Case Reports

Patients with cutaneous T-cell lymphoma (CTCL) often are diagnosed with atopic dermatitis (AD) or psoriasis before receiving their CTCL diagnosis. The effects of new biologic therapies for AD such as dupilumab, an IL-4/IL-13 antagonist, on CTCL are unknown. Dupilumab may be beneficial in CTCL given that helper T cell (T_H2) cytokines are increased in advanced CTCL.¹ We present a patient with definitive CTCL and concomitant AD who was safely treated with dupilumab and experienced improvement in both CTCL and AD.

Case Report

A 68-year-old man presented with increased itching from AD and a new rash on the arms, neck, chest, back, and lower extremities (Figures 1A and 2A). He had a medical history of AD and CTCL diagnosed by biopsy and peripheral blood flow cytometry (stage IVA1 [T4N0M0B2]) that was being treated with comprehensive multimodality therapy consisting of bexarotene 375 mg daily, interferon alfa-2b 3 mIU 3 times weekly, interferon gamma-1b 2 mIU 3 times weekly, total skin electron beam therapy followed by narrowband UVB twice weekly, and extracorporeal photopheresis every 4 weeks, which resulted in a partial clinical response for 6 months. A biopsy performed at the current presentation showed focal spongiosis and features of lichen simplex chronicus with no evidence suggestive of CTCL. Peripheral blood flow cytometry showed stable B₁-staged disease burden (CD4/CD8, 2.6:1); CD4⁺/CD7⁻, 12% [91/µL]; CD4⁺/CD26⁻, 21% [155/µL]). Treatment with potent and superpotent topical steroids was attempted for more than 6 months and was unsuccessful in relieving the symptoms.

Given the recalcitrant nature of the patient’s rash and itching, dupilumab was added to his CTCL regimen. Prior to initiating dupilumab, the patient reported a numeric rating scale itch intensity of 7 out of 10. After 4 weeks of treatment with dupilumab, the patient reported a numeric rating scale itch intensity of 1. Over a 3-month period, the patient’s rash improved dramatically (Figures 1B and 2B), making it possible to decrease CTCL treatments—bexarotene decreased to 300 mg, interferon alfa-2b to 3 mIU twice weekly, interferon gamma-1b to 2 mIU twice weekly, extracorporeal photopheresis every 5 weeks, and narrowband UVB was discontinued completely. A comparison of the patient’s flow cytometry analysis from before treatment to 3 months after dupilumab showed an overall slight reduction in CTCL B₁ blood involvement and normalization of the patient’s absolute eosinophil count and serum lactate dehydrogenase level. The patient tolerated the treatment well without any adverse events and has maintained clinical response for 6 months.

Comment

Cutaneous T-cell lymphomas represent a heterogeneous group of T-cell lymphoproliferative disorders involving the skin.² The definitive diagnosis of CTCL is challenging, as the clinical and pathologic features often are nonspecific in early disease. Frequently, undiagnosed patients are treated empirically with immunosuppressive agents. Tumor necrosis factor inhibitors and cyclosporine are both associated with progression or worsening of undiagnosed CTCL.^3,4 Dupilumab was the first US Food and Drug Administration–approved biologic for the treatment of moderate to severe AD. Cutaneous T-cell lymphoma has immunologic features, such as T_H2 skewing, that overlap with AD; however, the effects of dupilumab in CTCL are not yet known.^5,6 Our group has seen patients initially thought to have AD who received dupilumab without improvement and were subsequently diagnosed with CTCL, suggesting dupilumab did not affect CTCL tumor cells. Given these findings, there was concern that dupilumab might exacerbate undiagnosed CTCL. Our patient with definitive, severe, refractory CTCL noted marked improvement in both AD and underlying CTCL with the addition of dupilumab. No other treatments were added. The response was so dramatic that we were able to wean the doses and frequencies of several CTCL treatments. Our findings suggest that dupilumab may be beneficial in a certain subset of CTCL patients with a history of AD or known concomitant AD. Prospective studies are needed to fully investigate dupilumab safety and efficacy in CTCL and whether it has any primary effects on tumor burden in addition to benefit for itch and skin symptom relief.

Patients with cutaneous T-cell lymphoma (CTCL) often are diagnosed with atopic dermatitis (AD) or psoriasis before receiving their CTCL diagnosis. The effects of new biologic therapies for AD such as dupilumab, an IL-4/IL-13 antagonist, on CTCL are unknown. Dupilumab may be beneficial in CTCL given that helper T cell (T_H2) cytokines are increased in advanced CTCL.¹ We present a patient with definitive CTCL and concomitant AD who was safely treated with dupilumab and experienced improvement in both CTCL and AD.

Case Report

A 68-year-old man presented with increased itching from AD and a new rash on the arms, neck, chest, back, and lower extremities (Figures 1A and 2A). He had a medical history of AD and CTCL diagnosed by biopsy and peripheral blood flow cytometry (stage IVA1 [T4N0M0B2]) that was being treated with comprehensive multimodality therapy consisting of bexarotene 375 mg daily, interferon alfa-2b 3 mIU 3 times weekly, interferon gamma-1b 2 mIU 3 times weekly, total skin electron beam therapy followed by narrowband UVB twice weekly, and extracorporeal photopheresis every 4 weeks, which resulted in a partial clinical response for 6 months. A biopsy performed at the current presentation showed focal spongiosis and features of lichen simplex chronicus with no evidence suggestive of CTCL. Peripheral blood flow cytometry showed stable B₁-staged disease burden (CD4/CD8, 2.6:1); CD4⁺/CD7⁻, 12% [91/µL]; CD4⁺/CD26⁻, 21% [155/µL]). Treatment with potent and superpotent topical steroids was attempted for more than 6 months and was unsuccessful in relieving the symptoms.

Given the recalcitrant nature of the patient’s rash and itching, dupilumab was added to his CTCL regimen. Prior to initiating dupilumab, the patient reported a numeric rating scale itch intensity of 7 out of 10. After 4 weeks of treatment with dupilumab, the patient reported a numeric rating scale itch intensity of 1. Over a 3-month period, the patient’s rash improved dramatically (Figures 1B and 2B), making it possible to decrease CTCL treatments—bexarotene decreased to 300 mg, interferon alfa-2b to 3 mIU twice weekly, interferon gamma-1b to 2 mIU twice weekly, extracorporeal photopheresis every 5 weeks, and narrowband UVB was discontinued completely. A comparison of the patient’s flow cytometry analysis from before treatment to 3 months after dupilumab showed an overall slight reduction in CTCL B₁ blood involvement and normalization of the patient’s absolute eosinophil count and serum lactate dehydrogenase level. The patient tolerated the treatment well without any adverse events and has maintained clinical response for 6 months.

Comment

Cutaneous T-cell lymphomas represent a heterogeneous group of T-cell lymphoproliferative disorders involving the skin.² The definitive diagnosis of CTCL is challenging, as the clinical and pathologic features often are nonspecific in early disease. Frequently, undiagnosed patients are treated empirically with immunosuppressive agents. Tumor necrosis factor inhibitors and cyclosporine are both associated with progression or worsening of undiagnosed CTCL.^3,4 Dupilumab was the first US Food and Drug Administration–approved biologic for the treatment of moderate to severe AD. Cutaneous T-cell lymphoma has immunologic features, such as T_H2 skewing, that overlap with AD; however, the effects of dupilumab in CTCL are not yet known.^5,6 Our group has seen patients initially thought to have AD who received dupilumab without improvement and were subsequently diagnosed with CTCL, suggesting dupilumab did not affect CTCL tumor cells. Given these findings, there was concern that dupilumab might exacerbate undiagnosed CTCL. Our patient with definitive, severe, refractory CTCL noted marked improvement in both AD and underlying CTCL with the addition of dupilumab. No other treatments were added. The response was so dramatic that we were able to wean the doses and frequencies of several CTCL treatments. Our findings suggest that dupilumab may be beneficial in a certain subset of CTCL patients with a history of AD or known concomitant AD. Prospective studies are needed to fully investigate dupilumab safety and efficacy in CTCL and whether it has any primary effects on tumor burden in addition to benefit for itch and skin symptom relief.

Patients with cutaneous T-cell lymphoma (CTCL) often are diagnosed with atopic dermatitis (AD) or psoriasis before receiving their CTCL diagnosis. The effects of new biologic therapies for AD such as dupilumab, an IL-4/IL-13 antagonist, on CTCL are unknown. Dupilumab may be beneficial in CTCL given that helper T cell (T_H2) cytokines are increased in advanced CTCL.¹ We present a patient with definitive CTCL and concomitant AD who was safely treated with dupilumab and experienced improvement in both CTCL and AD.

Case Report

A 68-year-old man presented with increased itching from AD and a new rash on the arms, neck, chest, back, and lower extremities (Figures 1A and 2A). He had a medical history of AD and CTCL diagnosed by biopsy and peripheral blood flow cytometry (stage IVA1 [T4N0M0B2]) that was being treated with comprehensive multimodality therapy consisting of bexarotene 375 mg daily, interferon alfa-2b 3 mIU 3 times weekly, interferon gamma-1b 2 mIU 3 times weekly, total skin electron beam therapy followed by narrowband UVB twice weekly, and extracorporeal photopheresis every 4 weeks, which resulted in a partial clinical response for 6 months. A biopsy performed at the current presentation showed focal spongiosis and features of lichen simplex chronicus with no evidence suggestive of CTCL. Peripheral blood flow cytometry showed stable B₁-staged disease burden (CD4/CD8, 2.6:1); CD4⁺/CD7⁻, 12% [91/µL]; CD4⁺/CD26⁻, 21% [155/µL]). Treatment with potent and superpotent topical steroids was attempted for more than 6 months and was unsuccessful in relieving the symptoms.

Given the recalcitrant nature of the patient’s rash and itching, dupilumab was added to his CTCL regimen. Prior to initiating dupilumab, the patient reported a numeric rating scale itch intensity of 7 out of 10. After 4 weeks of treatment with dupilumab, the patient reported a numeric rating scale itch intensity of 1. Over a 3-month period, the patient’s rash improved dramatically (Figures 1B and 2B), making it possible to decrease CTCL treatments—bexarotene decreased to 300 mg, interferon alfa-2b to 3 mIU twice weekly, interferon gamma-1b to 2 mIU twice weekly, extracorporeal photopheresis every 5 weeks, and narrowband UVB was discontinued completely. A comparison of the patient’s flow cytometry analysis from before treatment to 3 months after dupilumab showed an overall slight reduction in CTCL B₁ blood involvement and normalization of the patient’s absolute eosinophil count and serum lactate dehydrogenase level. The patient tolerated the treatment well without any adverse events and has maintained clinical response for 6 months.

Comment

Cutaneous T-cell lymphomas represent a heterogeneous group of T-cell lymphoproliferative disorders involving the skin.² The definitive diagnosis of CTCL is challenging, as the clinical and pathologic features often are nonspecific in early disease. Frequently, undiagnosed patients are treated empirically with immunosuppressive agents. Tumor necrosis factor inhibitors and cyclosporine are both associated with progression or worsening of undiagnosed CTCL.^3,4 Dupilumab was the first US Food and Drug Administration–approved biologic for the treatment of moderate to severe AD. Cutaneous T-cell lymphoma has immunologic features, such as T_H2 skewing, that overlap with AD; however, the effects of dupilumab in CTCL are not yet known.^5,6 Our group has seen patients initially thought to have AD who received dupilumab without improvement and were subsequently diagnosed with CTCL, suggesting dupilumab did not affect CTCL tumor cells. Given these findings, there was concern that dupilumab might exacerbate undiagnosed CTCL. Our patient with definitive, severe, refractory CTCL noted marked improvement in both AD and underlying CTCL with the addition of dupilumab. No other treatments were added. The response was so dramatic that we were able to wean the doses and frequencies of several CTCL treatments. Our findings suggest that dupilumab may be beneficial in a certain subset of CTCL patients with a history of AD or known concomitant AD. Prospective studies are needed to fully investigate dupilumab safety and efficacy in CTCL and whether it has any primary effects on tumor burden in addition to benefit for itch and skin symptom relief.

THE CASE

A 4-year-old girl was triaged to the Pediatric Emergency Department (PED) Fast Track, complaining of pain and limited movement in both arms. For an unknown reason, she had attempted to lift a heavy, 3-person sofa several hours earlier.

Her prior medical history included left nursemaid elbow (NME) at both 15 months and 33 months of age. Neither event had a known mechanism of injury. In both episodes, it was noted in the medical record that the child was not using her arm, “was holding it funny,” and was complaining of pain. Each time, she presented about 24 hours after symptom onset.

During the physical exam in the PED, the patient showed no signs of acute distress. She held both arms close to her body, with a slight flexion at the elbows, and her hands were pronated. She could not pinpoint the location of her discomfort and described diffuse pain in her forearms, elbows, and upper arms. Examination revealed no localized pain or tenderness in her hands, wrists, or clavicles. Radial pulses were easily palpated, and capillary refill was less than 2 seconds. There was no swelling or bruising. The rest of her physical exam was normal.

DIAGNOSIS

The patient was given a diagnosis of self-inflicted bilateral nursemaid elbows (BNME). Reductions were performed by individually stabilizing the elbows and hyper-pronating the forearms, with palpable clicks felt at the proximal radius. Even though a palpable click was felt, this motion was immediately followed by supination of the forearm and flexion at the elbow. The patient tolerated the procedures well and was using both arms normally within 10 minutes. She was discharged home shortly thereafter.

DISCUSSION

BNME is an uncommon diagnosis; a literature review of reported cases indicates none were self-inflicted.^1-4 However, NME is a common injury and is easily reduced. The classic mechanism of injury for NME involves the elbow in extension, while the forearm is pronated, and a sudden brisk axial traction is applied. This combination of motions causes the annular ligament to slip over the head of the radius and become displaced downward into the radiohumeral joint, where it becomes entrapped. In this case, the patient apparently exerted enough longitudinal traction while trying to lift the couch to produce the injury.

NME occurs most commonly in the left arm of girls between the ages of 4 months and 7 years and peaks at around the age of 2 years.⁵ A 2014 study by Irie et al⁶ corroborated the findings on left-side predominance and increased incidence with age, noting that frequency of injury peaked at 6 months in those younger than 1 year of age and at 2 years for those 1 year or older. However, the researchers found no significant sex difference.⁶

NME is radiographically indistinguishable from a healthy elbow.⁷ To prevent unnecessary expense and radiation exposure in young children, prereduction radiographs should only be used to rule out the possibility of fracture or other injury.⁷ Krul et al⁸ recommend restricting x-ray use to cases with an unclear history or those that are due to trauma other than an arm pull.

Continue to: Methods of reduction

Methods of reduction. Once NME is diagnosed, there are 2 methods of reduction: hyper-pronation and supination-flexion. Reduction is best performed with the child sitting in the parent’s lap with the injured arm facing the examiner.

Nursemaid’s elbow is radiographically indistinguishable from a healthy elbow.

Success rates for both methods of NME reduction are statistically similar; however, first-attempt success rates are significantly higher with the hyper-pronation method than with supination-flexion.⁹ Furthermore, physicians have deemed the hyper-­pronation method significantly easier to perform than supination-flexion.⁹ A Cochrane review by Krul et al¹⁰ concluded that the hyper-­pronation method may result in lower failure rates than supination-flexion, but due to limited evidence, the researchers were unable to draw any conclusions on other outcomes, such as pain. Green et al¹¹ noted that hyper-pronation is perceived by parents of children with NME as being less painful. For these reasons, hyper-pronation should be utilized as the first method of reduction, followed by supination-flexion if the former does not work.¹²

Additional management. In a limited study of 50 children with pulled-elbow injuries, ultrasound revealed that 78% had an intact yet interposed radial annular ligament and 22% had a tear in the radial annular ligament.¹³ The authors propose that if, after appropriate reduction methods are attempted, no pop is felt, or there is no prompt clinical improvement, and ultrasound is not available to assess the integrity of the annular ligament, the child should be placed in a splint for 7 days and referred for orthopedic intervention.¹³

Our patient returned to the PED 3 days later, complaining of pain and an inability to move her left arm after her older sibling pulled her by her outstretched arms. She was once again diagnosed with NME, the injury was reduced, and she was using the arm within minutes. She has not presented to either the PED or the pediatric clinic with a similar complaint since. Discarding outliers, NME recurrence rates fall within a range of 23.7% to 32.9%.^14,15

THE TAKEAWAY

Pre-reduction x-rays are not warranted in cases of NME unless there is suspicion for fracture or another injury. The 2 reduction methods, hyper-pronation and supination-flexion, are easily mastered. Any reduction should be quick, easy, and as painless as possible. Hyper-pronation should be utilized first, as this maneuver seems to be the more successful and is perceived by parents as being less painful. However, it is always most helpful to be proficient in both methods. If, after appropriate attempts at reduction, the child has not regained the use of the arm, 7 days of splinting is recommended, along with an orthopedic referral.

CORRESPONDENCE
Robert N. Anderson, DNP, APRN, (F)NP-C, ENP-BC, Vanderbilt Health, 512 Autumn Springs Court, Suite 100 C, Franklin, TN 37067; [email protected]

THE CASE

A 4-year-old girl was triaged to the Pediatric Emergency Department (PED) Fast Track, complaining of pain and limited movement in both arms. For an unknown reason, she had attempted to lift a heavy, 3-person sofa several hours earlier.

Her prior medical history included left nursemaid elbow (NME) at both 15 months and 33 months of age. Neither event had a known mechanism of injury. In both episodes, it was noted in the medical record that the child was not using her arm, “was holding it funny,” and was complaining of pain. Each time, she presented about 24 hours after symptom onset.

During the physical exam in the PED, the patient showed no signs of acute distress. She held both arms close to her body, with a slight flexion at the elbows, and her hands were pronated. She could not pinpoint the location of her discomfort and described diffuse pain in her forearms, elbows, and upper arms. Examination revealed no localized pain or tenderness in her hands, wrists, or clavicles. Radial pulses were easily palpated, and capillary refill was less than 2 seconds. There was no swelling or bruising. The rest of her physical exam was normal.

DIAGNOSIS

The patient was given a diagnosis of self-inflicted bilateral nursemaid elbows (BNME). Reductions were performed by individually stabilizing the elbows and hyper-pronating the forearms, with palpable clicks felt at the proximal radius. Even though a palpable click was felt, this motion was immediately followed by supination of the forearm and flexion at the elbow. The patient tolerated the procedures well and was using both arms normally within 10 minutes. She was discharged home shortly thereafter.

DISCUSSION

BNME is an uncommon diagnosis; a literature review of reported cases indicates none were self-inflicted.^1-4 However, NME is a common injury and is easily reduced. The classic mechanism of injury for NME involves the elbow in extension, while the forearm is pronated, and a sudden brisk axial traction is applied. This combination of motions causes the annular ligament to slip over the head of the radius and become displaced downward into the radiohumeral joint, where it becomes entrapped. In this case, the patient apparently exerted enough longitudinal traction while trying to lift the couch to produce the injury.

NME occurs most commonly in the left arm of girls between the ages of 4 months and 7 years and peaks at around the age of 2 years.⁵ A 2014 study by Irie et al⁶ corroborated the findings on left-side predominance and increased incidence with age, noting that frequency of injury peaked at 6 months in those younger than 1 year of age and at 2 years for those 1 year or older. However, the researchers found no significant sex difference.⁶

NME is radiographically indistinguishable from a healthy elbow.⁷ To prevent unnecessary expense and radiation exposure in young children, prereduction radiographs should only be used to rule out the possibility of fracture or other injury.⁷ Krul et al⁸ recommend restricting x-ray use to cases with an unclear history or those that are due to trauma other than an arm pull.

Continue to: Methods of reduction

Methods of reduction. Once NME is diagnosed, there are 2 methods of reduction: hyper-pronation and supination-flexion. Reduction is best performed with the child sitting in the parent’s lap with the injured arm facing the examiner.

Nursemaid’s elbow is radiographically indistinguishable from a healthy elbow.

Success rates for both methods of NME reduction are statistically similar; however, first-attempt success rates are significantly higher with the hyper-pronation method than with supination-flexion.⁹ Furthermore, physicians have deemed the hyper-­pronation method significantly easier to perform than supination-flexion.⁹ A Cochrane review by Krul et al¹⁰ concluded that the hyper-­pronation method may result in lower failure rates than supination-flexion, but due to limited evidence, the researchers were unable to draw any conclusions on other outcomes, such as pain. Green et al¹¹ noted that hyper-pronation is perceived by parents of children with NME as being less painful. For these reasons, hyper-pronation should be utilized as the first method of reduction, followed by supination-flexion if the former does not work.¹²

Additional management. In a limited study of 50 children with pulled-elbow injuries, ultrasound revealed that 78% had an intact yet interposed radial annular ligament and 22% had a tear in the radial annular ligament.¹³ The authors propose that if, after appropriate reduction methods are attempted, no pop is felt, or there is no prompt clinical improvement, and ultrasound is not available to assess the integrity of the annular ligament, the child should be placed in a splint for 7 days and referred for orthopedic intervention.¹³

Our patient returned to the PED 3 days later, complaining of pain and an inability to move her left arm after her older sibling pulled her by her outstretched arms. She was once again diagnosed with NME, the injury was reduced, and she was using the arm within minutes. She has not presented to either the PED or the pediatric clinic with a similar complaint since. Discarding outliers, NME recurrence rates fall within a range of 23.7% to 32.9%.^14,15

THE TAKEAWAY

Pre-reduction x-rays are not warranted in cases of NME unless there is suspicion for fracture or another injury. The 2 reduction methods, hyper-pronation and supination-flexion, are easily mastered. Any reduction should be quick, easy, and as painless as possible. Hyper-pronation should be utilized first, as this maneuver seems to be the more successful and is perceived by parents as being less painful. However, it is always most helpful to be proficient in both methods. If, after appropriate attempts at reduction, the child has not regained the use of the arm, 7 days of splinting is recommended, along with an orthopedic referral.

CORRESPONDENCE
Robert N. Anderson, DNP, APRN, (F)NP-C, ENP-BC, Vanderbilt Health, 512 Autumn Springs Court, Suite 100 C, Franklin, TN 37067; [email protected]

THE CASE

A 4-year-old girl was triaged to the Pediatric Emergency Department (PED) Fast Track, complaining of pain and limited movement in both arms. For an unknown reason, she had attempted to lift a heavy, 3-person sofa several hours earlier.

Her prior medical history included left nursemaid elbow (NME) at both 15 months and 33 months of age. Neither event had a known mechanism of injury. In both episodes, it was noted in the medical record that the child was not using her arm, “was holding it funny,” and was complaining of pain. Each time, she presented about 24 hours after symptom onset.

During the physical exam in the PED, the patient showed no signs of acute distress. She held both arms close to her body, with a slight flexion at the elbows, and her hands were pronated. She could not pinpoint the location of her discomfort and described diffuse pain in her forearms, elbows, and upper arms. Examination revealed no localized pain or tenderness in her hands, wrists, or clavicles. Radial pulses were easily palpated, and capillary refill was less than 2 seconds. There was no swelling or bruising. The rest of her physical exam was normal.

DIAGNOSIS

The patient was given a diagnosis of self-inflicted bilateral nursemaid elbows (BNME). Reductions were performed by individually stabilizing the elbows and hyper-pronating the forearms, with palpable clicks felt at the proximal radius. Even though a palpable click was felt, this motion was immediately followed by supination of the forearm and flexion at the elbow. The patient tolerated the procedures well and was using both arms normally within 10 minutes. She was discharged home shortly thereafter.

DISCUSSION

BNME is an uncommon diagnosis; a literature review of reported cases indicates none were self-inflicted.^1-4 However, NME is a common injury and is easily reduced. The classic mechanism of injury for NME involves the elbow in extension, while the forearm is pronated, and a sudden brisk axial traction is applied. This combination of motions causes the annular ligament to slip over the head of the radius and become displaced downward into the radiohumeral joint, where it becomes entrapped. In this case, the patient apparently exerted enough longitudinal traction while trying to lift the couch to produce the injury.

NME occurs most commonly in the left arm of girls between the ages of 4 months and 7 years and peaks at around the age of 2 years.⁵ A 2014 study by Irie et al⁶ corroborated the findings on left-side predominance and increased incidence with age, noting that frequency of injury peaked at 6 months in those younger than 1 year of age and at 2 years for those 1 year or older. However, the researchers found no significant sex difference.⁶

NME is radiographically indistinguishable from a healthy elbow.⁷ To prevent unnecessary expense and radiation exposure in young children, prereduction radiographs should only be used to rule out the possibility of fracture or other injury.⁷ Krul et al⁸ recommend restricting x-ray use to cases with an unclear history or those that are due to trauma other than an arm pull.

Continue to: Methods of reduction

Methods of reduction. Once NME is diagnosed, there are 2 methods of reduction: hyper-pronation and supination-flexion. Reduction is best performed with the child sitting in the parent’s lap with the injured arm facing the examiner.

Nursemaid’s elbow is radiographically indistinguishable from a healthy elbow.

Success rates for both methods of NME reduction are statistically similar; however, first-attempt success rates are significantly higher with the hyper-pronation method than with supination-flexion.⁹ Furthermore, physicians have deemed the hyper-­pronation method significantly easier to perform than supination-flexion.⁹ A Cochrane review by Krul et al¹⁰ concluded that the hyper-­pronation method may result in lower failure rates than supination-flexion, but due to limited evidence, the researchers were unable to draw any conclusions on other outcomes, such as pain. Green et al¹¹ noted that hyper-pronation is perceived by parents of children with NME as being less painful. For these reasons, hyper-pronation should be utilized as the first method of reduction, followed by supination-flexion if the former does not work.¹²

Additional management. In a limited study of 50 children with pulled-elbow injuries, ultrasound revealed that 78% had an intact yet interposed radial annular ligament and 22% had a tear in the radial annular ligament.¹³ The authors propose that if, after appropriate reduction methods are attempted, no pop is felt, or there is no prompt clinical improvement, and ultrasound is not available to assess the integrity of the annular ligament, the child should be placed in a splint for 7 days and referred for orthopedic intervention.¹³

Our patient returned to the PED 3 days later, complaining of pain and an inability to move her left arm after her older sibling pulled her by her outstretched arms. She was once again diagnosed with NME, the injury was reduced, and she was using the arm within minutes. She has not presented to either the PED or the pediatric clinic with a similar complaint since. Discarding outliers, NME recurrence rates fall within a range of 23.7% to 32.9%.^14,15

THE TAKEAWAY

Pre-reduction x-rays are not warranted in cases of NME unless there is suspicion for fracture or another injury. The 2 reduction methods, hyper-pronation and supination-flexion, are easily mastered. Any reduction should be quick, easy, and as painless as possible. Hyper-pronation should be utilized first, as this maneuver seems to be the more successful and is perceived by parents as being less painful. However, it is always most helpful to be proficient in both methods. If, after appropriate attempts at reduction, the child has not regained the use of the arm, 7 days of splinting is recommended, along with an orthopedic referral.

CORRESPONDENCE
Robert N. Anderson, DNP, APRN, (F)NP-C, ENP-BC, Vanderbilt Health, 512 Autumn Springs Court, Suite 100 C, Franklin, TN 37067; [email protected]

THE CASE

A 45-year-old man was admitted to the hospital with a fever and generalized rash. For the previous 2 weeks, he had been treated at a skilled nursing facility with IV vancomycin and cefepime for left calcaneal osteomyelitis. He reported that the rash was pruritic and started 2 days prior to hospital admission.

His past medical history was significant for type 2 diabetes mellitus and polysubstance drug abuse. Medical and travel history were otherwise unremarkable. The patient was taking the following medications at the time of presentation: hydrocodone-acetaminophen, cyclobenzaprine, melatonin, and metformin.

Initial vital signs included a temperature of 102.9°F; respiratory rate, 22 breaths/min; heart rate, 97 beats/min; and blood pressure, 89/50 mm Hg. Physical exam was notable for left anterior cervical and axillary lymphadenopathy. The patient had no facial edema, but he did have a diffuse, morbilliform rash on his bilateral upper and lower extremities, encompassing about 54% of his body surface area (FIGURE 1).

Laboratory studies revealed a white blood cell count of 4.7/mcL, with 3.4% eosinophils and 10.9% monocytes; an erythrocyte sedimentation rate of 60 mm/h; and a C-reactive protein level of 1 mg/dL. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were both elevated (AST: 95 U/L [normal range, 8 - 48 U/L]; ALT: 115 U/L [normal range: 7 - 55 U/L]). A chest x-ray was obtained and showed new lung infiltrates (FIGURE 2).

Linezolid and meropenem were initiated for a presumed health care–associated pneumonia, and a sepsis work-up was initiated.

THE DIAGNOSIS

The patient’s rash and pruritus worsened after meropenem was introduced. A hepatitis panel was nonreactive except for prior hepatitis A exposure. Ultrasound of the liver and spleen was normal. Investigation of pneumonia pathogens including Legionella, Streptococcus, Mycoplasma, and Chlamydia psittaci did not reveal any causative agents. A skin biopsy revealed perivascular neutrophilic dermatitis with dyskeratosis.

The patient was diagnosed with DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome based on his fever, worsening morbilliform rash, lymphadenopathy, and elevated liver transaminase levels. Although he did not have marked eosinophilia, atypical lymphocytes were present. Serologies for human herpesvirus (HHV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) were all unremarkable.

Continue to: During discussions...

During discussions with an infectious disease specialist, it was concluded that the patient’s DRESS syndrome was likely secondary to beta-lactam antibiotics. The patient had been receiving cefepime prior to hospitalization. Meropenem was discontinued and aztreonam was started, with continued linezolid. This patient did not have a reactivation of a herpesvirus (HHV-6, HHV-7, EBV, or CMV), which has been previously reported in cases of DRESS syndrome.

DISCUSSION

DRESS syndrome is a challenging diagnosis to make due to the multiplicity of presenting symptoms. Skin rash, lymphadenopathy, hepatic involvement, and hypereosinophilia are characteristic findings.¹ Accurate diagnosis reduces fatal disease outcomes, which are estimated to occur in 5%-10% of cases.^1,2

Causative agents. DRESS syndrome typically occurs 2 to 6 weeks after the introduction of the causative agent, commonly an aromatic anticonvulsant or antibiotic.³ The incidence of DRESS syndrome in patients using carbamazepine and phenytoin is estimated to be 1 to 5 per 10,000 patients. The incidence of DRESS syndrome in patients using antibiotics is unknown. Frequently, the inducing antibiotic is a beta-lactam, as in this case.^4,5

The pathogenesis of DRESS syndrome is not well understood, although there appears to be an immune-mediated reaction that occurs in certain patients after viral reactivation, particularly with herpesviruses. In vitro studies have demonstrated that the culprit drug is able to induce viral reactivation leading to T-lymphocyte response and systemic inflammation, which occurs in multiple organs.^6,7 Reported long-term sequelae of DRESS syndrome include immune-mediated diseases such as thyroiditis and type 1 diabetes. In addition, it is hypothesized that there is a genetic predisposition involving human leukocyte antigens that increases the likelihood that individuals will develop DRESS syndrome.^5,8

Skin rash, lymphadenopathy, hepatic involvement, and hypereosinophilia are characteristic findings of DRESS syndrome.

Diagnosis. The Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) was developed to assist in the diagnosis of DRESS syndrome.⁹ Patients should be assessed for 11 criteria (outlined in the TABLE⁹), with points applied for the presence, absence, or unknown status of each. A total score of > 5 is consistent with definitive diagnosis of DRESS syndrome, while a score of > 2 indicates probable DRESS syndrome. Additionally, a skin biopsy may be contributory by revealing a dense infiltrate of eosinophils or lymphocytes in the papillary dermis, but this is not needed to make the diagnosis.^10,11

Continue to: Treatment

Treatment is aimed at stopping the causative agent and starting moderate- to high-dose systemic corticosteroids (from 0.5 to 2 mg/kg/d). If symptoms continue to progress, cyclosporine can be used. ­N-acetylcysteine may also be beneficial due to its ability to neutralize drug metabolites that can stimulate T-cell response.⁷ There has not been sufficient evidence to suggest that antiviral medication should be initiated.^1,7

Our patient was treated with 2 mg/kg/d of prednisone, along with triamcinolone cream, diphenhydramine, and ­N-acetylcysteine. His rash improved dramatically during his hospital stay and at the subsequent 1-month follow-up was completely resolved.

THE TAKEAWAY

DRESS syndrome should be suspected in patients presenting with fever, rash, lymphadenopathy, pulmonary infiltrates, and liver involvement after initiation of drugs commonly associated with this syndrome. Our case reinforces previous clinical evidence that beta-lactam antibiotics are a common cause of DRESS syndrome; patients taking these medications should be closely monitored. Cross-reactions are frequent, and it is imperative that patients avoid related drugs to prevent recurrence. Although glucocorticoids are the mainstay of treatment, further studies are needed to assess the benefits of N-acetylcysteine.

CORRESPONDENCE
W. Jacob Cobb, MD, JPS Health Network, 1500 South Main Street, Fort Worth, TX, 76104; [email protected]

THE CASE

A 45-year-old man was admitted to the hospital with a fever and generalized rash. For the previous 2 weeks, he had been treated at a skilled nursing facility with IV vancomycin and cefepime for left calcaneal osteomyelitis. He reported that the rash was pruritic and started 2 days prior to hospital admission.

His past medical history was significant for type 2 diabetes mellitus and polysubstance drug abuse. Medical and travel history were otherwise unremarkable. The patient was taking the following medications at the time of presentation: hydrocodone-acetaminophen, cyclobenzaprine, melatonin, and metformin.

Initial vital signs included a temperature of 102.9°F; respiratory rate, 22 breaths/min; heart rate, 97 beats/min; and blood pressure, 89/50 mm Hg. Physical exam was notable for left anterior cervical and axillary lymphadenopathy. The patient had no facial edema, but he did have a diffuse, morbilliform rash on his bilateral upper and lower extremities, encompassing about 54% of his body surface area (FIGURE 1).

Laboratory studies revealed a white blood cell count of 4.7/mcL, with 3.4% eosinophils and 10.9% monocytes; an erythrocyte sedimentation rate of 60 mm/h; and a C-reactive protein level of 1 mg/dL. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were both elevated (AST: 95 U/L [normal range, 8 - 48 U/L]; ALT: 115 U/L [normal range: 7 - 55 U/L]). A chest x-ray was obtained and showed new lung infiltrates (FIGURE 2).

Linezolid and meropenem were initiated for a presumed health care–associated pneumonia, and a sepsis work-up was initiated.

THE DIAGNOSIS

The patient’s rash and pruritus worsened after meropenem was introduced. A hepatitis panel was nonreactive except for prior hepatitis A exposure. Ultrasound of the liver and spleen was normal. Investigation of pneumonia pathogens including Legionella, Streptococcus, Mycoplasma, and Chlamydia psittaci did not reveal any causative agents. A skin biopsy revealed perivascular neutrophilic dermatitis with dyskeratosis.

The patient was diagnosed with DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome based on his fever, worsening morbilliform rash, lymphadenopathy, and elevated liver transaminase levels. Although he did not have marked eosinophilia, atypical lymphocytes were present. Serologies for human herpesvirus (HHV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) were all unremarkable.

Continue to: During discussions...

During discussions with an infectious disease specialist, it was concluded that the patient’s DRESS syndrome was likely secondary to beta-lactam antibiotics. The patient had been receiving cefepime prior to hospitalization. Meropenem was discontinued and aztreonam was started, with continued linezolid. This patient did not have a reactivation of a herpesvirus (HHV-6, HHV-7, EBV, or CMV), which has been previously reported in cases of DRESS syndrome.

DISCUSSION

DRESS syndrome is a challenging diagnosis to make due to the multiplicity of presenting symptoms. Skin rash, lymphadenopathy, hepatic involvement, and hypereosinophilia are characteristic findings.¹ Accurate diagnosis reduces fatal disease outcomes, which are estimated to occur in 5%-10% of cases.^1,2

Causative agents. DRESS syndrome typically occurs 2 to 6 weeks after the introduction of the causative agent, commonly an aromatic anticonvulsant or antibiotic.³ The incidence of DRESS syndrome in patients using carbamazepine and phenytoin is estimated to be 1 to 5 per 10,000 patients. The incidence of DRESS syndrome in patients using antibiotics is unknown. Frequently, the inducing antibiotic is a beta-lactam, as in this case.^4,5

The pathogenesis of DRESS syndrome is not well understood, although there appears to be an immune-mediated reaction that occurs in certain patients after viral reactivation, particularly with herpesviruses. In vitro studies have demonstrated that the culprit drug is able to induce viral reactivation leading to T-lymphocyte response and systemic inflammation, which occurs in multiple organs.^6,7 Reported long-term sequelae of DRESS syndrome include immune-mediated diseases such as thyroiditis and type 1 diabetes. In addition, it is hypothesized that there is a genetic predisposition involving human leukocyte antigens that increases the likelihood that individuals will develop DRESS syndrome.^5,8

Skin rash, lymphadenopathy, hepatic involvement, and hypereosinophilia are characteristic findings of DRESS syndrome.

Diagnosis. The Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) was developed to assist in the diagnosis of DRESS syndrome.⁹ Patients should be assessed for 11 criteria (outlined in the TABLE⁹), with points applied for the presence, absence, or unknown status of each. A total score of > 5 is consistent with definitive diagnosis of DRESS syndrome, while a score of > 2 indicates probable DRESS syndrome. Additionally, a skin biopsy may be contributory by revealing a dense infiltrate of eosinophils or lymphocytes in the papillary dermis, but this is not needed to make the diagnosis.^10,11

Continue to: Treatment

Treatment is aimed at stopping the causative agent and starting moderate- to high-dose systemic corticosteroids (from 0.5 to 2 mg/kg/d). If symptoms continue to progress, cyclosporine can be used. ­N-acetylcysteine may also be beneficial due to its ability to neutralize drug metabolites that can stimulate T-cell response.⁷ There has not been sufficient evidence to suggest that antiviral medication should be initiated.^1,7

Our patient was treated with 2 mg/kg/d of prednisone, along with triamcinolone cream, diphenhydramine, and ­N-acetylcysteine. His rash improved dramatically during his hospital stay and at the subsequent 1-month follow-up was completely resolved.

THE TAKEAWAY

DRESS syndrome should be suspected in patients presenting with fever, rash, lymphadenopathy, pulmonary infiltrates, and liver involvement after initiation of drugs commonly associated with this syndrome. Our case reinforces previous clinical evidence that beta-lactam antibiotics are a common cause of DRESS syndrome; patients taking these medications should be closely monitored. Cross-reactions are frequent, and it is imperative that patients avoid related drugs to prevent recurrence. Although glucocorticoids are the mainstay of treatment, further studies are needed to assess the benefits of N-acetylcysteine.

CORRESPONDENCE
W. Jacob Cobb, MD, JPS Health Network, 1500 South Main Street, Fort Worth, TX, 76104; [email protected]

THE CASE

A 45-year-old man was admitted to the hospital with a fever and generalized rash. For the previous 2 weeks, he had been treated at a skilled nursing facility with IV vancomycin and cefepime for left calcaneal osteomyelitis. He reported that the rash was pruritic and started 2 days prior to hospital admission.

His past medical history was significant for type 2 diabetes mellitus and polysubstance drug abuse. Medical and travel history were otherwise unremarkable. The patient was taking the following medications at the time of presentation: hydrocodone-acetaminophen, cyclobenzaprine, melatonin, and metformin.

Initial vital signs included a temperature of 102.9°F; respiratory rate, 22 breaths/min; heart rate, 97 beats/min; and blood pressure, 89/50 mm Hg. Physical exam was notable for left anterior cervical and axillary lymphadenopathy. The patient had no facial edema, but he did have a diffuse, morbilliform rash on his bilateral upper and lower extremities, encompassing about 54% of his body surface area (FIGURE 1).

Laboratory studies revealed a white blood cell count of 4.7/mcL, with 3.4% eosinophils and 10.9% monocytes; an erythrocyte sedimentation rate of 60 mm/h; and a C-reactive protein level of 1 mg/dL. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were both elevated (AST: 95 U/L [normal range, 8 - 48 U/L]; ALT: 115 U/L [normal range: 7 - 55 U/L]). A chest x-ray was obtained and showed new lung infiltrates (FIGURE 2).

Linezolid and meropenem were initiated for a presumed health care–associated pneumonia, and a sepsis work-up was initiated.

THE DIAGNOSIS

The patient’s rash and pruritus worsened after meropenem was introduced. A hepatitis panel was nonreactive except for prior hepatitis A exposure. Ultrasound of the liver and spleen was normal. Investigation of pneumonia pathogens including Legionella, Streptococcus, Mycoplasma, and Chlamydia psittaci did not reveal any causative agents. A skin biopsy revealed perivascular neutrophilic dermatitis with dyskeratosis.

The patient was diagnosed with DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome based on his fever, worsening morbilliform rash, lymphadenopathy, and elevated liver transaminase levels. Although he did not have marked eosinophilia, atypical lymphocytes were present. Serologies for human herpesvirus (HHV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) were all unremarkable.

Continue to: During discussions...

During discussions with an infectious disease specialist, it was concluded that the patient’s DRESS syndrome was likely secondary to beta-lactam antibiotics. The patient had been receiving cefepime prior to hospitalization. Meropenem was discontinued and aztreonam was started, with continued linezolid. This patient did not have a reactivation of a herpesvirus (HHV-6, HHV-7, EBV, or CMV), which has been previously reported in cases of DRESS syndrome.

DISCUSSION

DRESS syndrome is a challenging diagnosis to make due to the multiplicity of presenting symptoms. Skin rash, lymphadenopathy, hepatic involvement, and hypereosinophilia are characteristic findings.¹ Accurate diagnosis reduces fatal disease outcomes, which are estimated to occur in 5%-10% of cases.^1,2

Causative agents. DRESS syndrome typically occurs 2 to 6 weeks after the introduction of the causative agent, commonly an aromatic anticonvulsant or antibiotic.³ The incidence of DRESS syndrome in patients using carbamazepine and phenytoin is estimated to be 1 to 5 per 10,000 patients. The incidence of DRESS syndrome in patients using antibiotics is unknown. Frequently, the inducing antibiotic is a beta-lactam, as in this case.^4,5

The pathogenesis of DRESS syndrome is not well understood, although there appears to be an immune-mediated reaction that occurs in certain patients after viral reactivation, particularly with herpesviruses. In vitro studies have demonstrated that the culprit drug is able to induce viral reactivation leading to T-lymphocyte response and systemic inflammation, which occurs in multiple organs.^6,7 Reported long-term sequelae of DRESS syndrome include immune-mediated diseases such as thyroiditis and type 1 diabetes. In addition, it is hypothesized that there is a genetic predisposition involving human leukocyte antigens that increases the likelihood that individuals will develop DRESS syndrome.^5,8

Skin rash, lymphadenopathy, hepatic involvement, and hypereosinophilia are characteristic findings of DRESS syndrome.

Diagnosis. The Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) was developed to assist in the diagnosis of DRESS syndrome.⁹ Patients should be assessed for 11 criteria (outlined in the TABLE⁹), with points applied for the presence, absence, or unknown status of each. A total score of > 5 is consistent with definitive diagnosis of DRESS syndrome, while a score of > 2 indicates probable DRESS syndrome. Additionally, a skin biopsy may be contributory by revealing a dense infiltrate of eosinophils or lymphocytes in the papillary dermis, but this is not needed to make the diagnosis.^10,11

Continue to: Treatment

Treatment is aimed at stopping the causative agent and starting moderate- to high-dose systemic corticosteroids (from 0.5 to 2 mg/kg/d). If symptoms continue to progress, cyclosporine can be used. ­N-acetylcysteine may also be beneficial due to its ability to neutralize drug metabolites that can stimulate T-cell response.⁷ There has not been sufficient evidence to suggest that antiviral medication should be initiated.^1,7

Our patient was treated with 2 mg/kg/d of prednisone, along with triamcinolone cream, diphenhydramine, and ­N-acetylcysteine. His rash improved dramatically during his hospital stay and at the subsequent 1-month follow-up was completely resolved.

THE TAKEAWAY

DRESS syndrome should be suspected in patients presenting with fever, rash, lymphadenopathy, pulmonary infiltrates, and liver involvement after initiation of drugs commonly associated with this syndrome. Our case reinforces previous clinical evidence that beta-lactam antibiotics are a common cause of DRESS syndrome; patients taking these medications should be closely monitored. Cross-reactions are frequent, and it is imperative that patients avoid related drugs to prevent recurrence. Although glucocorticoids are the mainstay of treatment, further studies are needed to assess the benefits of N-acetylcysteine.

CORRESPONDENCE
W. Jacob Cobb, MD, JPS Health Network, 1500 South Main Street, Fort Worth, TX, 76104; [email protected]

Wernicke-Korsakoff syndrome is a cluster of symptoms attributed to a disorder of vitamin B1 (thiamine) deficiency, manifesting as a combined presentation of alcohol-induced Wernicke encephalopathy (WE) and Korsakoff syndrome (KS).¹ While there is consensus on the characteristic presentation and symptoms of WE, there is a lack of agreement on the exact definition of KS. The classic triad describing WE consists of ataxia, ophthalmoplegia, and confusion; however, reports now suggest that a majority of patients exhibit only 1 or 2 of the elements of the triad. KS is often seen as a condition of chronic thiamine deficiency manifesting as memory impairment alongside a cognitive and behavioral decline, with no clear consensus on the sequence of appearance of symptoms. The typical relationship is thought to be a progression of WE to KS if untreated.

From a mental health perspective, WE presents with delirium and confusion whereas KS manifests with irreversible dementia and a cognitive deterioration. Though it is commonly taught that KS-induced memory loss is permanent due to neuronal damage (classically identified as damage to the mammillary bodies - though other structures have been implicated as well), more recent research suggest otherwise.² A review published in 2018, for example, gathered several case reports and case series that suggest significant improvement in memory and cognition attributed to behavioral and pharmacologic interventions, indicating this as an area deserving of further study.³ About 20% of patients diagnosed with WE by autopsy exhibited none of the classical triad symptoms prior to death.⁴ Hence, these conditions are surmised to be significantly underdiagnosed and misdiagnosed.

Though consensus regarding the appropriate treatment regimen is lacking for WE, a common protocol consists of high-dose parenteral thiamine for 4 to 7 days.⁵ This is usually followed by daily oral thiamine repletion until the patient either achieves complete abstinence from alcohol (ideal) or decreases consumption. The goal is to allow thiamine stores to replete and maintain at minimum required body levels moving forward. In this case report, we highlight the utilization of a long-term, unconventional intramuscular (IM) thiamine repletion regimen to ensure maintenance of a patient’s mental status, highlighting discrepancies in our understanding of the mechanisms at play in WE and its treatment.

Case Presentation

A 65-year-old male patient with a more than 3-decade history of daily hard liquor intake, multiple psychiatric hospitalizations for WE, and a prior suicide attempt, presented to the emergency department (ED) with increased frequency of falls, poor oral intake, confabulation, and diminished verbal communication. A chart review revealed memory impairment alongside the diagnoses of schizoaffective disorder and WE, and confusion that was responsive to thiamine administration as well as a history of hypertension, hyperlipidemia, osteoarthritis, and urinary retention secondary to benign prostatic hyperplasia (BPH).

On examination the patient was found to be disoriented with a clouded sensorium. While the history of heavy daily alcohol use was clear in the chart and confirmed by other sources, it appeared unlikely that the patient had been using alcohol in the preceding month due to restricted access in his most recent living environment (a shared apartment with daily nursing assistance). He reported no lightheadedness, dizziness, palpitations, numbness, tingling, or any head trauma. He also negated the presence of active mood symptoms, auditory or visual hallucinations or suicidal ideation (SI)

The patient was admitted to the Internal Medicine Service and received a workup for the causes of delirium, including consideration of normal pressure hydrocephalus (NPH) and other neurologic conditions. Laboratory tests including a comprehensive metabolic panel, thyroid stimulating hormone, urinalysis, urine toxicology screen, and vitamin B12 and folate levels were in normal ranges. Although brain imaging revealed enlarged ventricles, NPH was considered unlikely because of the absence of ophthalmologic abnormalities, like gaze nystagmus, and urinary incontinence; conversely, there was some presence of urinary retention attributed to BPH and required an admission a few months prior. Moreover, magnetic resonance images showed that the ventricles were enlarged slightly out of proportion to the sulci, which can be seen with predominantly central volume loss compared with the pattern typically seen in NPH.

In light of concern for WE and the patient's history, treatment with IV thiamine and IV fluids was initiated and the Liaison Psychiatry Service was consulted for cognitive disability and treatment of his mood. Administration of IV thiamine rapidly restored his sensorium, but he became abruptly disorganized as the IV regimen graduated to an oral thiamine dose of 200 mg 3 times daily. Simultaneously, as medical stabilization was achieved, the patient was transferred to the inpatient psychiatry unit to address the nonresolving cognitive impairment and behavioral disorganization. This specifically involved newly emerging, impulsive, self-harming behaviors like throwing himself on the ground and banging his head on the floor. Such behaviors along with paucity of speech and decreased oral intake, ultimately warranted constant observation, which led to a decrease in self-harming activity. All this behavior was noted even though the patient was adherent to oral administration of thiamine. Throughout this time, the patient underwent several transfers back and forth between the Psychiatry and Internal Medicine services due to ongoing concern for the possibility of delirium or WE. However, the Neurology and Internal Medicine services did not feel that WE would explain the patient’s mental and behavioral status, in part due to his ongoing adherence with daily oral thiamine dosing that was not associated with improvement in mental status.

Recollecting the patient’s improvement with the parenteral thiamine regimen (IV and IM), the psychiatry unit tried a thiamine regimen of 200 mg IM and 100 mg oral 2 times daily. After about 2 weeks on this regimen, the patient subsequently achieved remarkable improvement in his cognitive and behavioral status, with resolution of selfharming behaviors. The patient was noted to be calmer, more linear, and more oriented, though he remained incompletely oriented throughout his hospitalization. As improvement in sensorium was established and the patient’s hospital stay prolonged (Figure), his mood symptoms began manifesting as guilt, low energy, decreased appetite, withdrawal, and passive SI. This was followed by a trial of lithium that was discontinued due to elevated creatine levels. As the patient continued to report depression, a multidrug regimen of divalproex, fluoxetine, and quetiapine was administered, which lead to remarkable improvement.

At this time, it was concluded that the stores of thiamine in the patient’s body may have been replenished, the alcohol intake completely ceased and that he needed to be weaned off of thiamine. The next step taken was reduction of the twice daily 200 mg IM thiamine dose to a once daily regimen, and oral thiamine was put on hold. Over the next 48 hours, the patient became less verbal, more withdrawn, incontinent of urine, and delirious. The twice daily IM 200 mg thiamine was restarted, but this time the patient demonstrated very slow improvement. After 2 weeks, the IM thiamine 200 mg was increased to 3 times daily, and the patient showed marked improvement in recall, mood, and effect.

Several attempts were made to reduce the IM thiamine burden on the patient and/ or transition to an exclusively oral regimen. However, he rapidly decompensated within hours of each attempt to taper the IM dose and required immediate reinstation. On the IM thiamine regimen, he eventually appeared to reach a stable cognitive and affective baseline marked by incomplete orientation but pleasant affect, he reported no mood complaints, behavioral stability, and an ability to comply with care needs and have simple conversations. Some speech content remained disorganized particularly if engaged beyond simple exchanges.

The patient was discharged to a skilled nursing facility after a month of 3 times daily IM administration of thiamine. Within the next 24 hours, the patient returned to the ED with the originally reported symptoms of ataxia, agitation, and confusion. On inquiry, it was revealed that the ordered vials of IM thiamine for injection had not arrived with him at the nursing facility and he had missed 2 doses. The blood laboratory results, scans, and all other parameters were otherwise found to be normal and the patient was adherent to his prescribed antipsychotics and antidepressants. As anticipated, restoration of the IM thiamine regimen revived his baseline within hours. While confusion and delirium resolved completely with treatment, the memory impairments persisted. This patient has been administered a 3 times daily IM dose of 200 mg thiamine for more than 2 years with a stable cognitive clinical picture.

Discussion

According to data from the 2016 National Survey on Drug Use and Health, 16 million individuals in the US aged ≥ 12 years reported heavy alcohol use, which is defined as binge drinking on ≥ 5 days in the past month.6,7 Thiamine deficiency is an alcoholrelated disorder that is frequently encountered in hospital settings. This deficiency can also occur in the context of malabsorption, malnutrition, a prolonged course of vomiting, and bariatric surgery.^8,9

The deficiency in thiamine, which is sometimes known as WE, manifests rarely with all 3 of the classic triad of gait disturbances, abnormal eye movements, and mental status changes, with only 16.5% of patients displaying all of the triad.⁴ Moreover, there may be additional symptoms not listed in this triad, such as memory impairment, bilateral sixth nerve palsy, ptosis, hypotension, and hypothermia.^10.11 This inconsistent presentation makes the diagnosis challenging and therefore requires a higher threshold for suspicion. If undiagnosed and/or untreated, WE can lead to chronic thiamine deficiency causing permanent brain damage in the guise of KS. This further increases the importance of timely diagnosis and treatment.

Our case highlights the utilization of an unconventional thiamine regimen that appeared to be temporally associated with mental status improvement. The patient’s clouded sensorium and confusion could not be attributed to metabolic, encephalopathic, or infectious pathologies due to the absence of supportive laboratory evidence. He responded to IV and IM doses of thiamine, but repeated attempts to taper the IM doses with the objective of transitioning to oral thiamine supplementation were followed by immediate decompensations in mental status. This was atypical of WE as the patient seemed adequately replete with thiamine, and missing a few doses should not be enough to deplete his stores. Thus, reflecting a unique case of thiamine-dependent chronically set WE when even a single missed dose of thiamine adversely affected the patient’s cognitive baseline. Interesting to note is this patient’s memory issue, as evident by clinical examination and dating back at least 5 years as per chart review. This premature amnestic component of his presentation indicates a likely parallel running KS component of his presentation. Conversely, the patient’s long history of alcohol use disorder, prior episodes of WE, and ideal response achieved only on parenteral thiamine repletion further supported the diagnosis of WE and our impression of the scenario.

Even though this patient had prior episodes of WE, there remained diagnostic uncertainty regarding his altered mental status for some time before the nonoral thiamine repletion treatment was implemented. Particularly in this admission, the patient’s mental status frequently waxed and waned and there was the additional confusion of whether a potential psychiatric etiology contributed to some of the elements of his presentation, such as his impulsive self-harm behaviors. This behavior led to recurrent transfers among the Psychiatry Service, Internal Medicine Service, and the ED.

The patient’s presentation did not reflect the classical triad of WE, and while this is consistent with the majority of clinical manifestations, various services were reluctant to attribute his symptoms to WE. Once the threshold of suspicion of thiamine deficiency was lowered and the deficit treated more aggressively, the patient seemed to improve tremendously. Presence of memory problems and confabulation, both of which this patient exhibited, are suggestive of KS and are not expected to recover with treatment, yet for this patient there did seem to be some improvement—though not complete resolution. This is consistent with newer evidence suggesting that some recovery from the deficits seen in KS is possible.³

Once diagnosed, the treatment objective is the replenishment of thiamine stores and optimization of the metabolic scenario of the body to prevent recurrence. For acute WE symptoms, many regimens call for 250 to 500 mg of IV thiamine supplementation 2 to 3 times daily for 3 to 5 days. High dose IV thiamine (≥ 500 mg daily) has been proposed to be efficacious and free of considerable adverse effects.¹² A study conducted at the University of North Carolina described thiamine prescribing practices in a large academic hospital, analyzing data with the objective of assessing outcomes of ordering high-dose IV thiamine (HDIV, ≥ 200 mg IV twice daily) to patients with encephalopathy. ¹³ The researchers concluded that HDIV, even though rarely prescribed, was associated with decreased inpatient mortality in bivariable models. However, in multivariable analyses this decrease was found to be clinically insignificant. Our patient benefitted from both IV and IM delivery.

Ideally, after the initial IV thiamine dose, oral administration of thiamine 250 to 1,000 mg is continued until a reduction, if not abstinence, from alcohol use is achieved.⁵ Many patients are discharged on an oral maintenance dose of thiamine 100 mg. Oral thiamine is poorly absorbed and less effective in both prophylaxis and treatment of newly diagnosed WE; therefore, it is typically used only after IM or IV replenishment. It remains unclear why this patient required IM thiamine multiple times per day to maintain his mental status, and why he would present with selfinjurious behaviors after missing doses. The patient’s response can be attributed to late-onset defects in oral thiamine absorption at the carrier protein level of the brush border and basolateral membranes of his jejunum; however, an invasive procedure like a jejunal biopsy to establish the definitive etiology was neither necessary nor practical once treatment response was observed. ¹⁴ Other possible explanations include rapid thiamine metabolism, poor gastrointestinal absorption and a late-onset deficit in the thiamine diffusion mechanisms, and active transport systems (thiamine utilization depends on active transport in low availability states and passive transport when readily available). The nature of these mechanisms deserves further study. Less data have been reported on the administration and utility of IM thiamine for chronic WE; hence, our case report is one of the first illustrating the role of this method for sustained repletion.

Conclusions

This case presented a clinical dilemma because the conventional treatment regimen for WE didn’t yield the desired outcome until the mode and duration of thiamine administration were adjusted. It illustrates the utility of a sustained intensive thiamine regimen irrespective of sobriety status, as opposed to the traditional regimen of parenteral (primarily IV) thiamine for 3 to 7 days, followed by oral repletion until the patient achieves sustained abstinence. In this patient’s case, access to nursing care postdischarge facilitated his continued adherence to IM thiamine therapy.

The longitudinal time course of this case suggests a relationship between this route of administration and improvement in symptom burden and indicates that this patient may have a long-term need for IM thiamine to maintain his baseline mental status. Of great benefit in such patients would be the availability of a long-acting IM thiamine therapy. Risk of overdose is unlikely due to the water solubility of B group vitamins.

This case report highlights the importance of setting a high clinical suspicion for WE due to its ever-increasing incidence in these times. We also wish to direct researchers to consider other out-of-the-box treatment options in case of failure of the conventional regime. In documenting this patient report, we invite more medical providers to investigate and explore other therapeutic options for WE treatment with the aim of decreasing both morbidity and mortality secondary to the condition.

Wernicke-Korsakoff syndrome is a cluster of symptoms attributed to a disorder of vitamin B1 (thiamine) deficiency, manifesting as a combined presentation of alcohol-induced Wernicke encephalopathy (WE) and Korsakoff syndrome (KS).¹ While there is consensus on the characteristic presentation and symptoms of WE, there is a lack of agreement on the exact definition of KS. The classic triad describing WE consists of ataxia, ophthalmoplegia, and confusion; however, reports now suggest that a majority of patients exhibit only 1 or 2 of the elements of the triad. KS is often seen as a condition of chronic thiamine deficiency manifesting as memory impairment alongside a cognitive and behavioral decline, with no clear consensus on the sequence of appearance of symptoms. The typical relationship is thought to be a progression of WE to KS if untreated.

From a mental health perspective, WE presents with delirium and confusion whereas KS manifests with irreversible dementia and a cognitive deterioration. Though it is commonly taught that KS-induced memory loss is permanent due to neuronal damage (classically identified as damage to the mammillary bodies - though other structures have been implicated as well), more recent research suggest otherwise.² A review published in 2018, for example, gathered several case reports and case series that suggest significant improvement in memory and cognition attributed to behavioral and pharmacologic interventions, indicating this as an area deserving of further study.³ About 20% of patients diagnosed with WE by autopsy exhibited none of the classical triad symptoms prior to death.⁴ Hence, these conditions are surmised to be significantly underdiagnosed and misdiagnosed.

Though consensus regarding the appropriate treatment regimen is lacking for WE, a common protocol consists of high-dose parenteral thiamine for 4 to 7 days.⁵ This is usually followed by daily oral thiamine repletion until the patient either achieves complete abstinence from alcohol (ideal) or decreases consumption. The goal is to allow thiamine stores to replete and maintain at minimum required body levels moving forward. In this case report, we highlight the utilization of a long-term, unconventional intramuscular (IM) thiamine repletion regimen to ensure maintenance of a patient’s mental status, highlighting discrepancies in our understanding of the mechanisms at play in WE and its treatment.

Case Presentation

A 65-year-old male patient with a more than 3-decade history of daily hard liquor intake, multiple psychiatric hospitalizations for WE, and a prior suicide attempt, presented to the emergency department (ED) with increased frequency of falls, poor oral intake, confabulation, and diminished verbal communication. A chart review revealed memory impairment alongside the diagnoses of schizoaffective disorder and WE, and confusion that was responsive to thiamine administration as well as a history of hypertension, hyperlipidemia, osteoarthritis, and urinary retention secondary to benign prostatic hyperplasia (BPH).

On examination the patient was found to be disoriented with a clouded sensorium. While the history of heavy daily alcohol use was clear in the chart and confirmed by other sources, it appeared unlikely that the patient had been using alcohol in the preceding month due to restricted access in his most recent living environment (a shared apartment with daily nursing assistance). He reported no lightheadedness, dizziness, palpitations, numbness, tingling, or any head trauma. He also negated the presence of active mood symptoms, auditory or visual hallucinations or suicidal ideation (SI)

The patient was admitted to the Internal Medicine Service and received a workup for the causes of delirium, including consideration of normal pressure hydrocephalus (NPH) and other neurologic conditions. Laboratory tests including a comprehensive metabolic panel, thyroid stimulating hormone, urinalysis, urine toxicology screen, and vitamin B12 and folate levels were in normal ranges. Although brain imaging revealed enlarged ventricles, NPH was considered unlikely because of the absence of ophthalmologic abnormalities, like gaze nystagmus, and urinary incontinence; conversely, there was some presence of urinary retention attributed to BPH and required an admission a few months prior. Moreover, magnetic resonance images showed that the ventricles were enlarged slightly out of proportion to the sulci, which can be seen with predominantly central volume loss compared with the pattern typically seen in NPH.

In light of concern for WE and the patient's history, treatment with IV thiamine and IV fluids was initiated and the Liaison Psychiatry Service was consulted for cognitive disability and treatment of his mood. Administration of IV thiamine rapidly restored his sensorium, but he became abruptly disorganized as the IV regimen graduated to an oral thiamine dose of 200 mg 3 times daily. Simultaneously, as medical stabilization was achieved, the patient was transferred to the inpatient psychiatry unit to address the nonresolving cognitive impairment and behavioral disorganization. This specifically involved newly emerging, impulsive, self-harming behaviors like throwing himself on the ground and banging his head on the floor. Such behaviors along with paucity of speech and decreased oral intake, ultimately warranted constant observation, which led to a decrease in self-harming activity. All this behavior was noted even though the patient was adherent to oral administration of thiamine. Throughout this time, the patient underwent several transfers back and forth between the Psychiatry and Internal Medicine services due to ongoing concern for the possibility of delirium or WE. However, the Neurology and Internal Medicine services did not feel that WE would explain the patient’s mental and behavioral status, in part due to his ongoing adherence with daily oral thiamine dosing that was not associated with improvement in mental status.

Recollecting the patient’s improvement with the parenteral thiamine regimen (IV and IM), the psychiatry unit tried a thiamine regimen of 200 mg IM and 100 mg oral 2 times daily. After about 2 weeks on this regimen, the patient subsequently achieved remarkable improvement in his cognitive and behavioral status, with resolution of selfharming behaviors. The patient was noted to be calmer, more linear, and more oriented, though he remained incompletely oriented throughout his hospitalization. As improvement in sensorium was established and the patient’s hospital stay prolonged (Figure), his mood symptoms began manifesting as guilt, low energy, decreased appetite, withdrawal, and passive SI. This was followed by a trial of lithium that was discontinued due to elevated creatine levels. As the patient continued to report depression, a multidrug regimen of divalproex, fluoxetine, and quetiapine was administered, which lead to remarkable improvement.

At this time, it was concluded that the stores of thiamine in the patient’s body may have been replenished, the alcohol intake completely ceased and that he needed to be weaned off of thiamine. The next step taken was reduction of the twice daily 200 mg IM thiamine dose to a once daily regimen, and oral thiamine was put on hold. Over the next 48 hours, the patient became less verbal, more withdrawn, incontinent of urine, and delirious. The twice daily IM 200 mg thiamine was restarted, but this time the patient demonstrated very slow improvement. After 2 weeks, the IM thiamine 200 mg was increased to 3 times daily, and the patient showed marked improvement in recall, mood, and effect.

Several attempts were made to reduce the IM thiamine burden on the patient and/ or transition to an exclusively oral regimen. However, he rapidly decompensated within hours of each attempt to taper the IM dose and required immediate reinstation. On the IM thiamine regimen, he eventually appeared to reach a stable cognitive and affective baseline marked by incomplete orientation but pleasant affect, he reported no mood complaints, behavioral stability, and an ability to comply with care needs and have simple conversations. Some speech content remained disorganized particularly if engaged beyond simple exchanges.

The patient was discharged to a skilled nursing facility after a month of 3 times daily IM administration of thiamine. Within the next 24 hours, the patient returned to the ED with the originally reported symptoms of ataxia, agitation, and confusion. On inquiry, it was revealed that the ordered vials of IM thiamine for injection had not arrived with him at the nursing facility and he had missed 2 doses. The blood laboratory results, scans, and all other parameters were otherwise found to be normal and the patient was adherent to his prescribed antipsychotics and antidepressants. As anticipated, restoration of the IM thiamine regimen revived his baseline within hours. While confusion and delirium resolved completely with treatment, the memory impairments persisted. This patient has been administered a 3 times daily IM dose of 200 mg thiamine for more than 2 years with a stable cognitive clinical picture.

Discussion

According to data from the 2016 National Survey on Drug Use and Health, 16 million individuals in the US aged ≥ 12 years reported heavy alcohol use, which is defined as binge drinking on ≥ 5 days in the past month.6,7 Thiamine deficiency is an alcoholrelated disorder that is frequently encountered in hospital settings. This deficiency can also occur in the context of malabsorption, malnutrition, a prolonged course of vomiting, and bariatric surgery.^8,9

The deficiency in thiamine, which is sometimes known as WE, manifests rarely with all 3 of the classic triad of gait disturbances, abnormal eye movements, and mental status changes, with only 16.5% of patients displaying all of the triad.⁴ Moreover, there may be additional symptoms not listed in this triad, such as memory impairment, bilateral sixth nerve palsy, ptosis, hypotension, and hypothermia.^10.11 This inconsistent presentation makes the diagnosis challenging and therefore requires a higher threshold for suspicion. If undiagnosed and/or untreated, WE can lead to chronic thiamine deficiency causing permanent brain damage in the guise of KS. This further increases the importance of timely diagnosis and treatment.

Our case highlights the utilization of an unconventional thiamine regimen that appeared to be temporally associated with mental status improvement. The patient’s clouded sensorium and confusion could not be attributed to metabolic, encephalopathic, or infectious pathologies due to the absence of supportive laboratory evidence. He responded to IV and IM doses of thiamine, but repeated attempts to taper the IM doses with the objective of transitioning to oral thiamine supplementation were followed by immediate decompensations in mental status. This was atypical of WE as the patient seemed adequately replete with thiamine, and missing a few doses should not be enough to deplete his stores. Thus, reflecting a unique case of thiamine-dependent chronically set WE when even a single missed dose of thiamine adversely affected the patient’s cognitive baseline. Interesting to note is this patient’s memory issue, as evident by clinical examination and dating back at least 5 years as per chart review. This premature amnestic component of his presentation indicates a likely parallel running KS component of his presentation. Conversely, the patient’s long history of alcohol use disorder, prior episodes of WE, and ideal response achieved only on parenteral thiamine repletion further supported the diagnosis of WE and our impression of the scenario.

Even though this patient had prior episodes of WE, there remained diagnostic uncertainty regarding his altered mental status for some time before the nonoral thiamine repletion treatment was implemented. Particularly in this admission, the patient’s mental status frequently waxed and waned and there was the additional confusion of whether a potential psychiatric etiology contributed to some of the elements of his presentation, such as his impulsive self-harm behaviors. This behavior led to recurrent transfers among the Psychiatry Service, Internal Medicine Service, and the ED.

The patient’s presentation did not reflect the classical triad of WE, and while this is consistent with the majority of clinical manifestations, various services were reluctant to attribute his symptoms to WE. Once the threshold of suspicion of thiamine deficiency was lowered and the deficit treated more aggressively, the patient seemed to improve tremendously. Presence of memory problems and confabulation, both of which this patient exhibited, are suggestive of KS and are not expected to recover with treatment, yet for this patient there did seem to be some improvement—though not complete resolution. This is consistent with newer evidence suggesting that some recovery from the deficits seen in KS is possible.³

Once diagnosed, the treatment objective is the replenishment of thiamine stores and optimization of the metabolic scenario of the body to prevent recurrence. For acute WE symptoms, many regimens call for 250 to 500 mg of IV thiamine supplementation 2 to 3 times daily for 3 to 5 days. High dose IV thiamine (≥ 500 mg daily) has been proposed to be efficacious and free of considerable adverse effects.¹² A study conducted at the University of North Carolina described thiamine prescribing practices in a large academic hospital, analyzing data with the objective of assessing outcomes of ordering high-dose IV thiamine (HDIV, ≥ 200 mg IV twice daily) to patients with encephalopathy. ¹³ The researchers concluded that HDIV, even though rarely prescribed, was associated with decreased inpatient mortality in bivariable models. However, in multivariable analyses this decrease was found to be clinically insignificant. Our patient benefitted from both IV and IM delivery.

Ideally, after the initial IV thiamine dose, oral administration of thiamine 250 to 1,000 mg is continued until a reduction, if not abstinence, from alcohol use is achieved.⁵ Many patients are discharged on an oral maintenance dose of thiamine 100 mg. Oral thiamine is poorly absorbed and less effective in both prophylaxis and treatment of newly diagnosed WE; therefore, it is typically used only after IM or IV replenishment. It remains unclear why this patient required IM thiamine multiple times per day to maintain his mental status, and why he would present with selfinjurious behaviors after missing doses. The patient’s response can be attributed to late-onset defects in oral thiamine absorption at the carrier protein level of the brush border and basolateral membranes of his jejunum; however, an invasive procedure like a jejunal biopsy to establish the definitive etiology was neither necessary nor practical once treatment response was observed. ¹⁴ Other possible explanations include rapid thiamine metabolism, poor gastrointestinal absorption and a late-onset deficit in the thiamine diffusion mechanisms, and active transport systems (thiamine utilization depends on active transport in low availability states and passive transport when readily available). The nature of these mechanisms deserves further study. Less data have been reported on the administration and utility of IM thiamine for chronic WE; hence, our case report is one of the first illustrating the role of this method for sustained repletion.

Conclusions

This case presented a clinical dilemma because the conventional treatment regimen for WE didn’t yield the desired outcome until the mode and duration of thiamine administration were adjusted. It illustrates the utility of a sustained intensive thiamine regimen irrespective of sobriety status, as opposed to the traditional regimen of parenteral (primarily IV) thiamine for 3 to 7 days, followed by oral repletion until the patient achieves sustained abstinence. In this patient’s case, access to nursing care postdischarge facilitated his continued adherence to IM thiamine therapy.

The longitudinal time course of this case suggests a relationship between this route of administration and improvement in symptom burden and indicates that this patient may have a long-term need for IM thiamine to maintain his baseline mental status. Of great benefit in such patients would be the availability of a long-acting IM thiamine therapy. Risk of overdose is unlikely due to the water solubility of B group vitamins.

This case report highlights the importance of setting a high clinical suspicion for WE due to its ever-increasing incidence in these times. We also wish to direct researchers to consider other out-of-the-box treatment options in case of failure of the conventional regime. In documenting this patient report, we invite more medical providers to investigate and explore other therapeutic options for WE treatment with the aim of decreasing both morbidity and mortality secondary to the condition.

Wernicke-Korsakoff syndrome is a cluster of symptoms attributed to a disorder of vitamin B1 (thiamine) deficiency, manifesting as a combined presentation of alcohol-induced Wernicke encephalopathy (WE) and Korsakoff syndrome (KS).¹ While there is consensus on the characteristic presentation and symptoms of WE, there is a lack of agreement on the exact definition of KS. The classic triad describing WE consists of ataxia, ophthalmoplegia, and confusion; however, reports now suggest that a majority of patients exhibit only 1 or 2 of the elements of the triad. KS is often seen as a condition of chronic thiamine deficiency manifesting as memory impairment alongside a cognitive and behavioral decline, with no clear consensus on the sequence of appearance of symptoms. The typical relationship is thought to be a progression of WE to KS if untreated.

From a mental health perspective, WE presents with delirium and confusion whereas KS manifests with irreversible dementia and a cognitive deterioration. Though it is commonly taught that KS-induced memory loss is permanent due to neuronal damage (classically identified as damage to the mammillary bodies - though other structures have been implicated as well), more recent research suggest otherwise.² A review published in 2018, for example, gathered several case reports and case series that suggest significant improvement in memory and cognition attributed to behavioral and pharmacologic interventions, indicating this as an area deserving of further study.³ About 20% of patients diagnosed with WE by autopsy exhibited none of the classical triad symptoms prior to death.⁴ Hence, these conditions are surmised to be significantly underdiagnosed and misdiagnosed.

Though consensus regarding the appropriate treatment regimen is lacking for WE, a common protocol consists of high-dose parenteral thiamine for 4 to 7 days.⁵ This is usually followed by daily oral thiamine repletion until the patient either achieves complete abstinence from alcohol (ideal) or decreases consumption. The goal is to allow thiamine stores to replete and maintain at minimum required body levels moving forward. In this case report, we highlight the utilization of a long-term, unconventional intramuscular (IM) thiamine repletion regimen to ensure maintenance of a patient’s mental status, highlighting discrepancies in our understanding of the mechanisms at play in WE and its treatment.

Case Presentation

A 65-year-old male patient with a more than 3-decade history of daily hard liquor intake, multiple psychiatric hospitalizations for WE, and a prior suicide attempt, presented to the emergency department (ED) with increased frequency of falls, poor oral intake, confabulation, and diminished verbal communication. A chart review revealed memory impairment alongside the diagnoses of schizoaffective disorder and WE, and confusion that was responsive to thiamine administration as well as a history of hypertension, hyperlipidemia, osteoarthritis, and urinary retention secondary to benign prostatic hyperplasia (BPH).

On examination the patient was found to be disoriented with a clouded sensorium. While the history of heavy daily alcohol use was clear in the chart and confirmed by other sources, it appeared unlikely that the patient had been using alcohol in the preceding month due to restricted access in his most recent living environment (a shared apartment with daily nursing assistance). He reported no lightheadedness, dizziness, palpitations, numbness, tingling, or any head trauma. He also negated the presence of active mood symptoms, auditory or visual hallucinations or suicidal ideation (SI)

The patient was admitted to the Internal Medicine Service and received a workup for the causes of delirium, including consideration of normal pressure hydrocephalus (NPH) and other neurologic conditions. Laboratory tests including a comprehensive metabolic panel, thyroid stimulating hormone, urinalysis, urine toxicology screen, and vitamin B12 and folate levels were in normal ranges. Although brain imaging revealed enlarged ventricles, NPH was considered unlikely because of the absence of ophthalmologic abnormalities, like gaze nystagmus, and urinary incontinence; conversely, there was some presence of urinary retention attributed to BPH and required an admission a few months prior. Moreover, magnetic resonance images showed that the ventricles were enlarged slightly out of proportion to the sulci, which can be seen with predominantly central volume loss compared with the pattern typically seen in NPH.

In light of concern for WE and the patient's history, treatment with IV thiamine and IV fluids was initiated and the Liaison Psychiatry Service was consulted for cognitive disability and treatment of his mood. Administration of IV thiamine rapidly restored his sensorium, but he became abruptly disorganized as the IV regimen graduated to an oral thiamine dose of 200 mg 3 times daily. Simultaneously, as medical stabilization was achieved, the patient was transferred to the inpatient psychiatry unit to address the nonresolving cognitive impairment and behavioral disorganization. This specifically involved newly emerging, impulsive, self-harming behaviors like throwing himself on the ground and banging his head on the floor. Such behaviors along with paucity of speech and decreased oral intake, ultimately warranted constant observation, which led to a decrease in self-harming activity. All this behavior was noted even though the patient was adherent to oral administration of thiamine. Throughout this time, the patient underwent several transfers back and forth between the Psychiatry and Internal Medicine services due to ongoing concern for the possibility of delirium or WE. However, the Neurology and Internal Medicine services did not feel that WE would explain the patient’s mental and behavioral status, in part due to his ongoing adherence with daily oral thiamine dosing that was not associated with improvement in mental status.

Recollecting the patient’s improvement with the parenteral thiamine regimen (IV and IM), the psychiatry unit tried a thiamine regimen of 200 mg IM and 100 mg oral 2 times daily. After about 2 weeks on this regimen, the patient subsequently achieved remarkable improvement in his cognitive and behavioral status, with resolution of selfharming behaviors. The patient was noted to be calmer, more linear, and more oriented, though he remained incompletely oriented throughout his hospitalization. As improvement in sensorium was established and the patient’s hospital stay prolonged (Figure), his mood symptoms began manifesting as guilt, low energy, decreased appetite, withdrawal, and passive SI. This was followed by a trial of lithium that was discontinued due to elevated creatine levels. As the patient continued to report depression, a multidrug regimen of divalproex, fluoxetine, and quetiapine was administered, which lead to remarkable improvement.

At this time, it was concluded that the stores of thiamine in the patient’s body may have been replenished, the alcohol intake completely ceased and that he needed to be weaned off of thiamine. The next step taken was reduction of the twice daily 200 mg IM thiamine dose to a once daily regimen, and oral thiamine was put on hold. Over the next 48 hours, the patient became less verbal, more withdrawn, incontinent of urine, and delirious. The twice daily IM 200 mg thiamine was restarted, but this time the patient demonstrated very slow improvement. After 2 weeks, the IM thiamine 200 mg was increased to 3 times daily, and the patient showed marked improvement in recall, mood, and effect.

Several attempts were made to reduce the IM thiamine burden on the patient and/ or transition to an exclusively oral regimen. However, he rapidly decompensated within hours of each attempt to taper the IM dose and required immediate reinstation. On the IM thiamine regimen, he eventually appeared to reach a stable cognitive and affective baseline marked by incomplete orientation but pleasant affect, he reported no mood complaints, behavioral stability, and an ability to comply with care needs and have simple conversations. Some speech content remained disorganized particularly if engaged beyond simple exchanges.

The patient was discharged to a skilled nursing facility after a month of 3 times daily IM administration of thiamine. Within the next 24 hours, the patient returned to the ED with the originally reported symptoms of ataxia, agitation, and confusion. On inquiry, it was revealed that the ordered vials of IM thiamine for injection had not arrived with him at the nursing facility and he had missed 2 doses. The blood laboratory results, scans, and all other parameters were otherwise found to be normal and the patient was adherent to his prescribed antipsychotics and antidepressants. As anticipated, restoration of the IM thiamine regimen revived his baseline within hours. While confusion and delirium resolved completely with treatment, the memory impairments persisted. This patient has been administered a 3 times daily IM dose of 200 mg thiamine for more than 2 years with a stable cognitive clinical picture.

Discussion

According to data from the 2016 National Survey on Drug Use and Health, 16 million individuals in the US aged ≥ 12 years reported heavy alcohol use, which is defined as binge drinking on ≥ 5 days in the past month.6,7 Thiamine deficiency is an alcoholrelated disorder that is frequently encountered in hospital settings. This deficiency can also occur in the context of malabsorption, malnutrition, a prolonged course of vomiting, and bariatric surgery.^8,9

The deficiency in thiamine, which is sometimes known as WE, manifests rarely with all 3 of the classic triad of gait disturbances, abnormal eye movements, and mental status changes, with only 16.5% of patients displaying all of the triad.⁴ Moreover, there may be additional symptoms not listed in this triad, such as memory impairment, bilateral sixth nerve palsy, ptosis, hypotension, and hypothermia.^10.11 This inconsistent presentation makes the diagnosis challenging and therefore requires a higher threshold for suspicion. If undiagnosed and/or untreated, WE can lead to chronic thiamine deficiency causing permanent brain damage in the guise of KS. This further increases the importance of timely diagnosis and treatment.

Our case highlights the utilization of an unconventional thiamine regimen that appeared to be temporally associated with mental status improvement. The patient’s clouded sensorium and confusion could not be attributed to metabolic, encephalopathic, or infectious pathologies due to the absence of supportive laboratory evidence. He responded to IV and IM doses of thiamine, but repeated attempts to taper the IM doses with the objective of transitioning to oral thiamine supplementation were followed by immediate decompensations in mental status. This was atypical of WE as the patient seemed adequately replete with thiamine, and missing a few doses should not be enough to deplete his stores. Thus, reflecting a unique case of thiamine-dependent chronically set WE when even a single missed dose of thiamine adversely affected the patient’s cognitive baseline. Interesting to note is this patient’s memory issue, as evident by clinical examination and dating back at least 5 years as per chart review. This premature amnestic component of his presentation indicates a likely parallel running KS component of his presentation. Conversely, the patient’s long history of alcohol use disorder, prior episodes of WE, and ideal response achieved only on parenteral thiamine repletion further supported the diagnosis of WE and our impression of the scenario.

Even though this patient had prior episodes of WE, there remained diagnostic uncertainty regarding his altered mental status for some time before the nonoral thiamine repletion treatment was implemented. Particularly in this admission, the patient’s mental status frequently waxed and waned and there was the additional confusion of whether a potential psychiatric etiology contributed to some of the elements of his presentation, such as his impulsive self-harm behaviors. This behavior led to recurrent transfers among the Psychiatry Service, Internal Medicine Service, and the ED.

The patient’s presentation did not reflect the classical triad of WE, and while this is consistent with the majority of clinical manifestations, various services were reluctant to attribute his symptoms to WE. Once the threshold of suspicion of thiamine deficiency was lowered and the deficit treated more aggressively, the patient seemed to improve tremendously. Presence of memory problems and confabulation, both of which this patient exhibited, are suggestive of KS and are not expected to recover with treatment, yet for this patient there did seem to be some improvement—though not complete resolution. This is consistent with newer evidence suggesting that some recovery from the deficits seen in KS is possible.³

Once diagnosed, the treatment objective is the replenishment of thiamine stores and optimization of the metabolic scenario of the body to prevent recurrence. For acute WE symptoms, many regimens call for 250 to 500 mg of IV thiamine supplementation 2 to 3 times daily for 3 to 5 days. High dose IV thiamine (≥ 500 mg daily) has been proposed to be efficacious and free of considerable adverse effects.¹² A study conducted at the University of North Carolina described thiamine prescribing practices in a large academic hospital, analyzing data with the objective of assessing outcomes of ordering high-dose IV thiamine (HDIV, ≥ 200 mg IV twice daily) to patients with encephalopathy. ¹³ The researchers concluded that HDIV, even though rarely prescribed, was associated with decreased inpatient mortality in bivariable models. However, in multivariable analyses this decrease was found to be clinically insignificant. Our patient benefitted from both IV and IM delivery.

Ideally, after the initial IV thiamine dose, oral administration of thiamine 250 to 1,000 mg is continued until a reduction, if not abstinence, from alcohol use is achieved.⁵ Many patients are discharged on an oral maintenance dose of thiamine 100 mg. Oral thiamine is poorly absorbed and less effective in both prophylaxis and treatment of newly diagnosed WE; therefore, it is typically used only after IM or IV replenishment. It remains unclear why this patient required IM thiamine multiple times per day to maintain his mental status, and why he would present with selfinjurious behaviors after missing doses. The patient’s response can be attributed to late-onset defects in oral thiamine absorption at the carrier protein level of the brush border and basolateral membranes of his jejunum; however, an invasive procedure like a jejunal biopsy to establish the definitive etiology was neither necessary nor practical once treatment response was observed. ¹⁴ Other possible explanations include rapid thiamine metabolism, poor gastrointestinal absorption and a late-onset deficit in the thiamine diffusion mechanisms, and active transport systems (thiamine utilization depends on active transport in low availability states and passive transport when readily available). The nature of these mechanisms deserves further study. Less data have been reported on the administration and utility of IM thiamine for chronic WE; hence, our case report is one of the first illustrating the role of this method for sustained repletion.

Conclusions

This case presented a clinical dilemma because the conventional treatment regimen for WE didn’t yield the desired outcome until the mode and duration of thiamine administration were adjusted. It illustrates the utility of a sustained intensive thiamine regimen irrespective of sobriety status, as opposed to the traditional regimen of parenteral (primarily IV) thiamine for 3 to 7 days, followed by oral repletion until the patient achieves sustained abstinence. In this patient’s case, access to nursing care postdischarge facilitated his continued adherence to IM thiamine therapy.

The longitudinal time course of this case suggests a relationship between this route of administration and improvement in symptom burden and indicates that this patient may have a long-term need for IM thiamine to maintain his baseline mental status. Of great benefit in such patients would be the availability of a long-acting IM thiamine therapy. Risk of overdose is unlikely due to the water solubility of B group vitamins.

This case report highlights the importance of setting a high clinical suspicion for WE due to its ever-increasing incidence in these times. We also wish to direct researchers to consider other out-of-the-box treatment options in case of failure of the conventional regime. In documenting this patient report, we invite more medical providers to investigate and explore other therapeutic options for WE treatment with the aim of decreasing both morbidity and mortality secondary to the condition.

A renewed effort to vaccinate service members fighting the global war on terrorism has brought new diagnostic challenges. Vaccinations not generally given to the public are routinely given to service members when they deploy to various parts of the world. Examples include anthrax, yellow fever, Japanese encephalitis, rabies, polio, and smallpox. Every vaccination has potential for adverse effects (AEs), which can range from mild to severe life-threatening complications. These AEs often go unrecognized and untreated because physicians are not routinely screening for vaccination administration.

Background

Smallpox (Variola major) was successfully eradicated in 1977 due to worldwide vaccination efforts.¹ However, the threat of bioterrorism has renewed mandatory smallpox vaccinations for high-risk individuals, such as active-duty military personnel.^1,2 A notable increase in myopericarditis has been reported with the new generation of smallpox vaccination, ACAM2000.³ We present a case of a 27-year-old healthy male who presented with chest pain and diffuse ST segment elevations consistent with myopericarditis after vaccination with ACAM2000.

Case Presentation

A healthy 27-year-old soldier presented to the emergency department with sudden, new onset, sharp-stabbing, substernal chest pain, which was made worse with lying flat and better with leaning forward. Vital signs were unremarkable. He recently enlisted in the US Army and received the smallpox vaccination about 11 days before as part of a routine predeployment checklist. The patient reported he did not have any viral symptoms, such as fever, chills, nausea, vomiting, diarrhea, shortness of breath, sore throat, rhinorrhea, or sputum production. He also reported having no prior illness for the past 3 months, sick contacts at home or work, or recent travel outside the US. He reported no tobacco use, alcohol use, or illicit drug use. The patient’s family history was negative for significant cardiac disease.

A physical examination was unremarkable. The initial laboratory report showed no leukocytosis, anemia, thrombocytopenia, electrolytes derangement, abnormal kidney function, or abnormal liver function tests. Initial troponin was 0.25 ng/mL, erythrocyte sedimentation rate (ESR) was 40 mmol/h and C-reactive protein (CRP) was 120.2 mg/L suggestive of acute inflammation. A urine drug screen was negative. D-dimer was < 0.27. An electrocardiogram (ECG) showed diffuse ST segment elevation (Figure 1). An echocardiogram showed normal left ventricle size, and function with ejection fraction 55 to 60%, normal diastolic dysfunction, and trivial pericardial effusion. Magnetic resonance imaging (MRI) showed increased T2 signal intensity of the myocardium suggestive of myopericarditis (Figure 2). A computed tomography (CT) angiogram of the coronary arteries showed no significant stenosis.

Discussion

Smallpox was a major worldwide cause of mortality; about 30% of those infected died because of smallpox.^2,4,5 Due to a worldwide vaccination effort, the World Health Organization declared smallpox was eradicated in 1977.^2,4,5 However, despite successful eradication, smallpox is considered a possible bioterrorism target, which prompted a resurgence of mandatory smallpox vaccinations for active-duty personnel.^2,5

Dryvax, a freeze-dried calf lymph smallpox vaccine was used extensively from the 1940s to the 1980s but was replaced in 2008 by ACAM2000, a smallpox vaccine cultured in kidney epithelial cells from African green monkeys.^3,5 Myopericarditis was rarely associated with the Dryvax, with only 5 cases reported from 1955 to 1986 after millions of doses of vaccines were administered; however, in 230,734 administered ACAM2000 doses, 18 cases of myopericarditis (incidence, 7.8 per 100,000) were reported during a surveillance study in 2002 and 2003.^3,5

Myopericarditis presents with a wide variety of symptoms, such as chest pain, palpitations, chills, shortness of breath, and fever.^6,7 Mainstay diagnostic criteria include ECG findings consistent with myopericarditis (such as diffuse ST segment elevations) and elevated cardiac biomarkers (elevated troponins).^5-7 An echocardiogram can be helpful in diagnosis, as most cases will not have regional wall motion abnormalities (to distinguish against coronary artery disease).^5-7 MRI with diffuse enhancement of the myocardium can be helpful in diagnosis.^5,6 The gold standard for diagnosis is an endomyocardial biopsy, which carries a significant risk of complications and is not routinely performed to diagnose myopericarditis.^5,6 US military smallpox vaccination data showed that the onset of vaccine-associated myopericarditis averaged (SD) 10.4 (3.6) days after vaccination.⁵

Vaccine-associated myopericarditis treatment is focused on decreasing inflammation.^5,6 Nonsteroidal anti-inflammatory drugs are advised for about 2 weeks with cessation of intensive cardiac activities for between 4 and 6 weeks due to risks of congestive heart failure and fatal cardiac arrhythmias.^5,6

Conclusions

Since the September 11 attacks, the US needs to be continually prepared for potential terrorism on American soil and abroad. The threat of bioterrorism has renewed efforts to vaccinate or revaccinate American service members deployed to high-risk regions. These vaccinations put them at risk for vaccination-induced complications that can range from mild fever to life-threatening complications.

A renewed effort to vaccinate service members fighting the global war on terrorism has brought new diagnostic challenges. Vaccinations not generally given to the public are routinely given to service members when they deploy to various parts of the world. Examples include anthrax, yellow fever, Japanese encephalitis, rabies, polio, and smallpox. Every vaccination has potential for adverse effects (AEs), which can range from mild to severe life-threatening complications. These AEs often go unrecognized and untreated because physicians are not routinely screening for vaccination administration.

Background

Smallpox (Variola major) was successfully eradicated in 1977 due to worldwide vaccination efforts.¹ However, the threat of bioterrorism has renewed mandatory smallpox vaccinations for high-risk individuals, such as active-duty military personnel.^1,2 A notable increase in myopericarditis has been reported with the new generation of smallpox vaccination, ACAM2000.³ We present a case of a 27-year-old healthy male who presented with chest pain and diffuse ST segment elevations consistent with myopericarditis after vaccination with ACAM2000.

Case Presentation

A healthy 27-year-old soldier presented to the emergency department with sudden, new onset, sharp-stabbing, substernal chest pain, which was made worse with lying flat and better with leaning forward. Vital signs were unremarkable. He recently enlisted in the US Army and received the smallpox vaccination about 11 days before as part of a routine predeployment checklist. The patient reported he did not have any viral symptoms, such as fever, chills, nausea, vomiting, diarrhea, shortness of breath, sore throat, rhinorrhea, or sputum production. He also reported having no prior illness for the past 3 months, sick contacts at home or work, or recent travel outside the US. He reported no tobacco use, alcohol use, or illicit drug use. The patient’s family history was negative for significant cardiac disease.

A physical examination was unremarkable. The initial laboratory report showed no leukocytosis, anemia, thrombocytopenia, electrolytes derangement, abnormal kidney function, or abnormal liver function tests. Initial troponin was 0.25 ng/mL, erythrocyte sedimentation rate (ESR) was 40 mmol/h and C-reactive protein (CRP) was 120.2 mg/L suggestive of acute inflammation. A urine drug screen was negative. D-dimer was < 0.27. An electrocardiogram (ECG) showed diffuse ST segment elevation (Figure 1). An echocardiogram showed normal left ventricle size, and function with ejection fraction 55 to 60%, normal diastolic dysfunction, and trivial pericardial effusion. Magnetic resonance imaging (MRI) showed increased T2 signal intensity of the myocardium suggestive of myopericarditis (Figure 2). A computed tomography (CT) angiogram of the coronary arteries showed no significant stenosis.

Discussion

Smallpox was a major worldwide cause of mortality; about 30% of those infected died because of smallpox.^2,4,5 Due to a worldwide vaccination effort, the World Health Organization declared smallpox was eradicated in 1977.^2,4,5 However, despite successful eradication, smallpox is considered a possible bioterrorism target, which prompted a resurgence of mandatory smallpox vaccinations for active-duty personnel.^2,5

Dryvax, a freeze-dried calf lymph smallpox vaccine was used extensively from the 1940s to the 1980s but was replaced in 2008 by ACAM2000, a smallpox vaccine cultured in kidney epithelial cells from African green monkeys.^3,5 Myopericarditis was rarely associated with the Dryvax, with only 5 cases reported from 1955 to 1986 after millions of doses of vaccines were administered; however, in 230,734 administered ACAM2000 doses, 18 cases of myopericarditis (incidence, 7.8 per 100,000) were reported during a surveillance study in 2002 and 2003.^3,5

Myopericarditis presents with a wide variety of symptoms, such as chest pain, palpitations, chills, shortness of breath, and fever.^6,7 Mainstay diagnostic criteria include ECG findings consistent with myopericarditis (such as diffuse ST segment elevations) and elevated cardiac biomarkers (elevated troponins).^5-7 An echocardiogram can be helpful in diagnosis, as most cases will not have regional wall motion abnormalities (to distinguish against coronary artery disease).^5-7 MRI with diffuse enhancement of the myocardium can be helpful in diagnosis.^5,6 The gold standard for diagnosis is an endomyocardial biopsy, which carries a significant risk of complications and is not routinely performed to diagnose myopericarditis.^5,6 US military smallpox vaccination data showed that the onset of vaccine-associated myopericarditis averaged (SD) 10.4 (3.6) days after vaccination.⁵

Vaccine-associated myopericarditis treatment is focused on decreasing inflammation.^5,6 Nonsteroidal anti-inflammatory drugs are advised for about 2 weeks with cessation of intensive cardiac activities for between 4 and 6 weeks due to risks of congestive heart failure and fatal cardiac arrhythmias.^5,6

Conclusions

Since the September 11 attacks, the US needs to be continually prepared for potential terrorism on American soil and abroad. The threat of bioterrorism has renewed efforts to vaccinate or revaccinate American service members deployed to high-risk regions. These vaccinations put them at risk for vaccination-induced complications that can range from mild fever to life-threatening complications.

A renewed effort to vaccinate service members fighting the global war on terrorism has brought new diagnostic challenges. Vaccinations not generally given to the public are routinely given to service members when they deploy to various parts of the world. Examples include anthrax, yellow fever, Japanese encephalitis, rabies, polio, and smallpox. Every vaccination has potential for adverse effects (AEs), which can range from mild to severe life-threatening complications. These AEs often go unrecognized and untreated because physicians are not routinely screening for vaccination administration.

Background

Smallpox (Variola major) was successfully eradicated in 1977 due to worldwide vaccination efforts.¹ However, the threat of bioterrorism has renewed mandatory smallpox vaccinations for high-risk individuals, such as active-duty military personnel.^1,2 A notable increase in myopericarditis has been reported with the new generation of smallpox vaccination, ACAM2000.³ We present a case of a 27-year-old healthy male who presented with chest pain and diffuse ST segment elevations consistent with myopericarditis after vaccination with ACAM2000.

Case Presentation

A healthy 27-year-old soldier presented to the emergency department with sudden, new onset, sharp-stabbing, substernal chest pain, which was made worse with lying flat and better with leaning forward. Vital signs were unremarkable. He recently enlisted in the US Army and received the smallpox vaccination about 11 days before as part of a routine predeployment checklist. The patient reported he did not have any viral symptoms, such as fever, chills, nausea, vomiting, diarrhea, shortness of breath, sore throat, rhinorrhea, or sputum production. He also reported having no prior illness for the past 3 months, sick contacts at home or work, or recent travel outside the US. He reported no tobacco use, alcohol use, or illicit drug use. The patient’s family history was negative for significant cardiac disease.

A physical examination was unremarkable. The initial laboratory report showed no leukocytosis, anemia, thrombocytopenia, electrolytes derangement, abnormal kidney function, or abnormal liver function tests. Initial troponin was 0.25 ng/mL, erythrocyte sedimentation rate (ESR) was 40 mmol/h and C-reactive protein (CRP) was 120.2 mg/L suggestive of acute inflammation. A urine drug screen was negative. D-dimer was < 0.27. An electrocardiogram (ECG) showed diffuse ST segment elevation (Figure 1). An echocardiogram showed normal left ventricle size, and function with ejection fraction 55 to 60%, normal diastolic dysfunction, and trivial pericardial effusion. Magnetic resonance imaging (MRI) showed increased T2 signal intensity of the myocardium suggestive of myopericarditis (Figure 2). A computed tomography (CT) angiogram of the coronary arteries showed no significant stenosis.

Discussion

Smallpox was a major worldwide cause of mortality; about 30% of those infected died because of smallpox.^2,4,5 Due to a worldwide vaccination effort, the World Health Organization declared smallpox was eradicated in 1977.^2,4,5 However, despite successful eradication, smallpox is considered a possible bioterrorism target, which prompted a resurgence of mandatory smallpox vaccinations for active-duty personnel.^2,5

Dryvax, a freeze-dried calf lymph smallpox vaccine was used extensively from the 1940s to the 1980s but was replaced in 2008 by ACAM2000, a smallpox vaccine cultured in kidney epithelial cells from African green monkeys.^3,5 Myopericarditis was rarely associated with the Dryvax, with only 5 cases reported from 1955 to 1986 after millions of doses of vaccines were administered; however, in 230,734 administered ACAM2000 doses, 18 cases of myopericarditis (incidence, 7.8 per 100,000) were reported during a surveillance study in 2002 and 2003.^3,5

Myopericarditis presents with a wide variety of symptoms, such as chest pain, palpitations, chills, shortness of breath, and fever.^6,7 Mainstay diagnostic criteria include ECG findings consistent with myopericarditis (such as diffuse ST segment elevations) and elevated cardiac biomarkers (elevated troponins).^5-7 An echocardiogram can be helpful in diagnosis, as most cases will not have regional wall motion abnormalities (to distinguish against coronary artery disease).^5-7 MRI with diffuse enhancement of the myocardium can be helpful in diagnosis.^5,6 The gold standard for diagnosis is an endomyocardial biopsy, which carries a significant risk of complications and is not routinely performed to diagnose myopericarditis.^5,6 US military smallpox vaccination data showed that the onset of vaccine-associated myopericarditis averaged (SD) 10.4 (3.6) days after vaccination.⁵

Vaccine-associated myopericarditis treatment is focused on decreasing inflammation.^5,6 Nonsteroidal anti-inflammatory drugs are advised for about 2 weeks with cessation of intensive cardiac activities for between 4 and 6 weeks due to risks of congestive heart failure and fatal cardiac arrhythmias.^5,6

Conclusions

Since the September 11 attacks, the US needs to be continually prepared for potential terrorism on American soil and abroad. The threat of bioterrorism has renewed efforts to vaccinate or revaccinate American service members deployed to high-risk regions. These vaccinations put them at risk for vaccination-induced complications that can range from mild fever to life-threatening complications.

Dupilumab is a novel medication that is approved by the US Food and Drug Administration to treat moderate to severe atopic dermatitis (AD) in patients 6 years and older. Dupilumab is an injectable fully human monoclonal antibody. It provides a giant leap toward a better quality of life for patients with AD. Dupilumab works by binding to the shared α subunit of the IL-4 receptor (IL-4R), thus inhibiting IL-4 and IL-13 from using that signaling pathway. The documented side-effect profile includes injection-site reaction, keratitis, nasopharyngitis, and headache.¹

We initiated off-label treatment with dupilumab in 3 adult patients who had a history of long-standing adult-onset dermatitis confirmed by histopathology. The 3 patients received a loading dose of 600 mg subcutaneously, followed by 300 mg every other week. Following treatment, the patients had expansion of their disease, with features consistent with cutaneous T-cell lymphoma (CTCL) on subsequent biopsies. These 3 cases demonstrate the well-known adage that the diagnosis of CTCL often requires multiple biopsies performed over time. Although dupilumab has proved efficacious and safe for treating AD, dermatologists should be cautious before starting this medication in an adult who has new-onset dermatitis and no history of atopy.

Case Reports

Patient 1
A 61-year-old man presented to dermatology after being lost to follow-up for several years and was started on dupilumab for long-standing nonspecific eczematous dermatitis based on histopathology. He had a pruritic rash of 10 years’ duration that had been biopsied multiple times and was found to be consistent with dermatitis and lichen simplex chronicus (Figure 1). He had been treated with triamcinolone ointment 0.1% and narrowband UVB as often as 3 times weekly over many years. The patient also had a history of idiopathic CD4 lymphopenia with consistently negative tests for human immunodeficiency virus.

At approximately the same time as dupilumab was initiated, he was started on 60 mg daily of prednisone by his pulmonologist because of a history of restrictive lung disease of unknown cause. While taking prednisone, he experienced notable improvement in his skin condition; however, as he was slowly tapered off prednisone, he noted remarkable worsening of the dermatitis. Dupilumab was discontinued. Two more biopsies were performed; findings on both were consistent with mycosis fungoides (MF)(Figure 2).

Upon initial evaluation in our clinic, there was concern for Sézary syndrome; however, peripheral blood studies were normal, and there was no monoclonal spike or irregularity in the patient’s Sézary flow cytometry panel. A biopsy demonstrated lichenoid dermatitis, possibly consistent with drug eruption. All supplements and likely medication culprits were discontinued without improvement.

Prior to follow-up in our clinic, the patient was again evaluated by an outside dermatologist and started on dupilumab. After 3 doses, she discontinued the medication because there was no improvement in the cutaneous symptoms. Findings on repeat biopsy following dupilumab treatment were consistent with MF.

Comment

Mycosis fungoides is a rare chronic T-cell lymphoma that can smolder for decades as nonspecific dermatitis before declaring itself fully on skin biopsy.² In many cases, MF masquerades as eczema, psoriasis, contact dermatitis, or other dermatitides, and it often responds to the same medications, making diagnosis even more challenging. Treatment options include topical steroids, narrowband UVB, topical nitrogen mustard, topical carmustine, and bexarotene gel for early-stage disease.³ Although it cannot be determined which patients will progress, some do, and therapies must then be upgraded.

We reported 3 patients with adult-onset dermatitis and multiple biopsies demonstrating nondiagnostic findings, which, in retrospect, likely represented early smoldering CTCL. Each of these patients was treated with dupilumab because multiple biopsies demonstrated findings consistent with nondiagnostic dermatitis, along with a lack of response to standard therapies. In all 3 cases, however, the patients had no history of eczema or atopy. After starting dupilumab, each patient had an acute exacerbation of dermatitis; immediately thereafter, biopsies were consistent with CTCL.

These patients most likely had smoldering CTCL that expressed itself fully after dupilumab was started. Biologic medications and their effects on the immune system have been shown to have multiple unanticipated effects on the skin.^4-6 We are not insinuating that dupilumab was the cause of our patients having developed CTCL, but we do propose that the underlying interplay of dupilumab with the immune system might have accelerated progression of underlying CTCL, resulting in the lymphoma presenting itself clinically and histopathologically. We also must mention that all 3 cases could represent a “true, true, and unrelated” phenomenon.

A proposed mechanism for how dupilumab might hasten progression of CTCL is based on a functional increase of IL-13 available for binding at the IL-13 receptor (IL-13R) α2 site following blockade of the IL-13Rα1 site by dupilumab (Figure 3). The pathway that is blocked by dupilumab provides improvement in AD by blocking the α subunit of the IL-4R, making it a receptor antagonist for both IL-4 and IL-13. The IL-4R forms a heterodimer with both γ c and separately with IL-13Rα1. As a result, IL-4 and IL-13 cannot bind to their respective targets; thus, downstream signaling that is required for AD is halted.⁷ IL-13, in addition to IL-4R, also binds to an IL-13Rα2. IL-13 and both of its receptors are upregulated in CTCL, particularly IL-13Rα2.⁸

Dupilumab is a novel medication that is approved by the US Food and Drug Administration to treat moderate to severe atopic dermatitis (AD) in patients 6 years and older. Dupilumab is an injectable fully human monoclonal antibody. It provides a giant leap toward a better quality of life for patients with AD. Dupilumab works by binding to the shared α subunit of the IL-4 receptor (IL-4R), thus inhibiting IL-4 and IL-13 from using that signaling pathway. The documented side-effect profile includes injection-site reaction, keratitis, nasopharyngitis, and headache.¹

We initiated off-label treatment with dupilumab in 3 adult patients who had a history of long-standing adult-onset dermatitis confirmed by histopathology. The 3 patients received a loading dose of 600 mg subcutaneously, followed by 300 mg every other week. Following treatment, the patients had expansion of their disease, with features consistent with cutaneous T-cell lymphoma (CTCL) on subsequent biopsies. These 3 cases demonstrate the well-known adage that the diagnosis of CTCL often requires multiple biopsies performed over time. Although dupilumab has proved efficacious and safe for treating AD, dermatologists should be cautious before starting this medication in an adult who has new-onset dermatitis and no history of atopy.

Case Reports

Patient 1
A 61-year-old man presented to dermatology after being lost to follow-up for several years and was started on dupilumab for long-standing nonspecific eczematous dermatitis based on histopathology. He had a pruritic rash of 10 years’ duration that had been biopsied multiple times and was found to be consistent with dermatitis and lichen simplex chronicus (Figure 1). He had been treated with triamcinolone ointment 0.1% and narrowband UVB as often as 3 times weekly over many years. The patient also had a history of idiopathic CD4 lymphopenia with consistently negative tests for human immunodeficiency virus.

At approximately the same time as dupilumab was initiated, he was started on 60 mg daily of prednisone by his pulmonologist because of a history of restrictive lung disease of unknown cause. While taking prednisone, he experienced notable improvement in his skin condition; however, as he was slowly tapered off prednisone, he noted remarkable worsening of the dermatitis. Dupilumab was discontinued. Two more biopsies were performed; findings on both were consistent with mycosis fungoides (MF)(Figure 2).

Upon initial evaluation in our clinic, there was concern for Sézary syndrome; however, peripheral blood studies were normal, and there was no monoclonal spike or irregularity in the patient’s Sézary flow cytometry panel. A biopsy demonstrated lichenoid dermatitis, possibly consistent with drug eruption. All supplements and likely medication culprits were discontinued without improvement.

Prior to follow-up in our clinic, the patient was again evaluated by an outside dermatologist and started on dupilumab. After 3 doses, she discontinued the medication because there was no improvement in the cutaneous symptoms. Findings on repeat biopsy following dupilumab treatment were consistent with MF.

Comment

Mycosis fungoides is a rare chronic T-cell lymphoma that can smolder for decades as nonspecific dermatitis before declaring itself fully on skin biopsy.² In many cases, MF masquerades as eczema, psoriasis, contact dermatitis, or other dermatitides, and it often responds to the same medications, making diagnosis even more challenging. Treatment options include topical steroids, narrowband UVB, topical nitrogen mustard, topical carmustine, and bexarotene gel for early-stage disease.³ Although it cannot be determined which patients will progress, some do, and therapies must then be upgraded.

We reported 3 patients with adult-onset dermatitis and multiple biopsies demonstrating nondiagnostic findings, which, in retrospect, likely represented early smoldering CTCL. Each of these patients was treated with dupilumab because multiple biopsies demonstrated findings consistent with nondiagnostic dermatitis, along with a lack of response to standard therapies. In all 3 cases, however, the patients had no history of eczema or atopy. After starting dupilumab, each patient had an acute exacerbation of dermatitis; immediately thereafter, biopsies were consistent with CTCL.

These patients most likely had smoldering CTCL that expressed itself fully after dupilumab was started. Biologic medications and their effects on the immune system have been shown to have multiple unanticipated effects on the skin.^4-6 We are not insinuating that dupilumab was the cause of our patients having developed CTCL, but we do propose that the underlying interplay of dupilumab with the immune system might have accelerated progression of underlying CTCL, resulting in the lymphoma presenting itself clinically and histopathologically. We also must mention that all 3 cases could represent a “true, true, and unrelated” phenomenon.

A proposed mechanism for how dupilumab might hasten progression of CTCL is based on a functional increase of IL-13 available for binding at the IL-13 receptor (IL-13R) α2 site following blockade of the IL-13Rα1 site by dupilumab (Figure 3). The pathway that is blocked by dupilumab provides improvement in AD by blocking the α subunit of the IL-4R, making it a receptor antagonist for both IL-4 and IL-13. The IL-4R forms a heterodimer with both γ c and separately with IL-13Rα1. As a result, IL-4 and IL-13 cannot bind to their respective targets; thus, downstream signaling that is required for AD is halted.⁷ IL-13, in addition to IL-4R, also binds to an IL-13Rα2. IL-13 and both of its receptors are upregulated in CTCL, particularly IL-13Rα2.⁸

Dupilumab is a novel medication that is approved by the US Food and Drug Administration to treat moderate to severe atopic dermatitis (AD) in patients 6 years and older. Dupilumab is an injectable fully human monoclonal antibody. It provides a giant leap toward a better quality of life for patients with AD. Dupilumab works by binding to the shared α subunit of the IL-4 receptor (IL-4R), thus inhibiting IL-4 and IL-13 from using that signaling pathway. The documented side-effect profile includes injection-site reaction, keratitis, nasopharyngitis, and headache.¹

We initiated off-label treatment with dupilumab in 3 adult patients who had a history of long-standing adult-onset dermatitis confirmed by histopathology. The 3 patients received a loading dose of 600 mg subcutaneously, followed by 300 mg every other week. Following treatment, the patients had expansion of their disease, with features consistent with cutaneous T-cell lymphoma (CTCL) on subsequent biopsies. These 3 cases demonstrate the well-known adage that the diagnosis of CTCL often requires multiple biopsies performed over time. Although dupilumab has proved efficacious and safe for treating AD, dermatologists should be cautious before starting this medication in an adult who has new-onset dermatitis and no history of atopy.

Case Reports

Patient 1
A 61-year-old man presented to dermatology after being lost to follow-up for several years and was started on dupilumab for long-standing nonspecific eczematous dermatitis based on histopathology. He had a pruritic rash of 10 years’ duration that had been biopsied multiple times and was found to be consistent with dermatitis and lichen simplex chronicus (Figure 1). He had been treated with triamcinolone ointment 0.1% and narrowband UVB as often as 3 times weekly over many years. The patient also had a history of idiopathic CD4 lymphopenia with consistently negative tests for human immunodeficiency virus.

At approximately the same time as dupilumab was initiated, he was started on 60 mg daily of prednisone by his pulmonologist because of a history of restrictive lung disease of unknown cause. While taking prednisone, he experienced notable improvement in his skin condition; however, as he was slowly tapered off prednisone, he noted remarkable worsening of the dermatitis. Dupilumab was discontinued. Two more biopsies were performed; findings on both were consistent with mycosis fungoides (MF)(Figure 2).

Upon initial evaluation in our clinic, there was concern for Sézary syndrome; however, peripheral blood studies were normal, and there was no monoclonal spike or irregularity in the patient’s Sézary flow cytometry panel. A biopsy demonstrated lichenoid dermatitis, possibly consistent with drug eruption. All supplements and likely medication culprits were discontinued without improvement.

Prior to follow-up in our clinic, the patient was again evaluated by an outside dermatologist and started on dupilumab. After 3 doses, she discontinued the medication because there was no improvement in the cutaneous symptoms. Findings on repeat biopsy following dupilumab treatment were consistent with MF.

Comment

Mycosis fungoides is a rare chronic T-cell lymphoma that can smolder for decades as nonspecific dermatitis before declaring itself fully on skin biopsy.² In many cases, MF masquerades as eczema, psoriasis, contact dermatitis, or other dermatitides, and it often responds to the same medications, making diagnosis even more challenging. Treatment options include topical steroids, narrowband UVB, topical nitrogen mustard, topical carmustine, and bexarotene gel for early-stage disease.³ Although it cannot be determined which patients will progress, some do, and therapies must then be upgraded.

We reported 3 patients with adult-onset dermatitis and multiple biopsies demonstrating nondiagnostic findings, which, in retrospect, likely represented early smoldering CTCL. Each of these patients was treated with dupilumab because multiple biopsies demonstrated findings consistent with nondiagnostic dermatitis, along with a lack of response to standard therapies. In all 3 cases, however, the patients had no history of eczema or atopy. After starting dupilumab, each patient had an acute exacerbation of dermatitis; immediately thereafter, biopsies were consistent with CTCL.

These patients most likely had smoldering CTCL that expressed itself fully after dupilumab was started. Biologic medications and their effects on the immune system have been shown to have multiple unanticipated effects on the skin.^4-6 We are not insinuating that dupilumab was the cause of our patients having developed CTCL, but we do propose that the underlying interplay of dupilumab with the immune system might have accelerated progression of underlying CTCL, resulting in the lymphoma presenting itself clinically and histopathologically. We also must mention that all 3 cases could represent a “true, true, and unrelated” phenomenon.

A proposed mechanism for how dupilumab might hasten progression of CTCL is based on a functional increase of IL-13 available for binding at the IL-13 receptor (IL-13R) α2 site following blockade of the IL-13Rα1 site by dupilumab (Figure 3). The pathway that is blocked by dupilumab provides improvement in AD by blocking the α subunit of the IL-4R, making it a receptor antagonist for both IL-4 and IL-13. The IL-4R forms a heterodimer with both γ c and separately with IL-13Rα1. As a result, IL-4 and IL-13 cannot bind to their respective targets; thus, downstream signaling that is required for AD is halted.⁷ IL-13, in addition to IL-4R, also binds to an IL-13Rα2. IL-13 and both of its receptors are upregulated in CTCL, particularly IL-13Rα2.⁸

Bilateral lower extremity edema is a common condition with a broad differential diagnosis. New, severe peripheral edema implies a more nefarious underlying etiology than chronic venous insufficiency and should prompt a thorough evaluation for underlying conditions, such as congestive heart failure (CHF), cirrhosis, nephrotic syndrome, hypoalbuminemia, or lymphatic or venous obstruction. We present a case of a patient with sudden onset new bilateral lower extremity edema due to a rare adverse drug reaction (ADR) from valproate.

Case Presentation

A 63-year-old male with a history of seizures, bipolar disorder type I, and memory impairment due to traumatic brain injury (TBI) from a gunshot wound 24 years prior presented to the emergency department for witnessed seizure activity in the community. The patient had been incarcerated for the past 20 years, throughout which he had been taking the antiepileptic drugs (AEDs) phenytoin and divalproex and did not have any seizure activity. No records prior to his incarceration were available for review.

The patient recently had been released from prison and was nonadherent with his AEDs, leading to a witnessed seizure. This episode was described as preceded by an electric sensation, followed by rhythmic shaking of the right upper extremity without loss of consciousness. His regimen prior to admission included divalproex 1,000 mg daily and phenytoin 200 mg daily. His only other medication was folic acid.

Neurology was consulted on admission. An awake and asleep 4-hour electroencephalogram showed intermittent focal slowing of the right frontocentral region and frequent epileptiform discharges in the right prefrontal region during sleep, corresponding to areas of chronic right anterior frontal and temporal encephalomalacia seen on brain imaging. His seizures were thought likely to be secondary to prior head trauma. While the described seizure activity involving the right upper extremity was not consistent with the location of his prior TBI, neurology considered that he might have simple partial seizures with multiple foci or that his seizure event prior to admission was not accurately described. The neurology consult recommended switching from phenytoin 200 mg daily to lacosamide 100 mg twice daily on admission. His prior dose of divalproex 1,000 mg daily also was resumed for its antiepileptic effect and the added benefit of mood stabilization, as the patient reported elevated mood and decreased need for sleep on admission.

Eight days after changing his AED regimen, the patient was found to have new onset bilateral grade 1+ pitting edema to the level of his shins. He had no history of dyspnea, orthopnea, paroxysmal nocturnal dyspnea, dysuria, or changes in his urination. Although medical records from his incarceration were not available for review, the patient reported that he had never had peripheral edema.

On physical examination, the patient had no periorbital edema, jugular venous pressure of 8 cm H₂O, negative hepatojugular reflex, unremarkable cardiac and lung examination, and grade 2+ posterior tibial and dorsalis pedis pulses bilaterally. He underwent extensive laboratory evaluation for potential underlying causes, including nephrotic syndrome, cirrhosis, hypothyroidism, and CHF (Table). Valproate levels were initially subtherapeutic on admission (< 10 µg/mL, reference range 50-125 µg/mL) then rose to within therapeutic range (54 µg/mL-80 µg/mL throughout admission) after neurology recommended increasing the dose from 1,000 mg daily to 1,500 mg daily. His measured valproate levels were never supratherapeutic.

An electrocardiogram showed normal sinus rhythm unchanged from admission. Transthoracic echocardiogram showed normal left ventricular (LV) size and estimated LV ejection fraction of 55 to 60%. Abdominal ultrasound showed no evidence of cirrhosis and normal portal vein flow. Ultrasound of the lower extremities showed no deep venous thrombosis or valvular insufficiency. The patient was prescribed compression stockings. However, due to memory impairment, he was relatively nonadherent, and his lower extremity edema worsened to grade 3+ over several days. Due to the progressive swelling with no identified cause, a computed tomographic venogram of the abdomen and pelvis was performed to determine whether an inferior vena cava (IVC) thrombus was present. This study was unremarkable and did not show any external IVC compression.

After extensive evaluation did not reveal any other cause, the temporal course of events suggested an association between the patient’s peripheral edema and resumption of divalproex. His swelling remained stable. Discontinuation of divalproex was considered, but the patient’s mood remained euthymic, and he had no further seizure activity while on this medication, so the benefit of continuation was felt to outweigh any risks of switching to another agent.

Discussion

Valproate and its related forms, such as divalproex, often are used in the treatment of generalized or partial seizures, psychiatric disorders, and the prophylaxis of migraine headaches. Common ADRs include gastrointestinal symptoms, sedation, and dose-related thrombocytopenia, among many others. Rare ADRs include fulminant hepatitis, pancreatitis, hyperammonemia, and peripheral edema.¹ There have been case reports of valproate-induced peripheral edema, which seems to be an idiosyncratic ADR that occurs after long-term administration of the medication.^2,3 Early studies reported valproate-related edema in the context of valproate-induced hepatic injury.⁴ However, in more recent case reports, valproate-related edema has been found in patients without hepatotoxicity or supratherapeutic drug levels.^1,2

The exact mechanism by which valproate causes peripheral edema is unknown. It has been reported that medications affecting the γ-aminobutyric acid (GABA) system such as benzodiazepines, for example, can cause this rare ADR.⁵ Unlike benzodiazepines, valproate has an indirect effect on the GABA system, through increasing availability of GABA.⁶ GABA receptors have been identified on peripheral tissues, suggesting that GABAergic medications also may have an effect on regional vascular resistance.⁷ This mechanism was proposed by prior case reports but has yet to be proven in studies.²

In this case, initiation of lacosamide temporally coinciding with development of the patient’s edema leads one to question whether lacosamide may have caused this ADR. Other medications commonly used in seizure management (such as benzodiazepines and gabapentin) have been reported to cause new onset peripheral edema.^5,8 To date, however, there are no reported cases of peripheral edema due to lacosamide. While there are known interactions between various AEDs that may impact drug levels of valproate, there are no reported drug-drug interactions between lacosamide and valproate.⁹

Conclusions

Our case adds to the small but growing body of literature that suggests peripheral edema is a rare but clinically significant ADR of valproate. With its broad differential diagnosis, new onset peripheral edema is a concern that often warrants an extensive evaluation for underlying causes. Clinicians should be aware of this ADR as use of valproate becomes increasingly common so that an extensive workup is not always performed on patients with peripheral edema.

Bilateral lower extremity edema is a common condition with a broad differential diagnosis. New, severe peripheral edema implies a more nefarious underlying etiology than chronic venous insufficiency and should prompt a thorough evaluation for underlying conditions, such as congestive heart failure (CHF), cirrhosis, nephrotic syndrome, hypoalbuminemia, or lymphatic or venous obstruction. We present a case of a patient with sudden onset new bilateral lower extremity edema due to a rare adverse drug reaction (ADR) from valproate.

Case Presentation

A 63-year-old male with a history of seizures, bipolar disorder type I, and memory impairment due to traumatic brain injury (TBI) from a gunshot wound 24 years prior presented to the emergency department for witnessed seizure activity in the community. The patient had been incarcerated for the past 20 years, throughout which he had been taking the antiepileptic drugs (AEDs) phenytoin and divalproex and did not have any seizure activity. No records prior to his incarceration were available for review.

The patient recently had been released from prison and was nonadherent with his AEDs, leading to a witnessed seizure. This episode was described as preceded by an electric sensation, followed by rhythmic shaking of the right upper extremity without loss of consciousness. His regimen prior to admission included divalproex 1,000 mg daily and phenytoin 200 mg daily. His only other medication was folic acid.

Neurology was consulted on admission. An awake and asleep 4-hour electroencephalogram showed intermittent focal slowing of the right frontocentral region and frequent epileptiform discharges in the right prefrontal region during sleep, corresponding to areas of chronic right anterior frontal and temporal encephalomalacia seen on brain imaging. His seizures were thought likely to be secondary to prior head trauma. While the described seizure activity involving the right upper extremity was not consistent with the location of his prior TBI, neurology considered that he might have simple partial seizures with multiple foci or that his seizure event prior to admission was not accurately described. The neurology consult recommended switching from phenytoin 200 mg daily to lacosamide 100 mg twice daily on admission. His prior dose of divalproex 1,000 mg daily also was resumed for its antiepileptic effect and the added benefit of mood stabilization, as the patient reported elevated mood and decreased need for sleep on admission.

Eight days after changing his AED regimen, the patient was found to have new onset bilateral grade 1+ pitting edema to the level of his shins. He had no history of dyspnea, orthopnea, paroxysmal nocturnal dyspnea, dysuria, or changes in his urination. Although medical records from his incarceration were not available for review, the patient reported that he had never had peripheral edema.

On physical examination, the patient had no periorbital edema, jugular venous pressure of 8 cm H₂O, negative hepatojugular reflex, unremarkable cardiac and lung examination, and grade 2+ posterior tibial and dorsalis pedis pulses bilaterally. He underwent extensive laboratory evaluation for potential underlying causes, including nephrotic syndrome, cirrhosis, hypothyroidism, and CHF (Table). Valproate levels were initially subtherapeutic on admission (< 10 µg/mL, reference range 50-125 µg/mL) then rose to within therapeutic range (54 µg/mL-80 µg/mL throughout admission) after neurology recommended increasing the dose from 1,000 mg daily to 1,500 mg daily. His measured valproate levels were never supratherapeutic.

An electrocardiogram showed normal sinus rhythm unchanged from admission. Transthoracic echocardiogram showed normal left ventricular (LV) size and estimated LV ejection fraction of 55 to 60%. Abdominal ultrasound showed no evidence of cirrhosis and normal portal vein flow. Ultrasound of the lower extremities showed no deep venous thrombosis or valvular insufficiency. The patient was prescribed compression stockings. However, due to memory impairment, he was relatively nonadherent, and his lower extremity edema worsened to grade 3+ over several days. Due to the progressive swelling with no identified cause, a computed tomographic venogram of the abdomen and pelvis was performed to determine whether an inferior vena cava (IVC) thrombus was present. This study was unremarkable and did not show any external IVC compression.

After extensive evaluation did not reveal any other cause, the temporal course of events suggested an association between the patient’s peripheral edema and resumption of divalproex. His swelling remained stable. Discontinuation of divalproex was considered, but the patient’s mood remained euthymic, and he had no further seizure activity while on this medication, so the benefit of continuation was felt to outweigh any risks of switching to another agent.

Discussion

Valproate and its related forms, such as divalproex, often are used in the treatment of generalized or partial seizures, psychiatric disorders, and the prophylaxis of migraine headaches. Common ADRs include gastrointestinal symptoms, sedation, and dose-related thrombocytopenia, among many others. Rare ADRs include fulminant hepatitis, pancreatitis, hyperammonemia, and peripheral edema.¹ There have been case reports of valproate-induced peripheral edema, which seems to be an idiosyncratic ADR that occurs after long-term administration of the medication.^2,3 Early studies reported valproate-related edema in the context of valproate-induced hepatic injury.⁴ However, in more recent case reports, valproate-related edema has been found in patients without hepatotoxicity or supratherapeutic drug levels.^1,2

The exact mechanism by which valproate causes peripheral edema is unknown. It has been reported that medications affecting the γ-aminobutyric acid (GABA) system such as benzodiazepines, for example, can cause this rare ADR.⁵ Unlike benzodiazepines, valproate has an indirect effect on the GABA system, through increasing availability of GABA.⁶ GABA receptors have been identified on peripheral tissues, suggesting that GABAergic medications also may have an effect on regional vascular resistance.⁷ This mechanism was proposed by prior case reports but has yet to be proven in studies.²

In this case, initiation of lacosamide temporally coinciding with development of the patient’s edema leads one to question whether lacosamide may have caused this ADR. Other medications commonly used in seizure management (such as benzodiazepines and gabapentin) have been reported to cause new onset peripheral edema.^5,8 To date, however, there are no reported cases of peripheral edema due to lacosamide. While there are known interactions between various AEDs that may impact drug levels of valproate, there are no reported drug-drug interactions between lacosamide and valproate.⁹

Conclusions

Our case adds to the small but growing body of literature that suggests peripheral edema is a rare but clinically significant ADR of valproate. With its broad differential diagnosis, new onset peripheral edema is a concern that often warrants an extensive evaluation for underlying causes. Clinicians should be aware of this ADR as use of valproate becomes increasingly common so that an extensive workup is not always performed on patients with peripheral edema.

Bilateral lower extremity edema is a common condition with a broad differential diagnosis. New, severe peripheral edema implies a more nefarious underlying etiology than chronic venous insufficiency and should prompt a thorough evaluation for underlying conditions, such as congestive heart failure (CHF), cirrhosis, nephrotic syndrome, hypoalbuminemia, or lymphatic or venous obstruction. We present a case of a patient with sudden onset new bilateral lower extremity edema due to a rare adverse drug reaction (ADR) from valproate.

Case Presentation

A 63-year-old male with a history of seizures, bipolar disorder type I, and memory impairment due to traumatic brain injury (TBI) from a gunshot wound 24 years prior presented to the emergency department for witnessed seizure activity in the community. The patient had been incarcerated for the past 20 years, throughout which he had been taking the antiepileptic drugs (AEDs) phenytoin and divalproex and did not have any seizure activity. No records prior to his incarceration were available for review.

The patient recently had been released from prison and was nonadherent with his AEDs, leading to a witnessed seizure. This episode was described as preceded by an electric sensation, followed by rhythmic shaking of the right upper extremity without loss of consciousness. His regimen prior to admission included divalproex 1,000 mg daily and phenytoin 200 mg daily. His only other medication was folic acid.

Neurology was consulted on admission. An awake and asleep 4-hour electroencephalogram showed intermittent focal slowing of the right frontocentral region and frequent epileptiform discharges in the right prefrontal region during sleep, corresponding to areas of chronic right anterior frontal and temporal encephalomalacia seen on brain imaging. His seizures were thought likely to be secondary to prior head trauma. While the described seizure activity involving the right upper extremity was not consistent with the location of his prior TBI, neurology considered that he might have simple partial seizures with multiple foci or that his seizure event prior to admission was not accurately described. The neurology consult recommended switching from phenytoin 200 mg daily to lacosamide 100 mg twice daily on admission. His prior dose of divalproex 1,000 mg daily also was resumed for its antiepileptic effect and the added benefit of mood stabilization, as the patient reported elevated mood and decreased need for sleep on admission.

Eight days after changing his AED regimen, the patient was found to have new onset bilateral grade 1+ pitting edema to the level of his shins. He had no history of dyspnea, orthopnea, paroxysmal nocturnal dyspnea, dysuria, or changes in his urination. Although medical records from his incarceration were not available for review, the patient reported that he had never had peripheral edema.

On physical examination, the patient had no periorbital edema, jugular venous pressure of 8 cm H₂O, negative hepatojugular reflex, unremarkable cardiac and lung examination, and grade 2+ posterior tibial and dorsalis pedis pulses bilaterally. He underwent extensive laboratory evaluation for potential underlying causes, including nephrotic syndrome, cirrhosis, hypothyroidism, and CHF (Table). Valproate levels were initially subtherapeutic on admission (< 10 µg/mL, reference range 50-125 µg/mL) then rose to within therapeutic range (54 µg/mL-80 µg/mL throughout admission) after neurology recommended increasing the dose from 1,000 mg daily to 1,500 mg daily. His measured valproate levels were never supratherapeutic.

An electrocardiogram showed normal sinus rhythm unchanged from admission. Transthoracic echocardiogram showed normal left ventricular (LV) size and estimated LV ejection fraction of 55 to 60%. Abdominal ultrasound showed no evidence of cirrhosis and normal portal vein flow. Ultrasound of the lower extremities showed no deep venous thrombosis or valvular insufficiency. The patient was prescribed compression stockings. However, due to memory impairment, he was relatively nonadherent, and his lower extremity edema worsened to grade 3+ over several days. Due to the progressive swelling with no identified cause, a computed tomographic venogram of the abdomen and pelvis was performed to determine whether an inferior vena cava (IVC) thrombus was present. This study was unremarkable and did not show any external IVC compression.

After extensive evaluation did not reveal any other cause, the temporal course of events suggested an association between the patient’s peripheral edema and resumption of divalproex. His swelling remained stable. Discontinuation of divalproex was considered, but the patient’s mood remained euthymic, and he had no further seizure activity while on this medication, so the benefit of continuation was felt to outweigh any risks of switching to another agent.

Discussion

Valproate and its related forms, such as divalproex, often are used in the treatment of generalized or partial seizures, psychiatric disorders, and the prophylaxis of migraine headaches. Common ADRs include gastrointestinal symptoms, sedation, and dose-related thrombocytopenia, among many others. Rare ADRs include fulminant hepatitis, pancreatitis, hyperammonemia, and peripheral edema.¹ There have been case reports of valproate-induced peripheral edema, which seems to be an idiosyncratic ADR that occurs after long-term administration of the medication.^2,3 Early studies reported valproate-related edema in the context of valproate-induced hepatic injury.⁴ However, in more recent case reports, valproate-related edema has been found in patients without hepatotoxicity or supratherapeutic drug levels.^1,2

The exact mechanism by which valproate causes peripheral edema is unknown. It has been reported that medications affecting the γ-aminobutyric acid (GABA) system such as benzodiazepines, for example, can cause this rare ADR.⁵ Unlike benzodiazepines, valproate has an indirect effect on the GABA system, through increasing availability of GABA.⁶ GABA receptors have been identified on peripheral tissues, suggesting that GABAergic medications also may have an effect on regional vascular resistance.⁷ This mechanism was proposed by prior case reports but has yet to be proven in studies.²

In this case, initiation of lacosamide temporally coinciding with development of the patient’s edema leads one to question whether lacosamide may have caused this ADR. Other medications commonly used in seizure management (such as benzodiazepines and gabapentin) have been reported to cause new onset peripheral edema.^5,8 To date, however, there are no reported cases of peripheral edema due to lacosamide. While there are known interactions between various AEDs that may impact drug levels of valproate, there are no reported drug-drug interactions between lacosamide and valproate.⁹

Conclusions

Our case adds to the small but growing body of literature that suggests peripheral edema is a rare but clinically significant ADR of valproate. With its broad differential diagnosis, new onset peripheral edema is a concern that often warrants an extensive evaluation for underlying causes. Clinicians should be aware of this ADR as use of valproate becomes increasingly common so that an extensive workup is not always performed on patients with peripheral edema.

Frailty is a highly prevalent syndrome in nursing homes, occurring in at least 50% of patients.¹ The frailty phenotype has been described by Fried and colleagues as impairment in ≥ 3 of 5 domains: unintentional weight loss, self-reported exhaustion, muscle weakness, slow gait speed, and low physical activity. By this definition, frailty is highly associated with poor quality of life and mortality.^2,3

In recent years, there has been evolving evidence of a relationship between frailty and chronic systemic inflammation.^4-6 Some degree of chronic inflammation is likely inherent to the aging process and increases the risk of frailty (so-called inflammaging) but is seen to a greater degree in many pathologic conditions in nursing homes, including cancer, organ failure, and chronic infection.^4,6-8

Dysphagia also is highly prevalent in nursing homes, affecting up to 60% of patients and is a strong predictor of hospital utilization and of mortality.^9,10 Overt aspiration pneumonitis and pneumonia are perhaps the best studied sequelae, but chronic occult microaspiration also is prevalent in this population.¹¹ Just as normal systemic inflammatory changes in aging may increase vulnerability to frailty with additional illness burden, normal aging changes in swallowing function may increase vulnerability to dysphagia and to microaspiration with additional illness burden.^12,13 In older adults, important risk factors for microaspiration include not only overt dysphagia, dementia, and other neurologic illnesses, but also general debility, weakness, and immobility.¹⁴

Matsuse and colleagues have described diffuse aspiration bronchiolitis (DAB) in patients with chronic microaspiration.¹⁴ DAB often goes undiagnosed.^14-16 As in frailty, weight loss and chronic anemia may be seen, and many of these patients are bedridden.^14,17 Episodes of macroaspiration and overt lobar pneumonia also may occur.¹⁴ Lung biopsy or autopsy reveals chronic bronchiolar inflammation and sometimes pulmonary fibrosis, but to date there have been no reports suggesting chronic systemic inflammation or elevated proinflammatory cytokines.^14,15,17 We present 3 patients with progressive weight loss, functional decline, and frailty in whom chronic microaspiration likely played a significant role.

Case 1 Presentation

A 68-year-old man with a 6-year history of rapidly progressive Parkinson disease was admitted to the Haley’s Cove Community Living Center (CLC) on the James A. Haley Veterans’ Hospital campus in Tampa, Florida for long-term care. The patient’s medical history also was significant for bipolar illness and for small cell carcinoma of the lung in sustained remission.

Medications included levodopa/carbidopa 50 mg/200 mg 4 times daily, entacapone 200 mg 4 times daily, lithium carbonate 600 mg every night at bedtime, lamotrigine 150 mg daily, quetiapine 200 mg every night at bedtime, pravastatin 40 mg every night at bedtime, omeprazole 20 mg daily, tamsulosin 0.4 mg every night at bedtime, and aspirin 81 mg daily. He initially did well, but after 6 months the nursing staff began to notice the patient coughing during and after meals. Speech pathology evaluation revealed moderate oropharyngeal dysphagia, and his diet was downgraded to nectar-thickened liquids.

Over the subsequent 10 months, he became progressively weaker in physical therapy and more inactive, with about a 20-lb weight loss and mild hypoalbuminemia of 3.0 gm/dL. He had developed 3 episodes of aspiration pneumonia during this period; a repeat swallow evaluation after the last episode revealed worsened dysphagia, and his physician suggested nil per os (NPO) status and an alternative feeding route. His guardian declined placement of a percutaneous endoscopic gastrostomy (PEG) tube, he was transferred to the inpatient hospice unit, and died 2 weeks later. An autopsy was declined.

Case 2 Presentation

A 66-year-old man with a medical history of multiple traumatic brain injuries (TBIs) was admitted to the CLC for long-term care. Sequelae of the TBIs included moderate dementia, spastic paraparesis with multiple pressure injuries, a well-controlled seizure disorder, and severe oropharyngeal dysphagia with NPO status and a percutaneous endoscopic gastrostomy (PEG) tube. His medical history included TBIs and hepatitis C virus infection; medications included levetiracetam 1,000 mg twice daily, lamotrigine 25 mg twice daily, and cholecalciferol 2,000 U daily. He had multiple stage III pressure injuries and an ischial stage IV injury at the time of admission.

His 11-month stay in the CLC was characterized by progressively worsening weakness and inactivity, with a 25-lb weight loss in spite of adequate tube feeding. Serum albumin remained in the 2.0 to 2.5 gm/dL range, hemoglobin in the 7 to 9 gm/dL range without any obvious source of anemia. Most of the pressure injuries worsened during his stay in spite of aggressive wound care, and he developed a second stage IV sacral wound. A single C-reactive protein (CRP) level 2 months prior to his death was markedly elevated at 19.5 mg/dL. In spite of maintaining NPO status, he developed 3 episodes of aspiration pneumonia, all of which responded well to treatment. Ultimately, he was found pulseless and apneic and resuscitation was unsuccessful. An autopsy revealed purulent material in the small airways.

Case 3 Presentation

A 65-year-old man with a long history of paranoid schizophrenia and severe gastroesophageal reflux disease had resided in the CLC for about 10 years. Medications included risperidone microspheres 37.5 mg every 2 weeks, valproic acid 500 mg 3 times daily and 1,000 mg every night at bedtime, lansoprazole 30 mg twice daily, ranitidine 150 mg every night at bedtime, sucralfate 1,000 mg 3 times daily, simvastatin 20 mg every night at bedtime, and tamsulosin 0.4 mg every night at bedtime. He had done well for many years but developed some drooling and a modest resting tremor (but no other signs of pseudoparkinsonism) about 8 years after admission.

There had been no changes to his risperidone dosage. He also lost about 20 lb over a period of 1 year and became increasingly weak and dependent in gait, serum albumin dropped as low as 1.6 gm/dL, hemoglobin dropped to the 7 to 8 gm/dL range (without any other obvious source of anemia), and he developed a gradually worsening right-sided pleural effusion. CRP was chronically elevated at this point, in the 6 to 15 mg/dL range and as high as 17.2 mg/dL. Ultimately, he developed 3 episodes of aspiration pneumonia over a period of 2 months. Swallowing evaluation at that time revealed severe oropharyngeal dysphagia and a PEG tube was placed. Due to concerns for possible antipsychotic-induced dysphagia, risperidone was discontinued, and quetiapine 400 mg a day was substituted. He did well over the subsequent year with no further pneumonia and advancement back to a regular diet. He regained all of the lost weight and began independent ambulation. Albumin improved to the 3 gm/dL range, hemoglobin to the 12 to 13 gm/dL range, and CRP had decreased to 0.7 mg/dL. The pleural effusion (believed to have been a parapneumonic effusion) had resolved.

Discussion

All 3 patients met the Fried criteria for frailty, although there were several confounding issues.² All 3 patients lost between 20 and 25 lb; all had clearly become weaker according to nursing and rehabilitation staff (although none were formally assessed for grip strength); and all had clear declines in their activity level. Patient 3 had a clear decrement in gait speed, but patient 1 had severe gait impairment due to Parkinson disease (although his gait in therapy had clearly worsened). Patient 2 was paraparetic and unable to ambulate. There also was evidence of limited biomarkers of systemic inflammation; all 3 patients’ albumin had decreased, and patients 2 and 3 had significant decrease in hemoglobin; but these commonplace clinical biomarkers are obviously multifactorially determined. We have limited data on our patients’ CRP levels; serial levels would have been more specific for systemic inflammation but were infrequently performed on the patients.

Multimorbidity and medical complexity are more the rule than the exception in frail geriatric patients,and it is difficult to separate the role of microaspiration from other confounding conditions that might have contributed to these patients’ evolving systemic inflammation and frailty.¹⁸ It might be argued that the decline for patient 1 was related to the underlying Parkinson disease (a progressive neurologic illness in which systemic inflammation has been reported), or that the decline of patient 2 was related to the worsening pressure injuries rather than to covert microaspiration.¹⁹ However, the TBIs for patient 2 and the schizophrenia for patient 3 would not be expected to be associated with frailty or with systemic inflammation. Furthermore, the frailty symptoms of patient 3 and inflammatory biomarkers improved after the risperidone, which was likely responsible for his microaspiration, was discontinued. All 3 patients were at risk for oropharyngeal dysphagia (antipsychotic medication is clearly associated with dysphagia²⁰); patient 2 demonstrated pathologic evidence of DAB at autopsy.

There is evolving evidence that chronic systemic inflammation and immune activation are key mechanisms in the pathogenesis of frailty.^4-6 It is known that elevated serum levels of proinflammatory cytokines, including tumor necrosis factor-α, interleukin-6, and CRP are directly associated with frailty and are inversely associated with levels of albumin, hemoglobin, insulin-like growth factor-1, and several micronutrients in frail individuals.^4-7,21,22 Chronic inflammation contributes to the pathophysiology of frailty through detrimental effects on a broad range of systems, including the musculoskeletal, endocrine, and hematopoietic systems and through nutritional dysregulation.^2,4,23 These changes may lead to further deleterious effects, creating a downward spiral of worsening frailty. For example, it seems likely that our patients’ progressive weakness further compromised airway protection, creating a vicious cycle of worsening microaspiration and chronic inflammation.

Conclusions

To date, the role of chronic microaspiration and DAB in chronic systemic inflammation or in frailty has not been explored. Given the prevalence of microaspiration in nursing home residents and the devastating consequences of frailty, though, this seems to be a crucial area of investigation. It is equally crucial for long-term care staff, both providers and nursing staff, to have a heightened awareness of covert microaspiration and a low threshold for referral to speech pathology for further investigation. Staff also should be aware of the utility of the Fried criteria to improve identification of frailty in general. It is probable that covert microaspiration will prove to be an important part of the differential diagnosis of frailty.

Frailty is a highly prevalent syndrome in nursing homes, occurring in at least 50% of patients.¹ The frailty phenotype has been described by Fried and colleagues as impairment in ≥ 3 of 5 domains: unintentional weight loss, self-reported exhaustion, muscle weakness, slow gait speed, and low physical activity. By this definition, frailty is highly associated with poor quality of life and mortality.^2,3

In recent years, there has been evolving evidence of a relationship between frailty and chronic systemic inflammation.^4-6 Some degree of chronic inflammation is likely inherent to the aging process and increases the risk of frailty (so-called inflammaging) but is seen to a greater degree in many pathologic conditions in nursing homes, including cancer, organ failure, and chronic infection.^4,6-8

Dysphagia also is highly prevalent in nursing homes, affecting up to 60% of patients and is a strong predictor of hospital utilization and of mortality.^9,10 Overt aspiration pneumonitis and pneumonia are perhaps the best studied sequelae, but chronic occult microaspiration also is prevalent in this population.¹¹ Just as normal systemic inflammatory changes in aging may increase vulnerability to frailty with additional illness burden, normal aging changes in swallowing function may increase vulnerability to dysphagia and to microaspiration with additional illness burden.^12,13 In older adults, important risk factors for microaspiration include not only overt dysphagia, dementia, and other neurologic illnesses, but also general debility, weakness, and immobility.¹⁴

Matsuse and colleagues have described diffuse aspiration bronchiolitis (DAB) in patients with chronic microaspiration.¹⁴ DAB often goes undiagnosed.^14-16 As in frailty, weight loss and chronic anemia may be seen, and many of these patients are bedridden.^14,17 Episodes of macroaspiration and overt lobar pneumonia also may occur.¹⁴ Lung biopsy or autopsy reveals chronic bronchiolar inflammation and sometimes pulmonary fibrosis, but to date there have been no reports suggesting chronic systemic inflammation or elevated proinflammatory cytokines.^14,15,17 We present 3 patients with progressive weight loss, functional decline, and frailty in whom chronic microaspiration likely played a significant role.

Case 1 Presentation

A 68-year-old man with a 6-year history of rapidly progressive Parkinson disease was admitted to the Haley’s Cove Community Living Center (CLC) on the James A. Haley Veterans’ Hospital campus in Tampa, Florida for long-term care. The patient’s medical history also was significant for bipolar illness and for small cell carcinoma of the lung in sustained remission.

Medications included levodopa/carbidopa 50 mg/200 mg 4 times daily, entacapone 200 mg 4 times daily, lithium carbonate 600 mg every night at bedtime, lamotrigine 150 mg daily, quetiapine 200 mg every night at bedtime, pravastatin 40 mg every night at bedtime, omeprazole 20 mg daily, tamsulosin 0.4 mg every night at bedtime, and aspirin 81 mg daily. He initially did well, but after 6 months the nursing staff began to notice the patient coughing during and after meals. Speech pathology evaluation revealed moderate oropharyngeal dysphagia, and his diet was downgraded to nectar-thickened liquids.

Over the subsequent 10 months, he became progressively weaker in physical therapy and more inactive, with about a 20-lb weight loss and mild hypoalbuminemia of 3.0 gm/dL. He had developed 3 episodes of aspiration pneumonia during this period; a repeat swallow evaluation after the last episode revealed worsened dysphagia, and his physician suggested nil per os (NPO) status and an alternative feeding route. His guardian declined placement of a percutaneous endoscopic gastrostomy (PEG) tube, he was transferred to the inpatient hospice unit, and died 2 weeks later. An autopsy was declined.

Case 2 Presentation

A 66-year-old man with a medical history of multiple traumatic brain injuries (TBIs) was admitted to the CLC for long-term care. Sequelae of the TBIs included moderate dementia, spastic paraparesis with multiple pressure injuries, a well-controlled seizure disorder, and severe oropharyngeal dysphagia with NPO status and a percutaneous endoscopic gastrostomy (PEG) tube. His medical history included TBIs and hepatitis C virus infection; medications included levetiracetam 1,000 mg twice daily, lamotrigine 25 mg twice daily, and cholecalciferol 2,000 U daily. He had multiple stage III pressure injuries and an ischial stage IV injury at the time of admission.

His 11-month stay in the CLC was characterized by progressively worsening weakness and inactivity, with a 25-lb weight loss in spite of adequate tube feeding. Serum albumin remained in the 2.0 to 2.5 gm/dL range, hemoglobin in the 7 to 9 gm/dL range without any obvious source of anemia. Most of the pressure injuries worsened during his stay in spite of aggressive wound care, and he developed a second stage IV sacral wound. A single C-reactive protein (CRP) level 2 months prior to his death was markedly elevated at 19.5 mg/dL. In spite of maintaining NPO status, he developed 3 episodes of aspiration pneumonia, all of which responded well to treatment. Ultimately, he was found pulseless and apneic and resuscitation was unsuccessful. An autopsy revealed purulent material in the small airways.

Case 3 Presentation

A 65-year-old man with a long history of paranoid schizophrenia and severe gastroesophageal reflux disease had resided in the CLC for about 10 years. Medications included risperidone microspheres 37.5 mg every 2 weeks, valproic acid 500 mg 3 times daily and 1,000 mg every night at bedtime, lansoprazole 30 mg twice daily, ranitidine 150 mg every night at bedtime, sucralfate 1,000 mg 3 times daily, simvastatin 20 mg every night at bedtime, and tamsulosin 0.4 mg every night at bedtime. He had done well for many years but developed some drooling and a modest resting tremor (but no other signs of pseudoparkinsonism) about 8 years after admission.

There had been no changes to his risperidone dosage. He also lost about 20 lb over a period of 1 year and became increasingly weak and dependent in gait, serum albumin dropped as low as 1.6 gm/dL, hemoglobin dropped to the 7 to 8 gm/dL range (without any other obvious source of anemia), and he developed a gradually worsening right-sided pleural effusion. CRP was chronically elevated at this point, in the 6 to 15 mg/dL range and as high as 17.2 mg/dL. Ultimately, he developed 3 episodes of aspiration pneumonia over a period of 2 months. Swallowing evaluation at that time revealed severe oropharyngeal dysphagia and a PEG tube was placed. Due to concerns for possible antipsychotic-induced dysphagia, risperidone was discontinued, and quetiapine 400 mg a day was substituted. He did well over the subsequent year with no further pneumonia and advancement back to a regular diet. He regained all of the lost weight and began independent ambulation. Albumin improved to the 3 gm/dL range, hemoglobin to the 12 to 13 gm/dL range, and CRP had decreased to 0.7 mg/dL. The pleural effusion (believed to have been a parapneumonic effusion) had resolved.

Discussion

All 3 patients met the Fried criteria for frailty, although there were several confounding issues.² All 3 patients lost between 20 and 25 lb; all had clearly become weaker according to nursing and rehabilitation staff (although none were formally assessed for grip strength); and all had clear declines in their activity level. Patient 3 had a clear decrement in gait speed, but patient 1 had severe gait impairment due to Parkinson disease (although his gait in therapy had clearly worsened). Patient 2 was paraparetic and unable to ambulate. There also was evidence of limited biomarkers of systemic inflammation; all 3 patients’ albumin had decreased, and patients 2 and 3 had significant decrease in hemoglobin; but these commonplace clinical biomarkers are obviously multifactorially determined. We have limited data on our patients’ CRP levels; serial levels would have been more specific for systemic inflammation but were infrequently performed on the patients.

Multimorbidity and medical complexity are more the rule than the exception in frail geriatric patients,and it is difficult to separate the role of microaspiration from other confounding conditions that might have contributed to these patients’ evolving systemic inflammation and frailty.¹⁸ It might be argued that the decline for patient 1 was related to the underlying Parkinson disease (a progressive neurologic illness in which systemic inflammation has been reported), or that the decline of patient 2 was related to the worsening pressure injuries rather than to covert microaspiration.¹⁹ However, the TBIs for patient 2 and the schizophrenia for patient 3 would not be expected to be associated with frailty or with systemic inflammation. Furthermore, the frailty symptoms of patient 3 and inflammatory biomarkers improved after the risperidone, which was likely responsible for his microaspiration, was discontinued. All 3 patients were at risk for oropharyngeal dysphagia (antipsychotic medication is clearly associated with dysphagia²⁰); patient 2 demonstrated pathologic evidence of DAB at autopsy.

There is evolving evidence that chronic systemic inflammation and immune activation are key mechanisms in the pathogenesis of frailty.^4-6 It is known that elevated serum levels of proinflammatory cytokines, including tumor necrosis factor-α, interleukin-6, and CRP are directly associated with frailty and are inversely associated with levels of albumin, hemoglobin, insulin-like growth factor-1, and several micronutrients in frail individuals.^4-7,21,22 Chronic inflammation contributes to the pathophysiology of frailty through detrimental effects on a broad range of systems, including the musculoskeletal, endocrine, and hematopoietic systems and through nutritional dysregulation.^2,4,23 These changes may lead to further deleterious effects, creating a downward spiral of worsening frailty. For example, it seems likely that our patients’ progressive weakness further compromised airway protection, creating a vicious cycle of worsening microaspiration and chronic inflammation.

Conclusions

To date, the role of chronic microaspiration and DAB in chronic systemic inflammation or in frailty has not been explored. Given the prevalence of microaspiration in nursing home residents and the devastating consequences of frailty, though, this seems to be a crucial area of investigation. It is equally crucial for long-term care staff, both providers and nursing staff, to have a heightened awareness of covert microaspiration and a low threshold for referral to speech pathology for further investigation. Staff also should be aware of the utility of the Fried criteria to improve identification of frailty in general. It is probable that covert microaspiration will prove to be an important part of the differential diagnosis of frailty.

Frailty is a highly prevalent syndrome in nursing homes, occurring in at least 50% of patients.¹ The frailty phenotype has been described by Fried and colleagues as impairment in ≥ 3 of 5 domains: unintentional weight loss, self-reported exhaustion, muscle weakness, slow gait speed, and low physical activity. By this definition, frailty is highly associated with poor quality of life and mortality.^2,3

In recent years, there has been evolving evidence of a relationship between frailty and chronic systemic inflammation.^4-6 Some degree of chronic inflammation is likely inherent to the aging process and increases the risk of frailty (so-called inflammaging) but is seen to a greater degree in many pathologic conditions in nursing homes, including cancer, organ failure, and chronic infection.^4,6-8

Dysphagia also is highly prevalent in nursing homes, affecting up to 60% of patients and is a strong predictor of hospital utilization and of mortality.^9,10 Overt aspiration pneumonitis and pneumonia are perhaps the best studied sequelae, but chronic occult microaspiration also is prevalent in this population.¹¹ Just as normal systemic inflammatory changes in aging may increase vulnerability to frailty with additional illness burden, normal aging changes in swallowing function may increase vulnerability to dysphagia and to microaspiration with additional illness burden.^12,13 In older adults, important risk factors for microaspiration include not only overt dysphagia, dementia, and other neurologic illnesses, but also general debility, weakness, and immobility.¹⁴

Matsuse and colleagues have described diffuse aspiration bronchiolitis (DAB) in patients with chronic microaspiration.¹⁴ DAB often goes undiagnosed.^14-16 As in frailty, weight loss and chronic anemia may be seen, and many of these patients are bedridden.^14,17 Episodes of macroaspiration and overt lobar pneumonia also may occur.¹⁴ Lung biopsy or autopsy reveals chronic bronchiolar inflammation and sometimes pulmonary fibrosis, but to date there have been no reports suggesting chronic systemic inflammation or elevated proinflammatory cytokines.^14,15,17 We present 3 patients with progressive weight loss, functional decline, and frailty in whom chronic microaspiration likely played a significant role.

Case 1 Presentation

A 68-year-old man with a 6-year history of rapidly progressive Parkinson disease was admitted to the Haley’s Cove Community Living Center (CLC) on the James A. Haley Veterans’ Hospital campus in Tampa, Florida for long-term care. The patient’s medical history also was significant for bipolar illness and for small cell carcinoma of the lung in sustained remission.

Medications included levodopa/carbidopa 50 mg/200 mg 4 times daily, entacapone 200 mg 4 times daily, lithium carbonate 600 mg every night at bedtime, lamotrigine 150 mg daily, quetiapine 200 mg every night at bedtime, pravastatin 40 mg every night at bedtime, omeprazole 20 mg daily, tamsulosin 0.4 mg every night at bedtime, and aspirin 81 mg daily. He initially did well, but after 6 months the nursing staff began to notice the patient coughing during and after meals. Speech pathology evaluation revealed moderate oropharyngeal dysphagia, and his diet was downgraded to nectar-thickened liquids.

Over the subsequent 10 months, he became progressively weaker in physical therapy and more inactive, with about a 20-lb weight loss and mild hypoalbuminemia of 3.0 gm/dL. He had developed 3 episodes of aspiration pneumonia during this period; a repeat swallow evaluation after the last episode revealed worsened dysphagia, and his physician suggested nil per os (NPO) status and an alternative feeding route. His guardian declined placement of a percutaneous endoscopic gastrostomy (PEG) tube, he was transferred to the inpatient hospice unit, and died 2 weeks later. An autopsy was declined.

Case 2 Presentation

A 66-year-old man with a medical history of multiple traumatic brain injuries (TBIs) was admitted to the CLC for long-term care. Sequelae of the TBIs included moderate dementia, spastic paraparesis with multiple pressure injuries, a well-controlled seizure disorder, and severe oropharyngeal dysphagia with NPO status and a percutaneous endoscopic gastrostomy (PEG) tube. His medical history included TBIs and hepatitis C virus infection; medications included levetiracetam 1,000 mg twice daily, lamotrigine 25 mg twice daily, and cholecalciferol 2,000 U daily. He had multiple stage III pressure injuries and an ischial stage IV injury at the time of admission.

His 11-month stay in the CLC was characterized by progressively worsening weakness and inactivity, with a 25-lb weight loss in spite of adequate tube feeding. Serum albumin remained in the 2.0 to 2.5 gm/dL range, hemoglobin in the 7 to 9 gm/dL range without any obvious source of anemia. Most of the pressure injuries worsened during his stay in spite of aggressive wound care, and he developed a second stage IV sacral wound. A single C-reactive protein (CRP) level 2 months prior to his death was markedly elevated at 19.5 mg/dL. In spite of maintaining NPO status, he developed 3 episodes of aspiration pneumonia, all of which responded well to treatment. Ultimately, he was found pulseless and apneic and resuscitation was unsuccessful. An autopsy revealed purulent material in the small airways.

Case 3 Presentation

A 65-year-old man with a long history of paranoid schizophrenia and severe gastroesophageal reflux disease had resided in the CLC for about 10 years. Medications included risperidone microspheres 37.5 mg every 2 weeks, valproic acid 500 mg 3 times daily and 1,000 mg every night at bedtime, lansoprazole 30 mg twice daily, ranitidine 150 mg every night at bedtime, sucralfate 1,000 mg 3 times daily, simvastatin 20 mg every night at bedtime, and tamsulosin 0.4 mg every night at bedtime. He had done well for many years but developed some drooling and a modest resting tremor (but no other signs of pseudoparkinsonism) about 8 years after admission.

There had been no changes to his risperidone dosage. He also lost about 20 lb over a period of 1 year and became increasingly weak and dependent in gait, serum albumin dropped as low as 1.6 gm/dL, hemoglobin dropped to the 7 to 8 gm/dL range (without any other obvious source of anemia), and he developed a gradually worsening right-sided pleural effusion. CRP was chronically elevated at this point, in the 6 to 15 mg/dL range and as high as 17.2 mg/dL. Ultimately, he developed 3 episodes of aspiration pneumonia over a period of 2 months. Swallowing evaluation at that time revealed severe oropharyngeal dysphagia and a PEG tube was placed. Due to concerns for possible antipsychotic-induced dysphagia, risperidone was discontinued, and quetiapine 400 mg a day was substituted. He did well over the subsequent year with no further pneumonia and advancement back to a regular diet. He regained all of the lost weight and began independent ambulation. Albumin improved to the 3 gm/dL range, hemoglobin to the 12 to 13 gm/dL range, and CRP had decreased to 0.7 mg/dL. The pleural effusion (believed to have been a parapneumonic effusion) had resolved.

Discussion

All 3 patients met the Fried criteria for frailty, although there were several confounding issues.² All 3 patients lost between 20 and 25 lb; all had clearly become weaker according to nursing and rehabilitation staff (although none were formally assessed for grip strength); and all had clear declines in their activity level. Patient 3 had a clear decrement in gait speed, but patient 1 had severe gait impairment due to Parkinson disease (although his gait in therapy had clearly worsened). Patient 2 was paraparetic and unable to ambulate. There also was evidence of limited biomarkers of systemic inflammation; all 3 patients’ albumin had decreased, and patients 2 and 3 had significant decrease in hemoglobin; but these commonplace clinical biomarkers are obviously multifactorially determined. We have limited data on our patients’ CRP levels; serial levels would have been more specific for systemic inflammation but were infrequently performed on the patients.

Multimorbidity and medical complexity are more the rule than the exception in frail geriatric patients,and it is difficult to separate the role of microaspiration from other confounding conditions that might have contributed to these patients’ evolving systemic inflammation and frailty.¹⁸ It might be argued that the decline for patient 1 was related to the underlying Parkinson disease (a progressive neurologic illness in which systemic inflammation has been reported), or that the decline of patient 2 was related to the worsening pressure injuries rather than to covert microaspiration.¹⁹ However, the TBIs for patient 2 and the schizophrenia for patient 3 would not be expected to be associated with frailty or with systemic inflammation. Furthermore, the frailty symptoms of patient 3 and inflammatory biomarkers improved after the risperidone, which was likely responsible for his microaspiration, was discontinued. All 3 patients were at risk for oropharyngeal dysphagia (antipsychotic medication is clearly associated with dysphagia²⁰); patient 2 demonstrated pathologic evidence of DAB at autopsy.

There is evolving evidence that chronic systemic inflammation and immune activation are key mechanisms in the pathogenesis of frailty.^4-6 It is known that elevated serum levels of proinflammatory cytokines, including tumor necrosis factor-α, interleukin-6, and CRP are directly associated with frailty and are inversely associated with levels of albumin, hemoglobin, insulin-like growth factor-1, and several micronutrients in frail individuals.^4-7,21,22 Chronic inflammation contributes to the pathophysiology of frailty through detrimental effects on a broad range of systems, including the musculoskeletal, endocrine, and hematopoietic systems and through nutritional dysregulation.^2,4,23 These changes may lead to further deleterious effects, creating a downward spiral of worsening frailty. For example, it seems likely that our patients’ progressive weakness further compromised airway protection, creating a vicious cycle of worsening microaspiration and chronic inflammation.

Conclusions

To date, the role of chronic microaspiration and DAB in chronic systemic inflammation or in frailty has not been explored. Given the prevalence of microaspiration in nursing home residents and the devastating consequences of frailty, though, this seems to be a crucial area of investigation. It is equally crucial for long-term care staff, both providers and nursing staff, to have a heightened awareness of covert microaspiration and a low threshold for referral to speech pathology for further investigation. Staff also should be aware of the utility of the Fried criteria to improve identification of frailty in general. It is probable that covert microaspiration will prove to be an important part of the differential diagnosis of frailty.