Case Reports

Atopic dermatitis (AD) and psoriasis are common skin diseases in which dysfunction of the epidermal barrier leads to skin inflammation and altered expression of proinflammatory cytokines.¹ There often is overlap in the clinical and histopathologic features of AD and psoriasis, which can make diagnosis a challenge. Persistent late-stage AD can present with psoriasiform lichenified changes, and psoriasis lesions in the acute stage can have an eczematous appearance.² Histologically, chronic psoriasis lesions share many overlapping features with AD, and some subsets of AD with IL-17 predominance (ie, intrinsic, pediatric, presentation in Asian patients) exhibit a psoriasiform appearance.^3,4

Atopic dermatitis and psoriasis are considered 2 distinct conditions because AD is a helper T cell (T_H2)–driven disease with subsequent overproduction of IL-4 and IL-13 and psoriasis is a T_H17 cell–driven disease with overproduction of IL-17³; however, the shared features of AD and psoriasis represent an underlying immunopathological spectrum^2,5,6 in which one condition can develop following treatment of the other condition (immunological shift in pathways), both conditions can occur at different times in a patient’s life with alternating cycles of disease flares, or both conditions can coexist as an overlapping syndrome.^1,2 A retrospective study from 2012 to 2019 estimated the prevalence of concomitant AD and psoriasis in the United States at 1.3%, with AD following the diagnosis of psoriasis in 67% of cases.¹ Concurrent AD and psoriasis—when both diseases flaresimultaneously—is the rarest scenario.^2,5

Treatment modalities for AD include topical corticosteroids, which act on immune cells to suppress the release of proinflammatory cytokines, as well as dupilumab, which offers targeted blockade of involved cytokines IL-4 and IL-13. Psoriasis can be treated with multiple immune modulators, including topical corticosteroids and vitamin D analogs, as well as systemic medications that reduce T-cell activation and inflammatory cytokines through targeting of IFN-γ, IL-2, tumor necrosis factor α, IL-17, and IL-23.^7,8

We present the case of a patient with long-standing concurrent, treatment-resistant AD and psoriasis who was successfully treated with dual biologic therapy with guselkumab and dupilumab.

Case Report

A 62-year-old woman presented to our dermatology clinic with red itchy scales and painful fissures on the palms, hands, and soles of more than 12 years’ duration. Her medical history included an allergy to amoxicillin-clavulanate as well as an allergy to both dog and cat dander on prick testing. Her family history included dyshidrotic eczema in her mother. A complete blood cell count with differential was within reference range. A shave biopsy of the right dorsal hand performed at the onset of symptoms at an outside facility revealed hyperkeratotic acanthotic epidermis with a mild perivascular lymphocytic infiltrate.

Results of patch testing indicated contact hypersensitivity to the botanical rosin colophonium (or colophony); carba mix (1, 3-diphenylguanidine, zinc dibutyldithiocarbamate, and zinc diethydithiocarbamate); thiuram mix (tetramethylthiuram disulfide, tetramethylthiuram monosulfide, and tetraethylthiuram disulfide); n,n-diphenylguanidine; and tixocortol-21-pivalate. Our patient was given guidance on avoiding these agents, as it was suspected that exposure may be exacerbating the psoriasis. The psoriasis was treated with topical corticosteroids, keratolytics, and calcineurin inhibitors, all of which offered minimal or no relief. Trials of systemic agents, including methotrexate (discontinued because transaminitis developed), etanercept, adalimumab, and apremilast for 6 to 10 months did not provide improvement.

Two years prior to the current presentation, our patient had been treated with the IL-23 inhibitor guselkumab, which provided moderate improvement. When she presented to our clinic, physical examination while she was taking guselkumab demonstrated prurigo with excoriations of the extremities, hyperkeratosis with scaling and fissures of the soles, erythematous scaly plaques on the palms and dorsal surface of the hands, and mild onycholysis of the nails (Figures 1 and 2). Because we were concerned about concomitant intrinsic AD, dupilumab was initiated in conjunction with guselkumab. A second biopsy was considered but deferred in favor of clinical monitoring.

After 1 year of dual biologic therapy, the patient experienced near-complete resolution of symptoms. The psoriasis completely resolved from an initial body surface area of 5%, and the AD body surface area decreased from 30% to 2% (Figure 3). The patient reported no adverse effects from treatment.

Comment

Atopic dermatitis and psoriasis involve complex immunopathology and a spectrum of cytokines that might explain the overlap in their clinical and histopathologic presentations.

Atopic dermatitis—Atopic dermatitis involves T_H1, T_H2, T_H9, T_H17, and T_H22 cells; T_H2 cells release IL-4, IL-5, and IL-13, all of which are key cytokines in the inflammatory pathway of AD.^9,10 Activation of the helper T-cell subset and the release of cytokines differ slightly based on the subcategory of AD and the stage of exacerbation. In addition to T_H2-cell activation, T_H1 cells and T_H22 cells—which release IL-12 and IL-22, respectively—are active in both intrinsic and extrinsic AD. T_H17 cells and T_H9 cells—which release IL-17 and IL-9, respectively—are more prominent in the intrinsic pathway than in the extrinsic pathway.⁹ Intrinsic AD is recognized by a lack of eosinophilia, female predominance, and delayed onset compared to extrinsic AD; there also is a lack of history of atopy.¹ Extrinsic AD is characterized by eosinophilia as well as a personal and family history of atopy.¹¹ Our patient—a female with onset in older adulthood, lack of eosinophilia, and a family history of atopy—displayed features of both intrinsic and extrinsic AD.

Psoriasis—The immunopathology of psoriasis involves stimulation of dendritic cells, which activate T_H17 cells through IL-23. T_H17 cells then release IL-17 and IL-22. Therefore, both AD and psoriasis involve activation of T_H22 and T_H1 cells, with increased IL-17 and IL-22 production.^3,10,12 IL-17 and IL-22 induce epidermal hyperplasia; IL-22 also contributes to skin barrier dysfunction.¹² Therefore, it might be reasonable to consider psoriasis and AD as diseases that exist across a T-cell axis spectrum, thereby accounting for some overlap in disease characteristics.³

Dual Biologic Therapy—Dupilumab blocks the IL-4 receptor α subunit, a receptor for IL-4 and IL-13, which are key cytokines in the pathogenesis of AD.¹⁰ Guselkumab inhibits IL-23, thus blocking the inflammatory cascade of T_H17 cell activation and release of IL-17 and IL-22 in the psoriasis pathway.¹³ Although an immunopathological spectrum exists between the 2 diseases, the continued presence of AD symptoms after blocking the IL-23 cascade suggests that additional blockade of T_H2 cells is required to control AD in patients with true concurrent disease.

Accurate diagnosis of AD and/or psoriasis is important when considering targeted treatment of these conditions with biologics. The use of dual biologics is limited by a paucity of data regarding the safety of these agents when given in combination. A recent meta-analysis of dual biologic therapy in patients with inflammatory bowel disease demonstrated acceptable safety results with a pooled adverse reaction rate of 31%.¹⁴

Anchoring Bias—Anchoring bias can occur when a clinician’s decisions are influenced by a particular event or reference point, which might cause them to disregard subsequent evidence. Our case illustrates the importance of critically assessing the response to treatment and being mindful of the potential influence of anchoring bias on the differential diagnosis. Although overcoming biases in conditions with clinical overlap can be challenging, it is important to consider coexisting AD and psoriasis in patients with extensive hand involvement when multiple treatments have failed and only a partial response to targeted pathways has been achieved. In our case, the patient also had contact hypersensitivity to tixocortol-21-pivalate, which indicates hypersensitivity to many prescription topical corticosteroids, oral prednisone, and over-the-counter hydrocortisone; however, topical corticosteroids continued to be prescribed for her, which might have contributed to the lack of improvement and even exacerbated the rash.

Future Considerations—A consideration for the future in this case is discontinuing guselkumab to observe whether symptoms recur. We discussed this option with the patient, but she opted to continue treatment with dupilumab and guselkumab because of the symptom resolution.

Conclusion

Concomitant disease can present as an overlapping pattern in the same area, whereas other regions might have geographically isolated disease. Our patient’s overlap of symptoms, the failure of multiple treatments, and the partial improvement she experienced on guselkumab made diagnosis and management challenging; however, dual biologic therapy was successful.

Atopic dermatitis (AD) and psoriasis are common skin diseases in which dysfunction of the epidermal barrier leads to skin inflammation and altered expression of proinflammatory cytokines.¹ There often is overlap in the clinical and histopathologic features of AD and psoriasis, which can make diagnosis a challenge. Persistent late-stage AD can present with psoriasiform lichenified changes, and psoriasis lesions in the acute stage can have an eczematous appearance.² Histologically, chronic psoriasis lesions share many overlapping features with AD, and some subsets of AD with IL-17 predominance (ie, intrinsic, pediatric, presentation in Asian patients) exhibit a psoriasiform appearance.^3,4

Atopic dermatitis and psoriasis are considered 2 distinct conditions because AD is a helper T cell (T_H2)–driven disease with subsequent overproduction of IL-4 and IL-13 and psoriasis is a T_H17 cell–driven disease with overproduction of IL-17³; however, the shared features of AD and psoriasis represent an underlying immunopathological spectrum^2,5,6 in which one condition can develop following treatment of the other condition (immunological shift in pathways), both conditions can occur at different times in a patient’s life with alternating cycles of disease flares, or both conditions can coexist as an overlapping syndrome.^1,2 A retrospective study from 2012 to 2019 estimated the prevalence of concomitant AD and psoriasis in the United States at 1.3%, with AD following the diagnosis of psoriasis in 67% of cases.¹ Concurrent AD and psoriasis—when both diseases flaresimultaneously—is the rarest scenario.^2,5

Treatment modalities for AD include topical corticosteroids, which act on immune cells to suppress the release of proinflammatory cytokines, as well as dupilumab, which offers targeted blockade of involved cytokines IL-4 and IL-13. Psoriasis can be treated with multiple immune modulators, including topical corticosteroids and vitamin D analogs, as well as systemic medications that reduce T-cell activation and inflammatory cytokines through targeting of IFN-γ, IL-2, tumor necrosis factor α, IL-17, and IL-23.^7,8

We present the case of a patient with long-standing concurrent, treatment-resistant AD and psoriasis who was successfully treated with dual biologic therapy with guselkumab and dupilumab.

Case Report

A 62-year-old woman presented to our dermatology clinic with red itchy scales and painful fissures on the palms, hands, and soles of more than 12 years’ duration. Her medical history included an allergy to amoxicillin-clavulanate as well as an allergy to both dog and cat dander on prick testing. Her family history included dyshidrotic eczema in her mother. A complete blood cell count with differential was within reference range. A shave biopsy of the right dorsal hand performed at the onset of symptoms at an outside facility revealed hyperkeratotic acanthotic epidermis with a mild perivascular lymphocytic infiltrate.

Results of patch testing indicated contact hypersensitivity to the botanical rosin colophonium (or colophony); carba mix (1, 3-diphenylguanidine, zinc dibutyldithiocarbamate, and zinc diethydithiocarbamate); thiuram mix (tetramethylthiuram disulfide, tetramethylthiuram monosulfide, and tetraethylthiuram disulfide); n,n-diphenylguanidine; and tixocortol-21-pivalate. Our patient was given guidance on avoiding these agents, as it was suspected that exposure may be exacerbating the psoriasis. The psoriasis was treated with topical corticosteroids, keratolytics, and calcineurin inhibitors, all of which offered minimal or no relief. Trials of systemic agents, including methotrexate (discontinued because transaminitis developed), etanercept, adalimumab, and apremilast for 6 to 10 months did not provide improvement.

Two years prior to the current presentation, our patient had been treated with the IL-23 inhibitor guselkumab, which provided moderate improvement. When she presented to our clinic, physical examination while she was taking guselkumab demonstrated prurigo with excoriations of the extremities, hyperkeratosis with scaling and fissures of the soles, erythematous scaly plaques on the palms and dorsal surface of the hands, and mild onycholysis of the nails (Figures 1 and 2). Because we were concerned about concomitant intrinsic AD, dupilumab was initiated in conjunction with guselkumab. A second biopsy was considered but deferred in favor of clinical monitoring.

After 1 year of dual biologic therapy, the patient experienced near-complete resolution of symptoms. The psoriasis completely resolved from an initial body surface area of 5%, and the AD body surface area decreased from 30% to 2% (Figure 3). The patient reported no adverse effects from treatment.

Comment

Atopic dermatitis and psoriasis involve complex immunopathology and a spectrum of cytokines that might explain the overlap in their clinical and histopathologic presentations.

Atopic dermatitis—Atopic dermatitis involves T_H1, T_H2, T_H9, T_H17, and T_H22 cells; T_H2 cells release IL-4, IL-5, and IL-13, all of which are key cytokines in the inflammatory pathway of AD.^9,10 Activation of the helper T-cell subset and the release of cytokines differ slightly based on the subcategory of AD and the stage of exacerbation. In addition to T_H2-cell activation, T_H1 cells and T_H22 cells—which release IL-12 and IL-22, respectively—are active in both intrinsic and extrinsic AD. T_H17 cells and T_H9 cells—which release IL-17 and IL-9, respectively—are more prominent in the intrinsic pathway than in the extrinsic pathway.⁹ Intrinsic AD is recognized by a lack of eosinophilia, female predominance, and delayed onset compared to extrinsic AD; there also is a lack of history of atopy.¹ Extrinsic AD is characterized by eosinophilia as well as a personal and family history of atopy.¹¹ Our patient—a female with onset in older adulthood, lack of eosinophilia, and a family history of atopy—displayed features of both intrinsic and extrinsic AD.

Psoriasis—The immunopathology of psoriasis involves stimulation of dendritic cells, which activate T_H17 cells through IL-23. T_H17 cells then release IL-17 and IL-22. Therefore, both AD and psoriasis involve activation of T_H22 and T_H1 cells, with increased IL-17 and IL-22 production.^3,10,12 IL-17 and IL-22 induce epidermal hyperplasia; IL-22 also contributes to skin barrier dysfunction.¹² Therefore, it might be reasonable to consider psoriasis and AD as diseases that exist across a T-cell axis spectrum, thereby accounting for some overlap in disease characteristics.³

Dual Biologic Therapy—Dupilumab blocks the IL-4 receptor α subunit, a receptor for IL-4 and IL-13, which are key cytokines in the pathogenesis of AD.¹⁰ Guselkumab inhibits IL-23, thus blocking the inflammatory cascade of T_H17 cell activation and release of IL-17 and IL-22 in the psoriasis pathway.¹³ Although an immunopathological spectrum exists between the 2 diseases, the continued presence of AD symptoms after blocking the IL-23 cascade suggests that additional blockade of T_H2 cells is required to control AD in patients with true concurrent disease.

Accurate diagnosis of AD and/or psoriasis is important when considering targeted treatment of these conditions with biologics. The use of dual biologics is limited by a paucity of data regarding the safety of these agents when given in combination. A recent meta-analysis of dual biologic therapy in patients with inflammatory bowel disease demonstrated acceptable safety results with a pooled adverse reaction rate of 31%.¹⁴

Anchoring Bias—Anchoring bias can occur when a clinician’s decisions are influenced by a particular event or reference point, which might cause them to disregard subsequent evidence. Our case illustrates the importance of critically assessing the response to treatment and being mindful of the potential influence of anchoring bias on the differential diagnosis. Although overcoming biases in conditions with clinical overlap can be challenging, it is important to consider coexisting AD and psoriasis in patients with extensive hand involvement when multiple treatments have failed and only a partial response to targeted pathways has been achieved. In our case, the patient also had contact hypersensitivity to tixocortol-21-pivalate, which indicates hypersensitivity to many prescription topical corticosteroids, oral prednisone, and over-the-counter hydrocortisone; however, topical corticosteroids continued to be prescribed for her, which might have contributed to the lack of improvement and even exacerbated the rash.

Future Considerations—A consideration for the future in this case is discontinuing guselkumab to observe whether symptoms recur. We discussed this option with the patient, but she opted to continue treatment with dupilumab and guselkumab because of the symptom resolution.

Conclusion

Concomitant disease can present as an overlapping pattern in the same area, whereas other regions might have geographically isolated disease. Our patient’s overlap of symptoms, the failure of multiple treatments, and the partial improvement she experienced on guselkumab made diagnosis and management challenging; however, dual biologic therapy was successful.

Atopic dermatitis (AD) and psoriasis are common skin diseases in which dysfunction of the epidermal barrier leads to skin inflammation and altered expression of proinflammatory cytokines.¹ There often is overlap in the clinical and histopathologic features of AD and psoriasis, which can make diagnosis a challenge. Persistent late-stage AD can present with psoriasiform lichenified changes, and psoriasis lesions in the acute stage can have an eczematous appearance.² Histologically, chronic psoriasis lesions share many overlapping features with AD, and some subsets of AD with IL-17 predominance (ie, intrinsic, pediatric, presentation in Asian patients) exhibit a psoriasiform appearance.^3,4

Atopic dermatitis and psoriasis are considered 2 distinct conditions because AD is a helper T cell (T_H2)–driven disease with subsequent overproduction of IL-4 and IL-13 and psoriasis is a T_H17 cell–driven disease with overproduction of IL-17³; however, the shared features of AD and psoriasis represent an underlying immunopathological spectrum^2,5,6 in which one condition can develop following treatment of the other condition (immunological shift in pathways), both conditions can occur at different times in a patient’s life with alternating cycles of disease flares, or both conditions can coexist as an overlapping syndrome.^1,2 A retrospective study from 2012 to 2019 estimated the prevalence of concomitant AD and psoriasis in the United States at 1.3%, with AD following the diagnosis of psoriasis in 67% of cases.¹ Concurrent AD and psoriasis—when both diseases flaresimultaneously—is the rarest scenario.^2,5

Treatment modalities for AD include topical corticosteroids, which act on immune cells to suppress the release of proinflammatory cytokines, as well as dupilumab, which offers targeted blockade of involved cytokines IL-4 and IL-13. Psoriasis can be treated with multiple immune modulators, including topical corticosteroids and vitamin D analogs, as well as systemic medications that reduce T-cell activation and inflammatory cytokines through targeting of IFN-γ, IL-2, tumor necrosis factor α, IL-17, and IL-23.^7,8

We present the case of a patient with long-standing concurrent, treatment-resistant AD and psoriasis who was successfully treated with dual biologic therapy with guselkumab and dupilumab.

Case Report

A 62-year-old woman presented to our dermatology clinic with red itchy scales and painful fissures on the palms, hands, and soles of more than 12 years’ duration. Her medical history included an allergy to amoxicillin-clavulanate as well as an allergy to both dog and cat dander on prick testing. Her family history included dyshidrotic eczema in her mother. A complete blood cell count with differential was within reference range. A shave biopsy of the right dorsal hand performed at the onset of symptoms at an outside facility revealed hyperkeratotic acanthotic epidermis with a mild perivascular lymphocytic infiltrate.

Results of patch testing indicated contact hypersensitivity to the botanical rosin colophonium (or colophony); carba mix (1, 3-diphenylguanidine, zinc dibutyldithiocarbamate, and zinc diethydithiocarbamate); thiuram mix (tetramethylthiuram disulfide, tetramethylthiuram monosulfide, and tetraethylthiuram disulfide); n,n-diphenylguanidine; and tixocortol-21-pivalate. Our patient was given guidance on avoiding these agents, as it was suspected that exposure may be exacerbating the psoriasis. The psoriasis was treated with topical corticosteroids, keratolytics, and calcineurin inhibitors, all of which offered minimal or no relief. Trials of systemic agents, including methotrexate (discontinued because transaminitis developed), etanercept, adalimumab, and apremilast for 6 to 10 months did not provide improvement.

Two years prior to the current presentation, our patient had been treated with the IL-23 inhibitor guselkumab, which provided moderate improvement. When she presented to our clinic, physical examination while she was taking guselkumab demonstrated prurigo with excoriations of the extremities, hyperkeratosis with scaling and fissures of the soles, erythematous scaly plaques on the palms and dorsal surface of the hands, and mild onycholysis of the nails (Figures 1 and 2). Because we were concerned about concomitant intrinsic AD, dupilumab was initiated in conjunction with guselkumab. A second biopsy was considered but deferred in favor of clinical monitoring.

After 1 year of dual biologic therapy, the patient experienced near-complete resolution of symptoms. The psoriasis completely resolved from an initial body surface area of 5%, and the AD body surface area decreased from 30% to 2% (Figure 3). The patient reported no adverse effects from treatment.

Comment

Atopic dermatitis and psoriasis involve complex immunopathology and a spectrum of cytokines that might explain the overlap in their clinical and histopathologic presentations.

Atopic dermatitis—Atopic dermatitis involves T_H1, T_H2, T_H9, T_H17, and T_H22 cells; T_H2 cells release IL-4, IL-5, and IL-13, all of which are key cytokines in the inflammatory pathway of AD.^9,10 Activation of the helper T-cell subset and the release of cytokines differ slightly based on the subcategory of AD and the stage of exacerbation. In addition to T_H2-cell activation, T_H1 cells and T_H22 cells—which release IL-12 and IL-22, respectively—are active in both intrinsic and extrinsic AD. T_H17 cells and T_H9 cells—which release IL-17 and IL-9, respectively—are more prominent in the intrinsic pathway than in the extrinsic pathway.⁹ Intrinsic AD is recognized by a lack of eosinophilia, female predominance, and delayed onset compared to extrinsic AD; there also is a lack of history of atopy.¹ Extrinsic AD is characterized by eosinophilia as well as a personal and family history of atopy.¹¹ Our patient—a female with onset in older adulthood, lack of eosinophilia, and a family history of atopy—displayed features of both intrinsic and extrinsic AD.

Psoriasis—The immunopathology of psoriasis involves stimulation of dendritic cells, which activate T_H17 cells through IL-23. T_H17 cells then release IL-17 and IL-22. Therefore, both AD and psoriasis involve activation of T_H22 and T_H1 cells, with increased IL-17 and IL-22 production.^3,10,12 IL-17 and IL-22 induce epidermal hyperplasia; IL-22 also contributes to skin barrier dysfunction.¹² Therefore, it might be reasonable to consider psoriasis and AD as diseases that exist across a T-cell axis spectrum, thereby accounting for some overlap in disease characteristics.³

Dual Biologic Therapy—Dupilumab blocks the IL-4 receptor α subunit, a receptor for IL-4 and IL-13, which are key cytokines in the pathogenesis of AD.¹⁰ Guselkumab inhibits IL-23, thus blocking the inflammatory cascade of T_H17 cell activation and release of IL-17 and IL-22 in the psoriasis pathway.¹³ Although an immunopathological spectrum exists between the 2 diseases, the continued presence of AD symptoms after blocking the IL-23 cascade suggests that additional blockade of T_H2 cells is required to control AD in patients with true concurrent disease.

Accurate diagnosis of AD and/or psoriasis is important when considering targeted treatment of these conditions with biologics. The use of dual biologics is limited by a paucity of data regarding the safety of these agents when given in combination. A recent meta-analysis of dual biologic therapy in patients with inflammatory bowel disease demonstrated acceptable safety results with a pooled adverse reaction rate of 31%.¹⁴

Anchoring Bias—Anchoring bias can occur when a clinician’s decisions are influenced by a particular event or reference point, which might cause them to disregard subsequent evidence. Our case illustrates the importance of critically assessing the response to treatment and being mindful of the potential influence of anchoring bias on the differential diagnosis. Although overcoming biases in conditions with clinical overlap can be challenging, it is important to consider coexisting AD and psoriasis in patients with extensive hand involvement when multiple treatments have failed and only a partial response to targeted pathways has been achieved. In our case, the patient also had contact hypersensitivity to tixocortol-21-pivalate, which indicates hypersensitivity to many prescription topical corticosteroids, oral prednisone, and over-the-counter hydrocortisone; however, topical corticosteroids continued to be prescribed for her, which might have contributed to the lack of improvement and even exacerbated the rash.

Future Considerations—A consideration for the future in this case is discontinuing guselkumab to observe whether symptoms recur. We discussed this option with the patient, but she opted to continue treatment with dupilumab and guselkumab because of the symptom resolution.

Conclusion

Concomitant disease can present as an overlapping pattern in the same area, whereas other regions might have geographically isolated disease. Our patient’s overlap of symptoms, the failure of multiple treatments, and the partial improvement she experienced on guselkumab made diagnosis and management challenging; however, dual biologic therapy was successful.

INTRODUCTION

Urinary bladder is an extremely rare site of extrapulmonary small cell cancer (EPSCC). Unlike small cell lung cancer (SCLC), there is no clear guideline for prophylactic cranial irradiation (PCI) for EPSCC. In this case report and literature review, we discuss small cell cancer of urinary bladder (SCCUB) and the role of PCI in SCCUB.

CASE PRESENTATION

A 74-year-old male presented with gross hematuria and an unremarkable physical examination. CT showed 1.7 cm right anterolateral bladder wall thickening. Cystoscopy revealed a 2-3 cm high-grade bladder lesion. Pathology from transurethral resection of the tumor was consistent with T1N0M0 small cell carcinoma. MRI brain and FDG-PET showed no extravesical disease. Patient received four cycles of neoadjuvant carboplatin/etoposide per his preference as he wanted to protect his hearing due to his profession followed by radical cystoprostatectomy. Post-op pathology showed clear margins. We decided to forego PCI in favor of interval surveillance with MRI and follow- up images remain negative for distant metastases.

DISCUSSION

EPSCC accounts for 2.5-5% of all SCC, very rare in male genitourinary tract. Treatment approach is derived from SCLC, guided by extent of disease and patient’s functional status. Role of PCI in EPSCC has not been clearly described, and even less evidence is available for SCCUB. From a review of eleven studies in PubMed for the role of PCI in SCCUB or EPSCC, we found that SCCUB has lower incidence of brain metastases than SCLC. One study suggested that SCCUB arises from totipotent cells in the submucosa, unlike Kulchitsky cell origin of SCLC. This difference might explain the difference in their metastatic behavior. With this background, PCI is not routinely recommended for limited- stage SCCUB. There might still be a role for PCI in extensive SCCUB with high metastatic burden. More studies are needed to update the guidelines for the role of PCI for these tumors.

CONCLUSIONS

Per this literature review, PCI is not routinely recommended for SCCUB, likely due to different cells of origin compared to SCLC. Future studies should focus on characterizing differences in their metastatic behavior and updating guidelines for PCI for SCCUB.

INTRODUCTION

Urinary bladder is an extremely rare site of extrapulmonary small cell cancer (EPSCC). Unlike small cell lung cancer (SCLC), there is no clear guideline for prophylactic cranial irradiation (PCI) for EPSCC. In this case report and literature review, we discuss small cell cancer of urinary bladder (SCCUB) and the role of PCI in SCCUB.

CASE PRESENTATION

A 74-year-old male presented with gross hematuria and an unremarkable physical examination. CT showed 1.7 cm right anterolateral bladder wall thickening. Cystoscopy revealed a 2-3 cm high-grade bladder lesion. Pathology from transurethral resection of the tumor was consistent with T1N0M0 small cell carcinoma. MRI brain and FDG-PET showed no extravesical disease. Patient received four cycles of neoadjuvant carboplatin/etoposide per his preference as he wanted to protect his hearing due to his profession followed by radical cystoprostatectomy. Post-op pathology showed clear margins. We decided to forego PCI in favor of interval surveillance with MRI and follow- up images remain negative for distant metastases.

DISCUSSION

EPSCC accounts for 2.5-5% of all SCC, very rare in male genitourinary tract. Treatment approach is derived from SCLC, guided by extent of disease and patient’s functional status. Role of PCI in EPSCC has not been clearly described, and even less evidence is available for SCCUB. From a review of eleven studies in PubMed for the role of PCI in SCCUB or EPSCC, we found that SCCUB has lower incidence of brain metastases than SCLC. One study suggested that SCCUB arises from totipotent cells in the submucosa, unlike Kulchitsky cell origin of SCLC. This difference might explain the difference in their metastatic behavior. With this background, PCI is not routinely recommended for limited- stage SCCUB. There might still be a role for PCI in extensive SCCUB with high metastatic burden. More studies are needed to update the guidelines for the role of PCI for these tumors.

CONCLUSIONS

Per this literature review, PCI is not routinely recommended for SCCUB, likely due to different cells of origin compared to SCLC. Future studies should focus on characterizing differences in their metastatic behavior and updating guidelines for PCI for SCCUB.

INTRODUCTION

Urinary bladder is an extremely rare site of extrapulmonary small cell cancer (EPSCC). Unlike small cell lung cancer (SCLC), there is no clear guideline for prophylactic cranial irradiation (PCI) for EPSCC. In this case report and literature review, we discuss small cell cancer of urinary bladder (SCCUB) and the role of PCI in SCCUB.

CASE PRESENTATION

A 74-year-old male presented with gross hematuria and an unremarkable physical examination. CT showed 1.7 cm right anterolateral bladder wall thickening. Cystoscopy revealed a 2-3 cm high-grade bladder lesion. Pathology from transurethral resection of the tumor was consistent with T1N0M0 small cell carcinoma. MRI brain and FDG-PET showed no extravesical disease. Patient received four cycles of neoadjuvant carboplatin/etoposide per his preference as he wanted to protect his hearing due to his profession followed by radical cystoprostatectomy. Post-op pathology showed clear margins. We decided to forego PCI in favor of interval surveillance with MRI and follow- up images remain negative for distant metastases.

DISCUSSION

EPSCC accounts for 2.5-5% of all SCC, very rare in male genitourinary tract. Treatment approach is derived from SCLC, guided by extent of disease and patient’s functional status. Role of PCI in EPSCC has not been clearly described, and even less evidence is available for SCCUB. From a review of eleven studies in PubMed for the role of PCI in SCCUB or EPSCC, we found that SCCUB has lower incidence of brain metastases than SCLC. One study suggested that SCCUB arises from totipotent cells in the submucosa, unlike Kulchitsky cell origin of SCLC. This difference might explain the difference in their metastatic behavior. With this background, PCI is not routinely recommended for limited- stage SCCUB. There might still be a role for PCI in extensive SCCUB with high metastatic burden. More studies are needed to update the guidelines for the role of PCI for these tumors.

CONCLUSIONS

Per this literature review, PCI is not routinely recommended for SCCUB, likely due to different cells of origin compared to SCLC. Future studies should focus on characterizing differences in their metastatic behavior and updating guidelines for PCI for SCCUB.

INTRODUCTION

Lymphadenopathy in Chronic Lymphocytic Leukemia (CLL) is a very common feature. However, sudden increase in lymphadenopathy or other symptoms like weight loss should be evaluated for possible metastatic malignancy. We describe a CLL patient with diffuse mediastinal lymphadenopathy who was diagnosed with metastatic bladder cancer without a primary bladder tumor mass on imaging.

CASE DESCRIPTION

A 60-year-old man with a 60 pack-year smoking history, alcoholic cirrhosis, and a 5-year history of stage 1 CLL presented with 3 months of progressive shortness of breath; persistent cough; chills; hemoptysis; and a steady weight loss of 35 lbs. Notably, he had no bladder symptoms. Initial labs showed leukocytosis of 35.8k with a lymphocytic predominance. Screening low-dose chest CT was positive for diffuse mediastinal lymphadenopathy. Subsequent PET/CT revealed numerous hypermetabolic lymph nodes in the neck, mediastinum, left hilum, and right periaortic abdominal region. CT Chest, Abdomen, Pelvis revealed progressive lymphadenopathy as seen in prior imaging, stable pulmonary nodules up to 4 mm in size, and splenomegaly. No distant primary sites, including of the bladder, were identified. Mediastinal lymph node biopsy confirmed metastatic poorly differentiated carcinoma with immunohistochemical staining negative for p40, p63, CK20, TTF-1, Napsin A, CDX2, CA19- 9, Calretinin, and D2-40 and positive for CK7, GATA3, Ber-EP4, and Uroplakin, supporting bladder as primary origin. Urology deferred a cystoscopy given his lack of urinary symptoms and positive biopsy and was started on Carboplatin/Gemcitabine for his metastatic disease. He was ineligible for Cisplatin given his cirrhosis and hearing impairment.

DISCUSSION

In patients with CLL, new onset mediastinal lymphadenopathy is concerning for disease progression and possible transformation to a diffuse b-cell lymphoma. However, this symptom has a broad differential, including primary lung carcinomas, sarcomas, and metastatic disease. While our patient’s PET/CT and pan-CT failed to identify a distant primary site, maintaining a low clinical suspicion for metastatic disease and doing a thorough work-up was paramount. Only through immunohistochemical staining were we able to diagnosis this patient with urothelial carcinoma.

CONCLUSIONS

Biopsy with immunohistochemical staining and maintaining a low suspicion for worsening lymphadenopathy can identify unusually presenting urothelial carcinomas in CLL patients.

INTRODUCTION

Lymphadenopathy in Chronic Lymphocytic Leukemia (CLL) is a very common feature. However, sudden increase in lymphadenopathy or other symptoms like weight loss should be evaluated for possible metastatic malignancy. We describe a CLL patient with diffuse mediastinal lymphadenopathy who was diagnosed with metastatic bladder cancer without a primary bladder tumor mass on imaging.

CASE DESCRIPTION

A 60-year-old man with a 60 pack-year smoking history, alcoholic cirrhosis, and a 5-year history of stage 1 CLL presented with 3 months of progressive shortness of breath; persistent cough; chills; hemoptysis; and a steady weight loss of 35 lbs. Notably, he had no bladder symptoms. Initial labs showed leukocytosis of 35.8k with a lymphocytic predominance. Screening low-dose chest CT was positive for diffuse mediastinal lymphadenopathy. Subsequent PET/CT revealed numerous hypermetabolic lymph nodes in the neck, mediastinum, left hilum, and right periaortic abdominal region. CT Chest, Abdomen, Pelvis revealed progressive lymphadenopathy as seen in prior imaging, stable pulmonary nodules up to 4 mm in size, and splenomegaly. No distant primary sites, including of the bladder, were identified. Mediastinal lymph node biopsy confirmed metastatic poorly differentiated carcinoma with immunohistochemical staining negative for p40, p63, CK20, TTF-1, Napsin A, CDX2, CA19- 9, Calretinin, and D2-40 and positive for CK7, GATA3, Ber-EP4, and Uroplakin, supporting bladder as primary origin. Urology deferred a cystoscopy given his lack of urinary symptoms and positive biopsy and was started on Carboplatin/Gemcitabine for his metastatic disease. He was ineligible for Cisplatin given his cirrhosis and hearing impairment.

DISCUSSION

In patients with CLL, new onset mediastinal lymphadenopathy is concerning for disease progression and possible transformation to a diffuse b-cell lymphoma. However, this symptom has a broad differential, including primary lung carcinomas, sarcomas, and metastatic disease. While our patient’s PET/CT and pan-CT failed to identify a distant primary site, maintaining a low clinical suspicion for metastatic disease and doing a thorough work-up was paramount. Only through immunohistochemical staining were we able to diagnosis this patient with urothelial carcinoma.

CONCLUSIONS

Biopsy with immunohistochemical staining and maintaining a low suspicion for worsening lymphadenopathy can identify unusually presenting urothelial carcinomas in CLL patients.

INTRODUCTION

Lymphadenopathy in Chronic Lymphocytic Leukemia (CLL) is a very common feature. However, sudden increase in lymphadenopathy or other symptoms like weight loss should be evaluated for possible metastatic malignancy. We describe a CLL patient with diffuse mediastinal lymphadenopathy who was diagnosed with metastatic bladder cancer without a primary bladder tumor mass on imaging.

CASE DESCRIPTION

A 60-year-old man with a 60 pack-year smoking history, alcoholic cirrhosis, and a 5-year history of stage 1 CLL presented with 3 months of progressive shortness of breath; persistent cough; chills; hemoptysis; and a steady weight loss of 35 lbs. Notably, he had no bladder symptoms. Initial labs showed leukocytosis of 35.8k with a lymphocytic predominance. Screening low-dose chest CT was positive for diffuse mediastinal lymphadenopathy. Subsequent PET/CT revealed numerous hypermetabolic lymph nodes in the neck, mediastinum, left hilum, and right periaortic abdominal region. CT Chest, Abdomen, Pelvis revealed progressive lymphadenopathy as seen in prior imaging, stable pulmonary nodules up to 4 mm in size, and splenomegaly. No distant primary sites, including of the bladder, were identified. Mediastinal lymph node biopsy confirmed metastatic poorly differentiated carcinoma with immunohistochemical staining negative for p40, p63, CK20, TTF-1, Napsin A, CDX2, CA19- 9, Calretinin, and D2-40 and positive for CK7, GATA3, Ber-EP4, and Uroplakin, supporting bladder as primary origin. Urology deferred a cystoscopy given his lack of urinary symptoms and positive biopsy and was started on Carboplatin/Gemcitabine for his metastatic disease. He was ineligible for Cisplatin given his cirrhosis and hearing impairment.

DISCUSSION

In patients with CLL, new onset mediastinal lymphadenopathy is concerning for disease progression and possible transformation to a diffuse b-cell lymphoma. However, this symptom has a broad differential, including primary lung carcinomas, sarcomas, and metastatic disease. While our patient’s PET/CT and pan-CT failed to identify a distant primary site, maintaining a low clinical suspicion for metastatic disease and doing a thorough work-up was paramount. Only through immunohistochemical staining were we able to diagnosis this patient with urothelial carcinoma.

CONCLUSIONS

Biopsy with immunohistochemical staining and maintaining a low suspicion for worsening lymphadenopathy can identify unusually presenting urothelial carcinomas in CLL patients.

THE CASE

A 24-year-old woman with a history of type 1 diabetes, seizure disorder, and migraines presented to a rural Federally Qualified Health Center (FQHC) with progressive and severe symmetric large joint arthralgias of several weeks’ duration. The patient’s existing medications included etonogestrel 68 mg subdermal implant, levetiracetam 1500 mg bid, insulin glargine 26 units subcutaneously nightly, and insulin lispro 20 units subcutaneously tid (before meals).

An examination revealed symmetrically edematous elbows, wrists, and fingers. Subsequent serologic analyses and a telemedicine consultation with a rheumatologist confirmed a diagnosis of rheumatoid arthritis (RA). The patient’s lab work was positive for antinuclear antibody titers (1:40), rheumatoid factor (513 IU/mL), and anticyclic citrullinated peptide antibodies (248 units/mL). Treatment was started with prednisone 60 mg PO daily, methotrexate 20 mg PO weekly, and hydroxychloroquine 400 mg PO daily. (The benefits of prednisone in treating this patient’s severe arthralgias outweighed concerns over its use in a patient with diabetes.)

After 2 months of receiving RA therapy, the patient underwent further work-up to assess its effectiveness. Liver function testing was performed, and she tested positive for hepatitis C virus (HCV) antibodies. Viral polymerase chain reaction confirmed active HCV infection. Lab work revealed a viral load of 15,000,000 IU/mL; transaminase, 173 U/L (normal range, 4-36 U/L); and aspartate aminotransferase, 246 U/L (normal range, 8-33 U/L). A liver sonogram demonstrated no findings of cirrhosis or fibrosis.

Upon receiving a diagnosis of active hepatitis C, the patient acknowledged that she’d had unprotected heterosexual intercourse and shared used insulin syringes with friends.

THE DIAGNOSIS

Consideration was given to a diagnosis of HCV arthropathy, which can present as an RA-like arthritis in HCV-infected individuals, in the differential diagnosis.¹ A cohort study found HCV-associated arthropathy occurred in 6.8% of those with chronic HCV infection.²

However, the symmetrical involvement of shoulders and knees as the patient’s primary arthralgias, and a rheumatologic work-up showing the presence of anticyclic citrullinated peptide antibody levels, confirmed the diagnosis of RA with coexisting HCV.

DISCUSSION

Delivering interdisciplinary care in a rural area

Although evidence-based guidelines and online HCV Treatment Path programs guided the initial evaluation of potential treatments for this patient, her multiple comorbidities prompted us to seek out additional, interdisciplinary advice through a resource for underserved communities called Project Extension for Community Healthcare Outcomes (ECHO; see “What is Project ECHO?^3,4”). The patient’s case was presented virtually, without identifying information, to a multidisciplinary HCV team. Two treatment options were suggested:

• sofosbuvir/velpatasvir (400 mg/100 mg) for 12 weeks or
• glecaprevir/pibrentasvir (100 mg/40 mg) for 8 weeks.

Both are evidence-based and recommended treatment options according to the HCV treatment guidelines issued jointly by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.⁵

In most patients with HCV, treatment is guided by a number of factors, including pill burden, access to care, duration of therapy, drug interactions, and patient-specific needs. After analyzing all aspects of this patient’s case, 2 major concerns guided our shared decision-making process on treatment.

The best treatment is what works for the patient

Owing to the patient’s multiple comorbidities and prescribed medications for chronic diseases, concerns about possible medication interactions with the HCV treatment options were a factor in her HCV treatment plan. Additionally, the patient had significant social determinants of health barriers that made continued treatment and follow-up challenging.

The potential interaction of HCV infection treatment with the patient’s current methotrexate therapy for her RA was a primary concern. To determine the risk for interactions, the team used the University of Liverpool HEP/HIV Drug Interactions Checker, which helps identify possible interactions with these disease-specific medication therapies.⁶

Both sofosbuvir/velpatasvir and glecaprevir/­pibrentasvir have a potential interaction with methotrexate and are driven by a similar mechanism. Methotrexate is a substrate of the Breast Cancer Resistance Protein efflux transporter (BCRP), and the components of both sofosbuvir/velpatasvir and glecaprevir/pibrentasvir are inhibitors of BCRP.⁷ The inhibition of this efflux transporter can lead to an increased concentration of methotrexate, increasing the risk for methotrexate toxicity.⁷

Since no quantitative data exist regarding the degree of inhibition that these HCV drugs exert on BCRP, the team considered ­sofosbuvir/velpatasvir and glecaprevir/­pibrentasvir to have equal risk with regard to potential for drug interactions.

The patient’s barriers to treatment were another area of concern that directed our therapy decision. The patient had multiple barriers, including poor access to health care because of transportation issues, multiple children requiring care, a variety of chronic diseases, and other life stressors. Shared decision­-making ensured our patient’s autonomy in choosing a specific treatment.

This case shines a light on the multiple challenges that could have come between our patient and proper treatment—but ultimately, did not.

The patient’s social situation and preference narrowed the team’s basis for medication choice primarily down to the duration of therapy: 8 weeks of glecaprevir/pibrentasvir vs 12 weeks of sofosbuvir/velpatasvir. The patient mentioned multiple transportation challenges for follow-up visits to the clinic and therefore wanted to utilize the shorter treatment duration. Follow-up is needed every 4 weeks, so the patient was able to go from 3 to 2 visits.

For problems, there are solutions. Following careful consideration of these patient-specific factors and preferences, the team decided to begin therapy with glecaprevir/pibrentasvir. The patient worked with an outreach specialist at the FQHC to coordinate care and complete paperwork for the Project ECHO consultation. The outreach specialist also assisted the patient in completing paperwork for the Patient Assistance Program for HCV treatment. Because the patient is being cared for at an FQHC, the clinic’s in-house pharmacy was able to utilize the 340B Federal Drug Pricing Program, which makes otherwise out-of-reach medicines affordable for patients such as ours.

Our patient has had no issues with treatment adherence, adverse effects, or follow­-up appointments. The patient’s RA symptoms have improved significantly without any discernable worsening of her HCV infection.

THE TAKEAWAY

This case shines a light on the multiple challenges (clinical, geographic, and financial) that could have come between our patient and proper treatment—but ultimately, did not. The Project ECHO model of care remains a viable way to provide patients who live in rural and underserved communities and who have active HCV and other underlying chronic conditions with interdisciplinary care that can improve health outcomes.

THE CASE

A 24-year-old woman with a history of type 1 diabetes, seizure disorder, and migraines presented to a rural Federally Qualified Health Center (FQHC) with progressive and severe symmetric large joint arthralgias of several weeks’ duration. The patient’s existing medications included etonogestrel 68 mg subdermal implant, levetiracetam 1500 mg bid, insulin glargine 26 units subcutaneously nightly, and insulin lispro 20 units subcutaneously tid (before meals).

An examination revealed symmetrically edematous elbows, wrists, and fingers. Subsequent serologic analyses and a telemedicine consultation with a rheumatologist confirmed a diagnosis of rheumatoid arthritis (RA). The patient’s lab work was positive for antinuclear antibody titers (1:40), rheumatoid factor (513 IU/mL), and anticyclic citrullinated peptide antibodies (248 units/mL). Treatment was started with prednisone 60 mg PO daily, methotrexate 20 mg PO weekly, and hydroxychloroquine 400 mg PO daily. (The benefits of prednisone in treating this patient’s severe arthralgias outweighed concerns over its use in a patient with diabetes.)

After 2 months of receiving RA therapy, the patient underwent further work-up to assess its effectiveness. Liver function testing was performed, and she tested positive for hepatitis C virus (HCV) antibodies. Viral polymerase chain reaction confirmed active HCV infection. Lab work revealed a viral load of 15,000,000 IU/mL; transaminase, 173 U/L (normal range, 4-36 U/L); and aspartate aminotransferase, 246 U/L (normal range, 8-33 U/L). A liver sonogram demonstrated no findings of cirrhosis or fibrosis.

Upon receiving a diagnosis of active hepatitis C, the patient acknowledged that she’d had unprotected heterosexual intercourse and shared used insulin syringes with friends.

THE DIAGNOSIS

Consideration was given to a diagnosis of HCV arthropathy, which can present as an RA-like arthritis in HCV-infected individuals, in the differential diagnosis.¹ A cohort study found HCV-associated arthropathy occurred in 6.8% of those with chronic HCV infection.²

However, the symmetrical involvement of shoulders and knees as the patient’s primary arthralgias, and a rheumatologic work-up showing the presence of anticyclic citrullinated peptide antibody levels, confirmed the diagnosis of RA with coexisting HCV.

DISCUSSION

Delivering interdisciplinary care in a rural area

Although evidence-based guidelines and online HCV Treatment Path programs guided the initial evaluation of potential treatments for this patient, her multiple comorbidities prompted us to seek out additional, interdisciplinary advice through a resource for underserved communities called Project Extension for Community Healthcare Outcomes (ECHO; see “What is Project ECHO?^3,4”). The patient’s case was presented virtually, without identifying information, to a multidisciplinary HCV team. Two treatment options were suggested:

• sofosbuvir/velpatasvir (400 mg/100 mg) for 12 weeks or
• glecaprevir/pibrentasvir (100 mg/40 mg) for 8 weeks.

Both are evidence-based and recommended treatment options according to the HCV treatment guidelines issued jointly by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.⁵

In most patients with HCV, treatment is guided by a number of factors, including pill burden, access to care, duration of therapy, drug interactions, and patient-specific needs. After analyzing all aspects of this patient’s case, 2 major concerns guided our shared decision-making process on treatment.

The best treatment is what works for the patient

Owing to the patient’s multiple comorbidities and prescribed medications for chronic diseases, concerns about possible medication interactions with the HCV treatment options were a factor in her HCV treatment plan. Additionally, the patient had significant social determinants of health barriers that made continued treatment and follow-up challenging.

The potential interaction of HCV infection treatment with the patient’s current methotrexate therapy for her RA was a primary concern. To determine the risk for interactions, the team used the University of Liverpool HEP/HIV Drug Interactions Checker, which helps identify possible interactions with these disease-specific medication therapies.⁶

Both sofosbuvir/velpatasvir and glecaprevir/­pibrentasvir have a potential interaction with methotrexate and are driven by a similar mechanism. Methotrexate is a substrate of the Breast Cancer Resistance Protein efflux transporter (BCRP), and the components of both sofosbuvir/velpatasvir and glecaprevir/pibrentasvir are inhibitors of BCRP.⁷ The inhibition of this efflux transporter can lead to an increased concentration of methotrexate, increasing the risk for methotrexate toxicity.⁷

Since no quantitative data exist regarding the degree of inhibition that these HCV drugs exert on BCRP, the team considered ­sofosbuvir/velpatasvir and glecaprevir/­pibrentasvir to have equal risk with regard to potential for drug interactions.

The patient’s barriers to treatment were another area of concern that directed our therapy decision. The patient had multiple barriers, including poor access to health care because of transportation issues, multiple children requiring care, a variety of chronic diseases, and other life stressors. Shared decision­-making ensured our patient’s autonomy in choosing a specific treatment.

This case shines a light on the multiple challenges that could have come between our patient and proper treatment—but ultimately, did not.

The patient’s social situation and preference narrowed the team’s basis for medication choice primarily down to the duration of therapy: 8 weeks of glecaprevir/pibrentasvir vs 12 weeks of sofosbuvir/velpatasvir. The patient mentioned multiple transportation challenges for follow-up visits to the clinic and therefore wanted to utilize the shorter treatment duration. Follow-up is needed every 4 weeks, so the patient was able to go from 3 to 2 visits.

For problems, there are solutions. Following careful consideration of these patient-specific factors and preferences, the team decided to begin therapy with glecaprevir/pibrentasvir. The patient worked with an outreach specialist at the FQHC to coordinate care and complete paperwork for the Project ECHO consultation. The outreach specialist also assisted the patient in completing paperwork for the Patient Assistance Program for HCV treatment. Because the patient is being cared for at an FQHC, the clinic’s in-house pharmacy was able to utilize the 340B Federal Drug Pricing Program, which makes otherwise out-of-reach medicines affordable for patients such as ours.

Our patient has had no issues with treatment adherence, adverse effects, or follow­-up appointments. The patient’s RA symptoms have improved significantly without any discernable worsening of her HCV infection.

THE TAKEAWAY

This case shines a light on the multiple challenges (clinical, geographic, and financial) that could have come between our patient and proper treatment—but ultimately, did not. The Project ECHO model of care remains a viable way to provide patients who live in rural and underserved communities and who have active HCV and other underlying chronic conditions with interdisciplinary care that can improve health outcomes.

THE CASE

A 24-year-old woman with a history of type 1 diabetes, seizure disorder, and migraines presented to a rural Federally Qualified Health Center (FQHC) with progressive and severe symmetric large joint arthralgias of several weeks’ duration. The patient’s existing medications included etonogestrel 68 mg subdermal implant, levetiracetam 1500 mg bid, insulin glargine 26 units subcutaneously nightly, and insulin lispro 20 units subcutaneously tid (before meals).

An examination revealed symmetrically edematous elbows, wrists, and fingers. Subsequent serologic analyses and a telemedicine consultation with a rheumatologist confirmed a diagnosis of rheumatoid arthritis (RA). The patient’s lab work was positive for antinuclear antibody titers (1:40), rheumatoid factor (513 IU/mL), and anticyclic citrullinated peptide antibodies (248 units/mL). Treatment was started with prednisone 60 mg PO daily, methotrexate 20 mg PO weekly, and hydroxychloroquine 400 mg PO daily. (The benefits of prednisone in treating this patient’s severe arthralgias outweighed concerns over its use in a patient with diabetes.)

After 2 months of receiving RA therapy, the patient underwent further work-up to assess its effectiveness. Liver function testing was performed, and she tested positive for hepatitis C virus (HCV) antibodies. Viral polymerase chain reaction confirmed active HCV infection. Lab work revealed a viral load of 15,000,000 IU/mL; transaminase, 173 U/L (normal range, 4-36 U/L); and aspartate aminotransferase, 246 U/L (normal range, 8-33 U/L). A liver sonogram demonstrated no findings of cirrhosis or fibrosis.

Upon receiving a diagnosis of active hepatitis C, the patient acknowledged that she’d had unprotected heterosexual intercourse and shared used insulin syringes with friends.

THE DIAGNOSIS

Consideration was given to a diagnosis of HCV arthropathy, which can present as an RA-like arthritis in HCV-infected individuals, in the differential diagnosis.¹ A cohort study found HCV-associated arthropathy occurred in 6.8% of those with chronic HCV infection.²

However, the symmetrical involvement of shoulders and knees as the patient’s primary arthralgias, and a rheumatologic work-up showing the presence of anticyclic citrullinated peptide antibody levels, confirmed the diagnosis of RA with coexisting HCV.

DISCUSSION

Delivering interdisciplinary care in a rural area

Although evidence-based guidelines and online HCV Treatment Path programs guided the initial evaluation of potential treatments for this patient, her multiple comorbidities prompted us to seek out additional, interdisciplinary advice through a resource for underserved communities called Project Extension for Community Healthcare Outcomes (ECHO; see “What is Project ECHO?^3,4”). The patient’s case was presented virtually, without identifying information, to a multidisciplinary HCV team. Two treatment options were suggested:

• sofosbuvir/velpatasvir (400 mg/100 mg) for 12 weeks or
• glecaprevir/pibrentasvir (100 mg/40 mg) for 8 weeks.

Both are evidence-based and recommended treatment options according to the HCV treatment guidelines issued jointly by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.⁵

In most patients with HCV, treatment is guided by a number of factors, including pill burden, access to care, duration of therapy, drug interactions, and patient-specific needs. After analyzing all aspects of this patient’s case, 2 major concerns guided our shared decision-making process on treatment.

The best treatment is what works for the patient

Owing to the patient’s multiple comorbidities and prescribed medications for chronic diseases, concerns about possible medication interactions with the HCV treatment options were a factor in her HCV treatment plan. Additionally, the patient had significant social determinants of health barriers that made continued treatment and follow-up challenging.

The potential interaction of HCV infection treatment with the patient’s current methotrexate therapy for her RA was a primary concern. To determine the risk for interactions, the team used the University of Liverpool HEP/HIV Drug Interactions Checker, which helps identify possible interactions with these disease-specific medication therapies.⁶

Both sofosbuvir/velpatasvir and glecaprevir/­pibrentasvir have a potential interaction with methotrexate and are driven by a similar mechanism. Methotrexate is a substrate of the Breast Cancer Resistance Protein efflux transporter (BCRP), and the components of both sofosbuvir/velpatasvir and glecaprevir/pibrentasvir are inhibitors of BCRP.⁷ The inhibition of this efflux transporter can lead to an increased concentration of methotrexate, increasing the risk for methotrexate toxicity.⁷

Since no quantitative data exist regarding the degree of inhibition that these HCV drugs exert on BCRP, the team considered ­sofosbuvir/velpatasvir and glecaprevir/­pibrentasvir to have equal risk with regard to potential for drug interactions.

The patient’s barriers to treatment were another area of concern that directed our therapy decision. The patient had multiple barriers, including poor access to health care because of transportation issues, multiple children requiring care, a variety of chronic diseases, and other life stressors. Shared decision­-making ensured our patient’s autonomy in choosing a specific treatment.

This case shines a light on the multiple challenges that could have come between our patient and proper treatment—but ultimately, did not.

The patient’s social situation and preference narrowed the team’s basis for medication choice primarily down to the duration of therapy: 8 weeks of glecaprevir/pibrentasvir vs 12 weeks of sofosbuvir/velpatasvir. The patient mentioned multiple transportation challenges for follow-up visits to the clinic and therefore wanted to utilize the shorter treatment duration. Follow-up is needed every 4 weeks, so the patient was able to go from 3 to 2 visits.

For problems, there are solutions. Following careful consideration of these patient-specific factors and preferences, the team decided to begin therapy with glecaprevir/pibrentasvir. The patient worked with an outreach specialist at the FQHC to coordinate care and complete paperwork for the Project ECHO consultation. The outreach specialist also assisted the patient in completing paperwork for the Patient Assistance Program for HCV treatment. Because the patient is being cared for at an FQHC, the clinic’s in-house pharmacy was able to utilize the 340B Federal Drug Pricing Program, which makes otherwise out-of-reach medicines affordable for patients such as ours.

Our patient has had no issues with treatment adherence, adverse effects, or follow­-up appointments. The patient’s RA symptoms have improved significantly without any discernable worsening of her HCV infection.

THE TAKEAWAY

This case shines a light on the multiple challenges (clinical, geographic, and financial) that could have come between our patient and proper treatment—but ultimately, did not. The Project ECHO model of care remains a viable way to provide patients who live in rural and underserved communities and who have active HCV and other underlying chronic conditions with interdisciplinary care that can improve health outcomes.

THE CASE

A 49-year-old woman was hospitalized with a headache and neck pain that radiated to her ears and eyes in the context of severe hypertension (270/150 mm Hg). Her medical history was significant for heterozygous factor V Leiden mutation, longstanding untreated hypertension, and multiple severe episodes of HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome during pregnancy.

After receiving antihypertensive treatment at a community hospital, her blood pressure gradually improved to 160/100 mm Hg with the addition of a third medication. However, on Day 3 of her stay, her systolic blood pressure rose to more than 200 mm Hg and was accompanied by somnolence, emesis, and paleness. She was transferred to a tertiary care center.

THE DIAGNOSIS

On admission, the patient had left-side hemiparesis and facial droop with dysarthria, resulting in a National Institutes of Health Stroke Scale (NIHSS) score of 7 (out of 42) and a Glasgow Coma Scale (GCS) score of 13 (out of 15). Noncontrast computed tomography (CT) and CT angiography of the head and neck were ordered and showed occlusion of both intracranial vertebral arteries. There were also signs of multifocal infarction in her occipital lobes, thus systemic recombinant human-tissue plasminogen activator (tPA) could not be administered.

The patient was next taken to the angiography suite, where a digital subtraction angiography confirmed the presence of bilateral vertebral artery occlusions (FIGURE 1A). A thrombectomy was performed to open the left occluded segment, resulting in recanalization; however, a high-grade stenosis remained in the intracranial left vertebral artery (FIGURE 1B). The right vertebral artery had a severe extracranial origin stenosis, and balloon angioplasty was performed in order to reach the intracranial circulation; however, the occlusion of the intracranial right vertebral artery segment could not be catheterized. Subsequent magnetic resonance imaging (MRI) with a time-of-flight magnetic resonance angiography showed that the intracranial left vertebral artery with high-grade stenosis had closed down again; thus, there was occlusion of both intracranial vertebral arteries and absent flow signal in the basilar artery (FIGURE 2). There were scattered small acute strokes within the cerebellum, brainstem, and occipital lobes.

Unfortunately, within 48 hours, the patient’s NIHSS score increased from 7 to 29. She developed tetraplegia, was significantly less responsive (GCS score, 3/15), and required intubation and mechanical ventilation. Reopening the stenosis and keeping it open with a stent would be an aggressive procedure with poor odds for success and would require antithrombotic medications with the associated risk for intracranial hemorrhage in the setting of demarcated strokes. Thus, no further intervention was pursued.

Further standard stroke work-up (echocardiography, extracranial ultrasound of the cerebral circulation, and vasculitis screening) was unremarkable. In the intensive care unit, intravenous therapeutic heparin was initiated because of the potential prothrombotic effect of the factor V Leiden mutation but was subsequently switched to dual anti-­aggregation therapy (aspirin 100 mg/d and clopidogrel 75 mg/d) as secondary stroke prevention given the final diagnosis of severe atherosclerosis. Nevertheless, the patient remained tetraplegic with a partial locked-in syndrome when she was discharged, after 2 weeks in the tertiary care center, to a rehabilitation center.

DISCUSSION

Posterior circulation strokes account for 20% to 25% of all ischemic strokes^1,2 and are associated with infarction within the vertebrobasilar arterial system. Common etiologies of these infarctions include atherosclerosis (as seen in our patient), embolism, small-artery penetrating disease, and arterial dissection.² Although the estimated overall mortality of these strokes is low (3.6% to 11%),² basilar occlusion syndrome, in particular, is a life-threatening condition with a high mortality rate of 80% to 90%.³

Continue to: Diagnosis can be particularly challenging...

Diagnosis can be particularly challenging due to the anatomic variations of posterior arterial circulation, as well as the fluctuating nonfocal or multifocal symptoms.² Specific symptoms include vertigo, ataxia, unilateral motor weakness, dysarthria, and oculomotor dysfunction. However, nonspecific symptoms such as headache, nausea, dizziness, hoarseness, falls, and Horner syndrome may be the only presenting signs of a posterior circulation stroke—as was the case with our patient.² Her radiating neck pain could have been interpreted as a pointer to vertebral artery dissection within the context of severe hypertension.⁴ Unfortunately, the diagnosis was delayed and head imaging was obtained only after her mental status deteriorated.

Immediate neuroimaging is necessary to guide treatment in patients with suspected acute posterior circulation stroke,^1,5,6 although it is not always definitive. While CT is pivotal in stroke work-up and may reliably exclude intracranial hemorrhage, its ability to detect acute posterior circulation ischemic strokes is limited given its poor visualization of the posterior fossa (as low as 16% sensitivity).⁵ Fortunately, CT angiography has a high sensitivity (nearing 100%) for large-vessel occlusion and high predictive values for dissection (65%-100% positive predictive value and 70%-98% negative predictive value).^5,7 ­Diffusion-weighted MRI (when available in the emergency setting) has the highest sensitivity for detecting acute infarcts, although posterior circulation infarcts still can be missed (19% false-negative rate).^5,8 Thus, correlative vessel imaging with magnetic resonance or CT angiography is very important, along with a high index of suspicion. In some instances, repeat MRI may be necessary to detect small strokes.

A patient-specific approach to management is key for individuals with suspected posterior circulation stroke.⁵ Because specific data for the appropriate management of posterior circulation ischemic stroke are lacking, current American Heart ­Association/American Stroke Association (AHA/ASA) guidelines apply to anterior and ­posterior circulation strokes.⁶ For eligible ­patients without multifocal disease, intravenous tPA is the first-line therapy and should be initiated according to guidelines within 4.5 hours of stroke onset⁹; it is important to note that these guidelines are based on studies that ­focused more on anterior circulation strokes than posterior circulation strokes.^6,9-13 This can be done in combination with ­endovascular therapy, which consists of ­mechanical thrombectomy, intra-arterial thrombolysis, or a combination of revascularization ­techniques.^3,5,6

Nonspecific symptoms such as headache, nausea, and dizziness may be the only presenting signs of a posterior circulation stroke.

Mechanical thrombectomy specifically has high proven recanalization rates for all target vessels.^3-6 The latest AHA/ASA guidelines recommend mechanical thrombectomy be performed within 6 hours of stroke onset.⁶ However, there is emerging evidence that suggests this timeframe should be ­extended—even beyond 24 hours—given the poor prognosis of posterior circulation strokes.^5,6,14 More data on the management of posterior circulation strokes are urgently needed to better understand which therapeutic approach is most efficient.

In patients such as ours, who have evidence of multifocal disease, treatment may be limited to endovascular therapy. Intracranial stenting of symptomatic lesions in particular has been controversial since the publication of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis trial, which found that aggressive medical management was superior to stenting in patients who recently had a transient ischemic attack or stroke attributed to stenosis.¹⁵ Although additional studies have been performed, there are no definitive data on the topic—and certainly no data in the emergency setting.¹⁶ Further challenges are raised in patients with bilateral disease, as was the case with this patient.

When our patient was admitted to the rehabilitation clinic, she had a GCS score of 10 to 11/15. After 9 months of rehabilitation, she was discharged home with a GCS score of 15/15 and persistent left-side hemiparesis.

THE TAKEAWAY

Posterior circulation stroke is a life-­threatening disease that may manifest with a variety of symptoms and be difficult to identify on emergent imaging. Thus, a high degree of clinical suspicion and additional follow-up are paramount to ensure prompt diagnosis and a patient-tailored treatment strategy.

CORRESPONDENCE
Kristine A. Blackham, MD, Associate Professor, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland; kristine.blackham@gmail.com Orcid no: 0000-0002-1620-1144 (Dr. Blackham); 0000-0002- 5225-5414 (Dr. Saleh)

THE CASE

A 49-year-old woman was hospitalized with a headache and neck pain that radiated to her ears and eyes in the context of severe hypertension (270/150 mm Hg). Her medical history was significant for heterozygous factor V Leiden mutation, longstanding untreated hypertension, and multiple severe episodes of HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome during pregnancy.

After receiving antihypertensive treatment at a community hospital, her blood pressure gradually improved to 160/100 mm Hg with the addition of a third medication. However, on Day 3 of her stay, her systolic blood pressure rose to more than 200 mm Hg and was accompanied by somnolence, emesis, and paleness. She was transferred to a tertiary care center.

THE DIAGNOSIS

On admission, the patient had left-side hemiparesis and facial droop with dysarthria, resulting in a National Institutes of Health Stroke Scale (NIHSS) score of 7 (out of 42) and a Glasgow Coma Scale (GCS) score of 13 (out of 15). Noncontrast computed tomography (CT) and CT angiography of the head and neck were ordered and showed occlusion of both intracranial vertebral arteries. There were also signs of multifocal infarction in her occipital lobes, thus systemic recombinant human-tissue plasminogen activator (tPA) could not be administered.

The patient was next taken to the angiography suite, where a digital subtraction angiography confirmed the presence of bilateral vertebral artery occlusions (FIGURE 1A). A thrombectomy was performed to open the left occluded segment, resulting in recanalization; however, a high-grade stenosis remained in the intracranial left vertebral artery (FIGURE 1B). The right vertebral artery had a severe extracranial origin stenosis, and balloon angioplasty was performed in order to reach the intracranial circulation; however, the occlusion of the intracranial right vertebral artery segment could not be catheterized. Subsequent magnetic resonance imaging (MRI) with a time-of-flight magnetic resonance angiography showed that the intracranial left vertebral artery with high-grade stenosis had closed down again; thus, there was occlusion of both intracranial vertebral arteries and absent flow signal in the basilar artery (FIGURE 2). There were scattered small acute strokes within the cerebellum, brainstem, and occipital lobes.

Unfortunately, within 48 hours, the patient’s NIHSS score increased from 7 to 29. She developed tetraplegia, was significantly less responsive (GCS score, 3/15), and required intubation and mechanical ventilation. Reopening the stenosis and keeping it open with a stent would be an aggressive procedure with poor odds for success and would require antithrombotic medications with the associated risk for intracranial hemorrhage in the setting of demarcated strokes. Thus, no further intervention was pursued.

Further standard stroke work-up (echocardiography, extracranial ultrasound of the cerebral circulation, and vasculitis screening) was unremarkable. In the intensive care unit, intravenous therapeutic heparin was initiated because of the potential prothrombotic effect of the factor V Leiden mutation but was subsequently switched to dual anti-­aggregation therapy (aspirin 100 mg/d and clopidogrel 75 mg/d) as secondary stroke prevention given the final diagnosis of severe atherosclerosis. Nevertheless, the patient remained tetraplegic with a partial locked-in syndrome when she was discharged, after 2 weeks in the tertiary care center, to a rehabilitation center.

DISCUSSION

Posterior circulation strokes account for 20% to 25% of all ischemic strokes^1,2 and are associated with infarction within the vertebrobasilar arterial system. Common etiologies of these infarctions include atherosclerosis (as seen in our patient), embolism, small-artery penetrating disease, and arterial dissection.² Although the estimated overall mortality of these strokes is low (3.6% to 11%),² basilar occlusion syndrome, in particular, is a life-threatening condition with a high mortality rate of 80% to 90%.³

Continue to: Diagnosis can be particularly challenging...

Diagnosis can be particularly challenging due to the anatomic variations of posterior arterial circulation, as well as the fluctuating nonfocal or multifocal symptoms.² Specific symptoms include vertigo, ataxia, unilateral motor weakness, dysarthria, and oculomotor dysfunction. However, nonspecific symptoms such as headache, nausea, dizziness, hoarseness, falls, and Horner syndrome may be the only presenting signs of a posterior circulation stroke—as was the case with our patient.² Her radiating neck pain could have been interpreted as a pointer to vertebral artery dissection within the context of severe hypertension.⁴ Unfortunately, the diagnosis was delayed and head imaging was obtained only after her mental status deteriorated.

Immediate neuroimaging is necessary to guide treatment in patients with suspected acute posterior circulation stroke,^1,5,6 although it is not always definitive. While CT is pivotal in stroke work-up and may reliably exclude intracranial hemorrhage, its ability to detect acute posterior circulation ischemic strokes is limited given its poor visualization of the posterior fossa (as low as 16% sensitivity).⁵ Fortunately, CT angiography has a high sensitivity (nearing 100%) for large-vessel occlusion and high predictive values for dissection (65%-100% positive predictive value and 70%-98% negative predictive value).^5,7 ­Diffusion-weighted MRI (when available in the emergency setting) has the highest sensitivity for detecting acute infarcts, although posterior circulation infarcts still can be missed (19% false-negative rate).^5,8 Thus, correlative vessel imaging with magnetic resonance or CT angiography is very important, along with a high index of suspicion. In some instances, repeat MRI may be necessary to detect small strokes.

A patient-specific approach to management is key for individuals with suspected posterior circulation stroke.⁵ Because specific data for the appropriate management of posterior circulation ischemic stroke are lacking, current American Heart ­Association/American Stroke Association (AHA/ASA) guidelines apply to anterior and ­posterior circulation strokes.⁶ For eligible ­patients without multifocal disease, intravenous tPA is the first-line therapy and should be initiated according to guidelines within 4.5 hours of stroke onset⁹; it is important to note that these guidelines are based on studies that ­focused more on anterior circulation strokes than posterior circulation strokes.^6,9-13 This can be done in combination with ­endovascular therapy, which consists of ­mechanical thrombectomy, intra-arterial thrombolysis, or a combination of revascularization ­techniques.^3,5,6

Nonspecific symptoms such as headache, nausea, and dizziness may be the only presenting signs of a posterior circulation stroke.

Mechanical thrombectomy specifically has high proven recanalization rates for all target vessels.^3-6 The latest AHA/ASA guidelines recommend mechanical thrombectomy be performed within 6 hours of stroke onset.⁶ However, there is emerging evidence that suggests this timeframe should be ­extended—even beyond 24 hours—given the poor prognosis of posterior circulation strokes.^5,6,14 More data on the management of posterior circulation strokes are urgently needed to better understand which therapeutic approach is most efficient.

In patients such as ours, who have evidence of multifocal disease, treatment may be limited to endovascular therapy. Intracranial stenting of symptomatic lesions in particular has been controversial since the publication of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis trial, which found that aggressive medical management was superior to stenting in patients who recently had a transient ischemic attack or stroke attributed to stenosis.¹⁵ Although additional studies have been performed, there are no definitive data on the topic—and certainly no data in the emergency setting.¹⁶ Further challenges are raised in patients with bilateral disease, as was the case with this patient.

When our patient was admitted to the rehabilitation clinic, she had a GCS score of 10 to 11/15. After 9 months of rehabilitation, she was discharged home with a GCS score of 15/15 and persistent left-side hemiparesis.

THE TAKEAWAY

Posterior circulation stroke is a life-­threatening disease that may manifest with a variety of symptoms and be difficult to identify on emergent imaging. Thus, a high degree of clinical suspicion and additional follow-up are paramount to ensure prompt diagnosis and a patient-tailored treatment strategy.

CORRESPONDENCE
Kristine A. Blackham, MD, Associate Professor, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland; kristine.blackham@gmail.com Orcid no: 0000-0002-1620-1144 (Dr. Blackham); 0000-0002- 5225-5414 (Dr. Saleh)

THE CASE

A 49-year-old woman was hospitalized with a headache and neck pain that radiated to her ears and eyes in the context of severe hypertension (270/150 mm Hg). Her medical history was significant for heterozygous factor V Leiden mutation, longstanding untreated hypertension, and multiple severe episodes of HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome during pregnancy.

After receiving antihypertensive treatment at a community hospital, her blood pressure gradually improved to 160/100 mm Hg with the addition of a third medication. However, on Day 3 of her stay, her systolic blood pressure rose to more than 200 mm Hg and was accompanied by somnolence, emesis, and paleness. She was transferred to a tertiary care center.

THE DIAGNOSIS

On admission, the patient had left-side hemiparesis and facial droop with dysarthria, resulting in a National Institutes of Health Stroke Scale (NIHSS) score of 7 (out of 42) and a Glasgow Coma Scale (GCS) score of 13 (out of 15). Noncontrast computed tomography (CT) and CT angiography of the head and neck were ordered and showed occlusion of both intracranial vertebral arteries. There were also signs of multifocal infarction in her occipital lobes, thus systemic recombinant human-tissue plasminogen activator (tPA) could not be administered.

The patient was next taken to the angiography suite, where a digital subtraction angiography confirmed the presence of bilateral vertebral artery occlusions (FIGURE 1A). A thrombectomy was performed to open the left occluded segment, resulting in recanalization; however, a high-grade stenosis remained in the intracranial left vertebral artery (FIGURE 1B). The right vertebral artery had a severe extracranial origin stenosis, and balloon angioplasty was performed in order to reach the intracranial circulation; however, the occlusion of the intracranial right vertebral artery segment could not be catheterized. Subsequent magnetic resonance imaging (MRI) with a time-of-flight magnetic resonance angiography showed that the intracranial left vertebral artery with high-grade stenosis had closed down again; thus, there was occlusion of both intracranial vertebral arteries and absent flow signal in the basilar artery (FIGURE 2). There were scattered small acute strokes within the cerebellum, brainstem, and occipital lobes.

Unfortunately, within 48 hours, the patient’s NIHSS score increased from 7 to 29. She developed tetraplegia, was significantly less responsive (GCS score, 3/15), and required intubation and mechanical ventilation. Reopening the stenosis and keeping it open with a stent would be an aggressive procedure with poor odds for success and would require antithrombotic medications with the associated risk for intracranial hemorrhage in the setting of demarcated strokes. Thus, no further intervention was pursued.

Further standard stroke work-up (echocardiography, extracranial ultrasound of the cerebral circulation, and vasculitis screening) was unremarkable. In the intensive care unit, intravenous therapeutic heparin was initiated because of the potential prothrombotic effect of the factor V Leiden mutation but was subsequently switched to dual anti-­aggregation therapy (aspirin 100 mg/d and clopidogrel 75 mg/d) as secondary stroke prevention given the final diagnosis of severe atherosclerosis. Nevertheless, the patient remained tetraplegic with a partial locked-in syndrome when she was discharged, after 2 weeks in the tertiary care center, to a rehabilitation center.

DISCUSSION

Posterior circulation strokes account for 20% to 25% of all ischemic strokes^1,2 and are associated with infarction within the vertebrobasilar arterial system. Common etiologies of these infarctions include atherosclerosis (as seen in our patient), embolism, small-artery penetrating disease, and arterial dissection.² Although the estimated overall mortality of these strokes is low (3.6% to 11%),² basilar occlusion syndrome, in particular, is a life-threatening condition with a high mortality rate of 80% to 90%.³

Continue to: Diagnosis can be particularly challenging...

Diagnosis can be particularly challenging due to the anatomic variations of posterior arterial circulation, as well as the fluctuating nonfocal or multifocal symptoms.² Specific symptoms include vertigo, ataxia, unilateral motor weakness, dysarthria, and oculomotor dysfunction. However, nonspecific symptoms such as headache, nausea, dizziness, hoarseness, falls, and Horner syndrome may be the only presenting signs of a posterior circulation stroke—as was the case with our patient.² Her radiating neck pain could have been interpreted as a pointer to vertebral artery dissection within the context of severe hypertension.⁴ Unfortunately, the diagnosis was delayed and head imaging was obtained only after her mental status deteriorated.

Immediate neuroimaging is necessary to guide treatment in patients with suspected acute posterior circulation stroke,^1,5,6 although it is not always definitive. While CT is pivotal in stroke work-up and may reliably exclude intracranial hemorrhage, its ability to detect acute posterior circulation ischemic strokes is limited given its poor visualization of the posterior fossa (as low as 16% sensitivity).⁵ Fortunately, CT angiography has a high sensitivity (nearing 100%) for large-vessel occlusion and high predictive values for dissection (65%-100% positive predictive value and 70%-98% negative predictive value).^5,7 ­Diffusion-weighted MRI (when available in the emergency setting) has the highest sensitivity for detecting acute infarcts, although posterior circulation infarcts still can be missed (19% false-negative rate).^5,8 Thus, correlative vessel imaging with magnetic resonance or CT angiography is very important, along with a high index of suspicion. In some instances, repeat MRI may be necessary to detect small strokes.

A patient-specific approach to management is key for individuals with suspected posterior circulation stroke.⁵ Because specific data for the appropriate management of posterior circulation ischemic stroke are lacking, current American Heart ­Association/American Stroke Association (AHA/ASA) guidelines apply to anterior and ­posterior circulation strokes.⁶ For eligible ­patients without multifocal disease, intravenous tPA is the first-line therapy and should be initiated according to guidelines within 4.5 hours of stroke onset⁹; it is important to note that these guidelines are based on studies that ­focused more on anterior circulation strokes than posterior circulation strokes.^6,9-13 This can be done in combination with ­endovascular therapy, which consists of ­mechanical thrombectomy, intra-arterial thrombolysis, or a combination of revascularization ­techniques.^3,5,6

Nonspecific symptoms such as headache, nausea, and dizziness may be the only presenting signs of a posterior circulation stroke.

Mechanical thrombectomy specifically has high proven recanalization rates for all target vessels.^3-6 The latest AHA/ASA guidelines recommend mechanical thrombectomy be performed within 6 hours of stroke onset.⁶ However, there is emerging evidence that suggests this timeframe should be ­extended—even beyond 24 hours—given the poor prognosis of posterior circulation strokes.^5,6,14 More data on the management of posterior circulation strokes are urgently needed to better understand which therapeutic approach is most efficient.

In patients such as ours, who have evidence of multifocal disease, treatment may be limited to endovascular therapy. Intracranial stenting of symptomatic lesions in particular has been controversial since the publication of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis trial, which found that aggressive medical management was superior to stenting in patients who recently had a transient ischemic attack or stroke attributed to stenosis.¹⁵ Although additional studies have been performed, there are no definitive data on the topic—and certainly no data in the emergency setting.¹⁶ Further challenges are raised in patients with bilateral disease, as was the case with this patient.

When our patient was admitted to the rehabilitation clinic, she had a GCS score of 10 to 11/15. After 9 months of rehabilitation, she was discharged home with a GCS score of 15/15 and persistent left-side hemiparesis.

THE TAKEAWAY

Posterior circulation stroke is a life-­threatening disease that may manifest with a variety of symptoms and be difficult to identify on emergent imaging. Thus, a high degree of clinical suspicion and additional follow-up are paramount to ensure prompt diagnosis and a patient-tailored treatment strategy.

CORRESPONDENCE
Kristine A. Blackham, MD, Associate Professor, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland; kristine.blackham@gmail.com Orcid no: 0000-0002-1620-1144 (Dr. Blackham); 0000-0002- 5225-5414 (Dr. Saleh)

BACKGROUND

There are 5 germline mutations that lead to hypercoagulability in the general population including: Factor V Leiden (FVL), Prothrombin G20210A (F2A), Protein C Deficiency (PCD), Protein S Deficiency (PSD), and Antithrombin Deficiency (ATD). Typical guidance is to defer testing, as it is thought not to change management.

CASE REPORT

We present a case of a patient who was found to be compound heterozygous mutations for FVL and F2A, who presented with two episodes of arterial thromboembolism resulting in cerebrovascular accident (CVA). A 63-year-old male with past medical history of hypertension, a CVA four years prior, and medication non-compliance presents with new onset left sided hemiparesis after an episode of convulsions. MRI and CT imaging of the head revealed ischemic CVA secondary to thromboembolism in the right posterior cerebral artery’s (PCA), P1 branch. Following administration of tissue plasminogen activator (tPA) he had rapid symptom improvement. This second ischemic CVA prompted a workup which was notable for: negative echocardiogram, negative 30-day cardiac monitor, CT chest negative for malignancy, no significant vascular findings, negative for antiphospholipid syndrome, but genetic testing revealed the patient to be heterozygous for FVL and F2A mutations. He was started on apixaban 5 mg twice daily for ongoing secondary prevention. Though medication compliance continues to be difficult, after being placed on direct anticoagulant (DOAC), he has not had recurrent venous or arterial thrombotic events. A small case series found double heterozygosity for FVL and F2A further increases the risk of venous thromboembolism up to 17% or more in a lifetime.

CONCLUSIONS

Although current recommendations advocate against testing for specific mutations in most cases as it is likely not to change management1, this case suggests that it may be of some benefit in patients that have a workup that does not yield a clear etiology, especially in cryptogenic stroke which is typically managed with aspirin rather than direct oral anticoagulant.

BACKGROUND

There are 5 germline mutations that lead to hypercoagulability in the general population including: Factor V Leiden (FVL), Prothrombin G20210A (F2A), Protein C Deficiency (PCD), Protein S Deficiency (PSD), and Antithrombin Deficiency (ATD). Typical guidance is to defer testing, as it is thought not to change management.

CASE REPORT

We present a case of a patient who was found to be compound heterozygous mutations for FVL and F2A, who presented with two episodes of arterial thromboembolism resulting in cerebrovascular accident (CVA). A 63-year-old male with past medical history of hypertension, a CVA four years prior, and medication non-compliance presents with new onset left sided hemiparesis after an episode of convulsions. MRI and CT imaging of the head revealed ischemic CVA secondary to thromboembolism in the right posterior cerebral artery’s (PCA), P1 branch. Following administration of tissue plasminogen activator (tPA) he had rapid symptom improvement. This second ischemic CVA prompted a workup which was notable for: negative echocardiogram, negative 30-day cardiac monitor, CT chest negative for malignancy, no significant vascular findings, negative for antiphospholipid syndrome, but genetic testing revealed the patient to be heterozygous for FVL and F2A mutations. He was started on apixaban 5 mg twice daily for ongoing secondary prevention. Though medication compliance continues to be difficult, after being placed on direct anticoagulant (DOAC), he has not had recurrent venous or arterial thrombotic events. A small case series found double heterozygosity for FVL and F2A further increases the risk of venous thromboembolism up to 17% or more in a lifetime.

CONCLUSIONS

Although current recommendations advocate against testing for specific mutations in most cases as it is likely not to change management1, this case suggests that it may be of some benefit in patients that have a workup that does not yield a clear etiology, especially in cryptogenic stroke which is typically managed with aspirin rather than direct oral anticoagulant.

BACKGROUND

There are 5 germline mutations that lead to hypercoagulability in the general population including: Factor V Leiden (FVL), Prothrombin G20210A (F2A), Protein C Deficiency (PCD), Protein S Deficiency (PSD), and Antithrombin Deficiency (ATD). Typical guidance is to defer testing, as it is thought not to change management.

CASE REPORT

We present a case of a patient who was found to be compound heterozygous mutations for FVL and F2A, who presented with two episodes of arterial thromboembolism resulting in cerebrovascular accident (CVA). A 63-year-old male with past medical history of hypertension, a CVA four years prior, and medication non-compliance presents with new onset left sided hemiparesis after an episode of convulsions. MRI and CT imaging of the head revealed ischemic CVA secondary to thromboembolism in the right posterior cerebral artery’s (PCA), P1 branch. Following administration of tissue plasminogen activator (tPA) he had rapid symptom improvement. This second ischemic CVA prompted a workup which was notable for: negative echocardiogram, negative 30-day cardiac monitor, CT chest negative for malignancy, no significant vascular findings, negative for antiphospholipid syndrome, but genetic testing revealed the patient to be heterozygous for FVL and F2A mutations. He was started on apixaban 5 mg twice daily for ongoing secondary prevention. Though medication compliance continues to be difficult, after being placed on direct anticoagulant (DOAC), he has not had recurrent venous or arterial thrombotic events. A small case series found double heterozygosity for FVL and F2A further increases the risk of venous thromboembolism up to 17% or more in a lifetime.

CONCLUSIONS

Although current recommendations advocate against testing for specific mutations in most cases as it is likely not to change management1, this case suggests that it may be of some benefit in patients that have a workup that does not yield a clear etiology, especially in cryptogenic stroke which is typically managed with aspirin rather than direct oral anticoagulant.

INTRODUCTION

We present an unusual case of autoimmune hemolytic anemia (AIHA) associated with Kikuchi-Fujimoto Disease (KFD) and systemic lupus erythematosus (SLE) that resolved with steroid therapy.

CASE PRESENTATION

A 25-year-old female with no medical history presented with 6 weeks of high fevers, syncope, and 10-lb weight loss. Exam revealed generalized lymphadenopathy (LAD) and tiny malar papules. Labs showed IgG and IgM Coombs-positivity, hemoglobin of 5 g/dL, hyperbilirubinemia, low haptoglobin, LDH >2000 IU/L, thrombocytopenia, and leukopenia. Cryoglobulins were absent. Hemophagocytic lymphohistiocytosis (HLH) markers showed ferritin of 18,000 ng/mL, moderately elevated soluble IL-2 receptor, negative CD107, minimally elevated CXCL9, borderline transaminitis, and high-normal triglycerides. ANA was 1:1280, speckled, with high anti-RNP, high anti-Smith, and negative anti-dsDNA antibodies. CT confirmed LAD without organomegaly. A 4cm excised node reviewed at 2 institutions showed necrotizing lymphadenitis without granulomas, consistent with KFD. Flow cytometry and gene rearrangement assay showed no monoclonality. Bone marrow biopsy demonstrated erythroid hyperplasia, normal flow cytometry, and no hemophagocytosis. Infectious workup was unremarkable. Treatment was initiated with 50mg prednisone daily, weaned off over 5 months. 2 months post-initiation, the fevers resolved, hemoglobin increased, and LDH normalized. 3 months later, rheumatology service diagnosed SLE based on 2019 ACR/EULAR Criteria and initiated hydroxychloroquine. 9 months later, patient remains without recurrence.

DISCUSSION

KFD presents subacutely with LAD, fever, weight loss, and varying skin findings, often self-resolving. Diagnosis requires lymph node biopsy. Etiology is unclear, with infectious, neoplastic, and autoimmune mechanisms implicated. Studies suggest up to 15% of patients have SLE.

CONCLUSIONS

This case is a rare combination of AIHA, KFD, and SLE successfully treated with steroids and, later, hydroxychloroquine. It calls for vigilance for KFD in patients with LAD and AIHA. A successful treatment strategy could include highdose steroids. The presentation may mimic lymphoma and HLH, which must be ruled out with careful pathologic and lab evaluation. To our knowledge, this is the 3rd reported case of KFD with AIHA, and 2nd case of concomitant SLE, KFD, and AIHA. The only similar patient was treated with methylprednisolone and cyclophosphamide and did not have longer-term follow-up.

INTRODUCTION

We present an unusual case of autoimmune hemolytic anemia (AIHA) associated with Kikuchi-Fujimoto Disease (KFD) and systemic lupus erythematosus (SLE) that resolved with steroid therapy.

CASE PRESENTATION

A 25-year-old female with no medical history presented with 6 weeks of high fevers, syncope, and 10-lb weight loss. Exam revealed generalized lymphadenopathy (LAD) and tiny malar papules. Labs showed IgG and IgM Coombs-positivity, hemoglobin of 5 g/dL, hyperbilirubinemia, low haptoglobin, LDH >2000 IU/L, thrombocytopenia, and leukopenia. Cryoglobulins were absent. Hemophagocytic lymphohistiocytosis (HLH) markers showed ferritin of 18,000 ng/mL, moderately elevated soluble IL-2 receptor, negative CD107, minimally elevated CXCL9, borderline transaminitis, and high-normal triglycerides. ANA was 1:1280, speckled, with high anti-RNP, high anti-Smith, and negative anti-dsDNA antibodies. CT confirmed LAD without organomegaly. A 4cm excised node reviewed at 2 institutions showed necrotizing lymphadenitis without granulomas, consistent with KFD. Flow cytometry and gene rearrangement assay showed no monoclonality. Bone marrow biopsy demonstrated erythroid hyperplasia, normal flow cytometry, and no hemophagocytosis. Infectious workup was unremarkable. Treatment was initiated with 50mg prednisone daily, weaned off over 5 months. 2 months post-initiation, the fevers resolved, hemoglobin increased, and LDH normalized. 3 months later, rheumatology service diagnosed SLE based on 2019 ACR/EULAR Criteria and initiated hydroxychloroquine. 9 months later, patient remains without recurrence.

DISCUSSION

KFD presents subacutely with LAD, fever, weight loss, and varying skin findings, often self-resolving. Diagnosis requires lymph node biopsy. Etiology is unclear, with infectious, neoplastic, and autoimmune mechanisms implicated. Studies suggest up to 15% of patients have SLE.

CONCLUSIONS

This case is a rare combination of AIHA, KFD, and SLE successfully treated with steroids and, later, hydroxychloroquine. It calls for vigilance for KFD in patients with LAD and AIHA. A successful treatment strategy could include highdose steroids. The presentation may mimic lymphoma and HLH, which must be ruled out with careful pathologic and lab evaluation. To our knowledge, this is the 3rd reported case of KFD with AIHA, and 2nd case of concomitant SLE, KFD, and AIHA. The only similar patient was treated with methylprednisolone and cyclophosphamide and did not have longer-term follow-up.

INTRODUCTION

We present an unusual case of autoimmune hemolytic anemia (AIHA) associated with Kikuchi-Fujimoto Disease (KFD) and systemic lupus erythematosus (SLE) that resolved with steroid therapy.

CASE PRESENTATION

A 25-year-old female with no medical history presented with 6 weeks of high fevers, syncope, and 10-lb weight loss. Exam revealed generalized lymphadenopathy (LAD) and tiny malar papules. Labs showed IgG and IgM Coombs-positivity, hemoglobin of 5 g/dL, hyperbilirubinemia, low haptoglobin, LDH >2000 IU/L, thrombocytopenia, and leukopenia. Cryoglobulins were absent. Hemophagocytic lymphohistiocytosis (HLH) markers showed ferritin of 18,000 ng/mL, moderately elevated soluble IL-2 receptor, negative CD107, minimally elevated CXCL9, borderline transaminitis, and high-normal triglycerides. ANA was 1:1280, speckled, with high anti-RNP, high anti-Smith, and negative anti-dsDNA antibodies. CT confirmed LAD without organomegaly. A 4cm excised node reviewed at 2 institutions showed necrotizing lymphadenitis without granulomas, consistent with KFD. Flow cytometry and gene rearrangement assay showed no monoclonality. Bone marrow biopsy demonstrated erythroid hyperplasia, normal flow cytometry, and no hemophagocytosis. Infectious workup was unremarkable. Treatment was initiated with 50mg prednisone daily, weaned off over 5 months. 2 months post-initiation, the fevers resolved, hemoglobin increased, and LDH normalized. 3 months later, rheumatology service diagnosed SLE based on 2019 ACR/EULAR Criteria and initiated hydroxychloroquine. 9 months later, patient remains without recurrence.

DISCUSSION

KFD presents subacutely with LAD, fever, weight loss, and varying skin findings, often self-resolving. Diagnosis requires lymph node biopsy. Etiology is unclear, with infectious, neoplastic, and autoimmune mechanisms implicated. Studies suggest up to 15% of patients have SLE.

CONCLUSIONS

This case is a rare combination of AIHA, KFD, and SLE successfully treated with steroids and, later, hydroxychloroquine. It calls for vigilance for KFD in patients with LAD and AIHA. A successful treatment strategy could include highdose steroids. The presentation may mimic lymphoma and HLH, which must be ruled out with careful pathologic and lab evaluation. To our knowledge, this is the 3rd reported case of KFD with AIHA, and 2nd case of concomitant SLE, KFD, and AIHA. The only similar patient was treated with methylprednisolone and cyclophosphamide and did not have longer-term follow-up.