taken during that period. Subsequently, he was admitted to our hospital because of large areas of erythema and erosions on the scalp, trunk, arms, and legs.

Since starting the prednisone regimen 4 years prior, the patient had experienced onset of hypertension, diabetes, glaucoma, cataracts, optic nerve atrophy, aseptic necrosis of the femoral head, and osteoporosis. Biopsy of a new skin lesion revealed suprabasal acantholysis (Figure 1). Direct immunofluorescence showed epidermal intercellular deposition of IgG and complement component 3. Laboratory testing showed a desmoglein 1 level of 142 U/mL (reference range, <14 U/mL) and desmoglein 3 level of 150 U/mL (reference range, <14 U/mL). Liver and kidney function; routine blood and urine tests; and antinuclear antibody, hepatitis B and C antibodies, syphilis, and human immunodeficiency virus antibody levels were normal. The biopsy and immunofluorescence results combined with clinical feature were consistent with a diagnosis of pemphigus vulgaris (PV).

The patient initially was started again prednisone 50 mg daily, to which the skin eruptions responded, and 2 weeks later, the disease was considered controlled. The prednisone dosage was tapered to 20 mg daily 3 months later with no new blister formation. However, 2 weeks later, the patient was diagnosed by a tuberculosis specialist with pulmonary tuberculosis, and a daily regimen of isoniazid, rifampicin, ethambutol, and levofloxacin was instituted.

Ten days after starting antituberculosis therapy, the patient developed new erythematous blisters that could not be controlled and self-adjusted the prednisone dose to 50 mg daily. Two months later, blister formation continued.

Six months after the initial presentation, the patient returned to our hospital because of uncontrollable rashes (Figure 2). On admission, he had a Pemphigus Disease Area Index (PDAI) score of 32 with disease involving 30% of the body surface area. Laboratory testing showed a desmoglein 1 level of 233 U/mL and desmoglein 3 level of 228 U/mL. A tuberculosis specialist from an outside hospital was consulted to evaluate the patient’s condition and assist in treatment. Based on findings from a pulmonary computed tomography scan, which showed the inflammation was considerably absorbed, treatment was adjusted to stop using ethambutol and levofloxacin and continue rifampicin and isoniazid. For the PV, prednisone was titrated upward to 75 mg daily, mycophenolate mofetil (MMF) 1 g twice daily was added, and IVIG 400 mg/kg daily was administered for 7 days. After 3 weeks, the rash still expanded.

In considering possible interactions between the drugs, we consulted the literature and found reports^1-3 that rifampicin accelerated glucocorticoid metabolism, of which the tuberculosis specialist that we consulted was not aware. Therefore, rifampicin was stopped, and the antituberculosis therapy was adjusted to levofloxacin and isoniazid. Meanwhile, the steroid was changed to methylprednisolone 120 mg daily for 3 days, then to 80 mg daily for 2 days.

After 5 days, the rash was controlled with no new development and the patient was discharged. He continued on prednisone 80 mg daily and MMF 1 g twice daily.

At 2-month follow-up, no new rash had developed. The patient had already self-discontinued the MMF for 1 month because it was difficult to obtain at local hospitals. The prednisone was reduced to 40 mg daily. Pulmonary computed tomography showed no signs of reactivation of tuberculosis.

Comment

The tuberculostatic compound rifampin induces expression of a number of drug metabolism-related genes associated with cytochromes (especially cytochrome P450 3A4), multidrug resistance (P-glycoprotein and multidrug resistance proteins 1 and 2), uridine 5’-diphospho-glucuronosyltransferase, monoamine oxidases, and glutathione S-transferases.

Drugs that depend on these enzymes for their metabolism are prone to drug interactions when co-administered with rifampicin.^4,5 It has been reported that rifampicin reduces the area under the concentration–time curve (AUC) of prednisolone by approximately 30% to 60%; some authors have suggested that, if rifampicin has to be prescribed, a 2- to 3-fold increase in the prednisolone dosage might be indicated.^1,4,6,7 Rifampicin also can influence immunosuppressive drugs in organ transplant recipients; for example, an 11-day course of rifampicin 600 mg daily was found to reduce the AUC of oral cyclosporine by approximately 70% and of intravenous cyclosporine by 28%.^4,8 Similarly, treatment with rifampicin 600 mg daily for 18 days reduced the AUC of oral tacrolimus by 68% and of intravenous tacrolimus by 35%.^4,9

Rifampicin causes a marked reduction in dose-corrected mycophenolic acid exposure when administered simultaneously with MMF through induction of glucuronidation activity and inhibition of enterohepatic recirculation.^5,10In in vitro studies, rifampin and other cytochrome P450 inducers have been identified as potentially useful for increasing the rate of cyclophosphamide and ifosfamide (an isomeric analogue of cyclophosphamide) 4-hydroxylation in the human liver in a manner that could have a favorable impact on the clinical pharmacokinetics of these anticancer prodrugs.¹¹ However, clinical analysis of 16 patients indicated that co-administration of ifosfamide with rifampin did not result in changes in the pharmacokinetics of the parent drug or its metabolites.¹²

The steroids and immunosuppressants mentioned above are widely used in the treatment of autoimmune diseases and drug hypersensitivity in dermatology. Drug interactions should be considered and drug concentrations closely monitored in cases of rifampin co-administration.

Conclusion

In our patient, the use of rifapentine resulted in a recurrence of previously controlled PV and resistance to treatment. The patient’s disease was quickly controlled after discontinuation of rifampicin and with a short-term course of high-dose methylprednisolone and remained stable when the dosages of MMF and prednisone were reduced. This case serves as a reminder for clinicians to consider a drug interaction when treatment fails in order to avoid harming patients, especially those who have an autoimmune disease.

Case Report

A 60-year-old man presented with eroded areas in the mouth and blistering eruptions on the scalp, face, trunk, arms, and legs. He initially presented to an outside hospital 4 years prior and was treated with oral prednisone 50 mg daily, to which the eruptions responded rapidly; however, following a nearly 5-mg reduction of the dose per week by the patient and irregular oral administration, he experienced several episodes of recurrence, but he could not remember the exact dosage of prednisone he had taken during that period. Subsequently, he was admitted to our hospital because of large areas of erythema and erosions on the scalp, trunk, arms, and legs.

Since starting the prednisone regimen 4 years prior, the patient had experienced onset of hypertension, diabetes, glaucoma, cataracts, optic nerve atrophy, aseptic necrosis of the femoral head, and osteoporosis. Biopsy of a new skin lesion revealed suprabasal acantholysis (Figure 1). Direct immunofluorescence showed epidermal intercellular deposition of IgG and complement component 3. Laboratory testing showed a desmoglein 1 level of 142 U/mL (reference range, <14 U/mL) and desmoglein 3 level of 150 U/mL (reference range, <14 U/mL). Liver and kidney function; routine blood and urine tests; and antinuclear antibody, hepatitis B and C antibodies, syphilis, and human immunodeficiency virus antibody levels were normal. The biopsy and immunofluorescence results combined with clinical feature were consistent with a diagnosis of pemphigus vulgaris (PV).

The patient initially was started again prednisone 50 mg daily, to which the skin eruptions responded, and 2 weeks later, the disease was considered controlled. The prednisone dosage was tapered to 20 mg daily 3 months later with no new blister formation. However, 2 weeks later, the patient was diagnosed by a tuberculosis specialist with pulmonary tuberculosis, and a daily regimen of isoniazid, rifampicin, ethambutol, and levofloxacin was instituted.

Ten days after starting antituberculosis therapy, the patient developed new erythematous blisters that could not be controlled and self-adjusted the prednisone dose to 50 mg daily. Two months later, blister formation continued.

Six months after the initial presentation, the patient returned to our hospital because of uncontrollable rashes (Figure 2). On admission, he had a Pemphigus Disease Area Index (PDAI) score of 32 with disease involving 30% of the body surface area. Laboratory testing showed a desmoglein 1 level of 233 U/mL and desmoglein 3 level of 228 U/mL. A tuberculosis specialist from an outside hospital was consulted to evaluate the patient’s condition and assist in treatment. Based on findings from a pulmonary computed tomography scan, which showed the inflammation was considerably absorbed, treatment was adjusted to stop using ethambutol and levofloxacin and continue rifampicin and isoniazid. For the PV, prednisone was titrated upward to 75 mg daily, mycophenolate mofetil (MMF) 1 g twice daily was added, and IVIG 400 mg/kg daily was administered for 7 days. After 3 weeks, the rash still expanded.

In considering possible interactions between the drugs, we consulted the literature and found reports^1-3 that rifampicin accelerated glucocorticoid metabolism, of which the tuberculosis specialist that we consulted was not aware. Therefore, rifampicin was stopped, and the antituberculosis therapy was adjusted to levofloxacin and isoniazid. Meanwhile, the steroid was changed to methylprednisolone 120 mg daily for 3 days, then to 80 mg daily for 2 days.

After 5 days, the rash was controlled with no new development and the patient was discharged. He continued on prednisone 80 mg daily and MMF 1 g twice daily.

At 2-month follow-up, no new rash had developed. The patient had already self-discontinued the MMF for 1 month because it was difficult to obtain at local hospitals. The prednisone was reduced to 40 mg daily. Pulmonary computed tomography showed no signs of reactivation of tuberculosis.

Comment

The tuberculostatic compound rifampin induces expression of a number of drug metabolism-related genes associated with cytochromes (especially cytochrome P450 3A4), multidrug resistance (P-glycoprotein and multidrug resistance proteins 1 and 2), uridine 5’-diphospho-glucuronosyltransferase, monoamine oxidases, and glutathione S-transferases.

Drugs that depend on these enzymes for their metabolism are prone to drug interactions when co-administered with rifampicin.^4,5 It has been reported that rifampicin reduces the area under the concentration–time curve (AUC) of prednisolone by approximately 30% to 60%; some authors have suggested that, if rifampicin has to be prescribed, a 2- to 3-fold increase in the prednisolone dosage might be indicated.^1,4,6,7 Rifampicin also can influence immunosuppressive drugs in organ transplant recipients; for example, an 11-day course of rifampicin 600 mg daily was found to reduce the AUC of oral cyclosporine by approximately 70% and of intravenous cyclosporine by 28%.^4,8 Similarly, treatment with rifampicin 600 mg daily for 18 days reduced the AUC of oral tacrolimus by 68% and of intravenous tacrolimus by 35%.^4,9

Rifampicin causes a marked reduction in dose-corrected mycophenolic acid exposure when administered simultaneously with MMF through induction of glucuronidation activity and inhibition of enterohepatic recirculation.^5,10In in vitro studies, rifampin and other cytochrome P450 inducers have been identified as potentially useful for increasing the rate of cyclophosphamide and ifosfamide (an isomeric analogue of cyclophosphamide) 4-hydroxylation in the human liver in a manner that could have a favorable impact on the clinical pharmacokinetics of these anticancer prodrugs.¹¹ However, clinical analysis of 16 patients indicated that co-administration of ifosfamide with rifampin did not result in changes in the pharmacokinetics of the parent drug or its metabolites.¹²

The steroids and immunosuppressants mentioned above are widely used in the treatment of autoimmune diseases and drug hypersensitivity in dermatology. Drug interactions should be considered and drug concentrations closely monitored in cases of rifampin co-administration.

Conclusion

In our patient, the use of rifapentine resulted in a recurrence of previously controlled PV and resistance to treatment. The patient’s disease was quickly controlled after discontinuation of rifampicin and with a short-term course of high-dose methylprednisolone and remained stable when the dosages of MMF and prednisone were reduced. This case serves as a reminder for clinicians to consider a drug interaction when treatment fails in order to avoid harming patients, especially those who have an autoimmune disease.

Case Report

A 60-year-old man presented with eroded areas in the mouth and blistering eruptions on the scalp, face, trunk, arms, and legs. He initially presented to an outside hospital 4 years prior and was treated with oral prednisone 50 mg daily, to which the eruptions responded rapidly; however, following a nearly 5-mg reduction of the dose per week by the patient and irregular oral administration, he experienced several episodes of recurrence, but he could not remember the exact dosage of prednisone he had taken during that period. Subsequently, he was admitted to our hospital because of large areas of erythema and erosions on the scalp, trunk, arms, and legs.

Since starting the prednisone regimen 4 years prior, the patient had experienced onset of hypertension, diabetes, glaucoma, cataracts, optic nerve atrophy, aseptic necrosis of the femoral head, and osteoporosis. Biopsy of a new skin lesion revealed suprabasal acantholysis (Figure 1). Direct immunofluorescence showed epidermal intercellular deposition of IgG and complement component 3. Laboratory testing showed a desmoglein 1 level of 142 U/mL (reference range, <14 U/mL) and desmoglein 3 level of 150 U/mL (reference range, <14 U/mL). Liver and kidney function; routine blood and urine tests; and antinuclear antibody, hepatitis B and C antibodies, syphilis, and human immunodeficiency virus antibody levels were normal. The biopsy and immunofluorescence results combined with clinical feature were consistent with a diagnosis of pemphigus vulgaris (PV).

The patient initially was started again prednisone 50 mg daily, to which the skin eruptions responded, and 2 weeks later, the disease was considered controlled. The prednisone dosage was tapered to 20 mg daily 3 months later with no new blister formation. However, 2 weeks later, the patient was diagnosed by a tuberculosis specialist with pulmonary tuberculosis, and a daily regimen of isoniazid, rifampicin, ethambutol, and levofloxacin was instituted.

Ten days after starting antituberculosis therapy, the patient developed new erythematous blisters that could not be controlled and self-adjusted the prednisone dose to 50 mg daily. Two months later, blister formation continued.

Six months after the initial presentation, the patient returned to our hospital because of uncontrollable rashes (Figure 2). On admission, he had a Pemphigus Disease Area Index (PDAI) score of 32 with disease involving 30% of the body surface area. Laboratory testing showed a desmoglein 1 level of 233 U/mL and desmoglein 3 level of 228 U/mL. A tuberculosis specialist from an outside hospital was consulted to evaluate the patient’s condition and assist in treatment. Based on findings from a pulmonary computed tomography scan, which showed the inflammation was considerably absorbed, treatment was adjusted to stop using ethambutol and levofloxacin and continue rifampicin and isoniazid. For the PV, prednisone was titrated upward to 75 mg daily, mycophenolate mofetil (MMF) 1 g twice daily was added, and IVIG 400 mg/kg daily was administered for 7 days. After 3 weeks, the rash still expanded.

In considering possible interactions between the drugs, we consulted the literature and found reports^1-3 that rifampicin accelerated glucocorticoid metabolism, of which the tuberculosis specialist that we consulted was not aware. Therefore, rifampicin was stopped, and the antituberculosis therapy was adjusted to levofloxacin and isoniazid. Meanwhile, the steroid was changed to methylprednisolone 120 mg daily for 3 days, then to 80 mg daily for 2 days.

After 5 days, the rash was controlled with no new development and the patient was discharged. He continued on prednisone 80 mg daily and MMF 1 g twice daily.

At 2-month follow-up, no new rash had developed. The patient had already self-discontinued the MMF for 1 month because it was difficult to obtain at local hospitals. The prednisone was reduced to 40 mg daily. Pulmonary computed tomography showed no signs of reactivation of tuberculosis.

Comment

The tuberculostatic compound rifampin induces expression of a number of drug metabolism-related genes associated with cytochromes (especially cytochrome P450 3A4), multidrug resistance (P-glycoprotein and multidrug resistance proteins 1 and 2), uridine 5’-diphospho-glucuronosyltransferase, monoamine oxidases, and glutathione S-transferases.

Drugs that depend on these enzymes for their metabolism are prone to drug interactions when co-administered with rifampicin.^4,5 It has been reported that rifampicin reduces the area under the concentration–time curve (AUC) of prednisolone by approximately 30% to 60%; some authors have suggested that, if rifampicin has to be prescribed, a 2- to 3-fold increase in the prednisolone dosage might be indicated.^1,4,6,7 Rifampicin also can influence immunosuppressive drugs in organ transplant recipients; for example, an 11-day course of rifampicin 600 mg daily was found to reduce the AUC of oral cyclosporine by approximately 70% and of intravenous cyclosporine by 28%.^4,8 Similarly, treatment with rifampicin 600 mg daily for 18 days reduced the AUC of oral tacrolimus by 68% and of intravenous tacrolimus by 35%.^4,9

Rifampicin causes a marked reduction in dose-corrected mycophenolic acid exposure when administered simultaneously with MMF through induction of glucuronidation activity and inhibition of enterohepatic recirculation.^5,10In in vitro studies, rifampin and other cytochrome P450 inducers have been identified as potentially useful for increasing the rate of cyclophosphamide and ifosfamide (an isomeric analogue of cyclophosphamide) 4-hydroxylation in the human liver in a manner that could have a favorable impact on the clinical pharmacokinetics of these anticancer prodrugs.¹¹ However, clinical analysis of 16 patients indicated that co-administration of ifosfamide with rifampin did not result in changes in the pharmacokinetics of the parent drug or its metabolites.¹²

The steroids and immunosuppressants mentioned above are widely used in the treatment of autoimmune diseases and drug hypersensitivity in dermatology. Drug interactions should be considered and drug concentrations closely monitored in cases of rifampin co-administration.

Conclusion

In our patient, the use of rifapentine resulted in a recurrence of previously controlled PV and resistance to treatment. The patient’s disease was quickly controlled after discontinuation of rifampicin and with a short-term course of high-dose methylprednisolone and remained stable when the dosages of MMF and prednisone were reduced. This case serves as a reminder for clinicians to consider a drug interaction when treatment fails in order to avoid harming patients, especially those who have an autoimmune disease.

Penile cancer is rare with a worldwide incidence of 0.8 cases per 100,000 men.¹ The most common type is squamous cell carcinoma (SCC) followed by soft tissue sarcoma (STS) and Kaposi sarcoma.² Leiomyosarcoma (LMS) is the second most common STS subtype at this location.³ Approximately 50 cases of penile LMS have been reported in the English literature, most as isolated case reports while Fetsch and colleagues reported 14 cases from a single institute.⁴ We present a case of penile LMS with a review of 31 cases. We also describe presentation, treatment options, and recurrence pattern of this rare malignancy.

Case Presentation

A patient aged 70 years presented to the urology clinic with 1-year history of a slowly enlarging penile mass associated with phimosis. He reported no pain, dysuria, or hesitancy. On examination a 2 × 2-cm smooth, mobile, nonulcerating mass was seen on the tip of his left glans without inguinal lymphadenopathy. He underwent circumcision and excision biopsy that revealed an encapsulated tan-white mass measuring 3 × 2.2 × 1.5 cm under the surface of the foreskin. Histology showed a spindle cell tumor with areas of increased cellularity, prominent atypia, and pleomorphism, focal necrosis, and scattered mitoses, including atypical forms. The tumor stained positive for smooth muscle actin and desmin. Ki-67 staining showed foci with a very high proliferation index (Figure). Resection margins were negative. Final Fédération Nationale des Centres de Lutte Contre Le Cancer score was grade 2 (differentiation, 1; mitotic, 3; necrosis, 1). Computed tomography of the chest, abdomen, and pelvis did not show evidence of metastasis. The tumor was classified as superficial, stage IIA (pT1cN0cM0). Local excision with negative margins was deemed adequate treatment.

Discussion

Penile LMS is rare and arises from smooth muscles, which in the penis can be from dartos fascia, erector pili in the skin covering the shaft, or from tunica media of the superficial vessels and cavernosa.⁵ It commonly presents as a nodule or ulcer that might be accompanied by paraphimosis, phimosis, erectile dysfunction, and lower urinary tract symptoms depending on the extent of local tissue involvement. In our review of 31 cases, the age at presentation ranged from 38 to 85 years, with 1 case report of LMS in a 6-year-old. The highest incidence was in the 6th decade. Tumor behavior can be indolent or aggressive. Most patients in our review had asymptomatic, slow-growing lesions for 6 to 24 months before presentation—including our patient—while others had an aggressive tumor with symptoms for a few weeks followed by rapid metastatic spread.^6,7

Histology and Staging

Diagnosis requires biopsy followed by histologic examination and immunohistochemistry of the lesion. Typically, LMS shows fascicles of spindle cells with varying degrees of nuclear atypia, pleomorphisms, and necrotic regions. Mitotic rate is variable and usually > 5 per high power field. Cells stain positive for smooth muscle actin, desmin, and h-caldesmon.⁸ TNM (tumor, nodes, metastasis) stage is determined by the American Joint Committee on Cancer guidelines for STS.

Pratt and colleagues were the first to categorize penile LMS as superficial or deep.⁹ The former includes all lesions superficial to tunica albuginea while the latter run deep to this layer. Anatomical distinction is an important factor in tumor behavior, treatment selection, and prognosis. In our review, we found 14 cases of superficial and 17 cases of deep LMS.

Treatment

There are no established guidelines on optimum treatment of penile LMS. However, we can extrapolate principles from current guidelines on penile cancer, cutaneous leiomyosarcoma, and limb sarcomas. At present, the first-line treatment for superficial penile LMS is wide local excision to achieve negative margins. Circumcision alone might be sufficient for tumors of the distal prepuce, as in our case.¹⁰ Radical resection generally is not required for these early-stage tumors. In our review, no patient in this category developed recurrence or metastasis regardless of initial surgery type (Table 1).^6,11,12

For deep lesions, partial—if functional penile stump and negative margins can be achieved—or total penectomy is required.¹⁰ In our review, more conservative approaches to deep tumors were associated with local recurrences.^7,13,14 Lymphatic spread is rare for LMS. Additionally, involvement of local lymph nodes usually coincides with distant spread. Inguinal lymph node dissection is not indicated if initial negative surgical margins are achieved.

For STS at other sites in the body, radiation therapy is recommended postoperatively for high-grade lesions, which can be extrapolated to penile LMS as well. The benefit of preoperative radiation therapy is less certain. In limb sarcomas, radiation is associated with better local control for large-sized tumors and is used for patients with initial unresectable tumors.¹⁵ Similar recommendation could be extended to penile LMS with local spread to inguinal lymph nodes, scrotum, or abdominal wall. In our review, postoperative radiation therapy was used in 3 patients with deep tumors.^16-18 Of these, short-term relapse occurred in 1 patient.

Metastatic Disease

LMS tends to metastasize hematogenously and lymphatic spread is uncommon. In our review, 7 patients developed metastasis. These patients had deep tumors at presentation with tumor size > 3 cm. Five of 7 patients had involvement of corpora cavernosa at presentation. The lung was the most common site of metastasis, followed by local extension to lower abdominal wall and scrotum. Of the 7 patients, 3 were treated with initial limited excision or partial penectomy and then experienced local recurrence or distant metastasis.^7,13,14,23 This supports the use of radical surgery in large, deep tumors. In an additional 4 cases, metastasis occurred despite initial treatment with total penectomy and use of adjuvant chemoradiation therapy.

In most cases penile LMS is a de novo tumor, however, on occasion it could be accompanied by another epithelial malignancy. Similarly, penile LMS might be a site of recurrence for a primary LMS at another site, as seen in 3 of the reviewed cases. In the first, a patient presented with a nodule on the glans suspicious for SCC, second with synchronous SCC and LMS, and a third case where a patient presented with penile LMS 9 years after being treated for similar tumor in the epididymis.^17,24,25

Prognosis

Penile LMS prognosis is difficult to ascertain because reported cases are rare. In our review, the longest documented disease-free survival was 3.5 years for a patient with superficial LMS treated with local excision.²⁶ In cases of distant metastasis, average survival was 4.6 months, while the longest survival since initial presentation and last documented local recurrence was 16 years.¹⁴ Five-year survival has not been reported.

Conclusions

LMS of the penis is a rare and potentially aggressive malignancy. It can be classified as superficial or deep based on tumor relation to the tunica albuginea. Deep tumors, those > 3 cm, high-grade lesions, and tumors with involvement of corpora cavernosa, tend to spread locally, metastasize to distant areas, and require more radical surgery with or without postoperative radiation therapy. In comparison, superficial lesions can be treated with local excision only. Both superficial and deep tumors require close follow-up.

Penile cancer is rare with a worldwide incidence of 0.8 cases per 100,000 men.¹ The most common type is squamous cell carcinoma (SCC) followed by soft tissue sarcoma (STS) and Kaposi sarcoma.² Leiomyosarcoma (LMS) is the second most common STS subtype at this location.³ Approximately 50 cases of penile LMS have been reported in the English literature, most as isolated case reports while Fetsch and colleagues reported 14 cases from a single institute.⁴ We present a case of penile LMS with a review of 31 cases. We also describe presentation, treatment options, and recurrence pattern of this rare malignancy.

Case Presentation

A patient aged 70 years presented to the urology clinic with 1-year history of a slowly enlarging penile mass associated with phimosis. He reported no pain, dysuria, or hesitancy. On examination a 2 × 2-cm smooth, mobile, nonulcerating mass was seen on the tip of his left glans without inguinal lymphadenopathy. He underwent circumcision and excision biopsy that revealed an encapsulated tan-white mass measuring 3 × 2.2 × 1.5 cm under the surface of the foreskin. Histology showed a spindle cell tumor with areas of increased cellularity, prominent atypia, and pleomorphism, focal necrosis, and scattered mitoses, including atypical forms. The tumor stained positive for smooth muscle actin and desmin. Ki-67 staining showed foci with a very high proliferation index (Figure). Resection margins were negative. Final Fédération Nationale des Centres de Lutte Contre Le Cancer score was grade 2 (differentiation, 1; mitotic, 3; necrosis, 1). Computed tomography of the chest, abdomen, and pelvis did not show evidence of metastasis. The tumor was classified as superficial, stage IIA (pT1cN0cM0). Local excision with negative margins was deemed adequate treatment.

Discussion

Penile LMS is rare and arises from smooth muscles, which in the penis can be from dartos fascia, erector pili in the skin covering the shaft, or from tunica media of the superficial vessels and cavernosa.⁵ It commonly presents as a nodule or ulcer that might be accompanied by paraphimosis, phimosis, erectile dysfunction, and lower urinary tract symptoms depending on the extent of local tissue involvement. In our review of 31 cases, the age at presentation ranged from 38 to 85 years, with 1 case report of LMS in a 6-year-old. The highest incidence was in the 6th decade. Tumor behavior can be indolent or aggressive. Most patients in our review had asymptomatic, slow-growing lesions for 6 to 24 months before presentation—including our patient—while others had an aggressive tumor with symptoms for a few weeks followed by rapid metastatic spread.^6,7

Histology and Staging

Diagnosis requires biopsy followed by histologic examination and immunohistochemistry of the lesion. Typically, LMS shows fascicles of spindle cells with varying degrees of nuclear atypia, pleomorphisms, and necrotic regions. Mitotic rate is variable and usually > 5 per high power field. Cells stain positive for smooth muscle actin, desmin, and h-caldesmon.⁸ TNM (tumor, nodes, metastasis) stage is determined by the American Joint Committee on Cancer guidelines for STS.

Pratt and colleagues were the first to categorize penile LMS as superficial or deep.⁹ The former includes all lesions superficial to tunica albuginea while the latter run deep to this layer. Anatomical distinction is an important factor in tumor behavior, treatment selection, and prognosis. In our review, we found 14 cases of superficial and 17 cases of deep LMS.

Treatment

There are no established guidelines on optimum treatment of penile LMS. However, we can extrapolate principles from current guidelines on penile cancer, cutaneous leiomyosarcoma, and limb sarcomas. At present, the first-line treatment for superficial penile LMS is wide local excision to achieve negative margins. Circumcision alone might be sufficient for tumors of the distal prepuce, as in our case.¹⁰ Radical resection generally is not required for these early-stage tumors. In our review, no patient in this category developed recurrence or metastasis regardless of initial surgery type (Table 1).^6,11,12

For deep lesions, partial—if functional penile stump and negative margins can be achieved—or total penectomy is required.¹⁰ In our review, more conservative approaches to deep tumors were associated with local recurrences.^7,13,14 Lymphatic spread is rare for LMS. Additionally, involvement of local lymph nodes usually coincides with distant spread. Inguinal lymph node dissection is not indicated if initial negative surgical margins are achieved.

For STS at other sites in the body, radiation therapy is recommended postoperatively for high-grade lesions, which can be extrapolated to penile LMS as well. The benefit of preoperative radiation therapy is less certain. In limb sarcomas, radiation is associated with better local control for large-sized tumors and is used for patients with initial unresectable tumors.¹⁵ Similar recommendation could be extended to penile LMS with local spread to inguinal lymph nodes, scrotum, or abdominal wall. In our review, postoperative radiation therapy was used in 3 patients with deep tumors.^16-18 Of these, short-term relapse occurred in 1 patient.

Metastatic Disease

LMS tends to metastasize hematogenously and lymphatic spread is uncommon. In our review, 7 patients developed metastasis. These patients had deep tumors at presentation with tumor size > 3 cm. Five of 7 patients had involvement of corpora cavernosa at presentation. The lung was the most common site of metastasis, followed by local extension to lower abdominal wall and scrotum. Of the 7 patients, 3 were treated with initial limited excision or partial penectomy and then experienced local recurrence or distant metastasis.^7,13,14,23 This supports the use of radical surgery in large, deep tumors. In an additional 4 cases, metastasis occurred despite initial treatment with total penectomy and use of adjuvant chemoradiation therapy.

In most cases penile LMS is a de novo tumor, however, on occasion it could be accompanied by another epithelial malignancy. Similarly, penile LMS might be a site of recurrence for a primary LMS at another site, as seen in 3 of the reviewed cases. In the first, a patient presented with a nodule on the glans suspicious for SCC, second with synchronous SCC and LMS, and a third case where a patient presented with penile LMS 9 years after being treated for similar tumor in the epididymis.^17,24,25

Prognosis

Penile LMS prognosis is difficult to ascertain because reported cases are rare. In our review, the longest documented disease-free survival was 3.5 years for a patient with superficial LMS treated with local excision.²⁶ In cases of distant metastasis, average survival was 4.6 months, while the longest survival since initial presentation and last documented local recurrence was 16 years.¹⁴ Five-year survival has not been reported.

Conclusions

LMS of the penis is a rare and potentially aggressive malignancy. It can be classified as superficial or deep based on tumor relation to the tunica albuginea. Deep tumors, those > 3 cm, high-grade lesions, and tumors with involvement of corpora cavernosa, tend to spread locally, metastasize to distant areas, and require more radical surgery with or without postoperative radiation therapy. In comparison, superficial lesions can be treated with local excision only. Both superficial and deep tumors require close follow-up.

Penile cancer is rare with a worldwide incidence of 0.8 cases per 100,000 men.¹ The most common type is squamous cell carcinoma (SCC) followed by soft tissue sarcoma (STS) and Kaposi sarcoma.² Leiomyosarcoma (LMS) is the second most common STS subtype at this location.³ Approximately 50 cases of penile LMS have been reported in the English literature, most as isolated case reports while Fetsch and colleagues reported 14 cases from a single institute.⁴ We present a case of penile LMS with a review of 31 cases. We also describe presentation, treatment options, and recurrence pattern of this rare malignancy.

Case Presentation

A patient aged 70 years presented to the urology clinic with 1-year history of a slowly enlarging penile mass associated with phimosis. He reported no pain, dysuria, or hesitancy. On examination a 2 × 2-cm smooth, mobile, nonulcerating mass was seen on the tip of his left glans without inguinal lymphadenopathy. He underwent circumcision and excision biopsy that revealed an encapsulated tan-white mass measuring 3 × 2.2 × 1.5 cm under the surface of the foreskin. Histology showed a spindle cell tumor with areas of increased cellularity, prominent atypia, and pleomorphism, focal necrosis, and scattered mitoses, including atypical forms. The tumor stained positive for smooth muscle actin and desmin. Ki-67 staining showed foci with a very high proliferation index (Figure). Resection margins were negative. Final Fédération Nationale des Centres de Lutte Contre Le Cancer score was grade 2 (differentiation, 1; mitotic, 3; necrosis, 1). Computed tomography of the chest, abdomen, and pelvis did not show evidence of metastasis. The tumor was classified as superficial, stage IIA (pT1cN0cM0). Local excision with negative margins was deemed adequate treatment.

Discussion

Penile LMS is rare and arises from smooth muscles, which in the penis can be from dartos fascia, erector pili in the skin covering the shaft, or from tunica media of the superficial vessels and cavernosa.⁵ It commonly presents as a nodule or ulcer that might be accompanied by paraphimosis, phimosis, erectile dysfunction, and lower urinary tract symptoms depending on the extent of local tissue involvement. In our review of 31 cases, the age at presentation ranged from 38 to 85 years, with 1 case report of LMS in a 6-year-old. The highest incidence was in the 6th decade. Tumor behavior can be indolent or aggressive. Most patients in our review had asymptomatic, slow-growing lesions for 6 to 24 months before presentation—including our patient—while others had an aggressive tumor with symptoms for a few weeks followed by rapid metastatic spread.^6,7

Histology and Staging

Diagnosis requires biopsy followed by histologic examination and immunohistochemistry of the lesion. Typically, LMS shows fascicles of spindle cells with varying degrees of nuclear atypia, pleomorphisms, and necrotic regions. Mitotic rate is variable and usually > 5 per high power field. Cells stain positive for smooth muscle actin, desmin, and h-caldesmon.⁸ TNM (tumor, nodes, metastasis) stage is determined by the American Joint Committee on Cancer guidelines for STS.

Pratt and colleagues were the first to categorize penile LMS as superficial or deep.⁹ The former includes all lesions superficial to tunica albuginea while the latter run deep to this layer. Anatomical distinction is an important factor in tumor behavior, treatment selection, and prognosis. In our review, we found 14 cases of superficial and 17 cases of deep LMS.

Treatment

There are no established guidelines on optimum treatment of penile LMS. However, we can extrapolate principles from current guidelines on penile cancer, cutaneous leiomyosarcoma, and limb sarcomas. At present, the first-line treatment for superficial penile LMS is wide local excision to achieve negative margins. Circumcision alone might be sufficient for tumors of the distal prepuce, as in our case.¹⁰ Radical resection generally is not required for these early-stage tumors. In our review, no patient in this category developed recurrence or metastasis regardless of initial surgery type (Table 1).^6,11,12

For deep lesions, partial—if functional penile stump and negative margins can be achieved—or total penectomy is required.¹⁰ In our review, more conservative approaches to deep tumors were associated with local recurrences.^7,13,14 Lymphatic spread is rare for LMS. Additionally, involvement of local lymph nodes usually coincides with distant spread. Inguinal lymph node dissection is not indicated if initial negative surgical margins are achieved.

For STS at other sites in the body, radiation therapy is recommended postoperatively for high-grade lesions, which can be extrapolated to penile LMS as well. The benefit of preoperative radiation therapy is less certain. In limb sarcomas, radiation is associated with better local control for large-sized tumors and is used for patients with initial unresectable tumors.¹⁵ Similar recommendation could be extended to penile LMS with local spread to inguinal lymph nodes, scrotum, or abdominal wall. In our review, postoperative radiation therapy was used in 3 patients with deep tumors.^16-18 Of these, short-term relapse occurred in 1 patient.

Metastatic Disease

LMS tends to metastasize hematogenously and lymphatic spread is uncommon. In our review, 7 patients developed metastasis. These patients had deep tumors at presentation with tumor size > 3 cm. Five of 7 patients had involvement of corpora cavernosa at presentation. The lung was the most common site of metastasis, followed by local extension to lower abdominal wall and scrotum. Of the 7 patients, 3 were treated with initial limited excision or partial penectomy and then experienced local recurrence or distant metastasis.^7,13,14,23 This supports the use of radical surgery in large, deep tumors. In an additional 4 cases, metastasis occurred despite initial treatment with total penectomy and use of adjuvant chemoradiation therapy.

In most cases penile LMS is a de novo tumor, however, on occasion it could be accompanied by another epithelial malignancy. Similarly, penile LMS might be a site of recurrence for a primary LMS at another site, as seen in 3 of the reviewed cases. In the first, a patient presented with a nodule on the glans suspicious for SCC, second with synchronous SCC and LMS, and a third case where a patient presented with penile LMS 9 years after being treated for similar tumor in the epididymis.^17,24,25

Prognosis

Penile LMS prognosis is difficult to ascertain because reported cases are rare. In our review, the longest documented disease-free survival was 3.5 years for a patient with superficial LMS treated with local excision.²⁶ In cases of distant metastasis, average survival was 4.6 months, while the longest survival since initial presentation and last documented local recurrence was 16 years.¹⁴ Five-year survival has not been reported.

Conclusions

LMS of the penis is a rare and potentially aggressive malignancy. It can be classified as superficial or deep based on tumor relation to the tunica albuginea. Deep tumors, those > 3 cm, high-grade lesions, and tumors with involvement of corpora cavernosa, tend to spread locally, metastasize to distant areas, and require more radical surgery with or without postoperative radiation therapy. In comparison, superficial lesions can be treated with local excision only. Both superficial and deep tumors require close follow-up.

Appendiceal mucinous neoplasms (AMNs) are rare tumors of the appendix that can be asymptomatic or present with acute right lower quadrant (RLQ) pain mimicking appendicitis. Due to their potential to cause either no symptoms or nonspecific symptoms, such as abdominal pain, nausea, or vomiting, AMNs are often found incidentally during appendectomies or, even more rarely, colonoscopies. Most AMNs grow slowly and have little metastatic potential. However, due to potential complications, such as bowel obstruction and rupture, timely detection and removal of AMN is essential. We describe the case of a patient who appeared to have acute appendicitis complicated by rupture on imaging who was found instead to have a perforated low-grade AMN during surgery.

Case Presentation

A male patient aged 72 years with a history of type 2 diabetes mellitus, hypertension, and aortic stenosis, but no prior abdominal surgery, presented with a chief concern of generalized weakness. As part of the workup for his weakness, a computed tomography (CT) scan of the abdomen was performed which showed an RLQ phlegmon and mild fat stranding in the area. Imaging also revealed an asymptomatic gallstone measuring 1.5 cm with no evidence of cholecystitis. The patient had no fever and reported no abdominal pain, nausea, vomiting, or change in bowel habits. On physical examination, the patient’s abdomen was soft, nontender, and nondistended with normoactive bowel sounds and no rebound or guarding.

To manage the appendicitis, the patient started a 2-week course of amoxicillin clavulanate 875 mg twice daily and was instructed to schedule an interval appendectomy in the coming months. Four days later, during a follow-up with his primary care physician, he was found to be asymptomatic. However, at this visit his stool was found to be positive for occult blood. Given this finding and the lack of a previous colonoscopy, the patient underwent a colonoscopy, which revealed bulging at the appendiceal orifice, consistent with an inverted appendix. Portions of the appendix were biopsied (Figure 1). Histologic analysis of the appendiceal biopsies revealed no dysplasia or malignancy. The colonoscopy also revealed an 8-mm sessile polyp in the ascending colon which was resected, and histologic analysis of this polyp revealed a low-grade tubular adenoma. Additionally, a large angiodysplastic lesion was found in the ascending colon as well as external and medium-sized internal hemorrhoids.

Histologic specimens of the appendix were notable for evidence of perforation and neoplasia leading to a diagnosis of low-grade AMN. The presence of atypical mucinous epithelial cells on the serosal surface of the appendix, confirmed with a positive pancytokeratin stain, provided histologic evidence of appendiceal perforation (Figure 3). The presence of nuclear atypia demonstrated that the appendix was involved by a neoplastic process. Additionally, attenuation of the normal appendiceal epithelium, evidence of a chronic process, further helped to differentiate the AMN from complicated appendicitis. The presence of mucin involving the serosa of the appendix led to the classification of this patient’s neoplasm as grade pT4a. Of note, histologic examination demonstrated that the surgical margins contained tumor cells.

Discussion

AMNs are rare tumors with an annual age-adjusted incidence of approximately 0.12 per 1,000,000 people.¹ These neoplasms can present as acute or chronic abdominal pain, gastrointestinal bleeding, intestinal obstruction, or acute abdomen.^2-4 Most AMNs, however, are asymptomatic and are usually found incidentally during appendectomies for appendicitis, and can even be found during colonoscopies,such as in this case.^5,6

Low-grade AMNs are distinguished from appendiceal mucinous adenocarcinomas by their lack of wall invasion.⁷ Additionally, low-grade AMNs have a very good prognosis as even neoplasms that have spread outside of the appendix have a 5-year overall survival rate of 79 to 86%.⁸ These low-grade neoplasms also have extremely low rates of recurrence after resection.⁹ In contrast, appendiceal mucinous adenocarcinomas have a much worse prognosis with a 5-year overall survival rate of 53.6%.¹⁰

Conclusions

AMNs can present with nonspecific symptoms or can be completely asymptomatic and are often found incidentally during colonoscopies or appendectomies for acute appendicitis. While it is true that AMNs have low metastatic potential and grow slowly, AMNs can rupture leading to pseudomyxoma peritonei or even cause bowel obstruction warranting timely identification and removal of these neoplasms. Laparoscopic evaluation in cases of ruptured appendices is critical not only for treatment, but also for determining the presence of a potential underlying appendiceal malignancy. Although AMNs are a rare pathology, physicians should still consider the possibility of these neoplasms even when imaging findings suggest appendicitis. Having AMNs as part of the differential diagnosis is especially necessary in cases, such as this one, in which the patient has appendiceal inversion, is aged > 50 years, and has concurrent colorectal neoplasms.

Appendiceal mucinous neoplasms (AMNs) are rare tumors of the appendix that can be asymptomatic or present with acute right lower quadrant (RLQ) pain mimicking appendicitis. Due to their potential to cause either no symptoms or nonspecific symptoms, such as abdominal pain, nausea, or vomiting, AMNs are often found incidentally during appendectomies or, even more rarely, colonoscopies. Most AMNs grow slowly and have little metastatic potential. However, due to potential complications, such as bowel obstruction and rupture, timely detection and removal of AMN is essential. We describe the case of a patient who appeared to have acute appendicitis complicated by rupture on imaging who was found instead to have a perforated low-grade AMN during surgery.

Case Presentation

A male patient aged 72 years with a history of type 2 diabetes mellitus, hypertension, and aortic stenosis, but no prior abdominal surgery, presented with a chief concern of generalized weakness. As part of the workup for his weakness, a computed tomography (CT) scan of the abdomen was performed which showed an RLQ phlegmon and mild fat stranding in the area. Imaging also revealed an asymptomatic gallstone measuring 1.5 cm with no evidence of cholecystitis. The patient had no fever and reported no abdominal pain, nausea, vomiting, or change in bowel habits. On physical examination, the patient’s abdomen was soft, nontender, and nondistended with normoactive bowel sounds and no rebound or guarding.

To manage the appendicitis, the patient started a 2-week course of amoxicillin clavulanate 875 mg twice daily and was instructed to schedule an interval appendectomy in the coming months. Four days later, during a follow-up with his primary care physician, he was found to be asymptomatic. However, at this visit his stool was found to be positive for occult blood. Given this finding and the lack of a previous colonoscopy, the patient underwent a colonoscopy, which revealed bulging at the appendiceal orifice, consistent with an inverted appendix. Portions of the appendix were biopsied (Figure 1). Histologic analysis of the appendiceal biopsies revealed no dysplasia or malignancy. The colonoscopy also revealed an 8-mm sessile polyp in the ascending colon which was resected, and histologic analysis of this polyp revealed a low-grade tubular adenoma. Additionally, a large angiodysplastic lesion was found in the ascending colon as well as external and medium-sized internal hemorrhoids.

Histologic specimens of the appendix were notable for evidence of perforation and neoplasia leading to a diagnosis of low-grade AMN. The presence of atypical mucinous epithelial cells on the serosal surface of the appendix, confirmed with a positive pancytokeratin stain, provided histologic evidence of appendiceal perforation (Figure 3). The presence of nuclear atypia demonstrated that the appendix was involved by a neoplastic process. Additionally, attenuation of the normal appendiceal epithelium, evidence of a chronic process, further helped to differentiate the AMN from complicated appendicitis. The presence of mucin involving the serosa of the appendix led to the classification of this patient’s neoplasm as grade pT4a. Of note, histologic examination demonstrated that the surgical margins contained tumor cells.

Discussion

AMNs are rare tumors with an annual age-adjusted incidence of approximately 0.12 per 1,000,000 people.¹ These neoplasms can present as acute or chronic abdominal pain, gastrointestinal bleeding, intestinal obstruction, or acute abdomen.^2-4 Most AMNs, however, are asymptomatic and are usually found incidentally during appendectomies for appendicitis, and can even be found during colonoscopies,such as in this case.^5,6

Low-grade AMNs are distinguished from appendiceal mucinous adenocarcinomas by their lack of wall invasion.⁷ Additionally, low-grade AMNs have a very good prognosis as even neoplasms that have spread outside of the appendix have a 5-year overall survival rate of 79 to 86%.⁸ These low-grade neoplasms also have extremely low rates of recurrence after resection.⁹ In contrast, appendiceal mucinous adenocarcinomas have a much worse prognosis with a 5-year overall survival rate of 53.6%.¹⁰

Conclusions

AMNs can present with nonspecific symptoms or can be completely asymptomatic and are often found incidentally during colonoscopies or appendectomies for acute appendicitis. While it is true that AMNs have low metastatic potential and grow slowly, AMNs can rupture leading to pseudomyxoma peritonei or even cause bowel obstruction warranting timely identification and removal of these neoplasms. Laparoscopic evaluation in cases of ruptured appendices is critical not only for treatment, but also for determining the presence of a potential underlying appendiceal malignancy. Although AMNs are a rare pathology, physicians should still consider the possibility of these neoplasms even when imaging findings suggest appendicitis. Having AMNs as part of the differential diagnosis is especially necessary in cases, such as this one, in which the patient has appendiceal inversion, is aged > 50 years, and has concurrent colorectal neoplasms.

Appendiceal mucinous neoplasms (AMNs) are rare tumors of the appendix that can be asymptomatic or present with acute right lower quadrant (RLQ) pain mimicking appendicitis. Due to their potential to cause either no symptoms or nonspecific symptoms, such as abdominal pain, nausea, or vomiting, AMNs are often found incidentally during appendectomies or, even more rarely, colonoscopies. Most AMNs grow slowly and have little metastatic potential. However, due to potential complications, such as bowel obstruction and rupture, timely detection and removal of AMN is essential. We describe the case of a patient who appeared to have acute appendicitis complicated by rupture on imaging who was found instead to have a perforated low-grade AMN during surgery.

Case Presentation

A male patient aged 72 years with a history of type 2 diabetes mellitus, hypertension, and aortic stenosis, but no prior abdominal surgery, presented with a chief concern of generalized weakness. As part of the workup for his weakness, a computed tomography (CT) scan of the abdomen was performed which showed an RLQ phlegmon and mild fat stranding in the area. Imaging also revealed an asymptomatic gallstone measuring 1.5 cm with no evidence of cholecystitis. The patient had no fever and reported no abdominal pain, nausea, vomiting, or change in bowel habits. On physical examination, the patient’s abdomen was soft, nontender, and nondistended with normoactive bowel sounds and no rebound or guarding.

To manage the appendicitis, the patient started a 2-week course of amoxicillin clavulanate 875 mg twice daily and was instructed to schedule an interval appendectomy in the coming months. Four days later, during a follow-up with his primary care physician, he was found to be asymptomatic. However, at this visit his stool was found to be positive for occult blood. Given this finding and the lack of a previous colonoscopy, the patient underwent a colonoscopy, which revealed bulging at the appendiceal orifice, consistent with an inverted appendix. Portions of the appendix were biopsied (Figure 1). Histologic analysis of the appendiceal biopsies revealed no dysplasia or malignancy. The colonoscopy also revealed an 8-mm sessile polyp in the ascending colon which was resected, and histologic analysis of this polyp revealed a low-grade tubular adenoma. Additionally, a large angiodysplastic lesion was found in the ascending colon as well as external and medium-sized internal hemorrhoids.

Histologic specimens of the appendix were notable for evidence of perforation and neoplasia leading to a diagnosis of low-grade AMN. The presence of atypical mucinous epithelial cells on the serosal surface of the appendix, confirmed with a positive pancytokeratin stain, provided histologic evidence of appendiceal perforation (Figure 3). The presence of nuclear atypia demonstrated that the appendix was involved by a neoplastic process. Additionally, attenuation of the normal appendiceal epithelium, evidence of a chronic process, further helped to differentiate the AMN from complicated appendicitis. The presence of mucin involving the serosa of the appendix led to the classification of this patient’s neoplasm as grade pT4a. Of note, histologic examination demonstrated that the surgical margins contained tumor cells.

Discussion

AMNs are rare tumors with an annual age-adjusted incidence of approximately 0.12 per 1,000,000 people.¹ These neoplasms can present as acute or chronic abdominal pain, gastrointestinal bleeding, intestinal obstruction, or acute abdomen.^2-4 Most AMNs, however, are asymptomatic and are usually found incidentally during appendectomies for appendicitis, and can even be found during colonoscopies,such as in this case.^5,6

Low-grade AMNs are distinguished from appendiceal mucinous adenocarcinomas by their lack of wall invasion.⁷ Additionally, low-grade AMNs have a very good prognosis as even neoplasms that have spread outside of the appendix have a 5-year overall survival rate of 79 to 86%.⁸ These low-grade neoplasms also have extremely low rates of recurrence after resection.⁹ In contrast, appendiceal mucinous adenocarcinomas have a much worse prognosis with a 5-year overall survival rate of 53.6%.¹⁰

Conclusions

AMNs can present with nonspecific symptoms or can be completely asymptomatic and are often found incidentally during colonoscopies or appendectomies for acute appendicitis. While it is true that AMNs have low metastatic potential and grow slowly, AMNs can rupture leading to pseudomyxoma peritonei or even cause bowel obstruction warranting timely identification and removal of these neoplasms. Laparoscopic evaluation in cases of ruptured appendices is critical not only for treatment, but also for determining the presence of a potential underlying appendiceal malignancy. Although AMNs are a rare pathology, physicians should still consider the possibility of these neoplasms even when imaging findings suggest appendicitis. Having AMNs as part of the differential diagnosis is especially necessary in cases, such as this one, in which the patient has appendiceal inversion, is aged > 50 years, and has concurrent colorectal neoplasms.

Caregiving for a person with dementia in the community can be extremely difficult work. Much of this work falls on unpaid or informal caregivers. Sixty-three percent of older adults with dementia depend completely on unpaid caregivers, and an additional 26% receive some combination of paid and unpaid support, together comprising nearly 90% of the more than 3 million older Americans with dementia.¹ In-home care is preferable for these patients. For veterans, the Caregiver Support Program (CSP) is the only US Department of Veterans Affairs (VA) program that exclusively supports caregivers. Although the CSP is not a nursing home diversion or cost savings program, successfully enabling at-home living in lieu of facility living also has the potential to reduce overall cost of care, and most importantly, to enable veterans who desire it to age at home.^2,3

The CSP has 2 unique programs for caregivers of eligible veterans. The Program of General Caregiver Support Services (PGCSS) provides resources, education, and support to caregivers of all veterans enrolled in the Veterans Health Administration (VHA). The Program of Comprehensive Assistance for Family Caregivers (PCAFC) provides education and training, access to health care insurance if eligible, mental health counseling, access to a monthly caregiver stipend, enhanced respite care, wellness contacts, and travel compensation for VA health care appointments (Table 1).^4,5

Patients undergo a rigorous assessment and highly specialized and individualized clinical decision-making process to confirm the service is appropriate for the patient. PCAFC was restructured and expanded on October 1, 2020.⁶ Currently, veterans who incurred or aggravated a serious injury (defined by a single or combined service-connection rating of ≥ 70%) in active military service before May 8, 1975, or after September 10, 2001, are eligible for PCAFC.⁶ Most notably, these changes opened eligibility in the PCAFC to caregivers of veterans from the Vietnam, Korean, and World War II eras of conflict and veterans with dependence in activities of daily living (ADL) due to a wider variety of illnesses, including dementia.⁶ The PCAFC is set to further expand to caregivers of otherwise eligible veterans of all eras of service on October 1, 2022, 2 years after the initial expansion, as laid out in the 2018 VA MISSION Act.⁶ Additional information on the history of the PGCSS and PCAFC and eligibility criteria for veterans and their family caregivers can be found in Tables 2 and 3.

Case Presentation

A male combat veteran presented to his primary care practitioner (PCP) with concerns of several years of progressive changes in gait, forgetfulness, and a gradual decline in the ability to live independently without assistance. At that time, his medical history was notable for PTSD (50% service connection), which had been diagnosed over a decade prior (but for which the veteran had refused medication or therapy on multiple occasions, stating he preferred to “breathe through” his intrusive symptom flare-ups), localized prostate cancer with a radical prostatectomy (100% service connection), multiple kidney stones with persistent left ureteral inflammation, and arteriosclerotic heart disease (10% service connection). A Saint Louis University Mental Status Exam (SLUMS) performed by the PCP was notable for a score of 9/30, in the dementia range. A computed tomography of the brain demonstrated scattered foci of hypoattenuation attributable to normal aging without any other pathology noted.

The veteran was referred to the Cognitive Care clinic, a local longitudinal multidisciplinary dementia care clinic, along with his spouse/caregiver. Cognitive testing was performed by a licensed clinical psychologist in the clinic and was notable for a Mini-Mental State Exam (MMSE) score of 18/30, also in the dementia range, and a more robust neuropsychiatric battery demonstrated borderline intact memory and language function but impairments in executive function and visuospatial skills. The patient’s clinical history included functional loss over time, with total dependence in instrumental activities of daily living (IADL), or tasks necessary to be fully independent or manage a household, including inability to manage finances, and some need for assistance in ADL, or personal care tasks such as dressing or grooming, including bathing. Physical examination was notable for bradykinesia, a shuffling gait, and rare episodes of speaking to someone who was not in the room, thought to be due to mild nondistressing hallucinations.

A diagnosis of LBD was made. At time of diagnosis, the patient met criteria for probable dementia with Lewy bodies, with 2 of 4 core clinical features (hallucinations and Parkinsonism), and multiple supportive features (gait disturbance, sensory disturbance, and altered mood).^10,11 The veteran continued to develop more supportive features for diagnosis of LBD over time, including evidence of autonomic instability.

The veteran and his caregiver were educated on his diagnosis, and longitudinal support was offered. The veteran was no longer driving, and due to the severity of his symptoms, the importance of driving cessation was reinforced by the care team. Over the course of the next year, his illness progressed, with more frequent behaviors and psychological symptoms of dementia (BPSD). He began to exhibit nighttime wandering throughout the house and became more anxious and restless during the day. He lost the ability to make his own health care decisions, and his spouse became his activated health care power of attorney (HCPOA). His BPSD became more disruptive to daily life and was accompanied by a change in the character of his hallucinations, with prior nondistressing visions of other people being replaced with visions of war, burning bodies, and violence, much of it related to combat experiences in Vietnam. The BPSD began to include hiding behind furniture, running out of the house, and shouting and crying in response to hallucinations. At times, his BPSD became violent, lashing out in fear against his hallucinations and caregiver.

The veteran’s change in BPSD was concerning for a new baseline, rather than being clearly related to an underlying unmet physical need, such as pain, hunger, sleep, or discomfort. Multiple hospital admissions during that year involved IV hydration and treatment for urinary tract infections (UTI) for several days of inpatient stay at a time, but these behaviors persisted despite infection treatment and hydration. The patient’s changes in BPSD were thought to be secondary to uncovered and intensified PTSD in the setting of progressive dementia. Due to the clear danger the patient posed to himself and others, potential treatment options for these PTSD-related hallucinations were discussed with his caregiver. The caregiver shared that the patient’s BPSD and hallucinations were so distressing that “he would never want to live like this,” and that things had progressed to the point that “he has no quality of life.”

Oral aripiprazole 2 mg twice daily was prescribed after the risks of infection, cardiac complications, and exacerbation of movement disorder symptoms, such as increased stiffness and falls, were discussed with the caregiver. The caregiver was employed and relied on continued employment for income, but the patient could not be safely left alone. As the patient and his caregiver had reached a crisis point and living at home no longer appeared to be safe, the patient was referred to a VA-contracted skilled nursing facility (SNF) for long-term care. The patient’s caregiver was also referred to CSP for support during this transition. Due to the patient’s level of service connection and personal needs, as well as the patient and caregiver’s preference for the veteran to remain in his home, they were evaluated for the PCAFC for enhanced support to enable home as an alternative to facility living, should the patient respond to the antipsychotic therapy sufficiently, which was evaluated on a regular basis.

After several months, the patient’s BPSD had improved significantly, and he was no longer experiencing distressing hallucinations. However, his mobility also declined, and he became fully dependent in most ADL, including transfers, hygiene, and toileting. Due to the COVID-19 pandemic, visitation was limited, which was difficult for both the patient and his caregiver. The veteran and caregiver were approved for PCAFC due to the veteran’s combination of service-connected illnesses > 70%, dependence for most ADLs, and need for continuous supervision. A transfer home from the SNF was arranged.

The PCAFC allowed the veteran’s caregiver and family members to provide in-home full-time caregiving, as an alternative to facility placement. The caregiver received a variety of support, including access to peer support, instruction on ways to assist in his toileting, hygiene, and transfers, and a caregiving stipend. In addition to offsetting lost wages, the stipend also helped offset the cost of care supplies which were not provided or were not readily available from the VA, which at the time included the patient’s preferred nutritional supplement and some supplies for personal care.

The veteran’s care needs continued to escalate. A fall at home resulted in a hip fracture, which was treated with surgical pinning. Postfracture physical therapy in a facility was considered, but ultimately was provided at home. The patient also experienced multiple UTIs and resulting delirium, with accompanying agitation and hallucinations. These episodes improved with IV antibiotics and hydration during short hospital stays. Ultimately, a computed tomography demonstrated overflow incontinence likely related to urologic damage from prior kidney stones and stent placement was recommended.

Visiting skilled nurses for the patient’s area were difficult to coordinate but were eventually arranged. The patient continued residing in his home with the support of his caregiver, the PCAFC, and the local VA medical center geriatric and transitional care services. The patient was also referred to the palliative care outpatient specialty clinic for discussion of goals of care and assistance with advance care planning as his illness progressed. Mental health and geriatric psychiatry consult teams were considered for this case but not utilized.

Discussion

Older adult Americans are at high risk of poor financial wellbeing, with nearly one quarter of Americans aged > 62 years experiencing financial insecurity.¹² Even in this case with health care provided by the VA, successful in-home care was challenging and required a dedicated live-in caregiver, care coordination resources, and financial support. As part of its mission of caring for veterans, the VA has instituted CSP, whose mission is to promote the health and well-being of family caregivers through education, support, and services.

PCAFC offers enhanced clinical support for caregivers of eligible veterans who are seriously injured. This includes resources, education, support, financial stipends, health insurance (if eligible), and beneficiary travel (if eligible) to primary caregivers of eligible veterans. PCAFC was originally reserved for veterans who had onset of service-related disability after September 11, 2001, with an associated personal care need. In this population, PCAFC demonstrated an increased usage of clinical resources, likely related to increased ease in accessing care.¹³

The cohort of post-9/11 veterans is very different from the cohort of veterans and their caregivers who may now qualify for the PCAFC after its October 2020 expansion. Veterans from the Vietnam, Korean, and World War II eras of conflict have rates of service-connected disability 2 to 3 times higher than those of post-9/11 era veterans and are at greater risk for dementia.⁹ Veterans aged ≥ 75 years who have service connection also report higher rates of difficulty with independent living and self-care compared with their younger peers.⁹ Since dementia and PTSD are common causes of service connection and disability it is likely that a significant proportion of older veterans will be eligible to apply for the newly expanded PCAFC.

To be eligible for PCAFC, a veteran must have a service-connected disability rating of ≥ 70% and must need in-person care services for ≥ 6 continuous months, based on either an inability to perform an ADL, or a need for supervision, protection, or instruction. PGCSS and PCAFC also may improve access to dementia-specific resources and care. These programs jointly improve access to care, clinical and community resources, and support, and serve to further support in-home care with consistent caregivers who have known the veterans for decades as an alternative to SNF care, as they did in this case. Although in-home care with appropriate support has not been found to be clinically superior, it has been found to be noninferior to SNF living for older adults.¹⁴ More familiar environments and caregivers such as those at home may also reduce the risk of long-term adverse outcomes such as delirium and falls, but there is still more research to be done to examine the ultimate clinical impact of aging in place for people with dementia. Most importantly, for many veterans and their family caregivers, living at home is preferable to SNF care, but may prove especially challenging in the context of advanced-stage dementia without CSP support.

It is not clear how CSP use or increased access to PCAFC will impact costs. However, the PCAFC monthly stipend is scaled to the median wage of a home health aide and to the location of the caregiver, which is considerably less than the cost of recurrent hospitalization or a year of facility-level care.¹⁵ The CSP may eventually be a successful long-term investment in cost savings. In order to ensure the process for PCAFC approval is uniform and prompt as the program expands, CSP has restructured, increasing the number of employees, improving the patient review process, and expanding staff training.¹⁶ The VA plans to continually re-assess CSP using the infrastructure of the Caregiver Record Management Application as it continues to expand.¹⁷

Conclusions

Dementia and PTSD commonly coexist and are a significant source of disability in the service-connected veteran population. This case brings attention to the recent expansion of PCAFC, which now has the potential to support eligible veterans from the World War II, Korean, and Vietnam-era conflicts, in whom these illnesses are more common. In this case, in-home care was preferred by the veteran and primary caregiver but would not have been possible without a complex intervention. There is still more research to be done on the best way to meet the needs of older adults with dementia, the impact of in-home care, and the system-wide implications of PCAFC, especially as the program grows. However, in-home care is preferable to SNF living for many veterans and caregivers, and CSP will continue to be an essential element of providing care for this population.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin. The authors would also like to thank the members of the Veterans Affairs Central Office and National Caregiver Support Program Office, including Elyse Kaplan, Melinda Hogue, Beth Wolfsohn, Colleen Richardson, and Timothy Jobin, for their thorough review of the work and edits to ensure accurate program description.

Caregiving for a person with dementia in the community can be extremely difficult work. Much of this work falls on unpaid or informal caregivers. Sixty-three percent of older adults with dementia depend completely on unpaid caregivers, and an additional 26% receive some combination of paid and unpaid support, together comprising nearly 90% of the more than 3 million older Americans with dementia.¹ In-home care is preferable for these patients. For veterans, the Caregiver Support Program (CSP) is the only US Department of Veterans Affairs (VA) program that exclusively supports caregivers. Although the CSP is not a nursing home diversion or cost savings program, successfully enabling at-home living in lieu of facility living also has the potential to reduce overall cost of care, and most importantly, to enable veterans who desire it to age at home.^2,3

The CSP has 2 unique programs for caregivers of eligible veterans. The Program of General Caregiver Support Services (PGCSS) provides resources, education, and support to caregivers of all veterans enrolled in the Veterans Health Administration (VHA). The Program of Comprehensive Assistance for Family Caregivers (PCAFC) provides education and training, access to health care insurance if eligible, mental health counseling, access to a monthly caregiver stipend, enhanced respite care, wellness contacts, and travel compensation for VA health care appointments (Table 1).^4,5

Patients undergo a rigorous assessment and highly specialized and individualized clinical decision-making process to confirm the service is appropriate for the patient. PCAFC was restructured and expanded on October 1, 2020.⁶ Currently, veterans who incurred or aggravated a serious injury (defined by a single or combined service-connection rating of ≥ 70%) in active military service before May 8, 1975, or after September 10, 2001, are eligible for PCAFC.⁶ Most notably, these changes opened eligibility in the PCAFC to caregivers of veterans from the Vietnam, Korean, and World War II eras of conflict and veterans with dependence in activities of daily living (ADL) due to a wider variety of illnesses, including dementia.⁶ The PCAFC is set to further expand to caregivers of otherwise eligible veterans of all eras of service on October 1, 2022, 2 years after the initial expansion, as laid out in the 2018 VA MISSION Act.⁶ Additional information on the history of the PGCSS and PCAFC and eligibility criteria for veterans and their family caregivers can be found in Tables 2 and 3.

Case Presentation

A male combat veteran presented to his primary care practitioner (PCP) with concerns of several years of progressive changes in gait, forgetfulness, and a gradual decline in the ability to live independently without assistance. At that time, his medical history was notable for PTSD (50% service connection), which had been diagnosed over a decade prior (but for which the veteran had refused medication or therapy on multiple occasions, stating he preferred to “breathe through” his intrusive symptom flare-ups), localized prostate cancer with a radical prostatectomy (100% service connection), multiple kidney stones with persistent left ureteral inflammation, and arteriosclerotic heart disease (10% service connection). A Saint Louis University Mental Status Exam (SLUMS) performed by the PCP was notable for a score of 9/30, in the dementia range. A computed tomography of the brain demonstrated scattered foci of hypoattenuation attributable to normal aging without any other pathology noted.

The veteran was referred to the Cognitive Care clinic, a local longitudinal multidisciplinary dementia care clinic, along with his spouse/caregiver. Cognitive testing was performed by a licensed clinical psychologist in the clinic and was notable for a Mini-Mental State Exam (MMSE) score of 18/30, also in the dementia range, and a more robust neuropsychiatric battery demonstrated borderline intact memory and language function but impairments in executive function and visuospatial skills. The patient’s clinical history included functional loss over time, with total dependence in instrumental activities of daily living (IADL), or tasks necessary to be fully independent or manage a household, including inability to manage finances, and some need for assistance in ADL, or personal care tasks such as dressing or grooming, including bathing. Physical examination was notable for bradykinesia, a shuffling gait, and rare episodes of speaking to someone who was not in the room, thought to be due to mild nondistressing hallucinations.

A diagnosis of LBD was made. At time of diagnosis, the patient met criteria for probable dementia with Lewy bodies, with 2 of 4 core clinical features (hallucinations and Parkinsonism), and multiple supportive features (gait disturbance, sensory disturbance, and altered mood).^10,11 The veteran continued to develop more supportive features for diagnosis of LBD over time, including evidence of autonomic instability.

The veteran and his caregiver were educated on his diagnosis, and longitudinal support was offered. The veteran was no longer driving, and due to the severity of his symptoms, the importance of driving cessation was reinforced by the care team. Over the course of the next year, his illness progressed, with more frequent behaviors and psychological symptoms of dementia (BPSD). He began to exhibit nighttime wandering throughout the house and became more anxious and restless during the day. He lost the ability to make his own health care decisions, and his spouse became his activated health care power of attorney (HCPOA). His BPSD became more disruptive to daily life and was accompanied by a change in the character of his hallucinations, with prior nondistressing visions of other people being replaced with visions of war, burning bodies, and violence, much of it related to combat experiences in Vietnam. The BPSD began to include hiding behind furniture, running out of the house, and shouting and crying in response to hallucinations. At times, his BPSD became violent, lashing out in fear against his hallucinations and caregiver.

The veteran’s change in BPSD was concerning for a new baseline, rather than being clearly related to an underlying unmet physical need, such as pain, hunger, sleep, or discomfort. Multiple hospital admissions during that year involved IV hydration and treatment for urinary tract infections (UTI) for several days of inpatient stay at a time, but these behaviors persisted despite infection treatment and hydration. The patient’s changes in BPSD were thought to be secondary to uncovered and intensified PTSD in the setting of progressive dementia. Due to the clear danger the patient posed to himself and others, potential treatment options for these PTSD-related hallucinations were discussed with his caregiver. The caregiver shared that the patient’s BPSD and hallucinations were so distressing that “he would never want to live like this,” and that things had progressed to the point that “he has no quality of life.”

Oral aripiprazole 2 mg twice daily was prescribed after the risks of infection, cardiac complications, and exacerbation of movement disorder symptoms, such as increased stiffness and falls, were discussed with the caregiver. The caregiver was employed and relied on continued employment for income, but the patient could not be safely left alone. As the patient and his caregiver had reached a crisis point and living at home no longer appeared to be safe, the patient was referred to a VA-contracted skilled nursing facility (SNF) for long-term care. The patient’s caregiver was also referred to CSP for support during this transition. Due to the patient’s level of service connection and personal needs, as well as the patient and caregiver’s preference for the veteran to remain in his home, they were evaluated for the PCAFC for enhanced support to enable home as an alternative to facility living, should the patient respond to the antipsychotic therapy sufficiently, which was evaluated on a regular basis.

After several months, the patient’s BPSD had improved significantly, and he was no longer experiencing distressing hallucinations. However, his mobility also declined, and he became fully dependent in most ADL, including transfers, hygiene, and toileting. Due to the COVID-19 pandemic, visitation was limited, which was difficult for both the patient and his caregiver. The veteran and caregiver were approved for PCAFC due to the veteran’s combination of service-connected illnesses > 70%, dependence for most ADLs, and need for continuous supervision. A transfer home from the SNF was arranged.

The PCAFC allowed the veteran’s caregiver and family members to provide in-home full-time caregiving, as an alternative to facility placement. The caregiver received a variety of support, including access to peer support, instruction on ways to assist in his toileting, hygiene, and transfers, and a caregiving stipend. In addition to offsetting lost wages, the stipend also helped offset the cost of care supplies which were not provided or were not readily available from the VA, which at the time included the patient’s preferred nutritional supplement and some supplies for personal care.

The veteran’s care needs continued to escalate. A fall at home resulted in a hip fracture, which was treated with surgical pinning. Postfracture physical therapy in a facility was considered, but ultimately was provided at home. The patient also experienced multiple UTIs and resulting delirium, with accompanying agitation and hallucinations. These episodes improved with IV antibiotics and hydration during short hospital stays. Ultimately, a computed tomography demonstrated overflow incontinence likely related to urologic damage from prior kidney stones and stent placement was recommended.

Visiting skilled nurses for the patient’s area were difficult to coordinate but were eventually arranged. The patient continued residing in his home with the support of his caregiver, the PCAFC, and the local VA medical center geriatric and transitional care services. The patient was also referred to the palliative care outpatient specialty clinic for discussion of goals of care and assistance with advance care planning as his illness progressed. Mental health and geriatric psychiatry consult teams were considered for this case but not utilized.

Discussion

Older adult Americans are at high risk of poor financial wellbeing, with nearly one quarter of Americans aged > 62 years experiencing financial insecurity.¹² Even in this case with health care provided by the VA, successful in-home care was challenging and required a dedicated live-in caregiver, care coordination resources, and financial support. As part of its mission of caring for veterans, the VA has instituted CSP, whose mission is to promote the health and well-being of family caregivers through education, support, and services.

PCAFC offers enhanced clinical support for caregivers of eligible veterans who are seriously injured. This includes resources, education, support, financial stipends, health insurance (if eligible), and beneficiary travel (if eligible) to primary caregivers of eligible veterans. PCAFC was originally reserved for veterans who had onset of service-related disability after September 11, 2001, with an associated personal care need. In this population, PCAFC demonstrated an increased usage of clinical resources, likely related to increased ease in accessing care.¹³

The cohort of post-9/11 veterans is very different from the cohort of veterans and their caregivers who may now qualify for the PCAFC after its October 2020 expansion. Veterans from the Vietnam, Korean, and World War II eras of conflict have rates of service-connected disability 2 to 3 times higher than those of post-9/11 era veterans and are at greater risk for dementia.⁹ Veterans aged ≥ 75 years who have service connection also report higher rates of difficulty with independent living and self-care compared with their younger peers.⁹ Since dementia and PTSD are common causes of service connection and disability it is likely that a significant proportion of older veterans will be eligible to apply for the newly expanded PCAFC.

To be eligible for PCAFC, a veteran must have a service-connected disability rating of ≥ 70% and must need in-person care services for ≥ 6 continuous months, based on either an inability to perform an ADL, or a need for supervision, protection, or instruction. PGCSS and PCAFC also may improve access to dementia-specific resources and care. These programs jointly improve access to care, clinical and community resources, and support, and serve to further support in-home care with consistent caregivers who have known the veterans for decades as an alternative to SNF care, as they did in this case. Although in-home care with appropriate support has not been found to be clinically superior, it has been found to be noninferior to SNF living for older adults.¹⁴ More familiar environments and caregivers such as those at home may also reduce the risk of long-term adverse outcomes such as delirium and falls, but there is still more research to be done to examine the ultimate clinical impact of aging in place for people with dementia. Most importantly, for many veterans and their family caregivers, living at home is preferable to SNF care, but may prove especially challenging in the context of advanced-stage dementia without CSP support.

It is not clear how CSP use or increased access to PCAFC will impact costs. However, the PCAFC monthly stipend is scaled to the median wage of a home health aide and to the location of the caregiver, which is considerably less than the cost of recurrent hospitalization or a year of facility-level care.¹⁵ The CSP may eventually be a successful long-term investment in cost savings. In order to ensure the process for PCAFC approval is uniform and prompt as the program expands, CSP has restructured, increasing the number of employees, improving the patient review process, and expanding staff training.¹⁶ The VA plans to continually re-assess CSP using the infrastructure of the Caregiver Record Management Application as it continues to expand.¹⁷

Conclusions

Dementia and PTSD commonly coexist and are a significant source of disability in the service-connected veteran population. This case brings attention to the recent expansion of PCAFC, which now has the potential to support eligible veterans from the World War II, Korean, and Vietnam-era conflicts, in whom these illnesses are more common. In this case, in-home care was preferred by the veteran and primary caregiver but would not have been possible without a complex intervention. There is still more research to be done on the best way to meet the needs of older adults with dementia, the impact of in-home care, and the system-wide implications of PCAFC, especially as the program grows. However, in-home care is preferable to SNF living for many veterans and caregivers, and CSP will continue to be an essential element of providing care for this population.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin. The authors would also like to thank the members of the Veterans Affairs Central Office and National Caregiver Support Program Office, including Elyse Kaplan, Melinda Hogue, Beth Wolfsohn, Colleen Richardson, and Timothy Jobin, for their thorough review of the work and edits to ensure accurate program description.

Caregiving for a person with dementia in the community can be extremely difficult work. Much of this work falls on unpaid or informal caregivers. Sixty-three percent of older adults with dementia depend completely on unpaid caregivers, and an additional 26% receive some combination of paid and unpaid support, together comprising nearly 90% of the more than 3 million older Americans with dementia.¹ In-home care is preferable for these patients. For veterans, the Caregiver Support Program (CSP) is the only US Department of Veterans Affairs (VA) program that exclusively supports caregivers. Although the CSP is not a nursing home diversion or cost savings program, successfully enabling at-home living in lieu of facility living also has the potential to reduce overall cost of care, and most importantly, to enable veterans who desire it to age at home.^2,3

The CSP has 2 unique programs for caregivers of eligible veterans. The Program of General Caregiver Support Services (PGCSS) provides resources, education, and support to caregivers of all veterans enrolled in the Veterans Health Administration (VHA). The Program of Comprehensive Assistance for Family Caregivers (PCAFC) provides education and training, access to health care insurance if eligible, mental health counseling, access to a monthly caregiver stipend, enhanced respite care, wellness contacts, and travel compensation for VA health care appointments (Table 1).^4,5

Patients undergo a rigorous assessment and highly specialized and individualized clinical decision-making process to confirm the service is appropriate for the patient. PCAFC was restructured and expanded on October 1, 2020.⁶ Currently, veterans who incurred or aggravated a serious injury (defined by a single or combined service-connection rating of ≥ 70%) in active military service before May 8, 1975, or after September 10, 2001, are eligible for PCAFC.⁶ Most notably, these changes opened eligibility in the PCAFC to caregivers of veterans from the Vietnam, Korean, and World War II eras of conflict and veterans with dependence in activities of daily living (ADL) due to a wider variety of illnesses, including dementia.⁶ The PCAFC is set to further expand to caregivers of otherwise eligible veterans of all eras of service on October 1, 2022, 2 years after the initial expansion, as laid out in the 2018 VA MISSION Act.⁶ Additional information on the history of the PGCSS and PCAFC and eligibility criteria for veterans and their family caregivers can be found in Tables 2 and 3.

Case Presentation

A male combat veteran presented to his primary care practitioner (PCP) with concerns of several years of progressive changes in gait, forgetfulness, and a gradual decline in the ability to live independently without assistance. At that time, his medical history was notable for PTSD (50% service connection), which had been diagnosed over a decade prior (but for which the veteran had refused medication or therapy on multiple occasions, stating he preferred to “breathe through” his intrusive symptom flare-ups), localized prostate cancer with a radical prostatectomy (100% service connection), multiple kidney stones with persistent left ureteral inflammation, and arteriosclerotic heart disease (10% service connection). A Saint Louis University Mental Status Exam (SLUMS) performed by the PCP was notable for a score of 9/30, in the dementia range. A computed tomography of the brain demonstrated scattered foci of hypoattenuation attributable to normal aging without any other pathology noted.

The veteran was referred to the Cognitive Care clinic, a local longitudinal multidisciplinary dementia care clinic, along with his spouse/caregiver. Cognitive testing was performed by a licensed clinical psychologist in the clinic and was notable for a Mini-Mental State Exam (MMSE) score of 18/30, also in the dementia range, and a more robust neuropsychiatric battery demonstrated borderline intact memory and language function but impairments in executive function and visuospatial skills. The patient’s clinical history included functional loss over time, with total dependence in instrumental activities of daily living (IADL), or tasks necessary to be fully independent or manage a household, including inability to manage finances, and some need for assistance in ADL, or personal care tasks such as dressing or grooming, including bathing. Physical examination was notable for bradykinesia, a shuffling gait, and rare episodes of speaking to someone who was not in the room, thought to be due to mild nondistressing hallucinations.

A diagnosis of LBD was made. At time of diagnosis, the patient met criteria for probable dementia with Lewy bodies, with 2 of 4 core clinical features (hallucinations and Parkinsonism), and multiple supportive features (gait disturbance, sensory disturbance, and altered mood).^10,11 The veteran continued to develop more supportive features for diagnosis of LBD over time, including evidence of autonomic instability.

The veteran and his caregiver were educated on his diagnosis, and longitudinal support was offered. The veteran was no longer driving, and due to the severity of his symptoms, the importance of driving cessation was reinforced by the care team. Over the course of the next year, his illness progressed, with more frequent behaviors and psychological symptoms of dementia (BPSD). He began to exhibit nighttime wandering throughout the house and became more anxious and restless during the day. He lost the ability to make his own health care decisions, and his spouse became his activated health care power of attorney (HCPOA). His BPSD became more disruptive to daily life and was accompanied by a change in the character of his hallucinations, with prior nondistressing visions of other people being replaced with visions of war, burning bodies, and violence, much of it related to combat experiences in Vietnam. The BPSD began to include hiding behind furniture, running out of the house, and shouting and crying in response to hallucinations. At times, his BPSD became violent, lashing out in fear against his hallucinations and caregiver.

The veteran’s change in BPSD was concerning for a new baseline, rather than being clearly related to an underlying unmet physical need, such as pain, hunger, sleep, or discomfort. Multiple hospital admissions during that year involved IV hydration and treatment for urinary tract infections (UTI) for several days of inpatient stay at a time, but these behaviors persisted despite infection treatment and hydration. The patient’s changes in BPSD were thought to be secondary to uncovered and intensified PTSD in the setting of progressive dementia. Due to the clear danger the patient posed to himself and others, potential treatment options for these PTSD-related hallucinations were discussed with his caregiver. The caregiver shared that the patient’s BPSD and hallucinations were so distressing that “he would never want to live like this,” and that things had progressed to the point that “he has no quality of life.”

Oral aripiprazole 2 mg twice daily was prescribed after the risks of infection, cardiac complications, and exacerbation of movement disorder symptoms, such as increased stiffness and falls, were discussed with the caregiver. The caregiver was employed and relied on continued employment for income, but the patient could not be safely left alone. As the patient and his caregiver had reached a crisis point and living at home no longer appeared to be safe, the patient was referred to a VA-contracted skilled nursing facility (SNF) for long-term care. The patient’s caregiver was also referred to CSP for support during this transition. Due to the patient’s level of service connection and personal needs, as well as the patient and caregiver’s preference for the veteran to remain in his home, they were evaluated for the PCAFC for enhanced support to enable home as an alternative to facility living, should the patient respond to the antipsychotic therapy sufficiently, which was evaluated on a regular basis.

After several months, the patient’s BPSD had improved significantly, and he was no longer experiencing distressing hallucinations. However, his mobility also declined, and he became fully dependent in most ADL, including transfers, hygiene, and toileting. Due to the COVID-19 pandemic, visitation was limited, which was difficult for both the patient and his caregiver. The veteran and caregiver were approved for PCAFC due to the veteran’s combination of service-connected illnesses > 70%, dependence for most ADLs, and need for continuous supervision. A transfer home from the SNF was arranged.

The PCAFC allowed the veteran’s caregiver and family members to provide in-home full-time caregiving, as an alternative to facility placement. The caregiver received a variety of support, including access to peer support, instruction on ways to assist in his toileting, hygiene, and transfers, and a caregiving stipend. In addition to offsetting lost wages, the stipend also helped offset the cost of care supplies which were not provided or were not readily available from the VA, which at the time included the patient’s preferred nutritional supplement and some supplies for personal care.

The veteran’s care needs continued to escalate. A fall at home resulted in a hip fracture, which was treated with surgical pinning. Postfracture physical therapy in a facility was considered, but ultimately was provided at home. The patient also experienced multiple UTIs and resulting delirium, with accompanying agitation and hallucinations. These episodes improved with IV antibiotics and hydration during short hospital stays. Ultimately, a computed tomography demonstrated overflow incontinence likely related to urologic damage from prior kidney stones and stent placement was recommended.

Visiting skilled nurses for the patient’s area were difficult to coordinate but were eventually arranged. The patient continued residing in his home with the support of his caregiver, the PCAFC, and the local VA medical center geriatric and transitional care services. The patient was also referred to the palliative care outpatient specialty clinic for discussion of goals of care and assistance with advance care planning as his illness progressed. Mental health and geriatric psychiatry consult teams were considered for this case but not utilized.

Discussion

Older adult Americans are at high risk of poor financial wellbeing, with nearly one quarter of Americans aged > 62 years experiencing financial insecurity.¹² Even in this case with health care provided by the VA, successful in-home care was challenging and required a dedicated live-in caregiver, care coordination resources, and financial support. As part of its mission of caring for veterans, the VA has instituted CSP, whose mission is to promote the health and well-being of family caregivers through education, support, and services.

PCAFC offers enhanced clinical support for caregivers of eligible veterans who are seriously injured. This includes resources, education, support, financial stipends, health insurance (if eligible), and beneficiary travel (if eligible) to primary caregivers of eligible veterans. PCAFC was originally reserved for veterans who had onset of service-related disability after September 11, 2001, with an associated personal care need. In this population, PCAFC demonstrated an increased usage of clinical resources, likely related to increased ease in accessing care.¹³

The cohort of post-9/11 veterans is very different from the cohort of veterans and their caregivers who may now qualify for the PCAFC after its October 2020 expansion. Veterans from the Vietnam, Korean, and World War II eras of conflict have rates of service-connected disability 2 to 3 times higher than those of post-9/11 era veterans and are at greater risk for dementia.⁹ Veterans aged ≥ 75 years who have service connection also report higher rates of difficulty with independent living and self-care compared with their younger peers.⁹ Since dementia and PTSD are common causes of service connection and disability it is likely that a significant proportion of older veterans will be eligible to apply for the newly expanded PCAFC.

To be eligible for PCAFC, a veteran must have a service-connected disability rating of ≥ 70% and must need in-person care services for ≥ 6 continuous months, based on either an inability to perform an ADL, or a need for supervision, protection, or instruction. PGCSS and PCAFC also may improve access to dementia-specific resources and care. These programs jointly improve access to care, clinical and community resources, and support, and serve to further support in-home care with consistent caregivers who have known the veterans for decades as an alternative to SNF care, as they did in this case. Although in-home care with appropriate support has not been found to be clinically superior, it has been found to be noninferior to SNF living for older adults.¹⁴ More familiar environments and caregivers such as those at home may also reduce the risk of long-term adverse outcomes such as delirium and falls, but there is still more research to be done to examine the ultimate clinical impact of aging in place for people with dementia. Most importantly, for many veterans and their family caregivers, living at home is preferable to SNF care, but may prove especially challenging in the context of advanced-stage dementia without CSP support.

It is not clear how CSP use or increased access to PCAFC will impact costs. However, the PCAFC monthly stipend is scaled to the median wage of a home health aide and to the location of the caregiver, which is considerably less than the cost of recurrent hospitalization or a year of facility-level care.¹⁵ The CSP may eventually be a successful long-term investment in cost savings. In order to ensure the process for PCAFC approval is uniform and prompt as the program expands, CSP has restructured, increasing the number of employees, improving the patient review process, and expanding staff training.¹⁶ The VA plans to continually re-assess CSP using the infrastructure of the Caregiver Record Management Application as it continues to expand.¹⁷

Conclusions

Dementia and PTSD commonly coexist and are a significant source of disability in the service-connected veteran population. This case brings attention to the recent expansion of PCAFC, which now has the potential to support eligible veterans from the World War II, Korean, and Vietnam-era conflicts, in whom these illnesses are more common. In this case, in-home care was preferred by the veteran and primary caregiver but would not have been possible without a complex intervention. There is still more research to be done on the best way to meet the needs of older adults with dementia, the impact of in-home care, and the system-wide implications of PCAFC, especially as the program grows. However, in-home care is preferable to SNF living for many veterans and caregivers, and CSP will continue to be an essential element of providing care for this population.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin. The authors would also like to thank the members of the Veterans Affairs Central Office and National Caregiver Support Program Office, including Elyse Kaplan, Melinda Hogue, Beth Wolfsohn, Colleen Richardson, and Timothy Jobin, for their thorough review of the work and edits to ensure accurate program description.