Article

To the Editor:

Millipedes do not have nearly as many feet as their name would suggest; most have fewer than 100.¹ They are not actually insects; they are a wormlike arthropod in the Diplopoda class. Generally these harmless animals can be a welcome resident in gardens because they break down decaying plant material and rejuvenate the soil.¹ However, they are less welcome in the home or underfoot because of what happens when these invertebrates are threatened or crushed.²

Millipedes, which typically have at least 30 pairs of legs, have 2 defense mechanisms: (1) body coiling to withstand external pressure, and (2) secretion of fluids with insecticidal properties from specialized glands distributed along their body.³ These secretions, which are used by the millipede to defend against predators, contain organic compounds including benzoquinone. When these secretions come into contact with skin, pigmentary changes resembling a burn or necrosis and irritation to the skin (pain, burning, itching) occur.^4,5

Millipedes typically are found in tropical and temperate regions worldwide, such as the Amazon rainforest, Southeast Asia, tropical areas of Africa, forests, grasslands, and gardens in North America and Europe.⁶ They also are found in every US state as well as Puerto Rico.¹ Millipedes are nocturnal, favor dark places, and can make their way into residential areas, including homes, basements, gardens, and yards.^2,6 Although millipede burns commonly are reported in tropical regions, we present a case in China.⁶A 33-year-old woman presented with purplish-red discoloration on all 5 toes on the left foot. The patient recounted that she discovered a millipede in her shoe earlier in the day, removed it, and crushed it with her bare foot. That night, while taking a bath, she noticed that the toes had turned purplish-red (Figure 1). The patient brought the crushed millipede with her to the emergency department where she sought treatment. The dermatologist confirmed that it was a millipede; however, the team was unable to determine the specific species because it had been crushed (Figure 2).

Physical examination of the affected toes showed a clear boundary and iodinelike staining. The patient did not report pain. The stained skin had a normal temperature, pulse, texture, and sensation. Dermoscopy revealed multiple black-brown patches on the toes (Figure 3). The pigmented area gradually faded over a 1-month period. Superficial damage to the toenail revealed evidence of black-brown pigmentation on both the nail and the skin underneath. The diagnosis in the dermoscopy report suggested exogenous pigmentation of the toes. The patient was advised that no treatment was needed and that the condition would resolve on its own. At 1-month follow-up, the patient’s toes had returned to their normal color (Figure 4).

The feet are common sites of millipede burns; other exposed areas, such as the arms, face, and eyes, also are potential sites of involvement.⁵ The cutaneous pigmentary changes seen on our patient’s foot were a result of the millipede’s defense mechanism—secreted toxic chemicals that stained the foot. It is important to note that the pigmentation was not associated with the death of the millipede, as the millipede was still alive upon initial contact with the patient’s foot in her shoe. 

When a patient presents with pigmentary changes, several conditions must be ruled out—notably acute arterial thrombosis. Patients with this condition will describe acute pain and weakness in the area of involvement. Physicians inspecting the area will note coldness and pallor in the affected limb as well as a diminished or absent pulse. In severe cases, the skin may exhibit a purplish-red appearance.⁵ Millipede burns also should be distinguished from bacterial endocarditis and cryoglobulinemia.⁷ All 3 conditions can manifest with redness, swelling, blisters, and purpuralike changes. Positive blood culture is an important diagnostic basis for bacterial endocarditis; in addition, routine blood tests will demonstrate a decrease in red blood cells and hemoglobin, and routine urinalysis may show proteinuria and microscopic hematuria. Patients with cryoglobulinemia will have a positive cryoglobulin assay, increased IgM, and often decreased complement.⁷ It also is worth noting that millipede burns might resemble child abuse in pediatric patients, necessitating further evaluation.⁵ 

It is unusual to see a millipede burn in nontropical regions. Therefore, the identification of our patient’s millipede burn was notable and serves as a reminder to keep this diagnosis in the differential when caring for patients with pigmentary changes. An accurate diagnosis hinges on being alert to a millipede exposure history and recognizing the clinical manifestations. For affected patients, it may be beneficial to recommend they advise friends and relatives to avoid skin contact with millipedes and most importantly to avoid stepping on them with bare feet.

To the Editor:

Millipedes do not have nearly as many feet as their name would suggest; most have fewer than 100.¹ They are not actually insects; they are a wormlike arthropod in the Diplopoda class. Generally these harmless animals can be a welcome resident in gardens because they break down decaying plant material and rejuvenate the soil.¹ However, they are less welcome in the home or underfoot because of what happens when these invertebrates are threatened or crushed.²

Millipedes, which typically have at least 30 pairs of legs, have 2 defense mechanisms: (1) body coiling to withstand external pressure, and (2) secretion of fluids with insecticidal properties from specialized glands distributed along their body.³ These secretions, which are used by the millipede to defend against predators, contain organic compounds including benzoquinone. When these secretions come into contact with skin, pigmentary changes resembling a burn or necrosis and irritation to the skin (pain, burning, itching) occur.^4,5

Millipedes typically are found in tropical and temperate regions worldwide, such as the Amazon rainforest, Southeast Asia, tropical areas of Africa, forests, grasslands, and gardens in North America and Europe.⁶ They also are found in every US state as well as Puerto Rico.¹ Millipedes are nocturnal, favor dark places, and can make their way into residential areas, including homes, basements, gardens, and yards.^2,6 Although millipede burns commonly are reported in tropical regions, we present a case in China.⁶A 33-year-old woman presented with purplish-red discoloration on all 5 toes on the left foot. The patient recounted that she discovered a millipede in her shoe earlier in the day, removed it, and crushed it with her bare foot. That night, while taking a bath, she noticed that the toes had turned purplish-red (Figure 1). The patient brought the crushed millipede with her to the emergency department where she sought treatment. The dermatologist confirmed that it was a millipede; however, the team was unable to determine the specific species because it had been crushed (Figure 2).

Physical examination of the affected toes showed a clear boundary and iodinelike staining. The patient did not report pain. The stained skin had a normal temperature, pulse, texture, and sensation. Dermoscopy revealed multiple black-brown patches on the toes (Figure 3). The pigmented area gradually faded over a 1-month period. Superficial damage to the toenail revealed evidence of black-brown pigmentation on both the nail and the skin underneath. The diagnosis in the dermoscopy report suggested exogenous pigmentation of the toes. The patient was advised that no treatment was needed and that the condition would resolve on its own. At 1-month follow-up, the patient’s toes had returned to their normal color (Figure 4).

The feet are common sites of millipede burns; other exposed areas, such as the arms, face, and eyes, also are potential sites of involvement.⁵ The cutaneous pigmentary changes seen on our patient’s foot were a result of the millipede’s defense mechanism—secreted toxic chemicals that stained the foot. It is important to note that the pigmentation was not associated with the death of the millipede, as the millipede was still alive upon initial contact with the patient’s foot in her shoe. 

When a patient presents with pigmentary changes, several conditions must be ruled out—notably acute arterial thrombosis. Patients with this condition will describe acute pain and weakness in the area of involvement. Physicians inspecting the area will note coldness and pallor in the affected limb as well as a diminished or absent pulse. In severe cases, the skin may exhibit a purplish-red appearance.⁵ Millipede burns also should be distinguished from bacterial endocarditis and cryoglobulinemia.⁷ All 3 conditions can manifest with redness, swelling, blisters, and purpuralike changes. Positive blood culture is an important diagnostic basis for bacterial endocarditis; in addition, routine blood tests will demonstrate a decrease in red blood cells and hemoglobin, and routine urinalysis may show proteinuria and microscopic hematuria. Patients with cryoglobulinemia will have a positive cryoglobulin assay, increased IgM, and often decreased complement.⁷ It also is worth noting that millipede burns might resemble child abuse in pediatric patients, necessitating further evaluation.⁵ 

It is unusual to see a millipede burn in nontropical regions. Therefore, the identification of our patient’s millipede burn was notable and serves as a reminder to keep this diagnosis in the differential when caring for patients with pigmentary changes. An accurate diagnosis hinges on being alert to a millipede exposure history and recognizing the clinical manifestations. For affected patients, it may be beneficial to recommend they advise friends and relatives to avoid skin contact with millipedes and most importantly to avoid stepping on them with bare feet.

To the Editor:

Millipedes do not have nearly as many feet as their name would suggest; most have fewer than 100.¹ They are not actually insects; they are a wormlike arthropod in the Diplopoda class. Generally these harmless animals can be a welcome resident in gardens because they break down decaying plant material and rejuvenate the soil.¹ However, they are less welcome in the home or underfoot because of what happens when these invertebrates are threatened or crushed.²

Millipedes, which typically have at least 30 pairs of legs, have 2 defense mechanisms: (1) body coiling to withstand external pressure, and (2) secretion of fluids with insecticidal properties from specialized glands distributed along their body.³ These secretions, which are used by the millipede to defend against predators, contain organic compounds including benzoquinone. When these secretions come into contact with skin, pigmentary changes resembling a burn or necrosis and irritation to the skin (pain, burning, itching) occur.^4,5

Millipedes typically are found in tropical and temperate regions worldwide, such as the Amazon rainforest, Southeast Asia, tropical areas of Africa, forests, grasslands, and gardens in North America and Europe.⁶ They also are found in every US state as well as Puerto Rico.¹ Millipedes are nocturnal, favor dark places, and can make their way into residential areas, including homes, basements, gardens, and yards.^2,6 Although millipede burns commonly are reported in tropical regions, we present a case in China.⁶A 33-year-old woman presented with purplish-red discoloration on all 5 toes on the left foot. The patient recounted that she discovered a millipede in her shoe earlier in the day, removed it, and crushed it with her bare foot. That night, while taking a bath, she noticed that the toes had turned purplish-red (Figure 1). The patient brought the crushed millipede with her to the emergency department where she sought treatment. The dermatologist confirmed that it was a millipede; however, the team was unable to determine the specific species because it had been crushed (Figure 2).

Physical examination of the affected toes showed a clear boundary and iodinelike staining. The patient did not report pain. The stained skin had a normal temperature, pulse, texture, and sensation. Dermoscopy revealed multiple black-brown patches on the toes (Figure 3). The pigmented area gradually faded over a 1-month period. Superficial damage to the toenail revealed evidence of black-brown pigmentation on both the nail and the skin underneath. The diagnosis in the dermoscopy report suggested exogenous pigmentation of the toes. The patient was advised that no treatment was needed and that the condition would resolve on its own. At 1-month follow-up, the patient’s toes had returned to their normal color (Figure 4).

The feet are common sites of millipede burns; other exposed areas, such as the arms, face, and eyes, also are potential sites of involvement.⁵ The cutaneous pigmentary changes seen on our patient’s foot were a result of the millipede’s defense mechanism—secreted toxic chemicals that stained the foot. It is important to note that the pigmentation was not associated with the death of the millipede, as the millipede was still alive upon initial contact with the patient’s foot in her shoe. 

When a patient presents with pigmentary changes, several conditions must be ruled out—notably acute arterial thrombosis. Patients with this condition will describe acute pain and weakness in the area of involvement. Physicians inspecting the area will note coldness and pallor in the affected limb as well as a diminished or absent pulse. In severe cases, the skin may exhibit a purplish-red appearance.⁵ Millipede burns also should be distinguished from bacterial endocarditis and cryoglobulinemia.⁷ All 3 conditions can manifest with redness, swelling, blisters, and purpuralike changes. Positive blood culture is an important diagnostic basis for bacterial endocarditis; in addition, routine blood tests will demonstrate a decrease in red blood cells and hemoglobin, and routine urinalysis may show proteinuria and microscopic hematuria. Patients with cryoglobulinemia will have a positive cryoglobulin assay, increased IgM, and often decreased complement.⁷ It also is worth noting that millipede burns might resemble child abuse in pediatric patients, necessitating further evaluation.⁵ 

It is unusual to see a millipede burn in nontropical regions. Therefore, the identification of our patient’s millipede burn was notable and serves as a reminder to keep this diagnosis in the differential when caring for patients with pigmentary changes. An accurate diagnosis hinges on being alert to a millipede exposure history and recognizing the clinical manifestations. For affected patients, it may be beneficial to recommend they advise friends and relatives to avoid skin contact with millipedes and most importantly to avoid stepping on them with bare feet.

THE DIAGNOSIS: Malignant Proliferating Trichilemmal Tumor

Biopsy revealed a squamous epithelium with cystic changes, trichilemmal differentiation, squamous eddy formation, keratinocyte atypia, focal necrotic changes, and a focus of atypical keratinocytes invading the dermis (Figure 1). Based on these findings, a diagnosis of malignant proliferating trichilemmal tumor (MPTT) was made.

Malignant proliferating trichilemmal tumor is a rare adnexal tumor that develops from the outer root sheath of the hair follicle. It often arises due to malignant transformation of pre-existing trichilemmal cysts, but some cases occur de novo.¹ Malignant transformation is thought to start from a trichilemmal cyst in an adenomatous histologic stage, progressing to a proliferating trichilemmal cyst (PTC) in an epitheliomatous phase, ultimately becoming carcinomatous with MPTT.^2-4 This transformation has been categorized into 3 morphologic groups to predict tumor behavior, including benign PTCs (curable by excision), low-grade malignant PTCs (minor risk for local recurrence), and high-grade malignant PTCs (risk for regional spread and metastasis with cytologic atypical features and potential for aggressive growth).¹

More commonly observed in women in the fourth to eighth decades of life, MPTT may manifest as a fast- growing, painless, solitary nodule or as a progressively enlarging nodule at the site of a previously stable, long-standing lesion. Malignant proliferating trichilemmal tumor manifests frequently on the scalp, face, or neck, but there are reports of MPTT manifesting on the trunk and even as multiple concurrent lesions.^1-4 The variability in clinical presentation and the potential to be mistaken for benign conditions makes excisional biopsy essential for diagnosis of MPTT. Histopathology classically demonstrates trichilemmal keratinization, a high mitotic index, and cellular atypia with invasion into the dermis.⁴ Malignant transformation frequently follows a prior history of trauma to the area or local inflammation.

Given the locally aggressive nature of MPTT, our patient was referred to a Mohs micrographic surgeon. While both wide excision with tumor-free margins and Mohs micrographic surgery are accepted surgical procedures for MPTT, there is no consensus in the literature on a standard treatment recommendation. Following surgery, close monitoring is needed for potential recurrence and metastases intracranially to the dura and muscles,⁵ as well as to the lungs.⁶ Further imaging using computed tomography or positron emission tomography can be ordered to rule out metastatic disease.⁴

Pilomatrixomas are benign neoplasms that arise from hair matrix cells and have been associated with catenin beta-1 gene mutations, as well as genetic syndromes and trauma.⁷ Clinically, pilomatrixomas manifest as solitary, firm, painless, slow-growing nodules that commonly are found in the head and neck region. This tumor has a slight predominance in women and occurs frequently in adolescent years. The overlying skin may appear normal or show grey-bluish discoloration.⁸ Histopathology shows basaloid cells resembling primitive hair matrix cells with an abrupt transition to shadow cells composed of transformed keratinocytes without nuclei and calcification.^7-8 This tumor can be differentiated by the presence of basaloid and shadow cells with calcification on histopathology, while MPTT will show atypical, mitotically active squamous cells with trichilemmal keratinization (Figure 2).

Proliferating trichilemmal cyst is a variant of trichilemmal cyst (TC) arising from the outer root sheath cells of the hair follicle. While TCs usually are slow growing and benign, the proliferating variant can be more aggressive with malignant potential. Patients often present with a solitary, well-circumscribed, rapidly growing nodule on the scalp. The lesion may be painful, and ulceration can occur, exposing the cystic contents. Histopathologically, PTCs resemble TCs with trichilemmal keratinization but also exhibit notable epithelial proliferation within the cystic space.⁹ While there can be considerable histopathologic overlap between PTC and MPTT—including extensive trichilemmal keratinization, variable atypia, and mitotic activity—PTC typically should not demonstrate invasion into the surrounding soft tissue or the degree of high-grade atypia, brisk mitoses, or necrosis seen in MPTT (eFigure 1).¹ Immunohistochemistry may help distinguish PTC from MPTT and squamous cell carcinoma (SCC).^10-11 The pattern of Ki-67 and p53 expression may be helpful with classification of PTC/MPTT into the 3 groups (benign, low-grade malignant, and high-grade malignant) proposed by Ye et al.¹ Other investigators have suggested that Ki-67 expression may correlate potential for recurrence and clinical prognosis.¹² Expression of CD34 (a marker that supports outer root sheath origin) might favor PTC/MPTT over SCC; however, cases of CD34- negative MPTT have been reported, particularly those with poorly differentiated histopathology.

Squamous cell carcinoma with cystic features is a histologic variant of SCC characterized by cystlike spaces containing malignant squamous epithelial cells.¹³ Squamous cell carcinoma with cystic features can manifest as a firm nodule with ulceration similar to MPTT or PTC but also can mimic a benign cyst.¹⁴ The diagnosis of invasive SCC with cystic features typically is straightforward and characterized by cords and nests of atypical keratinocytes extending into the dermis with areas of cystic architecture (eFigure 2). While both SCC with cystic features and MPTT may show cystic histopathologic architecture, MPTT typically shows areas of PTC, whereas SCC with cystic features lacks such areas.

Verrucous cysts refer to infundibular cysts or less commonly pilar cysts or hybrid pilar-epidermoid cysts that exhibit superimposed human papillomavirus (HPV) cytopathic changes. Clinically, a verrucous cyst manifests as a single, asymptomatic, slow-growing, firm lesion most commonly manifesting on the face and back. Histopathologically, the cyst wall may show acanthosis, papillomatosis, hypergranulosis with coarse keratohyalin granules, and koilocytic changes (eFigure 3). These histopathologic features are believed to be induced by secondary HPV infection. While HPV-related change, characterized by koilocytic alteration, papillomatosis, and verruciform hyperplasia, more commonly affects epidermal cysts, occasionally trichilemmal (pilar) cysts are involved. In these cases, verrucous cysts should be distinguished from MPTT. Verrucous cysts may contain rare normal mitotic figures, but do not contain atypical mitosis, marked cellular pleomorphism, or an infiltrating pattern similar to MPTT.¹⁵

THE DIAGNOSIS: Malignant Proliferating Trichilemmal Tumor

Biopsy revealed a squamous epithelium with cystic changes, trichilemmal differentiation, squamous eddy formation, keratinocyte atypia, focal necrotic changes, and a focus of atypical keratinocytes invading the dermis (Figure 1). Based on these findings, a diagnosis of malignant proliferating trichilemmal tumor (MPTT) was made.

Malignant proliferating trichilemmal tumor is a rare adnexal tumor that develops from the outer root sheath of the hair follicle. It often arises due to malignant transformation of pre-existing trichilemmal cysts, but some cases occur de novo.¹ Malignant transformation is thought to start from a trichilemmal cyst in an adenomatous histologic stage, progressing to a proliferating trichilemmal cyst (PTC) in an epitheliomatous phase, ultimately becoming carcinomatous with MPTT.^2-4 This transformation has been categorized into 3 morphologic groups to predict tumor behavior, including benign PTCs (curable by excision), low-grade malignant PTCs (minor risk for local recurrence), and high-grade malignant PTCs (risk for regional spread and metastasis with cytologic atypical features and potential for aggressive growth).¹

More commonly observed in women in the fourth to eighth decades of life, MPTT may manifest as a fast- growing, painless, solitary nodule or as a progressively enlarging nodule at the site of a previously stable, long-standing lesion. Malignant proliferating trichilemmal tumor manifests frequently on the scalp, face, or neck, but there are reports of MPTT manifesting on the trunk and even as multiple concurrent lesions.^1-4 The variability in clinical presentation and the potential to be mistaken for benign conditions makes excisional biopsy essential for diagnosis of MPTT. Histopathology classically demonstrates trichilemmal keratinization, a high mitotic index, and cellular atypia with invasion into the dermis.⁴ Malignant transformation frequently follows a prior history of trauma to the area or local inflammation.

Given the locally aggressive nature of MPTT, our patient was referred to a Mohs micrographic surgeon. While both wide excision with tumor-free margins and Mohs micrographic surgery are accepted surgical procedures for MPTT, there is no consensus in the literature on a standard treatment recommendation. Following surgery, close monitoring is needed for potential recurrence and metastases intracranially to the dura and muscles,⁵ as well as to the lungs.⁶ Further imaging using computed tomography or positron emission tomography can be ordered to rule out metastatic disease.⁴

Pilomatrixomas are benign neoplasms that arise from hair matrix cells and have been associated with catenin beta-1 gene mutations, as well as genetic syndromes and trauma.⁷ Clinically, pilomatrixomas manifest as solitary, firm, painless, slow-growing nodules that commonly are found in the head and neck region. This tumor has a slight predominance in women and occurs frequently in adolescent years. The overlying skin may appear normal or show grey-bluish discoloration.⁸ Histopathology shows basaloid cells resembling primitive hair matrix cells with an abrupt transition to shadow cells composed of transformed keratinocytes without nuclei and calcification.^7-8 This tumor can be differentiated by the presence of basaloid and shadow cells with calcification on histopathology, while MPTT will show atypical, mitotically active squamous cells with trichilemmal keratinization (Figure 2).

Proliferating trichilemmal cyst is a variant of trichilemmal cyst (TC) arising from the outer root sheath cells of the hair follicle. While TCs usually are slow growing and benign, the proliferating variant can be more aggressive with malignant potential. Patients often present with a solitary, well-circumscribed, rapidly growing nodule on the scalp. The lesion may be painful, and ulceration can occur, exposing the cystic contents. Histopathologically, PTCs resemble TCs with trichilemmal keratinization but also exhibit notable epithelial proliferation within the cystic space.⁹ While there can be considerable histopathologic overlap between PTC and MPTT—including extensive trichilemmal keratinization, variable atypia, and mitotic activity—PTC typically should not demonstrate invasion into the surrounding soft tissue or the degree of high-grade atypia, brisk mitoses, or necrosis seen in MPTT (eFigure 1).¹ Immunohistochemistry may help distinguish PTC from MPTT and squamous cell carcinoma (SCC).^10-11 The pattern of Ki-67 and p53 expression may be helpful with classification of PTC/MPTT into the 3 groups (benign, low-grade malignant, and high-grade malignant) proposed by Ye et al.¹ Other investigators have suggested that Ki-67 expression may correlate potential for recurrence and clinical prognosis.¹² Expression of CD34 (a marker that supports outer root sheath origin) might favor PTC/MPTT over SCC; however, cases of CD34- negative MPTT have been reported, particularly those with poorly differentiated histopathology.

Squamous cell carcinoma with cystic features is a histologic variant of SCC characterized by cystlike spaces containing malignant squamous epithelial cells.¹³ Squamous cell carcinoma with cystic features can manifest as a firm nodule with ulceration similar to MPTT or PTC but also can mimic a benign cyst.¹⁴ The diagnosis of invasive SCC with cystic features typically is straightforward and characterized by cords and nests of atypical keratinocytes extending into the dermis with areas of cystic architecture (eFigure 2). While both SCC with cystic features and MPTT may show cystic histopathologic architecture, MPTT typically shows areas of PTC, whereas SCC with cystic features lacks such areas.

Verrucous cysts refer to infundibular cysts or less commonly pilar cysts or hybrid pilar-epidermoid cysts that exhibit superimposed human papillomavirus (HPV) cytopathic changes. Clinically, a verrucous cyst manifests as a single, asymptomatic, slow-growing, firm lesion most commonly manifesting on the face and back. Histopathologically, the cyst wall may show acanthosis, papillomatosis, hypergranulosis with coarse keratohyalin granules, and koilocytic changes (eFigure 3). These histopathologic features are believed to be induced by secondary HPV infection. While HPV-related change, characterized by koilocytic alteration, papillomatosis, and verruciform hyperplasia, more commonly affects epidermal cysts, occasionally trichilemmal (pilar) cysts are involved. In these cases, verrucous cysts should be distinguished from MPTT. Verrucous cysts may contain rare normal mitotic figures, but do not contain atypical mitosis, marked cellular pleomorphism, or an infiltrating pattern similar to MPTT.¹⁵

THE DIAGNOSIS: Malignant Proliferating Trichilemmal Tumor

Biopsy revealed a squamous epithelium with cystic changes, trichilemmal differentiation, squamous eddy formation, keratinocyte atypia, focal necrotic changes, and a focus of atypical keratinocytes invading the dermis (Figure 1). Based on these findings, a diagnosis of malignant proliferating trichilemmal tumor (MPTT) was made.

Malignant proliferating trichilemmal tumor is a rare adnexal tumor that develops from the outer root sheath of the hair follicle. It often arises due to malignant transformation of pre-existing trichilemmal cysts, but some cases occur de novo.¹ Malignant transformation is thought to start from a trichilemmal cyst in an adenomatous histologic stage, progressing to a proliferating trichilemmal cyst (PTC) in an epitheliomatous phase, ultimately becoming carcinomatous with MPTT.^2-4 This transformation has been categorized into 3 morphologic groups to predict tumor behavior, including benign PTCs (curable by excision), low-grade malignant PTCs (minor risk for local recurrence), and high-grade malignant PTCs (risk for regional spread and metastasis with cytologic atypical features and potential for aggressive growth).¹

More commonly observed in women in the fourth to eighth decades of life, MPTT may manifest as a fast- growing, painless, solitary nodule or as a progressively enlarging nodule at the site of a previously stable, long-standing lesion. Malignant proliferating trichilemmal tumor manifests frequently on the scalp, face, or neck, but there are reports of MPTT manifesting on the trunk and even as multiple concurrent lesions.^1-4 The variability in clinical presentation and the potential to be mistaken for benign conditions makes excisional biopsy essential for diagnosis of MPTT. Histopathology classically demonstrates trichilemmal keratinization, a high mitotic index, and cellular atypia with invasion into the dermis.⁴ Malignant transformation frequently follows a prior history of trauma to the area or local inflammation.

Given the locally aggressive nature of MPTT, our patient was referred to a Mohs micrographic surgeon. While both wide excision with tumor-free margins and Mohs micrographic surgery are accepted surgical procedures for MPTT, there is no consensus in the literature on a standard treatment recommendation. Following surgery, close monitoring is needed for potential recurrence and metastases intracranially to the dura and muscles,⁵ as well as to the lungs.⁶ Further imaging using computed tomography or positron emission tomography can be ordered to rule out metastatic disease.⁴

Pilomatrixomas are benign neoplasms that arise from hair matrix cells and have been associated with catenin beta-1 gene mutations, as well as genetic syndromes and trauma.⁷ Clinically, pilomatrixomas manifest as solitary, firm, painless, slow-growing nodules that commonly are found in the head and neck region. This tumor has a slight predominance in women and occurs frequently in adolescent years. The overlying skin may appear normal or show grey-bluish discoloration.⁸ Histopathology shows basaloid cells resembling primitive hair matrix cells with an abrupt transition to shadow cells composed of transformed keratinocytes without nuclei and calcification.^7-8 This tumor can be differentiated by the presence of basaloid and shadow cells with calcification on histopathology, while MPTT will show atypical, mitotically active squamous cells with trichilemmal keratinization (Figure 2).

Proliferating trichilemmal cyst is a variant of trichilemmal cyst (TC) arising from the outer root sheath cells of the hair follicle. While TCs usually are slow growing and benign, the proliferating variant can be more aggressive with malignant potential. Patients often present with a solitary, well-circumscribed, rapidly growing nodule on the scalp. The lesion may be painful, and ulceration can occur, exposing the cystic contents. Histopathologically, PTCs resemble TCs with trichilemmal keratinization but also exhibit notable epithelial proliferation within the cystic space.⁹ While there can be considerable histopathologic overlap between PTC and MPTT—including extensive trichilemmal keratinization, variable atypia, and mitotic activity—PTC typically should not demonstrate invasion into the surrounding soft tissue or the degree of high-grade atypia, brisk mitoses, or necrosis seen in MPTT (eFigure 1).¹ Immunohistochemistry may help distinguish PTC from MPTT and squamous cell carcinoma (SCC).^10-11 The pattern of Ki-67 and p53 expression may be helpful with classification of PTC/MPTT into the 3 groups (benign, low-grade malignant, and high-grade malignant) proposed by Ye et al.¹ Other investigators have suggested that Ki-67 expression may correlate potential for recurrence and clinical prognosis.¹² Expression of CD34 (a marker that supports outer root sheath origin) might favor PTC/MPTT over SCC; however, cases of CD34- negative MPTT have been reported, particularly those with poorly differentiated histopathology.

Squamous cell carcinoma with cystic features is a histologic variant of SCC characterized by cystlike spaces containing malignant squamous epithelial cells.¹³ Squamous cell carcinoma with cystic features can manifest as a firm nodule with ulceration similar to MPTT or PTC but also can mimic a benign cyst.¹⁴ The diagnosis of invasive SCC with cystic features typically is straightforward and characterized by cords and nests of atypical keratinocytes extending into the dermis with areas of cystic architecture (eFigure 2). While both SCC with cystic features and MPTT may show cystic histopathologic architecture, MPTT typically shows areas of PTC, whereas SCC with cystic features lacks such areas.

Verrucous cysts refer to infundibular cysts or less commonly pilar cysts or hybrid pilar-epidermoid cysts that exhibit superimposed human papillomavirus (HPV) cytopathic changes. Clinically, a verrucous cyst manifests as a single, asymptomatic, slow-growing, firm lesion most commonly manifesting on the face and back. Histopathologically, the cyst wall may show acanthosis, papillomatosis, hypergranulosis with coarse keratohyalin granules, and koilocytic changes (eFigure 3). These histopathologic features are believed to be induced by secondary HPV infection. While HPV-related change, characterized by koilocytic alteration, papillomatosis, and verruciform hyperplasia, more commonly affects epidermal cysts, occasionally trichilemmal (pilar) cysts are involved. In these cases, verrucous cysts should be distinguished from MPTT. Verrucous cysts may contain rare normal mitotic figures, but do not contain atypical mitosis, marked cellular pleomorphism, or an infiltrating pattern similar to MPTT.¹⁵

Dermatologists have long relied on oral antibiotics to manage moderate to severe acne^1-4; however, it is critical to reassess how these medications are used in clinical practice as concerns about antibiotic resistance grow.⁵ The question is not whether antibiotics are effective for acne treatment—we know they are—but how to optimize their use to balance clinical benefit with responsible prescribing. Resistance in Cutibacterium acnes has been well documented in laboratory settings, but clinical treatment failure due to resistance remains rare and difficult to quantify.^6,7 Still, minimizing unnecessary exposure is good clinical practice. Whether antibiotic resistance ultimately proves to drive clinical failure or remains largely theoretical, stewardship safeguards future treatment options.

In this article, we present a practical, expert-based framework aligned with American Academy of Dermatology (AAD) guidelines to support responsible antibiotic use in acne management. Seven prescribing principles are outlined to help clinicians maintain efficacy while minimizing resistance risk. Mechanisms of resistance in C acnes and broader microbiome impacts also are discussed.

MECHANISMS OF RESISTANCE IN ACNE THERAPY

Antibiotic resistance in acne primarily involves C acnes and arises through selective pressure from prolonged or subtherapeutic antibiotic exposure. Resistance mechanisms include point mutations in ribosomal binding sites, leading to decreased binding affinity for tetracyclines and macrolides as well as efflux pump activation and biofilm formation.^8,9 Over time, resistant strains may proliferate and outcompete susceptible populations, potentially contributing to reduced clinical efficacy. Importantly, the use of broad-spectrum antibiotics may disrupt the skin and gut microbiota, promoting resistance among nontarget organisms.⁵ These concerns underscore the importance of limiting antibiotic use to appropriate indications, combining antibiotics with adjunctive nonantibiotic therapies, and avoiding monotherapy.

PRESCRIBING PRINCIPLES FOR RESPONSIBLE ORAL ANTIBIOTIC USE IN ACNE

The following principles are derived from our clinical experience and are aligned with AAD guidelines on acne treatment.¹⁰ This practical framework supports safe, effective, and streamlined prescribing.

Reserve Oral Antibiotics for Appropriate Cases

Oral antibiotics should be considered for patients with moderate to severe inflammatory acne when rapid anti-inflammatory control is needed. They are not indicated for comedonal or mild papulopustular acne. Before initiating treatment, clinicians should weigh the potential benefits against the risks associated with antibiotic exposure, including resistance and microbiome disruption.

Combine Oral Antibiotics With Topical Retinoids

Oral antibiotics should not be used as monotherapy. Topical retinoids should be initiated concurrently with oral antibiotics to maximize anti-inflammatory benefit, support transition to maintenance therapy, and reduce risk for resistance.

Consider Adding an Adjunctive Topical Antimicrobial Agent

Adjunctive topical antimicrobials can help reduce bacterial load. Benzoyl peroxide remains a first-line option due to its bactericidal activity and lack of resistance induction; however, recent product recalls involving benzene contamination may have raised safety concerns among some clinicians and patients.^11,12 While no definitive harm has been established, alternative topical agents approved by the US Food and Drug Administration (eg, azelaic acid) may be used based on shared decision-making, tolerability, cost, access, and patient preference. Use of topical antibiotics (eg, clindamycin, erythromycin) as monotherapy is discouraged due to their higher resistance potential, which is consistent with AAD guidance.

Limit Treatment Duration to 12 Weeks or Less

Antibiotic use should be time limited, with discontinuation ideally within 8 to 12 weeks as clinical improvement is demonstrated. Repeated or prolonged courses should be avoided to minimize risk for resistance.

Simplify Treatment Regimens to Enhance Adherence

Regimen simplicity improves adherence, especially in adolescents. A two-agent regimen of an oral antibiotic and a topical retinoid typically is sufficient during the induction phase.^13,14

Select Narrower-Spectrum Antibiotics When Feasible

Using a narrower-spectrum antibiotic may help minimize disruption to nontarget microbiota.^15,16 Sarecycline has shown narrower in vitro activity within the tetracycline class,^17,18 though clinical decisions should be informed by access, availability, and cost. Regardless of the agent used (eg, doxycycline, minocycline, or sarecycline), all antibiotics should be used judiciously and for the shortest effective duration.

Use Systemic Nonantibiotic Therapies When Appropriate

If there is inadequate response to oral antibiotic therapy, consider switching to systemic nonantibiotic options. Hormonal therapy may be appropriate for select female patients. Oral isotretinoin should be considered for patients with severe, recalcitrant, or scarring acne. Cycling between antibiotic classes without clear benefit is discouraged.

FINAL THOUGHTS

Oral antibiotics remain a foundational component in the management of moderate to severe acne; however, their use must be intentional, time limited, and guided by best practices to minimize the emergence of antimicrobial resistance. By adhering to the prescribing principles we have outlined here, which are rooted in clinical expertise and consistent with AAD guidelines, dermatologists can preserve antibiotic efficacy, optimize patient outcomes, and reduce long-term microbiologic risks. Stewardship is not about withholding treatment; it is about optimizing care today to protect treatment options for tomorrow.

Dermatologists have long relied on oral antibiotics to manage moderate to severe acne^1-4; however, it is critical to reassess how these medications are used in clinical practice as concerns about antibiotic resistance grow.⁵ The question is not whether antibiotics are effective for acne treatment—we know they are—but how to optimize their use to balance clinical benefit with responsible prescribing. Resistance in Cutibacterium acnes has been well documented in laboratory settings, but clinical treatment failure due to resistance remains rare and difficult to quantify.^6,7 Still, minimizing unnecessary exposure is good clinical practice. Whether antibiotic resistance ultimately proves to drive clinical failure or remains largely theoretical, stewardship safeguards future treatment options.

In this article, we present a practical, expert-based framework aligned with American Academy of Dermatology (AAD) guidelines to support responsible antibiotic use in acne management. Seven prescribing principles are outlined to help clinicians maintain efficacy while minimizing resistance risk. Mechanisms of resistance in C acnes and broader microbiome impacts also are discussed.

MECHANISMS OF RESISTANCE IN ACNE THERAPY

Antibiotic resistance in acne primarily involves C acnes and arises through selective pressure from prolonged or subtherapeutic antibiotic exposure. Resistance mechanisms include point mutations in ribosomal binding sites, leading to decreased binding affinity for tetracyclines and macrolides as well as efflux pump activation and biofilm formation.^8,9 Over time, resistant strains may proliferate and outcompete susceptible populations, potentially contributing to reduced clinical efficacy. Importantly, the use of broad-spectrum antibiotics may disrupt the skin and gut microbiota, promoting resistance among nontarget organisms.⁵ These concerns underscore the importance of limiting antibiotic use to appropriate indications, combining antibiotics with adjunctive nonantibiotic therapies, and avoiding monotherapy.

PRESCRIBING PRINCIPLES FOR RESPONSIBLE ORAL ANTIBIOTIC USE IN ACNE

The following principles are derived from our clinical experience and are aligned with AAD guidelines on acne treatment.¹⁰ This practical framework supports safe, effective, and streamlined prescribing.

Reserve Oral Antibiotics for Appropriate Cases

Oral antibiotics should be considered for patients with moderate to severe inflammatory acne when rapid anti-inflammatory control is needed. They are not indicated for comedonal or mild papulopustular acne. Before initiating treatment, clinicians should weigh the potential benefits against the risks associated with antibiotic exposure, including resistance and microbiome disruption.

Combine Oral Antibiotics With Topical Retinoids

Oral antibiotics should not be used as monotherapy. Topical retinoids should be initiated concurrently with oral antibiotics to maximize anti-inflammatory benefit, support transition to maintenance therapy, and reduce risk for resistance.

Consider Adding an Adjunctive Topical Antimicrobial Agent

Adjunctive topical antimicrobials can help reduce bacterial load. Benzoyl peroxide remains a first-line option due to its bactericidal activity and lack of resistance induction; however, recent product recalls involving benzene contamination may have raised safety concerns among some clinicians and patients.^11,12 While no definitive harm has been established, alternative topical agents approved by the US Food and Drug Administration (eg, azelaic acid) may be used based on shared decision-making, tolerability, cost, access, and patient preference. Use of topical antibiotics (eg, clindamycin, erythromycin) as monotherapy is discouraged due to their higher resistance potential, which is consistent with AAD guidance.

Limit Treatment Duration to 12 Weeks or Less

Antibiotic use should be time limited, with discontinuation ideally within 8 to 12 weeks as clinical improvement is demonstrated. Repeated or prolonged courses should be avoided to minimize risk for resistance.

Simplify Treatment Regimens to Enhance Adherence

Regimen simplicity improves adherence, especially in adolescents. A two-agent regimen of an oral antibiotic and a topical retinoid typically is sufficient during the induction phase.^13,14

Select Narrower-Spectrum Antibiotics When Feasible

Using a narrower-spectrum antibiotic may help minimize disruption to nontarget microbiota.^15,16 Sarecycline has shown narrower in vitro activity within the tetracycline class,^17,18 though clinical decisions should be informed by access, availability, and cost. Regardless of the agent used (eg, doxycycline, minocycline, or sarecycline), all antibiotics should be used judiciously and for the shortest effective duration.

Use Systemic Nonantibiotic Therapies When Appropriate

If there is inadequate response to oral antibiotic therapy, consider switching to systemic nonantibiotic options. Hormonal therapy may be appropriate for select female patients. Oral isotretinoin should be considered for patients with severe, recalcitrant, or scarring acne. Cycling between antibiotic classes without clear benefit is discouraged.

FINAL THOUGHTS

Oral antibiotics remain a foundational component in the management of moderate to severe acne; however, their use must be intentional, time limited, and guided by best practices to minimize the emergence of antimicrobial resistance. By adhering to the prescribing principles we have outlined here, which are rooted in clinical expertise and consistent with AAD guidelines, dermatologists can preserve antibiotic efficacy, optimize patient outcomes, and reduce long-term microbiologic risks. Stewardship is not about withholding treatment; it is about optimizing care today to protect treatment options for tomorrow.

Dermatologists have long relied on oral antibiotics to manage moderate to severe acne^1-4; however, it is critical to reassess how these medications are used in clinical practice as concerns about antibiotic resistance grow.⁵ The question is not whether antibiotics are effective for acne treatment—we know they are—but how to optimize their use to balance clinical benefit with responsible prescribing. Resistance in Cutibacterium acnes has been well documented in laboratory settings, but clinical treatment failure due to resistance remains rare and difficult to quantify.^6,7 Still, minimizing unnecessary exposure is good clinical practice. Whether antibiotic resistance ultimately proves to drive clinical failure or remains largely theoretical, stewardship safeguards future treatment options.

In this article, we present a practical, expert-based framework aligned with American Academy of Dermatology (AAD) guidelines to support responsible antibiotic use in acne management. Seven prescribing principles are outlined to help clinicians maintain efficacy while minimizing resistance risk. Mechanisms of resistance in C acnes and broader microbiome impacts also are discussed.

MECHANISMS OF RESISTANCE IN ACNE THERAPY

Antibiotic resistance in acne primarily involves C acnes and arises through selective pressure from prolonged or subtherapeutic antibiotic exposure. Resistance mechanisms include point mutations in ribosomal binding sites, leading to decreased binding affinity for tetracyclines and macrolides as well as efflux pump activation and biofilm formation.^8,9 Over time, resistant strains may proliferate and outcompete susceptible populations, potentially contributing to reduced clinical efficacy. Importantly, the use of broad-spectrum antibiotics may disrupt the skin and gut microbiota, promoting resistance among nontarget organisms.⁵ These concerns underscore the importance of limiting antibiotic use to appropriate indications, combining antibiotics with adjunctive nonantibiotic therapies, and avoiding monotherapy.

PRESCRIBING PRINCIPLES FOR RESPONSIBLE ORAL ANTIBIOTIC USE IN ACNE

The following principles are derived from our clinical experience and are aligned with AAD guidelines on acne treatment.¹⁰ This practical framework supports safe, effective, and streamlined prescribing.

Reserve Oral Antibiotics for Appropriate Cases

Oral antibiotics should be considered for patients with moderate to severe inflammatory acne when rapid anti-inflammatory control is needed. They are not indicated for comedonal or mild papulopustular acne. Before initiating treatment, clinicians should weigh the potential benefits against the risks associated with antibiotic exposure, including resistance and microbiome disruption.

Combine Oral Antibiotics With Topical Retinoids

Oral antibiotics should not be used as monotherapy. Topical retinoids should be initiated concurrently with oral antibiotics to maximize anti-inflammatory benefit, support transition to maintenance therapy, and reduce risk for resistance.

Consider Adding an Adjunctive Topical Antimicrobial Agent

Adjunctive topical antimicrobials can help reduce bacterial load. Benzoyl peroxide remains a first-line option due to its bactericidal activity and lack of resistance induction; however, recent product recalls involving benzene contamination may have raised safety concerns among some clinicians and patients.^11,12 While no definitive harm has been established, alternative topical agents approved by the US Food and Drug Administration (eg, azelaic acid) may be used based on shared decision-making, tolerability, cost, access, and patient preference. Use of topical antibiotics (eg, clindamycin, erythromycin) as monotherapy is discouraged due to their higher resistance potential, which is consistent with AAD guidance.

Limit Treatment Duration to 12 Weeks or Less

Antibiotic use should be time limited, with discontinuation ideally within 8 to 12 weeks as clinical improvement is demonstrated. Repeated or prolonged courses should be avoided to minimize risk for resistance.

Simplify Treatment Regimens to Enhance Adherence

Regimen simplicity improves adherence, especially in adolescents. A two-agent regimen of an oral antibiotic and a topical retinoid typically is sufficient during the induction phase.^13,14

Select Narrower-Spectrum Antibiotics When Feasible

Using a narrower-spectrum antibiotic may help minimize disruption to nontarget microbiota.^15,16 Sarecycline has shown narrower in vitro activity within the tetracycline class,^17,18 though clinical decisions should be informed by access, availability, and cost. Regardless of the agent used (eg, doxycycline, minocycline, or sarecycline), all antibiotics should be used judiciously and for the shortest effective duration.

Use Systemic Nonantibiotic Therapies When Appropriate

If there is inadequate response to oral antibiotic therapy, consider switching to systemic nonantibiotic options. Hormonal therapy may be appropriate for select female patients. Oral isotretinoin should be considered for patients with severe, recalcitrant, or scarring acne. Cycling between antibiotic classes without clear benefit is discouraged.

FINAL THOUGHTS

Oral antibiotics remain a foundational component in the management of moderate to severe acne; however, their use must be intentional, time limited, and guided by best practices to minimize the emergence of antimicrobial resistance. By adhering to the prescribing principles we have outlined here, which are rooted in clinical expertise and consistent with AAD guidelines, dermatologists can preserve antibiotic efficacy, optimize patient outcomes, and reduce long-term microbiologic risks. Stewardship is not about withholding treatment; it is about optimizing care today to protect treatment options for tomorrow.

Practice Gap

Lipoatrophy associated with HIV is characterized by loss of adipose tissue in distinctive anatomic areas, most prominently in the nasolabial folds, temples, and medial cheeks.¹ This adverse effect further stigmatizes patients with HIV, and its association with highly active antiretroviral therapy (HAART)—specifically protease inhibitors—may contribute to suboptimal adherence to treatment.^1,2 Moreover, this finding is not uncommon: The prevalence of facial lipoatrophy after receiving HAART can range from 28% in patients treated for less than 5 years to 54% in those treated for a median of 10 years.² The associated stigma, notable decrease in quality of life, and known affiliation as an adverse effect of HAART make correction of facial lipoatrophy in patients with HIV an important management option.

Poly-L-lactic acid is approved by the US Food and Drug Administration for addressing fat loss due to HAART in patients with HIV.^2,3 When used as a dermal filler for correction of facial lipoatrophy, PLLA is well tolerated and has been shown to improve quality of life.^2,3 Poly-L-lactic acid is available for clinical use as microparticles of lyophilized alpha hydroxy acid polymers. Once injected (after the carrier substance is absorbed), PLLA induces an inflammatory response that ultimately leads to the production of new collagen.³ Unfortunately, PLLA microparticles often obstruct needles and make the product difficult to use, potentially hindering effective injection; thus, it is in the best interest of the patient to mitigate needle obstruction during this procedure. In this article, we describe a simple and effective way to mitigate this problem by utilizing a water bath to warm the filler prior to injection.

Technique

The required supplies include a thermostatic water bath, reconstituted PLLA, a syringe, and a 26-gauge injection needle. Because laboratory-grade heated water baths typically cost between $300 and $3000,⁴ we recommend using a more affordable, commercially available thermostatic water bath (eg, baby bottle warmer)(Figure 1) to warm the filler prior to injection, as the optimal temperature for this technique can still be achieved while remaining cost effective. Vials of PLLA reconstituted with 7 mL of sterile water and 2 mL lidocaine hydrochloride 1% should be labeled with the date of reconstitution and manually agitated for 30 seconds. The reconstituted product should be stored for 24 hours to ensure even suspension and powder saturation.⁵ On the day of the procedure, the vial should be placed into the water bath (heated to 100 °C) for 10 minutes prior to injection (Figure 2) and agitated again immediately before withdrawal into the syringe. The clinician then should sterilize the rubber top and draw the product from the warmed vial using the same size needle that will be used for injection. Although a larger gauge needle may make drawing up the product easier in typical practice, drawing and injecting with the same gauge needle helps prevent larger particles from clogging a smaller injection needle. Using a 26-gauge injection needle for withdrawal further reduces clogging by serving as a filter to prevent larger product particles from entering the injection syringe. The vials of PLLA can be kept in the water bath throughout the procedure between uses to keep the filler at a consistent temperature.

Practice Implications

Although many clinicians reduce needle obstructions by warming PLLA before injection, a published protocol currently is not available. One consideration when utilizing this technique is the limited data on the clinical stability and efficacy of PLLA at varying temperatures. Two studies recommend bringing the reconstituted vial to room temperature prior to injection, while others have documented an endothermic melting point in the range of 120 °C to 180 °C for PLLA, which lies well above the physiologic temperature readily achievable by baby bottle warmers.^6,7 Easily accessible bottle warmers can maintain the suspension at approximately 100 °C, keeping it in its crystalline polymer form and preventing melting. With this technique, the authors observed an improvement in efficacy due to fewer clogged needles, resulting in the delivery of more filler to the patient. In addition to comparable clinical results to not warming the product, our experience has shown that warming the PLLA prior to injection is not associated with increased patient discomfort and is well tolerated. Furthermore, patients experience less bruising and bleeding, as fewer needle sticks are necessary. This combination of a consistently heated filler with the added benefit of needle filtration yields dramatically fewer needle obstructions, fewer needle sticks, and increased patient satisfaction, improving the experience of patients with HIV-associated lipoatrophy seeking correction.

Practice Gap

Lipoatrophy associated with HIV is characterized by loss of adipose tissue in distinctive anatomic areas, most prominently in the nasolabial folds, temples, and medial cheeks.¹ This adverse effect further stigmatizes patients with HIV, and its association with highly active antiretroviral therapy (HAART)—specifically protease inhibitors—may contribute to suboptimal adherence to treatment.^1,2 Moreover, this finding is not uncommon: The prevalence of facial lipoatrophy after receiving HAART can range from 28% in patients treated for less than 5 years to 54% in those treated for a median of 10 years.² The associated stigma, notable decrease in quality of life, and known affiliation as an adverse effect of HAART make correction of facial lipoatrophy in patients with HIV an important management option.

Poly-L-lactic acid is approved by the US Food and Drug Administration for addressing fat loss due to HAART in patients with HIV.^2,3 When used as a dermal filler for correction of facial lipoatrophy, PLLA is well tolerated and has been shown to improve quality of life.^2,3 Poly-L-lactic acid is available for clinical use as microparticles of lyophilized alpha hydroxy acid polymers. Once injected (after the carrier substance is absorbed), PLLA induces an inflammatory response that ultimately leads to the production of new collagen.³ Unfortunately, PLLA microparticles often obstruct needles and make the product difficult to use, potentially hindering effective injection; thus, it is in the best interest of the patient to mitigate needle obstruction during this procedure. In this article, we describe a simple and effective way to mitigate this problem by utilizing a water bath to warm the filler prior to injection.

Technique

The required supplies include a thermostatic water bath, reconstituted PLLA, a syringe, and a 26-gauge injection needle. Because laboratory-grade heated water baths typically cost between $300 and $3000,⁴ we recommend using a more affordable, commercially available thermostatic water bath (eg, baby bottle warmer)(Figure 1) to warm the filler prior to injection, as the optimal temperature for this technique can still be achieved while remaining cost effective. Vials of PLLA reconstituted with 7 mL of sterile water and 2 mL lidocaine hydrochloride 1% should be labeled with the date of reconstitution and manually agitated for 30 seconds. The reconstituted product should be stored for 24 hours to ensure even suspension and powder saturation.⁵ On the day of the procedure, the vial should be placed into the water bath (heated to 100 °C) for 10 minutes prior to injection (Figure 2) and agitated again immediately before withdrawal into the syringe. The clinician then should sterilize the rubber top and draw the product from the warmed vial using the same size needle that will be used for injection. Although a larger gauge needle may make drawing up the product easier in typical practice, drawing and injecting with the same gauge needle helps prevent larger particles from clogging a smaller injection needle. Using a 26-gauge injection needle for withdrawal further reduces clogging by serving as a filter to prevent larger product particles from entering the injection syringe. The vials of PLLA can be kept in the water bath throughout the procedure between uses to keep the filler at a consistent temperature.

Practice Implications

Although many clinicians reduce needle obstructions by warming PLLA before injection, a published protocol currently is not available. One consideration when utilizing this technique is the limited data on the clinical stability and efficacy of PLLA at varying temperatures. Two studies recommend bringing the reconstituted vial to room temperature prior to injection, while others have documented an endothermic melting point in the range of 120 °C to 180 °C for PLLA, which lies well above the physiologic temperature readily achievable by baby bottle warmers.^6,7 Easily accessible bottle warmers can maintain the suspension at approximately 100 °C, keeping it in its crystalline polymer form and preventing melting. With this technique, the authors observed an improvement in efficacy due to fewer clogged needles, resulting in the delivery of more filler to the patient. In addition to comparable clinical results to not warming the product, our experience has shown that warming the PLLA prior to injection is not associated with increased patient discomfort and is well tolerated. Furthermore, patients experience less bruising and bleeding, as fewer needle sticks are necessary. This combination of a consistently heated filler with the added benefit of needle filtration yields dramatically fewer needle obstructions, fewer needle sticks, and increased patient satisfaction, improving the experience of patients with HIV-associated lipoatrophy seeking correction.

Practice Gap

Lipoatrophy associated with HIV is characterized by loss of adipose tissue in distinctive anatomic areas, most prominently in the nasolabial folds, temples, and medial cheeks.¹ This adverse effect further stigmatizes patients with HIV, and its association with highly active antiretroviral therapy (HAART)—specifically protease inhibitors—may contribute to suboptimal adherence to treatment.^1,2 Moreover, this finding is not uncommon: The prevalence of facial lipoatrophy after receiving HAART can range from 28% in patients treated for less than 5 years to 54% in those treated for a median of 10 years.² The associated stigma, notable decrease in quality of life, and known affiliation as an adverse effect of HAART make correction of facial lipoatrophy in patients with HIV an important management option.

Poly-L-lactic acid is approved by the US Food and Drug Administration for addressing fat loss due to HAART in patients with HIV.^2,3 When used as a dermal filler for correction of facial lipoatrophy, PLLA is well tolerated and has been shown to improve quality of life.^2,3 Poly-L-lactic acid is available for clinical use as microparticles of lyophilized alpha hydroxy acid polymers. Once injected (after the carrier substance is absorbed), PLLA induces an inflammatory response that ultimately leads to the production of new collagen.³ Unfortunately, PLLA microparticles often obstruct needles and make the product difficult to use, potentially hindering effective injection; thus, it is in the best interest of the patient to mitigate needle obstruction during this procedure. In this article, we describe a simple and effective way to mitigate this problem by utilizing a water bath to warm the filler prior to injection.

Technique

The required supplies include a thermostatic water bath, reconstituted PLLA, a syringe, and a 26-gauge injection needle. Because laboratory-grade heated water baths typically cost between $300 and $3000,⁴ we recommend using a more affordable, commercially available thermostatic water bath (eg, baby bottle warmer)(Figure 1) to warm the filler prior to injection, as the optimal temperature for this technique can still be achieved while remaining cost effective. Vials of PLLA reconstituted with 7 mL of sterile water and 2 mL lidocaine hydrochloride 1% should be labeled with the date of reconstitution and manually agitated for 30 seconds. The reconstituted product should be stored for 24 hours to ensure even suspension and powder saturation.⁵ On the day of the procedure, the vial should be placed into the water bath (heated to 100 °C) for 10 minutes prior to injection (Figure 2) and agitated again immediately before withdrawal into the syringe. The clinician then should sterilize the rubber top and draw the product from the warmed vial using the same size needle that will be used for injection. Although a larger gauge needle may make drawing up the product easier in typical practice, drawing and injecting with the same gauge needle helps prevent larger particles from clogging a smaller injection needle. Using a 26-gauge injection needle for withdrawal further reduces clogging by serving as a filter to prevent larger product particles from entering the injection syringe. The vials of PLLA can be kept in the water bath throughout the procedure between uses to keep the filler at a consistent temperature.

Practice Implications

Although many clinicians reduce needle obstructions by warming PLLA before injection, a published protocol currently is not available. One consideration when utilizing this technique is the limited data on the clinical stability and efficacy of PLLA at varying temperatures. Two studies recommend bringing the reconstituted vial to room temperature prior to injection, while others have documented an endothermic melting point in the range of 120 °C to 180 °C for PLLA, which lies well above the physiologic temperature readily achievable by baby bottle warmers.^6,7 Easily accessible bottle warmers can maintain the suspension at approximately 100 °C, keeping it in its crystalline polymer form and preventing melting. With this technique, the authors observed an improvement in efficacy due to fewer clogged needles, resulting in the delivery of more filler to the patient. In addition to comparable clinical results to not warming the product, our experience has shown that warming the PLLA prior to injection is not associated with increased patient discomfort and is well tolerated. Furthermore, patients experience less bruising and bleeding, as fewer needle sticks are necessary. This combination of a consistently heated filler with the added benefit of needle filtration yields dramatically fewer needle obstructions, fewer needle sticks, and increased patient satisfaction, improving the experience of patients with HIV-associated lipoatrophy seeking correction.

Infantile hemangioma (IH) is the most common vascular tumor of infancy, appearing within the first few weeks of life and typically reaching peak size by age 3 to 5 months.¹ It classically manifests as a raised or flat bright-red lesion in the upper dermis of the skin and/or subcutaneous tissue and can vary in number, size, shape, and location.² It is characterized by a rapid proliferative phase, especially between 5 and 8 weeks of age, followed by gradual spontaneous regression over 1 to 10 years.^1-3

Infantile hemangiomas are categorized based on depth (superficial, deep, or mixed) and distribution pattern (focal, multifocal, segmental, or indeterminate).⁴ In most cases, complete regression occurs by age 4 years, but there can be residual telangiectasia, fibrofatty tissue, and/or scarring.^1,4 About 10% to 15% of IHs result in complications that require medical intervention (eg, visual, airway, or auditory compromise; ulceration; disfigurement); ideally, these patients should be referred to a specialist by 5 weeks of age.⁴ Prompt assessment of IH severity is essential to prevent or mitigate potential complications and ultimately improve outcomes.³ Social drivers of health contribute to delayed diagnosis and management of hemangiomas, leading to increased complications in some patient populations.^5-7

Epidemiology

Infantile hemangiomas are estimated to manifest in 4.5% of infants in the United States.¹ The most common type is superficial IH, typically found on the head or neck.⁵ Risk factors in infants include female sex, White race, premature birth, and low birth weight (<1000 g).^1,3 Maternal risk factors include advanced gestational age (ie, >35 years), multiple gestations, family history of IH, tobacco use, use of progesterone therapy during pregnancy, and pre-eclampsia.^1,3

Focal IH typically manifests as a single localized lesion that can occur anywhere on the body.^2,3 In contrast, segmental IH manifests in a linear pattern and/or is distributed on a large anatomic area, most commonly on the face and less frequently the extremities and trunk.^2,3 Segmental IHs are more common in Hispanic patients and carry a higher risk for morbidity, often complicated by ulceration that can lead to functional and cosmetic challenges.⁸

Key Clinical Features

Superficial IH in patients with darker skin tones may appear as a dark-red or violaceous papule or plaque compared to bright red in lighter skin tones.⁵ Deep IH may appear as a soft, round, flesh-colored or blue-hued subcutaneous mass, the color of which may be harder to appreciate in those with darker skin tones.⁵

Worth Noting

Complications from IH may require imaging, close follow-up, systemic therapy, multidisciplinary care, and advanced health literacy and patient/family navigation. Multifocal IHs (≥5 lesions) are more likely to be associated with infantile hepatic hemangiomas.^2,3 Large (>5 cm) segmental IHs on the face and lumbosacral area require further evaluation for PHACES (posterior fossa malformation, hemangiomas, arterial anomalies, cardiac defects, eye anomalies, and sternal raphe/cleft defects) and LUMBAR (lower-body segmental IH; urogenital anomalies and ulceration; ­myelopathy; bony deformities; anorectal malformations and arterial anomalies; and renal anomalies) syndromes, which are more common in patients of Hispanic ethnicity.^2,3

The Infantile Hemangioma Referral Score is a recently validated tool that can assist primary care physicians in timely referral of IHs requiring early specialist intervention.^4,9 It takes into account the location, number, and size of the lesions and the age of the patient; these factors help to determine which IHs may be managed conservatively vs those that may require treatment to prevent ­life-threatening complications.^1-3 

Systemic corticosteroids historically have been the primary treatment for IH; however, in the past decade, propranolol oral solution (4.28 mg/mL) has become the first-line therapy for most infants requiring systemic management.¹⁰ It is the only medication approved by the US Food and Drug Administration for proliferating IH, with treatment initiation as young as 5 weeks corrected age.¹¹ As a nonselective beta-blocker, propranolol is believed to reduce IHs through vasoconstriction or by inhibition of angiogenesis.^1,4,10 

For small superficial IHs, treatment options include timolol maleate ophthalmic solution 0.5% (one drop applied twice daily to the IH) or pulsed dye laser therapy.^4,10 Surgical excision typically is avoided during infancy due to concerns about anesthetic risks and potential blood loss.^4,10 Surgery is reserved for cases involving residual fibrofatty tissue, postinvolution scarring, obstruction of vital structures, or lesions in aesthetically sensitive areas as well as when propranolol is contraindicated.^4,10

Health Disparity Highlight

Infants with skin of color and those of lower socioeconomic status (SES) face a heightened risk for delayed diagnosis and more advanced disease at the initial evaluation for IH.^5,7 Access barriers such as geographic limitations to specialty services, lack of insurance, underinsurance, and language differences impact timely diagnosis and treatment.^5,6 Implementation of telemedicine services in areas with limited access to specialists can facilitate early evaluation and risk stratification for IH.¹²

A retrospective cohort study of 804 children seen at a large academic hospital found that those of lower SES were more likely to seek care after 3 months of age than their higher-SES counterparts.⁶ Those who presented after 6 months of age also had higher IH severity scores compared to their counterparts with higher SES.⁶ Delayed access to care may cause children to miss the critical treatment window during the rapid proliferative growth phase.^6,12 However, children insured through Medicaid or the Children’s Health Insurance Program who participated in institutional care management programs (which assist in scheduling specialty care appointments within the institution) sought treatment earlier regardless of their SES, suggesting that such programs may help reduce disparities in timely access for children of lower SES.⁶ 

An epidemiologic study analyzing the demographics of children hospitalized across the United States demonstrated that Black infants with IH were more likely to belong to the lowest income quartile compared with White infants or those of other races. They also were 2 times older on average at initial presentation (1.8 vs 1.0 years), experienced longer hospitalizations (16.4 vs 13.8 days), and underwent more IH-related procedures than White infants and infants of other races (2.4, 1.9, and 2.1, respectively).⁷

These and other factors may contribute to missed windows of opportunity for timely treatment of high-risk IHs in patients with darker skin tones and/or those facing challenges stemming from social drivers of health.

Infantile hemangioma (IH) is the most common vascular tumor of infancy, appearing within the first few weeks of life and typically reaching peak size by age 3 to 5 months.¹ It classically manifests as a raised or flat bright-red lesion in the upper dermis of the skin and/or subcutaneous tissue and can vary in number, size, shape, and location.² It is characterized by a rapid proliferative phase, especially between 5 and 8 weeks of age, followed by gradual spontaneous regression over 1 to 10 years.^1-3

Infantile hemangiomas are categorized based on depth (superficial, deep, or mixed) and distribution pattern (focal, multifocal, segmental, or indeterminate).⁴ In most cases, complete regression occurs by age 4 years, but there can be residual telangiectasia, fibrofatty tissue, and/or scarring.^1,4 About 10% to 15% of IHs result in complications that require medical intervention (eg, visual, airway, or auditory compromise; ulceration; disfigurement); ideally, these patients should be referred to a specialist by 5 weeks of age.⁴ Prompt assessment of IH severity is essential to prevent or mitigate potential complications and ultimately improve outcomes.³ Social drivers of health contribute to delayed diagnosis and management of hemangiomas, leading to increased complications in some patient populations.^5-7

Epidemiology

Infantile hemangiomas are estimated to manifest in 4.5% of infants in the United States.¹ The most common type is superficial IH, typically found on the head or neck.⁵ Risk factors in infants include female sex, White race, premature birth, and low birth weight (<1000 g).^1,3 Maternal risk factors include advanced gestational age (ie, >35 years), multiple gestations, family history of IH, tobacco use, use of progesterone therapy during pregnancy, and pre-eclampsia.^1,3

Focal IH typically manifests as a single localized lesion that can occur anywhere on the body.^2,3 In contrast, segmental IH manifests in a linear pattern and/or is distributed on a large anatomic area, most commonly on the face and less frequently the extremities and trunk.^2,3 Segmental IHs are more common in Hispanic patients and carry a higher risk for morbidity, often complicated by ulceration that can lead to functional and cosmetic challenges.⁸

Key Clinical Features

Superficial IH in patients with darker skin tones may appear as a dark-red or violaceous papule or plaque compared to bright red in lighter skin tones.⁵ Deep IH may appear as a soft, round, flesh-colored or blue-hued subcutaneous mass, the color of which may be harder to appreciate in those with darker skin tones.⁵

Worth Noting

Complications from IH may require imaging, close follow-up, systemic therapy, multidisciplinary care, and advanced health literacy and patient/family navigation. Multifocal IHs (≥5 lesions) are more likely to be associated with infantile hepatic hemangiomas.^2,3 Large (>5 cm) segmental IHs on the face and lumbosacral area require further evaluation for PHACES (posterior fossa malformation, hemangiomas, arterial anomalies, cardiac defects, eye anomalies, and sternal raphe/cleft defects) and LUMBAR (lower-body segmental IH; urogenital anomalies and ulceration; ­myelopathy; bony deformities; anorectal malformations and arterial anomalies; and renal anomalies) syndromes, which are more common in patients of Hispanic ethnicity.^2,3

The Infantile Hemangioma Referral Score is a recently validated tool that can assist primary care physicians in timely referral of IHs requiring early specialist intervention.^4,9 It takes into account the location, number, and size of the lesions and the age of the patient; these factors help to determine which IHs may be managed conservatively vs those that may require treatment to prevent ­life-threatening complications.^1-3 

Systemic corticosteroids historically have been the primary treatment for IH; however, in the past decade, propranolol oral solution (4.28 mg/mL) has become the first-line therapy for most infants requiring systemic management.¹⁰ It is the only medication approved by the US Food and Drug Administration for proliferating IH, with treatment initiation as young as 5 weeks corrected age.¹¹ As a nonselective beta-blocker, propranolol is believed to reduce IHs through vasoconstriction or by inhibition of angiogenesis.^1,4,10 

For small superficial IHs, treatment options include timolol maleate ophthalmic solution 0.5% (one drop applied twice daily to the IH) or pulsed dye laser therapy.^4,10 Surgical excision typically is avoided during infancy due to concerns about anesthetic risks and potential blood loss.^4,10 Surgery is reserved for cases involving residual fibrofatty tissue, postinvolution scarring, obstruction of vital structures, or lesions in aesthetically sensitive areas as well as when propranolol is contraindicated.^4,10

Health Disparity Highlight

Infants with skin of color and those of lower socioeconomic status (SES) face a heightened risk for delayed diagnosis and more advanced disease at the initial evaluation for IH.^5,7 Access barriers such as geographic limitations to specialty services, lack of insurance, underinsurance, and language differences impact timely diagnosis and treatment.^5,6 Implementation of telemedicine services in areas with limited access to specialists can facilitate early evaluation and risk stratification for IH.¹²

A retrospective cohort study of 804 children seen at a large academic hospital found that those of lower SES were more likely to seek care after 3 months of age than their higher-SES counterparts.⁶ Those who presented after 6 months of age also had higher IH severity scores compared to their counterparts with higher SES.⁶ Delayed access to care may cause children to miss the critical treatment window during the rapid proliferative growth phase.^6,12 However, children insured through Medicaid or the Children’s Health Insurance Program who participated in institutional care management programs (which assist in scheduling specialty care appointments within the institution) sought treatment earlier regardless of their SES, suggesting that such programs may help reduce disparities in timely access for children of lower SES.⁶ 

An epidemiologic study analyzing the demographics of children hospitalized across the United States demonstrated that Black infants with IH were more likely to belong to the lowest income quartile compared with White infants or those of other races. They also were 2 times older on average at initial presentation (1.8 vs 1.0 years), experienced longer hospitalizations (16.4 vs 13.8 days), and underwent more IH-related procedures than White infants and infants of other races (2.4, 1.9, and 2.1, respectively).⁷

These and other factors may contribute to missed windows of opportunity for timely treatment of high-risk IHs in patients with darker skin tones and/or those facing challenges stemming from social drivers of health.

Infantile hemangioma (IH) is the most common vascular tumor of infancy, appearing within the first few weeks of life and typically reaching peak size by age 3 to 5 months.¹ It classically manifests as a raised or flat bright-red lesion in the upper dermis of the skin and/or subcutaneous tissue and can vary in number, size, shape, and location.² It is characterized by a rapid proliferative phase, especially between 5 and 8 weeks of age, followed by gradual spontaneous regression over 1 to 10 years.^1-3

Infantile hemangiomas are categorized based on depth (superficial, deep, or mixed) and distribution pattern (focal, multifocal, segmental, or indeterminate).⁴ In most cases, complete regression occurs by age 4 years, but there can be residual telangiectasia, fibrofatty tissue, and/or scarring.^1,4 About 10% to 15% of IHs result in complications that require medical intervention (eg, visual, airway, or auditory compromise; ulceration; disfigurement); ideally, these patients should be referred to a specialist by 5 weeks of age.⁴ Prompt assessment of IH severity is essential to prevent or mitigate potential complications and ultimately improve outcomes.³ Social drivers of health contribute to delayed diagnosis and management of hemangiomas, leading to increased complications in some patient populations.^5-7

Epidemiology

Infantile hemangiomas are estimated to manifest in 4.5% of infants in the United States.¹ The most common type is superficial IH, typically found on the head or neck.⁵ Risk factors in infants include female sex, White race, premature birth, and low birth weight (<1000 g).^1,3 Maternal risk factors include advanced gestational age (ie, >35 years), multiple gestations, family history of IH, tobacco use, use of progesterone therapy during pregnancy, and pre-eclampsia.^1,3

Focal IH typically manifests as a single localized lesion that can occur anywhere on the body.^2,3 In contrast, segmental IH manifests in a linear pattern and/or is distributed on a large anatomic area, most commonly on the face and less frequently the extremities and trunk.^2,3 Segmental IHs are more common in Hispanic patients and carry a higher risk for morbidity, often complicated by ulceration that can lead to functional and cosmetic challenges.⁸

Key Clinical Features

Superficial IH in patients with darker skin tones may appear as a dark-red or violaceous papule or plaque compared to bright red in lighter skin tones.⁵ Deep IH may appear as a soft, round, flesh-colored or blue-hued subcutaneous mass, the color of which may be harder to appreciate in those with darker skin tones.⁵

Worth Noting

Complications from IH may require imaging, close follow-up, systemic therapy, multidisciplinary care, and advanced health literacy and patient/family navigation. Multifocal IHs (≥5 lesions) are more likely to be associated with infantile hepatic hemangiomas.^2,3 Large (>5 cm) segmental IHs on the face and lumbosacral area require further evaluation for PHACES (posterior fossa malformation, hemangiomas, arterial anomalies, cardiac defects, eye anomalies, and sternal raphe/cleft defects) and LUMBAR (lower-body segmental IH; urogenital anomalies and ulceration; ­myelopathy; bony deformities; anorectal malformations and arterial anomalies; and renal anomalies) syndromes, which are more common in patients of Hispanic ethnicity.^2,3

The Infantile Hemangioma Referral Score is a recently validated tool that can assist primary care physicians in timely referral of IHs requiring early specialist intervention.^4,9 It takes into account the location, number, and size of the lesions and the age of the patient; these factors help to determine which IHs may be managed conservatively vs those that may require treatment to prevent ­life-threatening complications.^1-3 

Systemic corticosteroids historically have been the primary treatment for IH; however, in the past decade, propranolol oral solution (4.28 mg/mL) has become the first-line therapy for most infants requiring systemic management.¹⁰ It is the only medication approved by the US Food and Drug Administration for proliferating IH, with treatment initiation as young as 5 weeks corrected age.¹¹ As a nonselective beta-blocker, propranolol is believed to reduce IHs through vasoconstriction or by inhibition of angiogenesis.^1,4,10 

For small superficial IHs, treatment options include timolol maleate ophthalmic solution 0.5% (one drop applied twice daily to the IH) or pulsed dye laser therapy.^4,10 Surgical excision typically is avoided during infancy due to concerns about anesthetic risks and potential blood loss.^4,10 Surgery is reserved for cases involving residual fibrofatty tissue, postinvolution scarring, obstruction of vital structures, or lesions in aesthetically sensitive areas as well as when propranolol is contraindicated.^4,10

Health Disparity Highlight

Infants with skin of color and those of lower socioeconomic status (SES) face a heightened risk for delayed diagnosis and more advanced disease at the initial evaluation for IH.^5,7 Access barriers such as geographic limitations to specialty services, lack of insurance, underinsurance, and language differences impact timely diagnosis and treatment.^5,6 Implementation of telemedicine services in areas with limited access to specialists can facilitate early evaluation and risk stratification for IH.¹²

A retrospective cohort study of 804 children seen at a large academic hospital found that those of lower SES were more likely to seek care after 3 months of age than their higher-SES counterparts.⁶ Those who presented after 6 months of age also had higher IH severity scores compared to their counterparts with higher SES.⁶ Delayed access to care may cause children to miss the critical treatment window during the rapid proliferative growth phase.^6,12 However, children insured through Medicaid or the Children’s Health Insurance Program who participated in institutional care management programs (which assist in scheduling specialty care appointments within the institution) sought treatment earlier regardless of their SES, suggesting that such programs may help reduce disparities in timely access for children of lower SES.⁶ 

An epidemiologic study analyzing the demographics of children hospitalized across the United States demonstrated that Black infants with IH were more likely to belong to the lowest income quartile compared with White infants or those of other races. They also were 2 times older on average at initial presentation (1.8 vs 1.0 years), experienced longer hospitalizations (16.4 vs 13.8 days), and underwent more IH-related procedures than White infants and infants of other races (2.4, 1.9, and 2.1, respectively).⁷

These and other factors may contribute to missed windows of opportunity for timely treatment of high-risk IHs in patients with darker skin tones and/or those facing challenges stemming from social drivers of health.

To the Editor:

Residency applicants, especially in competitive specialties such as dermatology, face major financial barriers due to the high costs of applications, interviews, and away rotations.¹ While several studies have examined application costs of other specialties, few have analyzed expenses associated with dermatology applications.^1,2 There are no data examining costs following the start of the COVID-19 pandemic in 2020; thus, our study evaluated dermatology application cost trends from 2021 to 2024 and compared them to other specialties to identify strategies to reduce the financial burden on applicants.

Self-reported total application costs, application fees, interview expenses, and away rotation costs from 2021 to 2024 were collected from the Texas Seeking Transparency in Application to Residency (STAR) database powered by the UT Southwestern Medical Center (Dallas, Texas).³ The mean total application expenses per year were compared among specialties, and an analysis of variance was used to determine if the differences were statistically significant.

The number of applicants who recorded information in the Texas STAR database was 110 in 2021, 163 in 2022, 136 in 2023, and 129 in 2024.³ The total dermatology application expenses increased from $2805 in 2021 to $6231 in 2024; interview costs increased from $404 in 2021 to $911 in 2024; and away rotation costs increased from $850 in 2021 to $3812 in 2024 (all P<.05)(Table). There was no significant change in application fees during the study period ($2176 in 2021 to $2125 in 2024 [P=.58]). Dermatology had the fourth highest average total cost over the study period compared to all other specialties, increasing from $2250 in 2021 to $5250 in 2024, following orthopedic surgery ($2250 in 2021 to $6750 in 2024), plastic surgery ($2250 in 2021 to $9750 in 2024), and neurosurgery ($1750 in 2021 to $11,250 in 2024).

Our study found that dermatology residency application costs have increased significantly from 2021 to 2024, primarily driven by rising interview and away rotation expenses (both P<.05). This trend places dermatology among the most expensive fields to apply to for residency. A cross-sectional survey of dermatology residency program directors identified away rotations as one of the top 5 selection criteria, underscoring their importance in the matching process.⁴ In addition, a cross-sectional analysis of 345 dermatology residents found that 26.2% matched at institutions where they had mentors, including those they connected with through away rotations.^5,6 Overall, the high cost of away rotations partially may reflect the competitive nature of the specialty, as building connections at programs may enhance the chances of matching. These costs also can vary based on geography, as rotating in high-cost urban centers can be more expensive than in rural areas; however, rural rotations may be less common due to limited program availability and applicant preferences. For example, nearly 50% of 2024 Electronic Residency Application Service applicants indicated a preference for urban settings, while fewer than 5% selected rural settings.⁷ Additionally, the high costs associated with applying to residency programs and completing away rotations can disproportionately impact students from rural backgrounds and underrepresented minorities, who may have fewer financial resources.

In our study, the lower application-related expenses in 2021 (during the pandemic) compared to those of 2024 (postpandemic) likely stem from the Association of American Medical Colleges’ recommendation to conduct virtual interviews during the pandemic.⁸ In 2024, some dermatology programs returned to in-person interviews, with some applicants consequently incurring higher costs related to travel, lodging, and other associated expenses.⁸ A cost-analysis study of 4153 dermatology applicants from 2016 to 2021 found that the average application costs were $1759 per applicant during the pandemic, when virtual interviews replaced in-person ones, whereas costs were $8476 per applicant during periods with in-person interviews and no COVID-19 restrictions.² However, we did not observe a significant change in application fees over our study period, likely because the pandemic did not affect application numbers. A cross-sectional analysis of dermatology applicants during the pandemic similarly reported reductions in application-related expenses during the period when interviews were conducted virtually,⁹ supporting the trend observed in our study. Overall, our findings taken together with other studies highlight the pandemic’s role in reducing expenses and underscore the potential for exploring additional cost-saving measures.

Implementing strategies to reduce these financial burdens—including virtual interviews, increasing student funding for away rotations, and limiting the number of applications individual students can submit—could help alleviate socioeconomic disparities. The new signaling system for residency programs aims to reduce the number of applications submitted, as applicants typically receive interviews only from the limited number of programs they signal, reducing overall application costs. However, our data from the Texas STAR database suggest that application numbers remained relatively stable from 2021 to 2024, indicating that, despite signaling, many applicants still may apply broadly in hopes of improving their chances in an increasingly competitive field. Although a definitive solution to reducing the financial burden on dermatology applicants remains elusive, these strategies can raise awareness and encourage important dialogues.

Limitations of our study include the voluntary nature of the Texas STAR survey, leading to potential voluntary response bias, as well as the small sample size. Students who choose to submit cost data may differ systematically from those who do not; for example, students who match may be more likely to report their outcomes, while those who do not match may be less likely to participate, potentially introducing selection bias. In addition, general awareness of the Texas STAR survey may vary across institutions and among students, further limiting the number of students who participate. Additionally, 2021 was the only presignaling year included, making it difficult to assess longer-term trends. Despite these limitations, the Texas STAR database remains a valuable resource for analyzing general residency application expenses and trends, as it offers comprehensive data from more than 100 medical schools and includes many variables.³

In conclusion, our study found that total dermatology residency application costs have increased significantly from 2021 to 2024 (all P<.05), making dermatology among the most expensive specialties for applying. This study sets the foundation for future survey-based research for applicants and program directors on strategies to alleviate financial burdens.

To the Editor:

Residency applicants, especially in competitive specialties such as dermatology, face major financial barriers due to the high costs of applications, interviews, and away rotations.¹ While several studies have examined application costs of other specialties, few have analyzed expenses associated with dermatology applications.^1,2 There are no data examining costs following the start of the COVID-19 pandemic in 2020; thus, our study evaluated dermatology application cost trends from 2021 to 2024 and compared them to other specialties to identify strategies to reduce the financial burden on applicants.

Self-reported total application costs, application fees, interview expenses, and away rotation costs from 2021 to 2024 were collected from the Texas Seeking Transparency in Application to Residency (STAR) database powered by the UT Southwestern Medical Center (Dallas, Texas).³ The mean total application expenses per year were compared among specialties, and an analysis of variance was used to determine if the differences were statistically significant.

The number of applicants who recorded information in the Texas STAR database was 110 in 2021, 163 in 2022, 136 in 2023, and 129 in 2024.³ The total dermatology application expenses increased from $2805 in 2021 to $6231 in 2024; interview costs increased from $404 in 2021 to $911 in 2024; and away rotation costs increased from $850 in 2021 to $3812 in 2024 (all P<.05)(Table). There was no significant change in application fees during the study period ($2176 in 2021 to $2125 in 2024 [P=.58]). Dermatology had the fourth highest average total cost over the study period compared to all other specialties, increasing from $2250 in 2021 to $5250 in 2024, following orthopedic surgery ($2250 in 2021 to $6750 in 2024), plastic surgery ($2250 in 2021 to $9750 in 2024), and neurosurgery ($1750 in 2021 to $11,250 in 2024).

Our study found that dermatology residency application costs have increased significantly from 2021 to 2024, primarily driven by rising interview and away rotation expenses (both P<.05). This trend places dermatology among the most expensive fields to apply to for residency. A cross-sectional survey of dermatology residency program directors identified away rotations as one of the top 5 selection criteria, underscoring their importance in the matching process.⁴ In addition, a cross-sectional analysis of 345 dermatology residents found that 26.2% matched at institutions where they had mentors, including those they connected with through away rotations.^5,6 Overall, the high cost of away rotations partially may reflect the competitive nature of the specialty, as building connections at programs may enhance the chances of matching. These costs also can vary based on geography, as rotating in high-cost urban centers can be more expensive than in rural areas; however, rural rotations may be less common due to limited program availability and applicant preferences. For example, nearly 50% of 2024 Electronic Residency Application Service applicants indicated a preference for urban settings, while fewer than 5% selected rural settings.⁷ Additionally, the high costs associated with applying to residency programs and completing away rotations can disproportionately impact students from rural backgrounds and underrepresented minorities, who may have fewer financial resources.

In our study, the lower application-related expenses in 2021 (during the pandemic) compared to those of 2024 (postpandemic) likely stem from the Association of American Medical Colleges’ recommendation to conduct virtual interviews during the pandemic.⁸ In 2024, some dermatology programs returned to in-person interviews, with some applicants consequently incurring higher costs related to travel, lodging, and other associated expenses.⁸ A cost-analysis study of 4153 dermatology applicants from 2016 to 2021 found that the average application costs were $1759 per applicant during the pandemic, when virtual interviews replaced in-person ones, whereas costs were $8476 per applicant during periods with in-person interviews and no COVID-19 restrictions.² However, we did not observe a significant change in application fees over our study period, likely because the pandemic did not affect application numbers. A cross-sectional analysis of dermatology applicants during the pandemic similarly reported reductions in application-related expenses during the period when interviews were conducted virtually,⁹ supporting the trend observed in our study. Overall, our findings taken together with other studies highlight the pandemic’s role in reducing expenses and underscore the potential for exploring additional cost-saving measures.

Implementing strategies to reduce these financial burdens—including virtual interviews, increasing student funding for away rotations, and limiting the number of applications individual students can submit—could help alleviate socioeconomic disparities. The new signaling system for residency programs aims to reduce the number of applications submitted, as applicants typically receive interviews only from the limited number of programs they signal, reducing overall application costs. However, our data from the Texas STAR database suggest that application numbers remained relatively stable from 2021 to 2024, indicating that, despite signaling, many applicants still may apply broadly in hopes of improving their chances in an increasingly competitive field. Although a definitive solution to reducing the financial burden on dermatology applicants remains elusive, these strategies can raise awareness and encourage important dialogues.

Limitations of our study include the voluntary nature of the Texas STAR survey, leading to potential voluntary response bias, as well as the small sample size. Students who choose to submit cost data may differ systematically from those who do not; for example, students who match may be more likely to report their outcomes, while those who do not match may be less likely to participate, potentially introducing selection bias. In addition, general awareness of the Texas STAR survey may vary across institutions and among students, further limiting the number of students who participate. Additionally, 2021 was the only presignaling year included, making it difficult to assess longer-term trends. Despite these limitations, the Texas STAR database remains a valuable resource for analyzing general residency application expenses and trends, as it offers comprehensive data from more than 100 medical schools and includes many variables.³

In conclusion, our study found that total dermatology residency application costs have increased significantly from 2021 to 2024 (all P<.05), making dermatology among the most expensive specialties for applying. This study sets the foundation for future survey-based research for applicants and program directors on strategies to alleviate financial burdens.

To the Editor:

Residency applicants, especially in competitive specialties such as dermatology, face major financial barriers due to the high costs of applications, interviews, and away rotations.¹ While several studies have examined application costs of other specialties, few have analyzed expenses associated with dermatology applications.^1,2 There are no data examining costs following the start of the COVID-19 pandemic in 2020; thus, our study evaluated dermatology application cost trends from 2021 to 2024 and compared them to other specialties to identify strategies to reduce the financial burden on applicants.

Self-reported total application costs, application fees, interview expenses, and away rotation costs from 2021 to 2024 were collected from the Texas Seeking Transparency in Application to Residency (STAR) database powered by the UT Southwestern Medical Center (Dallas, Texas).³ The mean total application expenses per year were compared among specialties, and an analysis of variance was used to determine if the differences were statistically significant.

The number of applicants who recorded information in the Texas STAR database was 110 in 2021, 163 in 2022, 136 in 2023, and 129 in 2024.³ The total dermatology application expenses increased from $2805 in 2021 to $6231 in 2024; interview costs increased from $404 in 2021 to $911 in 2024; and away rotation costs increased from $850 in 2021 to $3812 in 2024 (all P<.05)(Table). There was no significant change in application fees during the study period ($2176 in 2021 to $2125 in 2024 [P=.58]). Dermatology had the fourth highest average total cost over the study period compared to all other specialties, increasing from $2250 in 2021 to $5250 in 2024, following orthopedic surgery ($2250 in 2021 to $6750 in 2024), plastic surgery ($2250 in 2021 to $9750 in 2024), and neurosurgery ($1750 in 2021 to $11,250 in 2024).

Our study found that dermatology residency application costs have increased significantly from 2021 to 2024, primarily driven by rising interview and away rotation expenses (both P<.05). This trend places dermatology among the most expensive fields to apply to for residency. A cross-sectional survey of dermatology residency program directors identified away rotations as one of the top 5 selection criteria, underscoring their importance in the matching process.⁴ In addition, a cross-sectional analysis of 345 dermatology residents found that 26.2% matched at institutions where they had mentors, including those they connected with through away rotations.^5,6 Overall, the high cost of away rotations partially may reflect the competitive nature of the specialty, as building connections at programs may enhance the chances of matching. These costs also can vary based on geography, as rotating in high-cost urban centers can be more expensive than in rural areas; however, rural rotations may be less common due to limited program availability and applicant preferences. For example, nearly 50% of 2024 Electronic Residency Application Service applicants indicated a preference for urban settings, while fewer than 5% selected rural settings.⁷ Additionally, the high costs associated with applying to residency programs and completing away rotations can disproportionately impact students from rural backgrounds and underrepresented minorities, who may have fewer financial resources.

In our study, the lower application-related expenses in 2021 (during the pandemic) compared to those of 2024 (postpandemic) likely stem from the Association of American Medical Colleges’ recommendation to conduct virtual interviews during the pandemic.⁸ In 2024, some dermatology programs returned to in-person interviews, with some applicants consequently incurring higher costs related to travel, lodging, and other associated expenses.⁸ A cost-analysis study of 4153 dermatology applicants from 2016 to 2021 found that the average application costs were $1759 per applicant during the pandemic, when virtual interviews replaced in-person ones, whereas costs were $8476 per applicant during periods with in-person interviews and no COVID-19 restrictions.² However, we did not observe a significant change in application fees over our study period, likely because the pandemic did not affect application numbers. A cross-sectional analysis of dermatology applicants during the pandemic similarly reported reductions in application-related expenses during the period when interviews were conducted virtually,⁹ supporting the trend observed in our study. Overall, our findings taken together with other studies highlight the pandemic’s role in reducing expenses and underscore the potential for exploring additional cost-saving measures.

Implementing strategies to reduce these financial burdens—including virtual interviews, increasing student funding for away rotations, and limiting the number of applications individual students can submit—could help alleviate socioeconomic disparities. The new signaling system for residency programs aims to reduce the number of applications submitted, as applicants typically receive interviews only from the limited number of programs they signal, reducing overall application costs. However, our data from the Texas STAR database suggest that application numbers remained relatively stable from 2021 to 2024, indicating that, despite signaling, many applicants still may apply broadly in hopes of improving their chances in an increasingly competitive field. Although a definitive solution to reducing the financial burden on dermatology applicants remains elusive, these strategies can raise awareness and encourage important dialogues.

Limitations of our study include the voluntary nature of the Texas STAR survey, leading to potential voluntary response bias, as well as the small sample size. Students who choose to submit cost data may differ systematically from those who do not; for example, students who match may be more likely to report their outcomes, while those who do not match may be less likely to participate, potentially introducing selection bias. In addition, general awareness of the Texas STAR survey may vary across institutions and among students, further limiting the number of students who participate. Additionally, 2021 was the only presignaling year included, making it difficult to assess longer-term trends. Despite these limitations, the Texas STAR database remains a valuable resource for analyzing general residency application expenses and trends, as it offers comprehensive data from more than 100 medical schools and includes many variables.³

In conclusion, our study found that total dermatology residency application costs have increased significantly from 2021 to 2024 (all P<.05), making dermatology among the most expensive specialties for applying. This study sets the foundation for future survey-based research for applicants and program directors on strategies to alleviate financial burdens.

Pediatric alopecia areata (AA) is a chronic autoimmune disease of the hair follicles characterized by nonscarring hair loss. Its incidence in children in the United States ranges from 13.6 to 33.5 per 100,000 person-years, with a prevalence of 0.04% to 0.11%.¹ Alopecia areata has important effects on quality of life, particularly in children. Hair loss at an early age can decrease participation in school, sports, and extracurricular activities² and is associated with increased rates of comorbid anxiety and depression.³ Families also experience psychosocial stress, often comparable to other chronic pediatric illnesses.⁴ Thus, management requires not only medical therapy but also psychosocial support and school-based accommodations.

Systemic therapies for treatment of AA in adolescents and adults are increasingly available, including US Food and Drug Administration (FDA)–approved Janus kinase (JAK) inhibitors such as baricitinib, deuruxolitinib (for adults), and ritlecitinib (for adolescents and adults); however, no systemic therapies have been approved by the FDA for children younger than 12 years. The therapeutic gap is most acute for those aged 6 to 11 years, for whom the psychosocial burden is high but treatment options are limited.³

This article highlights options and strategies for managing AA in children aged 6 to 11 years, emphasizing supportive and psychosocial care (including camouflage techniques), topical therapies, and off-label systemic approaches.

Supportive and Psychosocial Care

Treatment of AA in children extends beyond the affected child to include parents, caregivers, and even school staff (eg, teachers, principals, nurses).⁴ Disease-specific organizations such as the National Alopecia Areata Foundation ­(naaf.org) and the Children’s Alopecia Project (childrensalopeciaproject.org) provide ­education, support groups, and advocacy resources. These organizations assist families in navigating school accommodations, including Section 504 plans that may allow children with AA to wear hats in school to mitigate stigma. Additional resources include handouts for teachers and school nurses developed by the Society for Pediatric Dermatology.⁵

Psychological support for these patients is critical. Many children benefit from seeing a psychologist, particularly if anxiety, depression, and/or bullying is present.³ In clinics without embedded psychology services, dermatologists should maintain referral lists or encourage families to seek guidance from their pediatrician.

Camouflage techniques can help children cope with visible hair loss. Wigs and hairpieces are available free of charge through charitable organizations for patients younger than 17; however, young children often find adhesives uncomfortable, and they will not wear nonadherent wigs for long periods of time. Alternatives include soft hats, bonnets, scarves, and beanies. For partial hair loss, root concealers, scalp powders, or hair mascara can be useful. Temporary eyebrow tattoos are a good cosmetic approach, whereas microblading generally is not advised in children younger than 12 due to procedural risks including pain.

Topical Therapies

Topical agents remain the mainstay of treatment for AA in children aged 6 to 11 years. Potent class 1 or class 2 topical corticosteroids commonly are used, sometimes in combination with calcineurin inhibitors or topical minoxidil. Off-label compounded topical JAK inhibitors also have been tried in this population and may be helpful for eyebrow hair loss,⁶ though data on their efficacy for scalp AA are mixed.⁷ Intralesional corticosteroid injections, effective in adolescents and adults, generally are poorly tolerated by younger children and may cause considerable distress. Contact immunotherapy with squaric acid dibutyl ester or anthralin can be considered, but these agents are designed to elicit irritation, which may be intolerable for young children.⁸ Shared decision-making with families is essential to balance efficacy, tolerability, and treatment burden.

Systemic Therapies

Systemic therapy generally is reserved for children with extensive or refractory AA. Low-dose oral minoxidil is emerging as an off-label option. One systematic review reported that low-dose oral minoxidil was well tolerated in pediatric patients with minimal adverse effects.⁹ Doses of 0.01 to 0.02 mg/kg/d are reasonable starting points, achieved by cutting tablets or compounding oral solutions.¹⁰

In children with AA and concurrent atopic dermatitis, dupilumab may offer dual benefit. A real-world observational study demonstrated hair regrowth in pediatric patients with AA treated with dupilumab.¹¹ Immunosuppressive options such as low-dose methotrexate or pulse corticosteroids (dexamethasone or prednisolone) also may be considered, although use of these agents requires careful monitoring due to increased risk for infection, clinically significant blood count and liver enzyme changes, and metabolic adverse effects related to long-term use of corticosteroids.

Clinical trials of JAK inhibitors in children aged 6 to 11 years are anticipated to begin in late 2025. Until then, off-label use of ritlecitinib, baricitinib, tofacitinib, or other JAK inhibitors may be considered in select cases with considerable disease burden and quality-of-life impairment following thorough discussion with the patient and their caregivers. Currently available pediatric data show few serious adverse events in children—the most common included upper respiratory infections (nasopharyngitis), acne, and headaches—but long-term risks remain unknown. Dosing challenges also exist for children who cannot swallow pills; currently ritlecitinib is available only as a capsule that cannot be opened while other JAK inhibitors are available in more accessible forms (baricitinib can be crushed and dissolved, and tofacitinib is available in liquid formulation for other pediatric indications). Insurance coverage is a major barrier, as these therapies are not FDA approved for AA in this age group.

Final Thoughts

Alopecia areata in children aged 6 to 11 years presents unique therapeutic challenges. While highly effective systemic therapies exist for older patients, younger children have limited options. For the 6-to-11 age group, management strategies should prioritize psychosocial support, topical therapy, and low-burden systemic alternatives such as low-dose oral minoxidil. Family education, school-based accommodations, and access to camouflage techniques are integral to holistic care. The commencement of pediatric clinical trials for JAK inhibitors offers hope for more robust treatment strategies in the near future. In the meantime, clinicians must engage in shared decision-making, tailoring therapy to the child’s disease severity, emotional well-being, and family priorities.

Pediatric alopecia areata (AA) is a chronic autoimmune disease of the hair follicles characterized by nonscarring hair loss. Its incidence in children in the United States ranges from 13.6 to 33.5 per 100,000 person-years, with a prevalence of 0.04% to 0.11%.¹ Alopecia areata has important effects on quality of life, particularly in children. Hair loss at an early age can decrease participation in school, sports, and extracurricular activities² and is associated with increased rates of comorbid anxiety and depression.³ Families also experience psychosocial stress, often comparable to other chronic pediatric illnesses.⁴ Thus, management requires not only medical therapy but also psychosocial support and school-based accommodations.

Systemic therapies for treatment of AA in adolescents and adults are increasingly available, including US Food and Drug Administration (FDA)–approved Janus kinase (JAK) inhibitors such as baricitinib, deuruxolitinib (for adults), and ritlecitinib (for adolescents and adults); however, no systemic therapies have been approved by the FDA for children younger than 12 years. The therapeutic gap is most acute for those aged 6 to 11 years, for whom the psychosocial burden is high but treatment options are limited.³

This article highlights options and strategies for managing AA in children aged 6 to 11 years, emphasizing supportive and psychosocial care (including camouflage techniques), topical therapies, and off-label systemic approaches.

Supportive and Psychosocial Care

Treatment of AA in children extends beyond the affected child to include parents, caregivers, and even school staff (eg, teachers, principals, nurses).⁴ Disease-specific organizations such as the National Alopecia Areata Foundation ­(naaf.org) and the Children’s Alopecia Project (childrensalopeciaproject.org) provide ­education, support groups, and advocacy resources. These organizations assist families in navigating school accommodations, including Section 504 plans that may allow children with AA to wear hats in school to mitigate stigma. Additional resources include handouts for teachers and school nurses developed by the Society for Pediatric Dermatology.⁵

Psychological support for these patients is critical. Many children benefit from seeing a psychologist, particularly if anxiety, depression, and/or bullying is present.³ In clinics without embedded psychology services, dermatologists should maintain referral lists or encourage families to seek guidance from their pediatrician.

Camouflage techniques can help children cope with visible hair loss. Wigs and hairpieces are available free of charge through charitable organizations for patients younger than 17; however, young children often find adhesives uncomfortable, and they will not wear nonadherent wigs for long periods of time. Alternatives include soft hats, bonnets, scarves, and beanies. For partial hair loss, root concealers, scalp powders, or hair mascara can be useful. Temporary eyebrow tattoos are a good cosmetic approach, whereas microblading generally is not advised in children younger than 12 due to procedural risks including pain.

Topical Therapies

Topical agents remain the mainstay of treatment for AA in children aged 6 to 11 years. Potent class 1 or class 2 topical corticosteroids commonly are used, sometimes in combination with calcineurin inhibitors or topical minoxidil. Off-label compounded topical JAK inhibitors also have been tried in this population and may be helpful for eyebrow hair loss,⁶ though data on their efficacy for scalp AA are mixed.⁷ Intralesional corticosteroid injections, effective in adolescents and adults, generally are poorly tolerated by younger children and may cause considerable distress. Contact immunotherapy with squaric acid dibutyl ester or anthralin can be considered, but these agents are designed to elicit irritation, which may be intolerable for young children.⁸ Shared decision-making with families is essential to balance efficacy, tolerability, and treatment burden.

Systemic Therapies

Systemic therapy generally is reserved for children with extensive or refractory AA. Low-dose oral minoxidil is emerging as an off-label option. One systematic review reported that low-dose oral minoxidil was well tolerated in pediatric patients with minimal adverse effects.⁹ Doses of 0.01 to 0.02 mg/kg/d are reasonable starting points, achieved by cutting tablets or compounding oral solutions.¹⁰

In children with AA and concurrent atopic dermatitis, dupilumab may offer dual benefit. A real-world observational study demonstrated hair regrowth in pediatric patients with AA treated with dupilumab.¹¹ Immunosuppressive options such as low-dose methotrexate or pulse corticosteroids (dexamethasone or prednisolone) also may be considered, although use of these agents requires careful monitoring due to increased risk for infection, clinically significant blood count and liver enzyme changes, and metabolic adverse effects related to long-term use of corticosteroids.

Clinical trials of JAK inhibitors in children aged 6 to 11 years are anticipated to begin in late 2025. Until then, off-label use of ritlecitinib, baricitinib, tofacitinib, or other JAK inhibitors may be considered in select cases with considerable disease burden and quality-of-life impairment following thorough discussion with the patient and their caregivers. Currently available pediatric data show few serious adverse events in children—the most common included upper respiratory infections (nasopharyngitis), acne, and headaches—but long-term risks remain unknown. Dosing challenges also exist for children who cannot swallow pills; currently ritlecitinib is available only as a capsule that cannot be opened while other JAK inhibitors are available in more accessible forms (baricitinib can be crushed and dissolved, and tofacitinib is available in liquid formulation for other pediatric indications). Insurance coverage is a major barrier, as these therapies are not FDA approved for AA in this age group.

Final Thoughts

Alopecia areata in children aged 6 to 11 years presents unique therapeutic challenges. While highly effective systemic therapies exist for older patients, younger children have limited options. For the 6-to-11 age group, management strategies should prioritize psychosocial support, topical therapy, and low-burden systemic alternatives such as low-dose oral minoxidil. Family education, school-based accommodations, and access to camouflage techniques are integral to holistic care. The commencement of pediatric clinical trials for JAK inhibitors offers hope for more robust treatment strategies in the near future. In the meantime, clinicians must engage in shared decision-making, tailoring therapy to the child’s disease severity, emotional well-being, and family priorities.

Pediatric alopecia areata (AA) is a chronic autoimmune disease of the hair follicles characterized by nonscarring hair loss. Its incidence in children in the United States ranges from 13.6 to 33.5 per 100,000 person-years, with a prevalence of 0.04% to 0.11%.¹ Alopecia areata has important effects on quality of life, particularly in children. Hair loss at an early age can decrease participation in school, sports, and extracurricular activities² and is associated with increased rates of comorbid anxiety and depression.³ Families also experience psychosocial stress, often comparable to other chronic pediatric illnesses.⁴ Thus, management requires not only medical therapy but also psychosocial support and school-based accommodations.

Systemic therapies for treatment of AA in adolescents and adults are increasingly available, including US Food and Drug Administration (FDA)–approved Janus kinase (JAK) inhibitors such as baricitinib, deuruxolitinib (for adults), and ritlecitinib (for adolescents and adults); however, no systemic therapies have been approved by the FDA for children younger than 12 years. The therapeutic gap is most acute for those aged 6 to 11 years, for whom the psychosocial burden is high but treatment options are limited.³

This article highlights options and strategies for managing AA in children aged 6 to 11 years, emphasizing supportive and psychosocial care (including camouflage techniques), topical therapies, and off-label systemic approaches.

Supportive and Psychosocial Care

Treatment of AA in children extends beyond the affected child to include parents, caregivers, and even school staff (eg, teachers, principals, nurses).⁴ Disease-specific organizations such as the National Alopecia Areata Foundation ­(naaf.org) and the Children’s Alopecia Project (childrensalopeciaproject.org) provide ­education, support groups, and advocacy resources. These organizations assist families in navigating school accommodations, including Section 504 plans that may allow children with AA to wear hats in school to mitigate stigma. Additional resources include handouts for teachers and school nurses developed by the Society for Pediatric Dermatology.⁵

Psychological support for these patients is critical. Many children benefit from seeing a psychologist, particularly if anxiety, depression, and/or bullying is present.³ In clinics without embedded psychology services, dermatologists should maintain referral lists or encourage families to seek guidance from their pediatrician.

Camouflage techniques can help children cope with visible hair loss. Wigs and hairpieces are available free of charge through charitable organizations for patients younger than 17; however, young children often find adhesives uncomfortable, and they will not wear nonadherent wigs for long periods of time. Alternatives include soft hats, bonnets, scarves, and beanies. For partial hair loss, root concealers, scalp powders, or hair mascara can be useful. Temporary eyebrow tattoos are a good cosmetic approach, whereas microblading generally is not advised in children younger than 12 due to procedural risks including pain.

Topical Therapies

Topical agents remain the mainstay of treatment for AA in children aged 6 to 11 years. Potent class 1 or class 2 topical corticosteroids commonly are used, sometimes in combination with calcineurin inhibitors or topical minoxidil. Off-label compounded topical JAK inhibitors also have been tried in this population and may be helpful for eyebrow hair loss,⁶ though data on their efficacy for scalp AA are mixed.⁷ Intralesional corticosteroid injections, effective in adolescents and adults, generally are poorly tolerated by younger children and may cause considerable distress. Contact immunotherapy with squaric acid dibutyl ester or anthralin can be considered, but these agents are designed to elicit irritation, which may be intolerable for young children.⁸ Shared decision-making with families is essential to balance efficacy, tolerability, and treatment burden.

Systemic Therapies

Systemic therapy generally is reserved for children with extensive or refractory AA. Low-dose oral minoxidil is emerging as an off-label option. One systematic review reported that low-dose oral minoxidil was well tolerated in pediatric patients with minimal adverse effects.⁹ Doses of 0.01 to 0.02 mg/kg/d are reasonable starting points, achieved by cutting tablets or compounding oral solutions.¹⁰

In children with AA and concurrent atopic dermatitis, dupilumab may offer dual benefit. A real-world observational study demonstrated hair regrowth in pediatric patients with AA treated with dupilumab.¹¹ Immunosuppressive options such as low-dose methotrexate or pulse corticosteroids (dexamethasone or prednisolone) also may be considered, although use of these agents requires careful monitoring due to increased risk for infection, clinically significant blood count and liver enzyme changes, and metabolic adverse effects related to long-term use of corticosteroids.

Clinical trials of JAK inhibitors in children aged 6 to 11 years are anticipated to begin in late 2025. Until then, off-label use of ritlecitinib, baricitinib, tofacitinib, or other JAK inhibitors may be considered in select cases with considerable disease burden and quality-of-life impairment following thorough discussion with the patient and their caregivers. Currently available pediatric data show few serious adverse events in children—the most common included upper respiratory infections (nasopharyngitis), acne, and headaches—but long-term risks remain unknown. Dosing challenges also exist for children who cannot swallow pills; currently ritlecitinib is available only as a capsule that cannot be opened while other JAK inhibitors are available in more accessible forms (baricitinib can be crushed and dissolved, and tofacitinib is available in liquid formulation for other pediatric indications). Insurance coverage is a major barrier, as these therapies are not FDA approved for AA in this age group.

Final Thoughts

Alopecia areata in children aged 6 to 11 years presents unique therapeutic challenges. While highly effective systemic therapies exist for older patients, younger children have limited options. For the 6-to-11 age group, management strategies should prioritize psychosocial support, topical therapy, and low-burden systemic alternatives such as low-dose oral minoxidil. Family education, school-based accommodations, and access to camouflage techniques are integral to holistic care. The commencement of pediatric clinical trials for JAK inhibitors offers hope for more robust treatment strategies in the near future. In the meantime, clinicians must engage in shared decision-making, tailoring therapy to the child’s disease severity, emotional well-being, and family priorities.

The Diagnosis: Juvenile Xanthogranuloma

Given the patient’s age, clinical features of the lesion, and characteristic setting-sun pattern on dermoscopy, a diagnosis of juvenile xanthogranuloma (JXG) was made. The patient showed no other signs of neurofibromatosis type 1 (NF1) or systemic disease and was managed conservatively with observation and routine follow-up. Minimal growth of the lesion was noted at 1-year follow-up, and he was meeting all age-appropriate developmental milestones and showed no other symptoms consistent with NF1. 

Juvenile xanthogranuloma is the most common childhood non–Langerhans cell histiocytosis. While it typically manifests as an isolated condition, JXG also can be associated with NF1 as well as juvenile myelomonocytic leukemia.^1-3 Neurofibromatosis type 1 is a multisystem disorder with variable clinical manifestations that commonly is associated with skin findings such as café au lait macules, intertriginous freckling, and neurofibromas, in addition to JXG.^2,3 Diagnosis of JXG should prompt noninvasive evaluation for further signs and symptoms of NF1, including thorough patient and family history and physical examination to identify other characteristic cutaneous findings, and can include consideration of slit lamp eye examination and radiography for identification of osseous findings. 

The pathogenesis of JXG is not fully known, though there is evidence that it may be associated with a mutation in the mitogen-activated protein kinase pathway.¹ The majority of cases appear in the first year of life.⁴ Clinically, JXG can manifest with extracutaneous lesions, including on the eyes and lungs.^5-7 Juvenile xanthogranuloma can be noninvasively diagnosed with dermoscopy. As seen in our patient, dermoscopic findings include a red-yellow or yellow-orange background with an erythematous border, typically described as a setting-sun pattern.^4,8 Biopsy can confirm the diagnosis; however, given the usually benign course, this often is unnecessary. Most pediatric patients with cutaneous manifestations have a self-limited course with regression over several months to years. Generally, no treatment is required for cutaneous manifestations alone; however, lesions can be removed for aesthetic concerns. For those with systemic involvement, a range of other treatments have been used, including chemotherapy, radiotherapy, systemic corticosteroids, and cyclosporine.^6,7 

The differential diagnosis for JXG includes Brooke-Spiegler syndrome, Fabry disease, solitary cutaneous mastocytoma, and tuberous sclerosis complex. Brooke-Spiegler syndrome is an autosomal-dominant condition characterized by the growth of adnexal neoplasms, including trichoepitheliomas, cylindromas, and spiradenomas. These lesions usually manifest on the face but can include other areas such as the trunk.⁹ Fabry disease is an X-linked recessive lysosomal storage disorder with cutaneous manifestations such as angiokeratoma corporis diffusum and hypohidrosis. Patients also may present with systemic symptoms including hypertension and renal and cardiovascular disease.¹⁰ Mastocytosis encompasses several clinical disorders defined by mast cell hyperplasia and accumulation in various organ systems, and solitary cutaneous mastocytoma is the most common manifestation in children.^11,12 Cutaneous mastocytoma can manifest as a single red-brown or yellow papule, usually located on the arms or legs.¹³ Solitary cutaneous mastocytomas in pediatric patients typically are diagnosed based on clinical appearance and the formation of a wheal upon firm palpation (Darier sign).^11-13 Our patient did not demonstrate the Darier sign, and the lesion was asymptomatic. Tuberous sclerosis complex is an autosomal-dominant neurocutaneous disorder with neurologic and skin findings that occur early in the disease course and include facial angiofibromas, hypomelanotic macules, shagreen patches, and café-au-lait macules.¹⁴

The Diagnosis: Juvenile Xanthogranuloma

Given the patient’s age, clinical features of the lesion, and characteristic setting-sun pattern on dermoscopy, a diagnosis of juvenile xanthogranuloma (JXG) was made. The patient showed no other signs of neurofibromatosis type 1 (NF1) or systemic disease and was managed conservatively with observation and routine follow-up. Minimal growth of the lesion was noted at 1-year follow-up, and he was meeting all age-appropriate developmental milestones and showed no other symptoms consistent with NF1. 

Juvenile xanthogranuloma is the most common childhood non–Langerhans cell histiocytosis. While it typically manifests as an isolated condition, JXG also can be associated with NF1 as well as juvenile myelomonocytic leukemia.^1-3 Neurofibromatosis type 1 is a multisystem disorder with variable clinical manifestations that commonly is associated with skin findings such as café au lait macules, intertriginous freckling, and neurofibromas, in addition to JXG.^2,3 Diagnosis of JXG should prompt noninvasive evaluation for further signs and symptoms of NF1, including thorough patient and family history and physical examination to identify other characteristic cutaneous findings, and can include consideration of slit lamp eye examination and radiography for identification of osseous findings. 

The pathogenesis of JXG is not fully known, though there is evidence that it may be associated with a mutation in the mitogen-activated protein kinase pathway.¹ The majority of cases appear in the first year of life.⁴ Clinically, JXG can manifest with extracutaneous lesions, including on the eyes and lungs.^5-7 Juvenile xanthogranuloma can be noninvasively diagnosed with dermoscopy. As seen in our patient, dermoscopic findings include a red-yellow or yellow-orange background with an erythematous border, typically described as a setting-sun pattern.^4,8 Biopsy can confirm the diagnosis; however, given the usually benign course, this often is unnecessary. Most pediatric patients with cutaneous manifestations have a self-limited course with regression over several months to years. Generally, no treatment is required for cutaneous manifestations alone; however, lesions can be removed for aesthetic concerns. For those with systemic involvement, a range of other treatments have been used, including chemotherapy, radiotherapy, systemic corticosteroids, and cyclosporine.^6,7 

The differential diagnosis for JXG includes Brooke-Spiegler syndrome, Fabry disease, solitary cutaneous mastocytoma, and tuberous sclerosis complex. Brooke-Spiegler syndrome is an autosomal-dominant condition characterized by the growth of adnexal neoplasms, including trichoepitheliomas, cylindromas, and spiradenomas. These lesions usually manifest on the face but can include other areas such as the trunk.⁹ Fabry disease is an X-linked recessive lysosomal storage disorder with cutaneous manifestations such as angiokeratoma corporis diffusum and hypohidrosis. Patients also may present with systemic symptoms including hypertension and renal and cardiovascular disease.¹⁰ Mastocytosis encompasses several clinical disorders defined by mast cell hyperplasia and accumulation in various organ systems, and solitary cutaneous mastocytoma is the most common manifestation in children.^11,12 Cutaneous mastocytoma can manifest as a single red-brown or yellow papule, usually located on the arms or legs.¹³ Solitary cutaneous mastocytomas in pediatric patients typically are diagnosed based on clinical appearance and the formation of a wheal upon firm palpation (Darier sign).^11-13 Our patient did not demonstrate the Darier sign, and the lesion was asymptomatic. Tuberous sclerosis complex is an autosomal-dominant neurocutaneous disorder with neurologic and skin findings that occur early in the disease course and include facial angiofibromas, hypomelanotic macules, shagreen patches, and café-au-lait macules.¹⁴

The Diagnosis: Juvenile Xanthogranuloma

Given the patient’s age, clinical features of the lesion, and characteristic setting-sun pattern on dermoscopy, a diagnosis of juvenile xanthogranuloma (JXG) was made. The patient showed no other signs of neurofibromatosis type 1 (NF1) or systemic disease and was managed conservatively with observation and routine follow-up. Minimal growth of the lesion was noted at 1-year follow-up, and he was meeting all age-appropriate developmental milestones and showed no other symptoms consistent with NF1. 

Juvenile xanthogranuloma is the most common childhood non–Langerhans cell histiocytosis. While it typically manifests as an isolated condition, JXG also can be associated with NF1 as well as juvenile myelomonocytic leukemia.^1-3 Neurofibromatosis type 1 is a multisystem disorder with variable clinical manifestations that commonly is associated with skin findings such as café au lait macules, intertriginous freckling, and neurofibromas, in addition to JXG.^2,3 Diagnosis of JXG should prompt noninvasive evaluation for further signs and symptoms of NF1, including thorough patient and family history and physical examination to identify other characteristic cutaneous findings, and can include consideration of slit lamp eye examination and radiography for identification of osseous findings. 

The pathogenesis of JXG is not fully known, though there is evidence that it may be associated with a mutation in the mitogen-activated protein kinase pathway.¹ The majority of cases appear in the first year of life.⁴ Clinically, JXG can manifest with extracutaneous lesions, including on the eyes and lungs.^5-7 Juvenile xanthogranuloma can be noninvasively diagnosed with dermoscopy. As seen in our patient, dermoscopic findings include a red-yellow or yellow-orange background with an erythematous border, typically described as a setting-sun pattern.^4,8 Biopsy can confirm the diagnosis; however, given the usually benign course, this often is unnecessary. Most pediatric patients with cutaneous manifestations have a self-limited course with regression over several months to years. Generally, no treatment is required for cutaneous manifestations alone; however, lesions can be removed for aesthetic concerns. For those with systemic involvement, a range of other treatments have been used, including chemotherapy, radiotherapy, systemic corticosteroids, and cyclosporine.^6,7 

The differential diagnosis for JXG includes Brooke-Spiegler syndrome, Fabry disease, solitary cutaneous mastocytoma, and tuberous sclerosis complex. Brooke-Spiegler syndrome is an autosomal-dominant condition characterized by the growth of adnexal neoplasms, including trichoepitheliomas, cylindromas, and spiradenomas. These lesions usually manifest on the face but can include other areas such as the trunk.⁹ Fabry disease is an X-linked recessive lysosomal storage disorder with cutaneous manifestations such as angiokeratoma corporis diffusum and hypohidrosis. Patients also may present with systemic symptoms including hypertension and renal and cardiovascular disease.¹⁰ Mastocytosis encompasses several clinical disorders defined by mast cell hyperplasia and accumulation in various organ systems, and solitary cutaneous mastocytoma is the most common manifestation in children.^11,12 Cutaneous mastocytoma can manifest as a single red-brown or yellow papule, usually located on the arms or legs.¹³ Solitary cutaneous mastocytomas in pediatric patients typically are diagnosed based on clinical appearance and the formation of a wheal upon firm palpation (Darier sign).^11-13 Our patient did not demonstrate the Darier sign, and the lesion was asymptomatic. Tuberous sclerosis complex is an autosomal-dominant neurocutaneous disorder with neurologic and skin findings that occur early in the disease course and include facial angiofibromas, hypomelanotic macules, shagreen patches, and café-au-lait macules.¹⁴

There are 2.7 million (48%) rural veterans enrolled in the Veterans Health Administration (VHA).¹ Many VHA-enrolled rural veterans are aged ≥ 65 years (54%), a medically complex population that requires more extensive health care.¹ These veterans may live far from US Department of Veterans Affairs (VA) medical centers (VAMCs) and often receive most of their care at rural community-based outpatient clinics (CBOCs). In addition to face-to-face (F2F) services provided at these clinics, many patient care needs may be met using telehealth technology, which can connect veterans at CBOCs with remote health care practitioners (HCPs).

This technology is used across medical specialties throughout the VA and has expanded into neuropsychology services to improve access amid the shortage of rural neuropsychologists. Prior research suggests that access to neuropsychology services improves the functional outcomes of people with diverse medical conditions, including dementia, brain injury, and epilepsy, and reduces emergency department visits, hospitalization duration, and health care costs.^2-6 Given that veterans unable to access neuropsychology services may be at risk for poorer outcomes, identifying ways to improve access is a priority. Tele-neuropsychology (teleNP) has been used to expand access for rural veterans in need of these services.^7,8 

TeleNP is the application of audiovisual technologies to enable remote clinical encounters for neuropsychological assessments.⁹ TeleNP has been shown to be generally equivalent to F2F care, without significant differences compared with in-person visits.^10-13 TeleNP was increasingly implemented following the COVID-19 pandemic and remains an enduring and expanding feature of neuropsychology care delivery.^8,14-18 TeleNP services can increase access to care, especially for rural veterans and those with limited transportation. 

Research in non-VA samples suggests a high level of clinician satisfaction with teleNP.16 In VA samples, research has found high levels of patient satisfaction with teleNP both within Veterans Integrated Services Network (VISN) 20 and in a VA health care system outside VISN 20.^7,19 Investigating staff perceptions of these services and their utility compared with non-VA F2F visits is pertinent to the overall feasibility and effectiveness of teleNP. 

TELE-NEUROPSYCHOLOGY PROGRAM 

A clinical resource hub (CRH) is a VISN-governed program that provides veteran health care when local VHA facilities have service gaps.^20,21 CRH 20 serves several Pacific Northwest VISN 20 health care systems and began providing teleNP in 2015. The CRH 20 teleNP service serves older adults in rural settings with > 570 teleNP evaluations completed over a recent 12-month period (May 2023 to May 2024). In the CRH 20 teleNP program, veterans are offered services by CRH 20 neuropsychologists via telehealth to a patient’s local VAMC, larger health care clinic, CBOC, or via Veterans Video Connect to the home. 

Referral pathways to the CRH 20 teleNP program differ across sites. For VISN 20 sites that do not have any in-house neuropsychology services, referrals are initiated by HCPs from any discipline. At 2 sites with in-house neuropsychology programs, CRH 20 teleNP referrals typically are forwarded from the inhouse service whenever the veteran prefers to be seen at an outlying clinic. All sites, including the CBOCs, are equipped fully for testing, and the HCP encounters veterans in a private office via video-based telehealth technology after a telehealth technician orients them to the space. The private office minimizes environmental disruptions and uses standardized technology to ensure valid results. A limited number of evaluations are offered at home (< 5% of the evaluations) if the veteran is unable to come to a VHA facility, has access to reliable internet, and a minimally distracting home setting. 

In VISN 20, teleNP is a routine practice for delivering services to rural sites, most of which lack neuropsychologists. However, there is limited information about the extent to which the referral sources find the service useful. This quality improvement (QI) project aimed to better understand how well-established teleNP services were received by referral sources/stakeholders and how services could be improved. Prior to the advent of the CRH 20 teleNP program, staff had the option of referring for F2F evaluations in the local community (outside the VA) at some sites, an option that remains. This QI project examined staff perspectives on the usefulness of CRH 20 teleNP services compared with non-VA F2F services. We administered an anonymous, confidential survey examining these factors to VISN 20 staff within 4 VA health care systems. 

METHODS 

This QI project used a mixed quantitative and qualitative descriptive survey design to elicit feedback. The authors (3 neuropsychologists, 1 geropsychologist, and 1 research coordinator) developed the survey questions. The 13-question survey was voluntary, anonymous, and confidential, and respondents were given an opportunity to ask questions, with the first author serving as the point of contact. 

The survey ascertained information about respondents and their work setting (ie, facility type, specific work setting and location, profession, and rurality of patients). First respondents were asked whether they have referred patients to neuropsychology services in the past year. Those who had not referred patients during the past year were asked about reasons for nonreferral with an option to provide an open-ended response. Respondents who did refer were asked how they refer for neuropsychology services and about the usefulness and timeliness of both teleNP and non-VA F2F services. Respondents were asked to respond with their preference for teleNP vs non-VA F2F with an open-ended prompt. Finally, respondents were invited to share any feedback for improvement regarding teleNP services. 

A link to the survey, hosted on the VA Research Electronic Data Capture system, was emailed to facility and service line leaders at the 4 VISN 20 health care systems for distribution to the staff. All staff were included because in many of the facilities, particularly those that are highly rural with low staffing, it is not uncommon for technicians, nurses, and other support staff to assist with placing consults. In particular, VISN 20 nurses often have an optimal understanding of referral pathways to care for patients and are positioned to give and receive feedback about the utility of neuropsychological evaluations. The Research and Development Committee at the Boise VA Medical Center determined this project to be QI and exempt from institutional review board oversight. The VISN 20 employee labor relations HR supervisor approved this survey, with union awareness. Responses were anonymous. 

Data were imported into Microsoft Excel and IBM SPSS Statistics for further analysis. Data were summarized using descriptive statistics, frequencies, and percentages. Nonparametric χ² and Wilcoxon signed-rank tests were used to test for differences. An inductive approach to develop codes was used for the 3 open-ended questions. Two authors (CC, CEG) independently coded the responses and reviewed discrepancies. Final code applications were based on consensus. 

RESULTS 

The survey was deployed for 1 month between February 7, 2024, and June 15, 2024, at each of the 4 health care systems. Thirty-three staff members responded; of these, 1 person did not respond to an item on whether they referred for neuropsychology services. Eighteen of 33 respondents reported referring patients to teleNP or F2F neuropsychology services in the past year. Fourteen of the 33 respondents stated they did not refer; of these, 2 were unfamiliar with the teleNP service and 12 provided other reasons (eg, new to VA, not in their professional scope to order consults, did not have patients needing services). 

The analysis focused on the 18 respondents who referred for neuropsychology services. Thirteen were within health care system A, and 5 were within health care system B (which had no nearby non-VA contracted neuropsychology services) and none were in the other 2 health care systems. Ten of 18 respondents (56%) stated they practiced primarily in a rural setting. Five respondents worked in a CBOC, 12 in a main VA facility, 9 in a primary care setting, 8 in a mental health setting, and 3 in other settings (eg, domiciliary). Participants could select > 1 setting. The 18 respondents who referred to neuropsychology services included 7 psychologists, 1 nurse, 2 social workers, 1 social services assistant, 4 nurse practitioners, 2 physicians, and 1 unknown HCP. 

When asked to categorize the usefulness of services, more respondents characterized teleNP as very much so (1 on a 5-point scale) than F2F referrals (Figure). The mean (SD) of 1.5 (0.8) for teleNP usefulness fell between very much so and mostly and 1 respondent indicated not applicable. Similarly, the mean (SD) for non-VA F2F usefulness was 1.7 (0.9); 9 respondents rated this item as not applicable. A Wilcoxon signed-rank test of related samples indicated no significant differences between the pairs of ratings (Z = 1.50; P = .41). 

Respondents with rural patients were more likely to refer them to teleNP services compared with respondents with nonrural patients (χ² = 5.7; P = .02). However, ratings of teleNP usefulness did not significantly differ for those serving rural vs with nonrural patients (χ² = 1.4; P = .49). Mean (SD) rating of teleNP usefulness was 1.3 (0.7) for the 9 rural subgroup respondents (between very much so and mostly) vs 1.8 (0.9) for the 8 nonrural subgroup respondents (between very much so and mostly). The mean (SD) rating for non-VA F2F usefulness was 1.8 (1.0) for the 4 rural subgroup respondents and 1.6 (0.8) for the 5 nonrural subgroup, between very much so and mostly for both groups. 

Most respondents had no preference between teleNP or F2F. Notably, the responses underlying this group were multifaceted and corresponded to multiple codes (ie, access, preference for in-person services, technology, space and logistics, and service boundaries and requirements). According to 1 respondent, “the logistics of scheduling/room availability, technological challenges, and client behavioral issues that are likely to occur could possibly be more easily addressed via in-person sessions for some clients and providers.” 

Six of 18 respondents preferred teleNP, citing timeliness, ease of access, and evaluation quality. One respondent noted that the “majority of my veterans live in extremely remote areas” and may need to take a plane for their visit. The 3 respondents who preferred in-person neuropsychology services cited veterans’ preference for in-person services. 

Open-Ended Feedback 

Thirteen respondents offered feedback on what is working well with teleNP services. Reasons mentioned were related to the service (ie, timeliness, access, quality) and the neuropsychologist (ie, communication and HCP skills). One respondent described the service and neuropsychologists positively, stating that they were “responsive, notes are readily available, clear assessments and recommendations, being available by [Microsoft] Teams/email.” 

Ten respondents provided suggestions for improvement. Suggestions focused on expanding services, such as to “all veterans with cognitive/memory concerns that desire testing,” individuals with attention-deficit/hyperactivity disorder and co-occurring mental health concerns, and those in residential programs. Suggestions included hiring psychology technicians or more staff and providing education at local clinics. 

DISCUSSION 

This QI project examines VA staff perspectives on the usefulness of CRH 20 teleNP services and non-VA F2F services. While the small sample size limits generalizability, this preliminary study suggests that VA teleNP evaluations were similar to those conducted F2F in non-VA settings. While ratings of teleNP usefulness did not differ significantly for those serving rural vs nonrural veterans, respondents serving rural patients were more likely to refer patients to teleNP, suggesting that teleNP may increase access in rural settings, consistent with other studies.^7,8,13 This article also presents qualitative suggestions for improving teleNP delivery within the VHA. This is the first known initiative to report on VHA staff satisfaction with a teleNP service and expands the limited literature to date on satisfaction with teleNP services. The findings provide initial support for continued use and, potentially, expansion of teleNP services within this CRH remote hub-and-spoke model. 

Limitations 

A significant limitation of the current work is the small sample size of survey respondents. In particular, while teleNP turnaround time was perceived as faster than non-VA F2F care, only 8 respondents reported on timeliness of F2F evaluation results, which renders it difficult to draw conclusions. Interestingly, not all respondents reported referring to neuropsychology services within the previous year; the most common reasons reflect the perception that referral to neuropsychology was outside of that staff member’s role or not clinically indicated. 

One additional possible explanation for the absence of reporting on utility of teleNP specifically is that respondents did not track whether their patient was seen by teleNP or F2F services, based on how the referral process varies at each health care system. For example, in health care system C, a large number of referrals are forwarded to the service by local VA F2F neuropsychologists. This may speak to the seamlessness of the teleNP process, such that local staff and/or referring HCPs are unaware of the modality over which neuropsychology is being conducted. It is plausible that the reason behind this smaller response rate in health care systems B and C relates to how neuropsychology consults are processed at these local VAMCs. We suspect that in these settings, the HCPs referring for neuropsychological evaluations (eg, primary care, mental health) may be unaware that their referrals are being triaged to neuropsychologists in a different program (CRH 20 teleNP). Therefore, they would not necessarily know that they used teleNP and didn’t complete the survey. 

The referral process for these 2 sites contrasts with the process for other VISN 20 sites where there is no local neuropsychology program triaging. In these settings, referrals from local HCPs come directly to teleNP; thus, it is more likely that these HCPs are aware of teleNP services. There were only 2 physicians who completed the survey, which may relate to their workload and a workflow where other staff have been increasingly requested to order the consults for the physician. This type of workflow results in an increase in the number of VHA staff involved in patient care. Ratings of usefulness were highest in health care system B, which does not have neuropsychology services at the facility or in the community; this may relate to elevated teleNP satisfaction ratings. 

Further work may help identify which aspects of a teleNP service make it more useful than F2F care for this population or determine whether there were HCPor setting-specific factors that influenced the ratings (ie, preference for VA care or comparison of favorability ratings for the HCPs who conduct teleNP and F2F within the same system). The latter comparisons could not be drawn in the current systems due to the absence of HCPs who provide both teleNP and F2F modalities within VISN 20. Another consideration for future work would be to use a previously published/validated survey measure and piloting of questions with a naive sample before implementation. 

CONCLUSIONS 

This analysis provides initial support for feasibility and acceptability of teleNP as an alternative to traditional in-person neuropsychological evaluations. The small number of survey respondents may reflect the multiple pathways through which consults are forwarded to CRH 20, which includes both direct HCP referrals and forwarded consults from local neuropsychology services. CRH 20 has completed > 570 teleNP evaluations within 1 year, suggesting that lack of awareness may not be hindering veteran access to the service. Replication with a larger sample that is more broadly representative of key stakeholders in veteran care, identification of populations that would benefit most from teleNP services, and dissemination studies of the expansion of teleNP services are all important directions for future work. The robustness and longevity of the VISN 20 teleNP program, coupled with the preliminary positive findings from this project, demonstrate support for further assessment of the potential impact of telehealth on neuropsychological care within the VHA and show that barriers associated with access to health care services in remote settings may be mitigated through teleNP service delivery.

There are 2.7 million (48%) rural veterans enrolled in the Veterans Health Administration (VHA).¹ Many VHA-enrolled rural veterans are aged ≥ 65 years (54%), a medically complex population that requires more extensive health care.¹ These veterans may live far from US Department of Veterans Affairs (VA) medical centers (VAMCs) and often receive most of their care at rural community-based outpatient clinics (CBOCs). In addition to face-to-face (F2F) services provided at these clinics, many patient care needs may be met using telehealth technology, which can connect veterans at CBOCs with remote health care practitioners (HCPs).

This technology is used across medical specialties throughout the VA and has expanded into neuropsychology services to improve access amid the shortage of rural neuropsychologists. Prior research suggests that access to neuropsychology services improves the functional outcomes of people with diverse medical conditions, including dementia, brain injury, and epilepsy, and reduces emergency department visits, hospitalization duration, and health care costs.^2-6 Given that veterans unable to access neuropsychology services may be at risk for poorer outcomes, identifying ways to improve access is a priority. Tele-neuropsychology (teleNP) has been used to expand access for rural veterans in need of these services.^7,8 

TeleNP is the application of audiovisual technologies to enable remote clinical encounters for neuropsychological assessments.⁹ TeleNP has been shown to be generally equivalent to F2F care, without significant differences compared with in-person visits.^10-13 TeleNP was increasingly implemented following the COVID-19 pandemic and remains an enduring and expanding feature of neuropsychology care delivery.^8,14-18 TeleNP services can increase access to care, especially for rural veterans and those with limited transportation. 

Research in non-VA samples suggests a high level of clinician satisfaction with teleNP.16 In VA samples, research has found high levels of patient satisfaction with teleNP both within Veterans Integrated Services Network (VISN) 20 and in a VA health care system outside VISN 20.^7,19 Investigating staff perceptions of these services and their utility compared with non-VA F2F visits is pertinent to the overall feasibility and effectiveness of teleNP. 

TELE-NEUROPSYCHOLOGY PROGRAM 

A clinical resource hub (CRH) is a VISN-governed program that provides veteran health care when local VHA facilities have service gaps.^20,21 CRH 20 serves several Pacific Northwest VISN 20 health care systems and began providing teleNP in 2015. The CRH 20 teleNP service serves older adults in rural settings with > 570 teleNP evaluations completed over a recent 12-month period (May 2023 to May 2024). In the CRH 20 teleNP program, veterans are offered services by CRH 20 neuropsychologists via telehealth to a patient’s local VAMC, larger health care clinic, CBOC, or via Veterans Video Connect to the home. 

Referral pathways to the CRH 20 teleNP program differ across sites. For VISN 20 sites that do not have any in-house neuropsychology services, referrals are initiated by HCPs from any discipline. At 2 sites with in-house neuropsychology programs, CRH 20 teleNP referrals typically are forwarded from the inhouse service whenever the veteran prefers to be seen at an outlying clinic. All sites, including the CBOCs, are equipped fully for testing, and the HCP encounters veterans in a private office via video-based telehealth technology after a telehealth technician orients them to the space. The private office minimizes environmental disruptions and uses standardized technology to ensure valid results. A limited number of evaluations are offered at home (< 5% of the evaluations) if the veteran is unable to come to a VHA facility, has access to reliable internet, and a minimally distracting home setting. 

In VISN 20, teleNP is a routine practice for delivering services to rural sites, most of which lack neuropsychologists. However, there is limited information about the extent to which the referral sources find the service useful. This quality improvement (QI) project aimed to better understand how well-established teleNP services were received by referral sources/stakeholders and how services could be improved. Prior to the advent of the CRH 20 teleNP program, staff had the option of referring for F2F evaluations in the local community (outside the VA) at some sites, an option that remains. This QI project examined staff perspectives on the usefulness of CRH 20 teleNP services compared with non-VA F2F services. We administered an anonymous, confidential survey examining these factors to VISN 20 staff within 4 VA health care systems. 

METHODS 

This QI project used a mixed quantitative and qualitative descriptive survey design to elicit feedback. The authors (3 neuropsychologists, 1 geropsychologist, and 1 research coordinator) developed the survey questions. The 13-question survey was voluntary, anonymous, and confidential, and respondents were given an opportunity to ask questions, with the first author serving as the point of contact. 

The survey ascertained information about respondents and their work setting (ie, facility type, specific work setting and location, profession, and rurality of patients). First respondents were asked whether they have referred patients to neuropsychology services in the past year. Those who had not referred patients during the past year were asked about reasons for nonreferral with an option to provide an open-ended response. Respondents who did refer were asked how they refer for neuropsychology services and about the usefulness and timeliness of both teleNP and non-VA F2F services. Respondents were asked to respond with their preference for teleNP vs non-VA F2F with an open-ended prompt. Finally, respondents were invited to share any feedback for improvement regarding teleNP services. 

A link to the survey, hosted on the VA Research Electronic Data Capture system, was emailed to facility and service line leaders at the 4 VISN 20 health care systems for distribution to the staff. All staff were included because in many of the facilities, particularly those that are highly rural with low staffing, it is not uncommon for technicians, nurses, and other support staff to assist with placing consults. In particular, VISN 20 nurses often have an optimal understanding of referral pathways to care for patients and are positioned to give and receive feedback about the utility of neuropsychological evaluations. The Research and Development Committee at the Boise VA Medical Center determined this project to be QI and exempt from institutional review board oversight. The VISN 20 employee labor relations HR supervisor approved this survey, with union awareness. Responses were anonymous. 

Data were imported into Microsoft Excel and IBM SPSS Statistics for further analysis. Data were summarized using descriptive statistics, frequencies, and percentages. Nonparametric χ² and Wilcoxon signed-rank tests were used to test for differences. An inductive approach to develop codes was used for the 3 open-ended questions. Two authors (CC, CEG) independently coded the responses and reviewed discrepancies. Final code applications were based on consensus. 

RESULTS 

The survey was deployed for 1 month between February 7, 2024, and June 15, 2024, at each of the 4 health care systems. Thirty-three staff members responded; of these, 1 person did not respond to an item on whether they referred for neuropsychology services. Eighteen of 33 respondents reported referring patients to teleNP or F2F neuropsychology services in the past year. Fourteen of the 33 respondents stated they did not refer; of these, 2 were unfamiliar with the teleNP service and 12 provided other reasons (eg, new to VA, not in their professional scope to order consults, did not have patients needing services). 

The analysis focused on the 18 respondents who referred for neuropsychology services. Thirteen were within health care system A, and 5 were within health care system B (which had no nearby non-VA contracted neuropsychology services) and none were in the other 2 health care systems. Ten of 18 respondents (56%) stated they practiced primarily in a rural setting. Five respondents worked in a CBOC, 12 in a main VA facility, 9 in a primary care setting, 8 in a mental health setting, and 3 in other settings (eg, domiciliary). Participants could select > 1 setting. The 18 respondents who referred to neuropsychology services included 7 psychologists, 1 nurse, 2 social workers, 1 social services assistant, 4 nurse practitioners, 2 physicians, and 1 unknown HCP. 

When asked to categorize the usefulness of services, more respondents characterized teleNP as very much so (1 on a 5-point scale) than F2F referrals (Figure). The mean (SD) of 1.5 (0.8) for teleNP usefulness fell between very much so and mostly and 1 respondent indicated not applicable. Similarly, the mean (SD) for non-VA F2F usefulness was 1.7 (0.9); 9 respondents rated this item as not applicable. A Wilcoxon signed-rank test of related samples indicated no significant differences between the pairs of ratings (Z = 1.50; P = .41). 

Respondents with rural patients were more likely to refer them to teleNP services compared with respondents with nonrural patients (χ² = 5.7; P = .02). However, ratings of teleNP usefulness did not significantly differ for those serving rural vs with nonrural patients (χ² = 1.4; P = .49). Mean (SD) rating of teleNP usefulness was 1.3 (0.7) for the 9 rural subgroup respondents (between very much so and mostly) vs 1.8 (0.9) for the 8 nonrural subgroup respondents (between very much so and mostly). The mean (SD) rating for non-VA F2F usefulness was 1.8 (1.0) for the 4 rural subgroup respondents and 1.6 (0.8) for the 5 nonrural subgroup, between very much so and mostly for both groups. 

Most respondents had no preference between teleNP or F2F. Notably, the responses underlying this group were multifaceted and corresponded to multiple codes (ie, access, preference for in-person services, technology, space and logistics, and service boundaries and requirements). According to 1 respondent, “the logistics of scheduling/room availability, technological challenges, and client behavioral issues that are likely to occur could possibly be more easily addressed via in-person sessions for some clients and providers.” 

Six of 18 respondents preferred teleNP, citing timeliness, ease of access, and evaluation quality. One respondent noted that the “majority of my veterans live in extremely remote areas” and may need to take a plane for their visit. The 3 respondents who preferred in-person neuropsychology services cited veterans’ preference for in-person services. 

Open-Ended Feedback 

Thirteen respondents offered feedback on what is working well with teleNP services. Reasons mentioned were related to the service (ie, timeliness, access, quality) and the neuropsychologist (ie, communication and HCP skills). One respondent described the service and neuropsychologists positively, stating that they were “responsive, notes are readily available, clear assessments and recommendations, being available by [Microsoft] Teams/email.” 

Ten respondents provided suggestions for improvement. Suggestions focused on expanding services, such as to “all veterans with cognitive/memory concerns that desire testing,” individuals with attention-deficit/hyperactivity disorder and co-occurring mental health concerns, and those in residential programs. Suggestions included hiring psychology technicians or more staff and providing education at local clinics. 

DISCUSSION 

This QI project examines VA staff perspectives on the usefulness of CRH 20 teleNP services and non-VA F2F services. While the small sample size limits generalizability, this preliminary study suggests that VA teleNP evaluations were similar to those conducted F2F in non-VA settings. While ratings of teleNP usefulness did not differ significantly for those serving rural vs nonrural veterans, respondents serving rural patients were more likely to refer patients to teleNP, suggesting that teleNP may increase access in rural settings, consistent with other studies.^7,8,13 This article also presents qualitative suggestions for improving teleNP delivery within the VHA. This is the first known initiative to report on VHA staff satisfaction with a teleNP service and expands the limited literature to date on satisfaction with teleNP services. The findings provide initial support for continued use and, potentially, expansion of teleNP services within this CRH remote hub-and-spoke model. 

Limitations 

A significant limitation of the current work is the small sample size of survey respondents. In particular, while teleNP turnaround time was perceived as faster than non-VA F2F care, only 8 respondents reported on timeliness of F2F evaluation results, which renders it difficult to draw conclusions. Interestingly, not all respondents reported referring to neuropsychology services within the previous year; the most common reasons reflect the perception that referral to neuropsychology was outside of that staff member’s role or not clinically indicated. 

One additional possible explanation for the absence of reporting on utility of teleNP specifically is that respondents did not track whether their patient was seen by teleNP or F2F services, based on how the referral process varies at each health care system. For example, in health care system C, a large number of referrals are forwarded to the service by local VA F2F neuropsychologists. This may speak to the seamlessness of the teleNP process, such that local staff and/or referring HCPs are unaware of the modality over which neuropsychology is being conducted. It is plausible that the reason behind this smaller response rate in health care systems B and C relates to how neuropsychology consults are processed at these local VAMCs. We suspect that in these settings, the HCPs referring for neuropsychological evaluations (eg, primary care, mental health) may be unaware that their referrals are being triaged to neuropsychologists in a different program (CRH 20 teleNP). Therefore, they would not necessarily know that they used teleNP and didn’t complete the survey. 

The referral process for these 2 sites contrasts with the process for other VISN 20 sites where there is no local neuropsychology program triaging. In these settings, referrals from local HCPs come directly to teleNP; thus, it is more likely that these HCPs are aware of teleNP services. There were only 2 physicians who completed the survey, which may relate to their workload and a workflow where other staff have been increasingly requested to order the consults for the physician. This type of workflow results in an increase in the number of VHA staff involved in patient care. Ratings of usefulness were highest in health care system B, which does not have neuropsychology services at the facility or in the community; this may relate to elevated teleNP satisfaction ratings. 

Further work may help identify which aspects of a teleNP service make it more useful than F2F care for this population or determine whether there were HCPor setting-specific factors that influenced the ratings (ie, preference for VA care or comparison of favorability ratings for the HCPs who conduct teleNP and F2F within the same system). The latter comparisons could not be drawn in the current systems due to the absence of HCPs who provide both teleNP and F2F modalities within VISN 20. Another consideration for future work would be to use a previously published/validated survey measure and piloting of questions with a naive sample before implementation. 

CONCLUSIONS 

This analysis provides initial support for feasibility and acceptability of teleNP as an alternative to traditional in-person neuropsychological evaluations. The small number of survey respondents may reflect the multiple pathways through which consults are forwarded to CRH 20, which includes both direct HCP referrals and forwarded consults from local neuropsychology services. CRH 20 has completed > 570 teleNP evaluations within 1 year, suggesting that lack of awareness may not be hindering veteran access to the service. Replication with a larger sample that is more broadly representative of key stakeholders in veteran care, identification of populations that would benefit most from teleNP services, and dissemination studies of the expansion of teleNP services are all important directions for future work. The robustness and longevity of the VISN 20 teleNP program, coupled with the preliminary positive findings from this project, demonstrate support for further assessment of the potential impact of telehealth on neuropsychological care within the VHA and show that barriers associated with access to health care services in remote settings may be mitigated through teleNP service delivery.

There are 2.7 million (48%) rural veterans enrolled in the Veterans Health Administration (VHA).¹ Many VHA-enrolled rural veterans are aged ≥ 65 years (54%), a medically complex population that requires more extensive health care.¹ These veterans may live far from US Department of Veterans Affairs (VA) medical centers (VAMCs) and often receive most of their care at rural community-based outpatient clinics (CBOCs). In addition to face-to-face (F2F) services provided at these clinics, many patient care needs may be met using telehealth technology, which can connect veterans at CBOCs with remote health care practitioners (HCPs).

This technology is used across medical specialties throughout the VA and has expanded into neuropsychology services to improve access amid the shortage of rural neuropsychologists. Prior research suggests that access to neuropsychology services improves the functional outcomes of people with diverse medical conditions, including dementia, brain injury, and epilepsy, and reduces emergency department visits, hospitalization duration, and health care costs.^2-6 Given that veterans unable to access neuropsychology services may be at risk for poorer outcomes, identifying ways to improve access is a priority. Tele-neuropsychology (teleNP) has been used to expand access for rural veterans in need of these services.^7,8 

TeleNP is the application of audiovisual technologies to enable remote clinical encounters for neuropsychological assessments.⁹ TeleNP has been shown to be generally equivalent to F2F care, without significant differences compared with in-person visits.^10-13 TeleNP was increasingly implemented following the COVID-19 pandemic and remains an enduring and expanding feature of neuropsychology care delivery.^8,14-18 TeleNP services can increase access to care, especially for rural veterans and those with limited transportation. 

Research in non-VA samples suggests a high level of clinician satisfaction with teleNP.16 In VA samples, research has found high levels of patient satisfaction with teleNP both within Veterans Integrated Services Network (VISN) 20 and in a VA health care system outside VISN 20.^7,19 Investigating staff perceptions of these services and their utility compared with non-VA F2F visits is pertinent to the overall feasibility and effectiveness of teleNP. 

TELE-NEUROPSYCHOLOGY PROGRAM 

A clinical resource hub (CRH) is a VISN-governed program that provides veteran health care when local VHA facilities have service gaps.^20,21 CRH 20 serves several Pacific Northwest VISN 20 health care systems and began providing teleNP in 2015. The CRH 20 teleNP service serves older adults in rural settings with > 570 teleNP evaluations completed over a recent 12-month period (May 2023 to May 2024). In the CRH 20 teleNP program, veterans are offered services by CRH 20 neuropsychologists via telehealth to a patient’s local VAMC, larger health care clinic, CBOC, or via Veterans Video Connect to the home. 

Referral pathways to the CRH 20 teleNP program differ across sites. For VISN 20 sites that do not have any in-house neuropsychology services, referrals are initiated by HCPs from any discipline. At 2 sites with in-house neuropsychology programs, CRH 20 teleNP referrals typically are forwarded from the inhouse service whenever the veteran prefers to be seen at an outlying clinic. All sites, including the CBOCs, are equipped fully for testing, and the HCP encounters veterans in a private office via video-based telehealth technology after a telehealth technician orients them to the space. The private office minimizes environmental disruptions and uses standardized technology to ensure valid results. A limited number of evaluations are offered at home (< 5% of the evaluations) if the veteran is unable to come to a VHA facility, has access to reliable internet, and a minimally distracting home setting. 

In VISN 20, teleNP is a routine practice for delivering services to rural sites, most of which lack neuropsychologists. However, there is limited information about the extent to which the referral sources find the service useful. This quality improvement (QI) project aimed to better understand how well-established teleNP services were received by referral sources/stakeholders and how services could be improved. Prior to the advent of the CRH 20 teleNP program, staff had the option of referring for F2F evaluations in the local community (outside the VA) at some sites, an option that remains. This QI project examined staff perspectives on the usefulness of CRH 20 teleNP services compared with non-VA F2F services. We administered an anonymous, confidential survey examining these factors to VISN 20 staff within 4 VA health care systems. 

METHODS 

This QI project used a mixed quantitative and qualitative descriptive survey design to elicit feedback. The authors (3 neuropsychologists, 1 geropsychologist, and 1 research coordinator) developed the survey questions. The 13-question survey was voluntary, anonymous, and confidential, and respondents were given an opportunity to ask questions, with the first author serving as the point of contact. 

The survey ascertained information about respondents and their work setting (ie, facility type, specific work setting and location, profession, and rurality of patients). First respondents were asked whether they have referred patients to neuropsychology services in the past year. Those who had not referred patients during the past year were asked about reasons for nonreferral with an option to provide an open-ended response. Respondents who did refer were asked how they refer for neuropsychology services and about the usefulness and timeliness of both teleNP and non-VA F2F services. Respondents were asked to respond with their preference for teleNP vs non-VA F2F with an open-ended prompt. Finally, respondents were invited to share any feedback for improvement regarding teleNP services. 

A link to the survey, hosted on the VA Research Electronic Data Capture system, was emailed to facility and service line leaders at the 4 VISN 20 health care systems for distribution to the staff. All staff were included because in many of the facilities, particularly those that are highly rural with low staffing, it is not uncommon for technicians, nurses, and other support staff to assist with placing consults. In particular, VISN 20 nurses often have an optimal understanding of referral pathways to care for patients and are positioned to give and receive feedback about the utility of neuropsychological evaluations. The Research and Development Committee at the Boise VA Medical Center determined this project to be QI and exempt from institutional review board oversight. The VISN 20 employee labor relations HR supervisor approved this survey, with union awareness. Responses were anonymous. 

Data were imported into Microsoft Excel and IBM SPSS Statistics for further analysis. Data were summarized using descriptive statistics, frequencies, and percentages. Nonparametric χ² and Wilcoxon signed-rank tests were used to test for differences. An inductive approach to develop codes was used for the 3 open-ended questions. Two authors (CC, CEG) independently coded the responses and reviewed discrepancies. Final code applications were based on consensus. 

RESULTS 

The survey was deployed for 1 month between February 7, 2024, and June 15, 2024, at each of the 4 health care systems. Thirty-three staff members responded; of these, 1 person did not respond to an item on whether they referred for neuropsychology services. Eighteen of 33 respondents reported referring patients to teleNP or F2F neuropsychology services in the past year. Fourteen of the 33 respondents stated they did not refer; of these, 2 were unfamiliar with the teleNP service and 12 provided other reasons (eg, new to VA, not in their professional scope to order consults, did not have patients needing services). 

The analysis focused on the 18 respondents who referred for neuropsychology services. Thirteen were within health care system A, and 5 were within health care system B (which had no nearby non-VA contracted neuropsychology services) and none were in the other 2 health care systems. Ten of 18 respondents (56%) stated they practiced primarily in a rural setting. Five respondents worked in a CBOC, 12 in a main VA facility, 9 in a primary care setting, 8 in a mental health setting, and 3 in other settings (eg, domiciliary). Participants could select > 1 setting. The 18 respondents who referred to neuropsychology services included 7 psychologists, 1 nurse, 2 social workers, 1 social services assistant, 4 nurse practitioners, 2 physicians, and 1 unknown HCP. 

When asked to categorize the usefulness of services, more respondents characterized teleNP as very much so (1 on a 5-point scale) than F2F referrals (Figure). The mean (SD) of 1.5 (0.8) for teleNP usefulness fell between very much so and mostly and 1 respondent indicated not applicable. Similarly, the mean (SD) for non-VA F2F usefulness was 1.7 (0.9); 9 respondents rated this item as not applicable. A Wilcoxon signed-rank test of related samples indicated no significant differences between the pairs of ratings (Z = 1.50; P = .41). 

Respondents with rural patients were more likely to refer them to teleNP services compared with respondents with nonrural patients (χ² = 5.7; P = .02). However, ratings of teleNP usefulness did not significantly differ for those serving rural vs with nonrural patients (χ² = 1.4; P = .49). Mean (SD) rating of teleNP usefulness was 1.3 (0.7) for the 9 rural subgroup respondents (between very much so and mostly) vs 1.8 (0.9) for the 8 nonrural subgroup respondents (between very much so and mostly). The mean (SD) rating for non-VA F2F usefulness was 1.8 (1.0) for the 4 rural subgroup respondents and 1.6 (0.8) for the 5 nonrural subgroup, between very much so and mostly for both groups. 

Most respondents had no preference between teleNP or F2F. Notably, the responses underlying this group were multifaceted and corresponded to multiple codes (ie, access, preference for in-person services, technology, space and logistics, and service boundaries and requirements). According to 1 respondent, “the logistics of scheduling/room availability, technological challenges, and client behavioral issues that are likely to occur could possibly be more easily addressed via in-person sessions for some clients and providers.” 

Six of 18 respondents preferred teleNP, citing timeliness, ease of access, and evaluation quality. One respondent noted that the “majority of my veterans live in extremely remote areas” and may need to take a plane for their visit. The 3 respondents who preferred in-person neuropsychology services cited veterans’ preference for in-person services. 

Open-Ended Feedback 

Thirteen respondents offered feedback on what is working well with teleNP services. Reasons mentioned were related to the service (ie, timeliness, access, quality) and the neuropsychologist (ie, communication and HCP skills). One respondent described the service and neuropsychologists positively, stating that they were “responsive, notes are readily available, clear assessments and recommendations, being available by [Microsoft] Teams/email.” 

Ten respondents provided suggestions for improvement. Suggestions focused on expanding services, such as to “all veterans with cognitive/memory concerns that desire testing,” individuals with attention-deficit/hyperactivity disorder and co-occurring mental health concerns, and those in residential programs. Suggestions included hiring psychology technicians or more staff and providing education at local clinics. 

DISCUSSION 

This QI project examines VA staff perspectives on the usefulness of CRH 20 teleNP services and non-VA F2F services. While the small sample size limits generalizability, this preliminary study suggests that VA teleNP evaluations were similar to those conducted F2F in non-VA settings. While ratings of teleNP usefulness did not differ significantly for those serving rural vs nonrural veterans, respondents serving rural patients were more likely to refer patients to teleNP, suggesting that teleNP may increase access in rural settings, consistent with other studies.^7,8,13 This article also presents qualitative suggestions for improving teleNP delivery within the VHA. This is the first known initiative to report on VHA staff satisfaction with a teleNP service and expands the limited literature to date on satisfaction with teleNP services. The findings provide initial support for continued use and, potentially, expansion of teleNP services within this CRH remote hub-and-spoke model. 

Limitations 

A significant limitation of the current work is the small sample size of survey respondents. In particular, while teleNP turnaround time was perceived as faster than non-VA F2F care, only 8 respondents reported on timeliness of F2F evaluation results, which renders it difficult to draw conclusions. Interestingly, not all respondents reported referring to neuropsychology services within the previous year; the most common reasons reflect the perception that referral to neuropsychology was outside of that staff member’s role or not clinically indicated. 

One additional possible explanation for the absence of reporting on utility of teleNP specifically is that respondents did not track whether their patient was seen by teleNP or F2F services, based on how the referral process varies at each health care system. For example, in health care system C, a large number of referrals are forwarded to the service by local VA F2F neuropsychologists. This may speak to the seamlessness of the teleNP process, such that local staff and/or referring HCPs are unaware of the modality over which neuropsychology is being conducted. It is plausible that the reason behind this smaller response rate in health care systems B and C relates to how neuropsychology consults are processed at these local VAMCs. We suspect that in these settings, the HCPs referring for neuropsychological evaluations (eg, primary care, mental health) may be unaware that their referrals are being triaged to neuropsychologists in a different program (CRH 20 teleNP). Therefore, they would not necessarily know that they used teleNP and didn’t complete the survey. 

The referral process for these 2 sites contrasts with the process for other VISN 20 sites where there is no local neuropsychology program triaging. In these settings, referrals from local HCPs come directly to teleNP; thus, it is more likely that these HCPs are aware of teleNP services. There were only 2 physicians who completed the survey, which may relate to their workload and a workflow where other staff have been increasingly requested to order the consults for the physician. This type of workflow results in an increase in the number of VHA staff involved in patient care. Ratings of usefulness were highest in health care system B, which does not have neuropsychology services at the facility or in the community; this may relate to elevated teleNP satisfaction ratings. 

Further work may help identify which aspects of a teleNP service make it more useful than F2F care for this population or determine whether there were HCPor setting-specific factors that influenced the ratings (ie, preference for VA care or comparison of favorability ratings for the HCPs who conduct teleNP and F2F within the same system). The latter comparisons could not be drawn in the current systems due to the absence of HCPs who provide both teleNP and F2F modalities within VISN 20. Another consideration for future work would be to use a previously published/validated survey measure and piloting of questions with a naive sample before implementation. 

CONCLUSIONS 

This analysis provides initial support for feasibility and acceptability of teleNP as an alternative to traditional in-person neuropsychological evaluations. The small number of survey respondents may reflect the multiple pathways through which consults are forwarded to CRH 20, which includes both direct HCP referrals and forwarded consults from local neuropsychology services. CRH 20 has completed > 570 teleNP evaluations within 1 year, suggesting that lack of awareness may not be hindering veteran access to the service. Replication with a larger sample that is more broadly representative of key stakeholders in veteran care, identification of populations that would benefit most from teleNP services, and dissemination studies of the expansion of teleNP services are all important directions for future work. The robustness and longevity of the VISN 20 teleNP program, coupled with the preliminary positive findings from this project, demonstrate support for further assessment of the potential impact of telehealth on neuropsychological care within the VHA and show that barriers associated with access to health care services in remote settings may be mitigated through teleNP service delivery.

Magnetic resonance image (MRI) contrast agents can induce profound complications, including gadolinium encephalopathy, kidney injury, gadolinium-associated plaques, and progressive systemic fibrosis, which can be fatal.^1-10 About 50% of MRIs use gadolinium-based contrast (Gd³⁺), a toxic rare earth metal ion that enhances imaging but requires binding with pharmaceutical ligands to reduce toxicity and promote renal elimination (Figure 1). Despite these measures, Gd³⁺ can persist in the body, including the brain.^11,12 Wastewater treatment fails to remove these agents, making Gd³⁺ a growing pollutant in water and the food chain.^13-15 Because Gd³⁺ is a rare earth metal ion in the milieu intérieur, there is an urgent need to study its biological and long-term effects (Appendix 1). 

Case Presentation

A 65-year-old Vietnam-era veteran presented to nephrology at the Raymond G. Murphy Veterans Affairs Medical Center (RGMVAMC) in Albuquerque, New Mexico, for evaluation of gadolinium-induced symptoms. His medical history included metabolic syndrome, hypertension, hyperlipidemia, hypogonadism, cervical spondylosis, and an elevated prostate-specific antigen, previously assessed with a contrast-enhanced MRI in 2019 (Gadobenic acid, 19 mL). Surgical history included cervical fusion and ankle hardware.

The patient had a scheduled MRI 25 days earlier, following an elevated prostate specific antigen test result, prompting urologic surveillance and concern for malignancy. In preparation for the contrast-enhanced MRI, his right arm was cannulated with a line primed with gadobenic acid contrast. Though the technician stated the infusion had not started, the patient’s symptoms began shortly after entry into the scanner, before any programmed pulse sequences. The patient experienced claustrophobia, diaphoresis, palpitations, xerostomia, dysgeusia, shortness of breath, and a sensation of heat in his groin, chest, “kidneys,” and lower back. The MRI was terminated prematurely in response to the patient’s acute symptomatology. The patient continued experiencing new symptoms intermittently during the following week, including lightheadedness, headaches, right clavicular pain, raspy voice, edema, and a sense of doom.

The patient presented to the RGMVAMC emergency department (ED) 8 days after the MRI with worsening symptoms and was hospitalized for 10 days. During this time, he was referred to nephrology for outpatient evaluation. While awaiting his nephrology appointment, the patient presented to the RGMVAMC ED 20 days after the initial episode with ongoing symptoms. “I thought I was dying,” he said. Laboratory results and a 12-lead electrocardiogram showed a finely static background, wide P waves (> 80 ms) with notching in lead II, sinusoidal P waves in V1, R transition in V2, RR’ in V2, ST flat in lead III, and sinus bradycardia (Table 1 and Appendix 2).

The patient’s medical and surgical histories were reviewed at the nephrology evaluation 25 days following the MRI. He reported that household water was sourced from a well and that he filtered his drinking water with a reverse osmosis system. He served in the US Army for 10 years as an engineer specializing in mechanical systems, power generation, and vehicles. Following Army retirement, the patient served in the US Air Force Reserves for 15 years, working as a crew chief in pneudraulics. The patient reported stopping tobacco use 1 year before and also reported regular use of a broad array of prescription medications and dietary supplements, including dexamethasone (4 mg twice daily), fluticasone nasal spray (50 mcg per nostril, twice daily), ibuprofen (400 mg twice daily, as needed), loratadine (10 mg daily), aspirin (81 mg daily), and metoprolol succinate (50 mg nightly). In addition, he reported consistent use of cholecalciferol (3000 IU daily), another supplemental vitamin D preparation, chelated magnesium glycinate (3 tablets daily for bone issues), turmeric (1 tablet daily), a multivitamin (Living Green Liquid Gel, daily), and a mega-B complex.

Physical examination revealed a well-nourished, tall man with hypertension (145/87 mmHg) and bilateral lower extremity edema. Oral examination showed poor dentition, including missing molars (#1-3, #14-16, #17-19, #30-31), with the anterior teeth replaced by bridges supported by dental implants. The review of systems was otherwise unremarkable, with nocturia noted before the consultation.

Serum and urine gadolinium testing, (Mayo Clinic Laboratories) revealed gadolinium levels of 0.3 mcg/24 h in the urine and 0.1 ng/mL in the serum. Nonzero values indicated detectable gadolinium, suggesting retention. The patient had a prior gadolinium exposure during a 2019 MRI (about 1340 days before) and suspected a repeat exposure on day 0, although the MRI technician stated that no contrast was administered. Given his elevated vitamin D levels, the patient was advised to minimize dietary supplements, particularly vitamin D, to avoid confounding symptoms. The plan included monitoring symptoms and a follow-up evaluation with repeat laboratory tests on day 116.

At the nephrology follow-up 4 months postexposure, the patient's symptoms had primarily abated, with a marked reduction in the previously noted metallic dysgeusia. Physical examination remained consistent with prior findings. He was afebrile (97.7 °F) with a blood pressure of 111/72 mmHg, a pulse of 63 beats per minute, and an oxygen saturation of 98% on ambient air. Laboratory analysis revealed serum and urine gadolinium levels below detectable thresholds (< 0.1 ng/mL and < 0.1 mcg/24 h). A 24-hour creatinine clearance, calculated from a urine volume of 1300 mL, measured at an optimal 106 mL/min, indicating preserved renal function (Tables 2 and 3). Of note, his 24-hour oxalate was above the reference range, with a urine pH below the reference range and a high supersaturation index for calcium oxalate.

Discussion

Use of enhanced MRI has increased in the Veterans Health Administration (Figure 2). A growing range of indications for enhanced procedures (eg, cardiac MRI) has contributed to this rise. The market has grown with new gadolinium-based contrast agents, such as gadopiclenol. However, reliance on untested assumptions about the safety of newer agents and need for robust clinical trials pose potential risks to patient safety.

Without prospective evidence, the American College of Radiology (ACR) classifies gadolinium-based contrast agents into 3 groups: Group 1, associated with the highest number of nephrogenic systemic fibrosis cases; Group 2, linked to few, if any, unconfounded cases; and Group 3, where data on nephrogenic systemic fibrosis risk have been limited. As of April 2024, the ACR reclassified Group 3 agents (Ablavar/Vasovist/Angiomark and Primovist/Eovist) into Group 2. Curiously, Vueway and Elucirem were approved in late 2022 and should clearly be categorized as Group 3 (Table 4).There were 19 cases of nephrogenic systemic fibrosis or similar manifestations, 8 of which were unconfounded by other factors. These patients had been exposed to gadobutrol, often combined with other agents. Gadobutrol—like other Group 2 agents—has been associated with nephrogenic systemic fibrosis.^16,17 Despite US Food and Drug Administration (FDA) documentation of rising reports, many clinicians remain unaware that nephrogenic systemic fibrosis is increasingly linked to Group 2 agents classified by the ACR.¹⁸ While declines in reported cases of nephrogenic systemic fibrosis may suggest reduced incidence, this trend may reflect diminished clinical vigilance and underreporting, particularly given emerging evidence implicating even Group 2 gadolinium-based contrast agents in delayed and underrecognized presentations. This information has yet to permeate the medical community, particularly among nephrologists. Considering these cases, revisiting the ACR guidelines may be prudent. 

To address this growing concern, clinicians must adopt stricter vigilance and actively pursue updated information to mitigate patient risks tied to these contrast agents. 

There exists an illusion of knowledge in disregarding the confounded exposures of MRI contrast agents. Ten distinct brands of contrast agents have been approved for clinical use. With repeated imaging, patients are often exposed to varying formulations of gadolinium-based agents. Yet investigators commonly discard these data points when assessing risk. By doing so, they assume—without evidence—that some formulations are inherently less likely to provoke adverse effects (AEs) than others. This untested presumption becomes perilous, especially given the limited understanding of the mechanisms underlying gadolinium-induced pathologies. As Aldous Huxley warned, “Facts do not cease to exist because they are ignored.”¹⁹

Gadolinium Persistence

Contrary to expectations, gadolinium persists in the body far longer than initially presumed. Symptoms associated with gadolinium exposure (SAGE) encapsulate the chronic, often enigmatic maladies tied to MRI contrast agents.²⁰ The prolonged retention of this rare earth metal offers a compelling hypothesis for the etiology of SAGE. It has been hypothesized that Lewis base-rich metabolites increase susceptibility to gadolinium-based contrast agent complications.²¹

The blood and urine concentration elimination curves of gadolinium are exponential and categorized as fast, intermediate, and long-term.¹ For urinary elimination, the function of the curves is exponential. The quantity of gadolinium in the urine at a time (t) after exposure (D_[Gd](t)) is equal to the product of the amount of gadolinium in the sample (urine or blood) at the end of the fast elimination period (D_[Gd](t₀)) and the exponential decay with k being a rate constant.

To the authors’ knowledge, we are the only research team currently investigating the rate constant for the intermediate- and long-term phase gadolinium elimination. The Retention and Toxicity of Gadolinium-based Contrast Agents study was approved by the University of New Mexico Health Sciences Center Institutional Review Board on May 27, 2020 (IRB ID 19-660). The data for the patient in this case were compared with preliminary results for patients with exposure-to-measurement intervals < 100 days. 

The patient in this case presented with detectable gadolinium levels in urine and serum shortly after an attempted contrast-enhanced MRI procedure (Figure 3). The presence of detectable gadolinium levels in the patient’s urine and serum suggests a likely exposure to a contrast agent about 27 days before his consultation. While the technician reported that no contrast was administered during the attempted MRI, it remains possible that a small amount was introduced during cannulation, potentially triggering the patient’s symptoms. Linear modeling of semilogarithmic plots for participants exposed to contrast agents within 100 days (urine: P = 1.8 × 10^ˉ8, adjusted r² = 0.62; blood: P = .005, adjusted r² = 0.21) provided clearance rates (k values) for urine and blood. Extrapolating from these models to the presumed exposure date, the intercepts estimate that the patient received between 0.5% and 8% of a standard contrast dose.

MRI contrast agents can cause skin disease. Systemic fibrosis is considered one of the most severe AEs. Skin pathophysiology involving myeloid cells is driven by elevated levels of monocyte chemoattractant protein-1, which recruits circulating fibroblasts via the C-C chemokine receptor 2.^22,23 This occurs alongside activation of NADPH oxidase Nox4.^4,24,25 Intracellular gadolinium-rich nanoparticles likely serve as catalysts for this reactive cascade.^{2,18,22,26,27} These particles assemble around intracellular lipid droplets and ferrule them in spiculated rare earth-rich shells that compromise cellular architecture.^{2,18,21,22,26,27} Frequently sequestered within endosomal compartments, they disrupt vesicular integrity and threaten cellular homeostasis. Interference with degradative systems such as the endolysosomal axis perturbs energy-recycling pathways—an insidious disturbance, particularly in cells with high metabolic demand. Skin-related symptoms are among the most frequently reported AEs, according to the FDA AE reporting system.¹⁸ 

Studies indicate repeated exposure to MRI contrast agents can lead to permanent gadolinium retention in the brain and other vital organs. Intravenous (IV) contrast agents cross the blood-brain barrier rapidly, while intrathecal administration has been linked to significant and lasting neurologic effects.¹⁸ 

Gadolinium is chemically bound to pharmaceutical ligands to enhance renal clearance and reduce toxicity. However, available data from human samples suggest potential ligand exchanges with undefined physiologic substances. This exchange may facilitate gadolinium precipitation and accumulation within cells into spiculated nanoparticles. Transmission electron microscopy reveals the formation of unilamellar bodies associated with mitochondriopathy and cellular damage, particularly in renal proximal tubules.^{2,18,22,26,27} It is proposed that intracellular nanoparticle formation represents a key mechanism driving the systemic symptoms observed in patients.^{1,2,18, 22,26,27} 

Any hypothesis based on free soluble gadolinium—or concept derived from it—should be discarded. The high affinity of pharmaceutical ligands for gadolinium suggests that the cationic rare earth metal remains predominantly in a ligand-bound, soluble form. It is hypothesized that gadolinium undergoes ligand exchange with physiologic substances, directly leading to nanoparticle formation. Current data demonstrate gadolinium precipitation according to the Le Chatelier’s principle. Since precipitated gadolinium does not readily re-equilibrate with pharmaceutical ligands, repeated administration of different contrast agent brands may contribute to nanoparticle growth.²⁶

Meanwhile, a growing number of patients are turning to chelation therapy, a largely untested treatment. The premise of chelation therapy is rooted in several unproven assumptions.^18,21 First, it assumes that clinically significant amounts of gadolinium persist in compartments such as the extracellular space, where they can be effectively chelated and cleared. Second, it presumes that free gadolinium is the primary driver of chronic symptoms, an assertion that remains scientifically unsubstantiated. Finally, chelation proponents overlook the potential harm caused by depleting essential physiological metals during the process, assuming without evidence that the scant removal of gadolinium outweighs the risk of physiological mineral depletion. 

These assumptions underpin an unproven remedy that demands critical scrutiny. Recent findings reveal that gadolinium deposits in the skin and kidney often take the form of intracellular nanoparticles, directly challenging the foundation of chelation therapy. Chelation advocates must demonstrate that these intracellular gadolinium deposits neither trigger cellular toxicity nor initiate a cytokine cascade. Chelation supporters must prove that the systemic response to these foreign particles is unrelated to the symptoms reported by patients. Until then, the validity of chelation therapy remains highly questionable.

The causality of the symptoms, mainly whether IV gadolinium was administered, was examined. The null hypothesis stated that the patient was not exposed to gadolinium. However, this hypothesis was contradicted by the detection of gadolinium in the serum and urine 27 days after the potential exposure. 

Two plausible explanations exist for the nonzero gadolinium levels detected in the serum and urine. The first possibility is that minute quantities of gadolinium were introduced during cannulation, with the amount being sufficient to persist in measurable concentrations 27 days postexposure. The second possibility is that the gadolinium originated from an MRI contrast agent administered 4 years earlier. In this scenario, gadolinium stored in organ reservoirs such as bone, liver, or kidneys may have been mobilized into the extracellular fluid compartment due to the administration of high-dose steroids 20 days after the recent contrast-enhanced MRI procedure attempt. Coyte et al reported elevated gadolinium levels in the serum, cord blood, breast milk, and placenta of pregnant women with prior exposure to MRI contrast agents.²⁸ These findings suggest that gadolinium, stored in organs such as bone may be remobilized by variables affecting bone remodeling (eg, high-dose steroids). 

Significantly, the patient exhibited elevated urinary oxalate levels. Previous research has found that oxalic acid reacts rapidly with MRI contrast agents, forming digadolinium trioxalate. While the gadolinium-rich nanoparticles identified in tissues such as the skin and kidney (including the human kidney) are amorphous, these in vitro findings establish a proof-of-concept: the intracellular environment facilitates gadolinium dissociation from pharmaceutical chelates. 

Furthermore, in vitro experiments show that proteins and lysosomal pH promote this dissociation, underscoring how human metabolic conditions—particularly oxalic acid concentration—may drive intracellular gadolinium deposition.

Patient Perspective

“They put something into my body that they cannot get out.” This stark realization underpins the patient’s profound concern about gadolinium-based contrast agents and their potential long-term effects. Reflecting on his experience, the patient expressed deep fears about the unknown future impacts: “I’m concerned about my kidneys, I’m concerned about my heart, and I’m concerned about my brain. I don’t know how this stuff is going to affect me in the future.”

He drew an unsettling parallel between gadolinium and heavy metals: “Heavy metal is poison. The body does not produce this kind of stuff on its own.” His reaction to the procedure left a lasting impression, prompting him to question the logic of using a substance that cannot be purged: “Why would you put something into someone’s body that you cannot extract? Nobody—nobody—should experience what I went through.”

The patient emphasized the lack of clear research on long-term outcomes, which compounds his anxiety: “If there was research that said, ‘Well, this is only going to affect these organs for this long,’ OK, I might be able to accept that. But there is no research like that. Nobody can tell me what’s going to happen in 5 years.”

Strengths and Limitations

A significant strength of this approach is the ability to track gadolinium elimination and symptom resolution over time, supported by unique access to intermediate and long-term clearance data from our ongoing research protocol. The investigators were equipped to back-extrapolate the exposure, which provided a rare opportunity to correlate gadolinium levels with clinical outcomes. The primary limitation is the lack of a defined clinical case definition for gadolinium toxicity and limited mechanistic understanding of SAGE, which hinders diagnosis and management.

Metabolites, proteins, and lipids rich in Lewis bases could initiate this process as substrates for intracellular gadolinium sedimentation. Future studies should investigate whether metabolic conditions such as oxalate burden or altered parathyroid hormone levels modulate gadolinium compartmentalization and tissue retention. If gadolinium-rich nanoparticle formation and accumulation disrupt cellular equilibrium, it underscores an urgent need to understand the implications of long-term gadolinium retention. The research team continues to gather evidence that the gadolinium cation remains chelated from the moment MRI contrast agents are administered through to the formation of intracellular nanoparticles. Retained gadolinium nanoparticles may act as a nidus, triggering cellular signaling cascades that lead to multisymptomatic illnesses. Intracellular and insoluble retained gadolinium challenges proponents of untested chelation therapies.

Conclusions

This case highlights emerging clinical and ethical concerns surrounding gadolinium-based contrast agent use. Clinicians may benefit from considering gadolinium retention as a contributor to persistent, unexplained symptoms—particularly in patients with recent imaging exposure. As contrast use continues to rise within federal health systems, regulatory and administrative stakeholders would do well to re-examine current safety frameworks. Informed consent should reflect what is known: gadolinium can remain in the body long after administration, potentially indefinitely. The long-term consequences of cumulative exposure remain poorly defined, but the presence of a lanthanide element in human tissue warrants greater attention from researchers and regulators alike. Interest in alternative imaging modalities and long-term safety monitoring would mark progress toward more transparent, accountable care.

Magnetic resonance image (MRI) contrast agents can induce profound complications, including gadolinium encephalopathy, kidney injury, gadolinium-associated plaques, and progressive systemic fibrosis, which can be fatal.^1-10 About 50% of MRIs use gadolinium-based contrast (Gd³⁺), a toxic rare earth metal ion that enhances imaging but requires binding with pharmaceutical ligands to reduce toxicity and promote renal elimination (Figure 1). Despite these measures, Gd³⁺ can persist in the body, including the brain.^11,12 Wastewater treatment fails to remove these agents, making Gd³⁺ a growing pollutant in water and the food chain.^13-15 Because Gd³⁺ is a rare earth metal ion in the milieu intérieur, there is an urgent need to study its biological and long-term effects (Appendix 1). 

Case Presentation

A 65-year-old Vietnam-era veteran presented to nephrology at the Raymond G. Murphy Veterans Affairs Medical Center (RGMVAMC) in Albuquerque, New Mexico, for evaluation of gadolinium-induced symptoms. His medical history included metabolic syndrome, hypertension, hyperlipidemia, hypogonadism, cervical spondylosis, and an elevated prostate-specific antigen, previously assessed with a contrast-enhanced MRI in 2019 (Gadobenic acid, 19 mL). Surgical history included cervical fusion and ankle hardware.

The patient had a scheduled MRI 25 days earlier, following an elevated prostate specific antigen test result, prompting urologic surveillance and concern for malignancy. In preparation for the contrast-enhanced MRI, his right arm was cannulated with a line primed with gadobenic acid contrast. Though the technician stated the infusion had not started, the patient’s symptoms began shortly after entry into the scanner, before any programmed pulse sequences. The patient experienced claustrophobia, diaphoresis, palpitations, xerostomia, dysgeusia, shortness of breath, and a sensation of heat in his groin, chest, “kidneys,” and lower back. The MRI was terminated prematurely in response to the patient’s acute symptomatology. The patient continued experiencing new symptoms intermittently during the following week, including lightheadedness, headaches, right clavicular pain, raspy voice, edema, and a sense of doom.

The patient presented to the RGMVAMC emergency department (ED) 8 days after the MRI with worsening symptoms and was hospitalized for 10 days. During this time, he was referred to nephrology for outpatient evaluation. While awaiting his nephrology appointment, the patient presented to the RGMVAMC ED 20 days after the initial episode with ongoing symptoms. “I thought I was dying,” he said. Laboratory results and a 12-lead electrocardiogram showed a finely static background, wide P waves (> 80 ms) with notching in lead II, sinusoidal P waves in V1, R transition in V2, RR’ in V2, ST flat in lead III, and sinus bradycardia (Table 1 and Appendix 2).

The patient’s medical and surgical histories were reviewed at the nephrology evaluation 25 days following the MRI. He reported that household water was sourced from a well and that he filtered his drinking water with a reverse osmosis system. He served in the US Army for 10 years as an engineer specializing in mechanical systems, power generation, and vehicles. Following Army retirement, the patient served in the US Air Force Reserves for 15 years, working as a crew chief in pneudraulics. The patient reported stopping tobacco use 1 year before and also reported regular use of a broad array of prescription medications and dietary supplements, including dexamethasone (4 mg twice daily), fluticasone nasal spray (50 mcg per nostril, twice daily), ibuprofen (400 mg twice daily, as needed), loratadine (10 mg daily), aspirin (81 mg daily), and metoprolol succinate (50 mg nightly). In addition, he reported consistent use of cholecalciferol (3000 IU daily), another supplemental vitamin D preparation, chelated magnesium glycinate (3 tablets daily for bone issues), turmeric (1 tablet daily), a multivitamin (Living Green Liquid Gel, daily), and a mega-B complex.

Physical examination revealed a well-nourished, tall man with hypertension (145/87 mmHg) and bilateral lower extremity edema. Oral examination showed poor dentition, including missing molars (#1-3, #14-16, #17-19, #30-31), with the anterior teeth replaced by bridges supported by dental implants. The review of systems was otherwise unremarkable, with nocturia noted before the consultation.

Serum and urine gadolinium testing, (Mayo Clinic Laboratories) revealed gadolinium levels of 0.3 mcg/24 h in the urine and 0.1 ng/mL in the serum. Nonzero values indicated detectable gadolinium, suggesting retention. The patient had a prior gadolinium exposure during a 2019 MRI (about 1340 days before) and suspected a repeat exposure on day 0, although the MRI technician stated that no contrast was administered. Given his elevated vitamin D levels, the patient was advised to minimize dietary supplements, particularly vitamin D, to avoid confounding symptoms. The plan included monitoring symptoms and a follow-up evaluation with repeat laboratory tests on day 116.

At the nephrology follow-up 4 months postexposure, the patient's symptoms had primarily abated, with a marked reduction in the previously noted metallic dysgeusia. Physical examination remained consistent with prior findings. He was afebrile (97.7 °F) with a blood pressure of 111/72 mmHg, a pulse of 63 beats per minute, and an oxygen saturation of 98% on ambient air. Laboratory analysis revealed serum and urine gadolinium levels below detectable thresholds (< 0.1 ng/mL and < 0.1 mcg/24 h). A 24-hour creatinine clearance, calculated from a urine volume of 1300 mL, measured at an optimal 106 mL/min, indicating preserved renal function (Tables 2 and 3). Of note, his 24-hour oxalate was above the reference range, with a urine pH below the reference range and a high supersaturation index for calcium oxalate.

Discussion

Use of enhanced MRI has increased in the Veterans Health Administration (Figure 2). A growing range of indications for enhanced procedures (eg, cardiac MRI) has contributed to this rise. The market has grown with new gadolinium-based contrast agents, such as gadopiclenol. However, reliance on untested assumptions about the safety of newer agents and need for robust clinical trials pose potential risks to patient safety.

Without prospective evidence, the American College of Radiology (ACR) classifies gadolinium-based contrast agents into 3 groups: Group 1, associated with the highest number of nephrogenic systemic fibrosis cases; Group 2, linked to few, if any, unconfounded cases; and Group 3, where data on nephrogenic systemic fibrosis risk have been limited. As of April 2024, the ACR reclassified Group 3 agents (Ablavar/Vasovist/Angiomark and Primovist/Eovist) into Group 2. Curiously, Vueway and Elucirem were approved in late 2022 and should clearly be categorized as Group 3 (Table 4).There were 19 cases of nephrogenic systemic fibrosis or similar manifestations, 8 of which were unconfounded by other factors. These patients had been exposed to gadobutrol, often combined with other agents. Gadobutrol—like other Group 2 agents—has been associated with nephrogenic systemic fibrosis.^16,17 Despite US Food and Drug Administration (FDA) documentation of rising reports, many clinicians remain unaware that nephrogenic systemic fibrosis is increasingly linked to Group 2 agents classified by the ACR.¹⁸ While declines in reported cases of nephrogenic systemic fibrosis may suggest reduced incidence, this trend may reflect diminished clinical vigilance and underreporting, particularly given emerging evidence implicating even Group 2 gadolinium-based contrast agents in delayed and underrecognized presentations. This information has yet to permeate the medical community, particularly among nephrologists. Considering these cases, revisiting the ACR guidelines may be prudent. 

To address this growing concern, clinicians must adopt stricter vigilance and actively pursue updated information to mitigate patient risks tied to these contrast agents. 

There exists an illusion of knowledge in disregarding the confounded exposures of MRI contrast agents. Ten distinct brands of contrast agents have been approved for clinical use. With repeated imaging, patients are often exposed to varying formulations of gadolinium-based agents. Yet investigators commonly discard these data points when assessing risk. By doing so, they assume—without evidence—that some formulations are inherently less likely to provoke adverse effects (AEs) than others. This untested presumption becomes perilous, especially given the limited understanding of the mechanisms underlying gadolinium-induced pathologies. As Aldous Huxley warned, “Facts do not cease to exist because they are ignored.”¹⁹

Gadolinium Persistence

Contrary to expectations, gadolinium persists in the body far longer than initially presumed. Symptoms associated with gadolinium exposure (SAGE) encapsulate the chronic, often enigmatic maladies tied to MRI contrast agents.²⁰ The prolonged retention of this rare earth metal offers a compelling hypothesis for the etiology of SAGE. It has been hypothesized that Lewis base-rich metabolites increase susceptibility to gadolinium-based contrast agent complications.²¹

The blood and urine concentration elimination curves of gadolinium are exponential and categorized as fast, intermediate, and long-term.¹ For urinary elimination, the function of the curves is exponential. The quantity of gadolinium in the urine at a time (t) after exposure (D_[Gd](t)) is equal to the product of the amount of gadolinium in the sample (urine or blood) at the end of the fast elimination period (D_[Gd](t₀)) and the exponential decay with k being a rate constant.

To the authors’ knowledge, we are the only research team currently investigating the rate constant for the intermediate- and long-term phase gadolinium elimination. The Retention and Toxicity of Gadolinium-based Contrast Agents study was approved by the University of New Mexico Health Sciences Center Institutional Review Board on May 27, 2020 (IRB ID 19-660). The data for the patient in this case were compared with preliminary results for patients with exposure-to-measurement intervals < 100 days. 

The patient in this case presented with detectable gadolinium levels in urine and serum shortly after an attempted contrast-enhanced MRI procedure (Figure 3). The presence of detectable gadolinium levels in the patient’s urine and serum suggests a likely exposure to a contrast agent about 27 days before his consultation. While the technician reported that no contrast was administered during the attempted MRI, it remains possible that a small amount was introduced during cannulation, potentially triggering the patient’s symptoms. Linear modeling of semilogarithmic plots for participants exposed to contrast agents within 100 days (urine: P = 1.8 × 10^ˉ8, adjusted r² = 0.62; blood: P = .005, adjusted r² = 0.21) provided clearance rates (k values) for urine and blood. Extrapolating from these models to the presumed exposure date, the intercepts estimate that the patient received between 0.5% and 8% of a standard contrast dose.

MRI contrast agents can cause skin disease. Systemic fibrosis is considered one of the most severe AEs. Skin pathophysiology involving myeloid cells is driven by elevated levels of monocyte chemoattractant protein-1, which recruits circulating fibroblasts via the C-C chemokine receptor 2.^22,23 This occurs alongside activation of NADPH oxidase Nox4.^4,24,25 Intracellular gadolinium-rich nanoparticles likely serve as catalysts for this reactive cascade.^{2,18,22,26,27} These particles assemble around intracellular lipid droplets and ferrule them in spiculated rare earth-rich shells that compromise cellular architecture.^{2,18,21,22,26,27} Frequently sequestered within endosomal compartments, they disrupt vesicular integrity and threaten cellular homeostasis. Interference with degradative systems such as the endolysosomal axis perturbs energy-recycling pathways—an insidious disturbance, particularly in cells with high metabolic demand. Skin-related symptoms are among the most frequently reported AEs, according to the FDA AE reporting system.¹⁸ 

Studies indicate repeated exposure to MRI contrast agents can lead to permanent gadolinium retention in the brain and other vital organs. Intravenous (IV) contrast agents cross the blood-brain barrier rapidly, while intrathecal administration has been linked to significant and lasting neurologic effects.¹⁸ 

Gadolinium is chemically bound to pharmaceutical ligands to enhance renal clearance and reduce toxicity. However, available data from human samples suggest potential ligand exchanges with undefined physiologic substances. This exchange may facilitate gadolinium precipitation and accumulation within cells into spiculated nanoparticles. Transmission electron microscopy reveals the formation of unilamellar bodies associated with mitochondriopathy and cellular damage, particularly in renal proximal tubules.^{2,18,22,26,27} It is proposed that intracellular nanoparticle formation represents a key mechanism driving the systemic symptoms observed in patients.^{1,2,18, 22,26,27} 

Any hypothesis based on free soluble gadolinium—or concept derived from it—should be discarded. The high affinity of pharmaceutical ligands for gadolinium suggests that the cationic rare earth metal remains predominantly in a ligand-bound, soluble form. It is hypothesized that gadolinium undergoes ligand exchange with physiologic substances, directly leading to nanoparticle formation. Current data demonstrate gadolinium precipitation according to the Le Chatelier’s principle. Since precipitated gadolinium does not readily re-equilibrate with pharmaceutical ligands, repeated administration of different contrast agent brands may contribute to nanoparticle growth.²⁶

Meanwhile, a growing number of patients are turning to chelation therapy, a largely untested treatment. The premise of chelation therapy is rooted in several unproven assumptions.^18,21 First, it assumes that clinically significant amounts of gadolinium persist in compartments such as the extracellular space, where they can be effectively chelated and cleared. Second, it presumes that free gadolinium is the primary driver of chronic symptoms, an assertion that remains scientifically unsubstantiated. Finally, chelation proponents overlook the potential harm caused by depleting essential physiological metals during the process, assuming without evidence that the scant removal of gadolinium outweighs the risk of physiological mineral depletion. 

These assumptions underpin an unproven remedy that demands critical scrutiny. Recent findings reveal that gadolinium deposits in the skin and kidney often take the form of intracellular nanoparticles, directly challenging the foundation of chelation therapy. Chelation advocates must demonstrate that these intracellular gadolinium deposits neither trigger cellular toxicity nor initiate a cytokine cascade. Chelation supporters must prove that the systemic response to these foreign particles is unrelated to the symptoms reported by patients. Until then, the validity of chelation therapy remains highly questionable.

The causality of the symptoms, mainly whether IV gadolinium was administered, was examined. The null hypothesis stated that the patient was not exposed to gadolinium. However, this hypothesis was contradicted by the detection of gadolinium in the serum and urine 27 days after the potential exposure. 

Two plausible explanations exist for the nonzero gadolinium levels detected in the serum and urine. The first possibility is that minute quantities of gadolinium were introduced during cannulation, with the amount being sufficient to persist in measurable concentrations 27 days postexposure. The second possibility is that the gadolinium originated from an MRI contrast agent administered 4 years earlier. In this scenario, gadolinium stored in organ reservoirs such as bone, liver, or kidneys may have been mobilized into the extracellular fluid compartment due to the administration of high-dose steroids 20 days after the recent contrast-enhanced MRI procedure attempt. Coyte et al reported elevated gadolinium levels in the serum, cord blood, breast milk, and placenta of pregnant women with prior exposure to MRI contrast agents.²⁸ These findings suggest that gadolinium, stored in organs such as bone may be remobilized by variables affecting bone remodeling (eg, high-dose steroids). 

Significantly, the patient exhibited elevated urinary oxalate levels. Previous research has found that oxalic acid reacts rapidly with MRI contrast agents, forming digadolinium trioxalate. While the gadolinium-rich nanoparticles identified in tissues such as the skin and kidney (including the human kidney) are amorphous, these in vitro findings establish a proof-of-concept: the intracellular environment facilitates gadolinium dissociation from pharmaceutical chelates. 

Furthermore, in vitro experiments show that proteins and lysosomal pH promote this dissociation, underscoring how human metabolic conditions—particularly oxalic acid concentration—may drive intracellular gadolinium deposition.

Patient Perspective

“They put something into my body that they cannot get out.” This stark realization underpins the patient’s profound concern about gadolinium-based contrast agents and their potential long-term effects. Reflecting on his experience, the patient expressed deep fears about the unknown future impacts: “I’m concerned about my kidneys, I’m concerned about my heart, and I’m concerned about my brain. I don’t know how this stuff is going to affect me in the future.”

He drew an unsettling parallel between gadolinium and heavy metals: “Heavy metal is poison. The body does not produce this kind of stuff on its own.” His reaction to the procedure left a lasting impression, prompting him to question the logic of using a substance that cannot be purged: “Why would you put something into someone’s body that you cannot extract? Nobody—nobody—should experience what I went through.”

The patient emphasized the lack of clear research on long-term outcomes, which compounds his anxiety: “If there was research that said, ‘Well, this is only going to affect these organs for this long,’ OK, I might be able to accept that. But there is no research like that. Nobody can tell me what’s going to happen in 5 years.”

Strengths and Limitations

A significant strength of this approach is the ability to track gadolinium elimination and symptom resolution over time, supported by unique access to intermediate and long-term clearance data from our ongoing research protocol. The investigators were equipped to back-extrapolate the exposure, which provided a rare opportunity to correlate gadolinium levels with clinical outcomes. The primary limitation is the lack of a defined clinical case definition for gadolinium toxicity and limited mechanistic understanding of SAGE, which hinders diagnosis and management.

Metabolites, proteins, and lipids rich in Lewis bases could initiate this process as substrates for intracellular gadolinium sedimentation. Future studies should investigate whether metabolic conditions such as oxalate burden or altered parathyroid hormone levels modulate gadolinium compartmentalization and tissue retention. If gadolinium-rich nanoparticle formation and accumulation disrupt cellular equilibrium, it underscores an urgent need to understand the implications of long-term gadolinium retention. The research team continues to gather evidence that the gadolinium cation remains chelated from the moment MRI contrast agents are administered through to the formation of intracellular nanoparticles. Retained gadolinium nanoparticles may act as a nidus, triggering cellular signaling cascades that lead to multisymptomatic illnesses. Intracellular and insoluble retained gadolinium challenges proponents of untested chelation therapies.

Conclusions

This case highlights emerging clinical and ethical concerns surrounding gadolinium-based contrast agent use. Clinicians may benefit from considering gadolinium retention as a contributor to persistent, unexplained symptoms—particularly in patients with recent imaging exposure. As contrast use continues to rise within federal health systems, regulatory and administrative stakeholders would do well to re-examine current safety frameworks. Informed consent should reflect what is known: gadolinium can remain in the body long after administration, potentially indefinitely. The long-term consequences of cumulative exposure remain poorly defined, but the presence of a lanthanide element in human tissue warrants greater attention from researchers and regulators alike. Interest in alternative imaging modalities and long-term safety monitoring would mark progress toward more transparent, accountable care.

Magnetic resonance image (MRI) contrast agents can induce profound complications, including gadolinium encephalopathy, kidney injury, gadolinium-associated plaques, and progressive systemic fibrosis, which can be fatal.^1-10 About 50% of MRIs use gadolinium-based contrast (Gd³⁺), a toxic rare earth metal ion that enhances imaging but requires binding with pharmaceutical ligands to reduce toxicity and promote renal elimination (Figure 1). Despite these measures, Gd³⁺ can persist in the body, including the brain.^11,12 Wastewater treatment fails to remove these agents, making Gd³⁺ a growing pollutant in water and the food chain.^13-15 Because Gd³⁺ is a rare earth metal ion in the milieu intérieur, there is an urgent need to study its biological and long-term effects (Appendix 1). 

Case Presentation

A 65-year-old Vietnam-era veteran presented to nephrology at the Raymond G. Murphy Veterans Affairs Medical Center (RGMVAMC) in Albuquerque, New Mexico, for evaluation of gadolinium-induced symptoms. His medical history included metabolic syndrome, hypertension, hyperlipidemia, hypogonadism, cervical spondylosis, and an elevated prostate-specific antigen, previously assessed with a contrast-enhanced MRI in 2019 (Gadobenic acid, 19 mL). Surgical history included cervical fusion and ankle hardware.

The patient had a scheduled MRI 25 days earlier, following an elevated prostate specific antigen test result, prompting urologic surveillance and concern for malignancy. In preparation for the contrast-enhanced MRI, his right arm was cannulated with a line primed with gadobenic acid contrast. Though the technician stated the infusion had not started, the patient’s symptoms began shortly after entry into the scanner, before any programmed pulse sequences. The patient experienced claustrophobia, diaphoresis, palpitations, xerostomia, dysgeusia, shortness of breath, and a sensation of heat in his groin, chest, “kidneys,” and lower back. The MRI was terminated prematurely in response to the patient’s acute symptomatology. The patient continued experiencing new symptoms intermittently during the following week, including lightheadedness, headaches, right clavicular pain, raspy voice, edema, and a sense of doom.

The patient presented to the RGMVAMC emergency department (ED) 8 days after the MRI with worsening symptoms and was hospitalized for 10 days. During this time, he was referred to nephrology for outpatient evaluation. While awaiting his nephrology appointment, the patient presented to the RGMVAMC ED 20 days after the initial episode with ongoing symptoms. “I thought I was dying,” he said. Laboratory results and a 12-lead electrocardiogram showed a finely static background, wide P waves (> 80 ms) with notching in lead II, sinusoidal P waves in V1, R transition in V2, RR’ in V2, ST flat in lead III, and sinus bradycardia (Table 1 and Appendix 2).

The patient’s medical and surgical histories were reviewed at the nephrology evaluation 25 days following the MRI. He reported that household water was sourced from a well and that he filtered his drinking water with a reverse osmosis system. He served in the US Army for 10 years as an engineer specializing in mechanical systems, power generation, and vehicles. Following Army retirement, the patient served in the US Air Force Reserves for 15 years, working as a crew chief in pneudraulics. The patient reported stopping tobacco use 1 year before and also reported regular use of a broad array of prescription medications and dietary supplements, including dexamethasone (4 mg twice daily), fluticasone nasal spray (50 mcg per nostril, twice daily), ibuprofen (400 mg twice daily, as needed), loratadine (10 mg daily), aspirin (81 mg daily), and metoprolol succinate (50 mg nightly). In addition, he reported consistent use of cholecalciferol (3000 IU daily), another supplemental vitamin D preparation, chelated magnesium glycinate (3 tablets daily for bone issues), turmeric (1 tablet daily), a multivitamin (Living Green Liquid Gel, daily), and a mega-B complex.

Physical examination revealed a well-nourished, tall man with hypertension (145/87 mmHg) and bilateral lower extremity edema. Oral examination showed poor dentition, including missing molars (#1-3, #14-16, #17-19, #30-31), with the anterior teeth replaced by bridges supported by dental implants. The review of systems was otherwise unremarkable, with nocturia noted before the consultation.

Serum and urine gadolinium testing, (Mayo Clinic Laboratories) revealed gadolinium levels of 0.3 mcg/24 h in the urine and 0.1 ng/mL in the serum. Nonzero values indicated detectable gadolinium, suggesting retention. The patient had a prior gadolinium exposure during a 2019 MRI (about 1340 days before) and suspected a repeat exposure on day 0, although the MRI technician stated that no contrast was administered. Given his elevated vitamin D levels, the patient was advised to minimize dietary supplements, particularly vitamin D, to avoid confounding symptoms. The plan included monitoring symptoms and a follow-up evaluation with repeat laboratory tests on day 116.

At the nephrology follow-up 4 months postexposure, the patient's symptoms had primarily abated, with a marked reduction in the previously noted metallic dysgeusia. Physical examination remained consistent with prior findings. He was afebrile (97.7 °F) with a blood pressure of 111/72 mmHg, a pulse of 63 beats per minute, and an oxygen saturation of 98% on ambient air. Laboratory analysis revealed serum and urine gadolinium levels below detectable thresholds (< 0.1 ng/mL and < 0.1 mcg/24 h). A 24-hour creatinine clearance, calculated from a urine volume of 1300 mL, measured at an optimal 106 mL/min, indicating preserved renal function (Tables 2 and 3). Of note, his 24-hour oxalate was above the reference range, with a urine pH below the reference range and a high supersaturation index for calcium oxalate.

Discussion

Use of enhanced MRI has increased in the Veterans Health Administration (Figure 2). A growing range of indications for enhanced procedures (eg, cardiac MRI) has contributed to this rise. The market has grown with new gadolinium-based contrast agents, such as gadopiclenol. However, reliance on untested assumptions about the safety of newer agents and need for robust clinical trials pose potential risks to patient safety.

Without prospective evidence, the American College of Radiology (ACR) classifies gadolinium-based contrast agents into 3 groups: Group 1, associated with the highest number of nephrogenic systemic fibrosis cases; Group 2, linked to few, if any, unconfounded cases; and Group 3, where data on nephrogenic systemic fibrosis risk have been limited. As of April 2024, the ACR reclassified Group 3 agents (Ablavar/Vasovist/Angiomark and Primovist/Eovist) into Group 2. Curiously, Vueway and Elucirem were approved in late 2022 and should clearly be categorized as Group 3 (Table 4).There were 19 cases of nephrogenic systemic fibrosis or similar manifestations, 8 of which were unconfounded by other factors. These patients had been exposed to gadobutrol, often combined with other agents. Gadobutrol—like other Group 2 agents—has been associated with nephrogenic systemic fibrosis.^16,17 Despite US Food and Drug Administration (FDA) documentation of rising reports, many clinicians remain unaware that nephrogenic systemic fibrosis is increasingly linked to Group 2 agents classified by the ACR.¹⁸ While declines in reported cases of nephrogenic systemic fibrosis may suggest reduced incidence, this trend may reflect diminished clinical vigilance and underreporting, particularly given emerging evidence implicating even Group 2 gadolinium-based contrast agents in delayed and underrecognized presentations. This information has yet to permeate the medical community, particularly among nephrologists. Considering these cases, revisiting the ACR guidelines may be prudent. 

To address this growing concern, clinicians must adopt stricter vigilance and actively pursue updated information to mitigate patient risks tied to these contrast agents. 

There exists an illusion of knowledge in disregarding the confounded exposures of MRI contrast agents. Ten distinct brands of contrast agents have been approved for clinical use. With repeated imaging, patients are often exposed to varying formulations of gadolinium-based agents. Yet investigators commonly discard these data points when assessing risk. By doing so, they assume—without evidence—that some formulations are inherently less likely to provoke adverse effects (AEs) than others. This untested presumption becomes perilous, especially given the limited understanding of the mechanisms underlying gadolinium-induced pathologies. As Aldous Huxley warned, “Facts do not cease to exist because they are ignored.”¹⁹

Gadolinium Persistence

Contrary to expectations, gadolinium persists in the body far longer than initially presumed. Symptoms associated with gadolinium exposure (SAGE) encapsulate the chronic, often enigmatic maladies tied to MRI contrast agents.²⁰ The prolonged retention of this rare earth metal offers a compelling hypothesis for the etiology of SAGE. It has been hypothesized that Lewis base-rich metabolites increase susceptibility to gadolinium-based contrast agent complications.²¹

The blood and urine concentration elimination curves of gadolinium are exponential and categorized as fast, intermediate, and long-term.¹ For urinary elimination, the function of the curves is exponential. The quantity of gadolinium in the urine at a time (t) after exposure (D_[Gd](t)) is equal to the product of the amount of gadolinium in the sample (urine or blood) at the end of the fast elimination period (D_[Gd](t₀)) and the exponential decay with k being a rate constant.

To the authors’ knowledge, we are the only research team currently investigating the rate constant for the intermediate- and long-term phase gadolinium elimination. The Retention and Toxicity of Gadolinium-based Contrast Agents study was approved by the University of New Mexico Health Sciences Center Institutional Review Board on May 27, 2020 (IRB ID 19-660). The data for the patient in this case were compared with preliminary results for patients with exposure-to-measurement intervals < 100 days. 

The patient in this case presented with detectable gadolinium levels in urine and serum shortly after an attempted contrast-enhanced MRI procedure (Figure 3). The presence of detectable gadolinium levels in the patient’s urine and serum suggests a likely exposure to a contrast agent about 27 days before his consultation. While the technician reported that no contrast was administered during the attempted MRI, it remains possible that a small amount was introduced during cannulation, potentially triggering the patient’s symptoms. Linear modeling of semilogarithmic plots for participants exposed to contrast agents within 100 days (urine: P = 1.8 × 10^ˉ8, adjusted r² = 0.62; blood: P = .005, adjusted r² = 0.21) provided clearance rates (k values) for urine and blood. Extrapolating from these models to the presumed exposure date, the intercepts estimate that the patient received between 0.5% and 8% of a standard contrast dose.

MRI contrast agents can cause skin disease. Systemic fibrosis is considered one of the most severe AEs. Skin pathophysiology involving myeloid cells is driven by elevated levels of monocyte chemoattractant protein-1, which recruits circulating fibroblasts via the C-C chemokine receptor 2.^22,23 This occurs alongside activation of NADPH oxidase Nox4.^4,24,25 Intracellular gadolinium-rich nanoparticles likely serve as catalysts for this reactive cascade.^{2,18,22,26,27} These particles assemble around intracellular lipid droplets and ferrule them in spiculated rare earth-rich shells that compromise cellular architecture.^{2,18,21,22,26,27} Frequently sequestered within endosomal compartments, they disrupt vesicular integrity and threaten cellular homeostasis. Interference with degradative systems such as the endolysosomal axis perturbs energy-recycling pathways—an insidious disturbance, particularly in cells with high metabolic demand. Skin-related symptoms are among the most frequently reported AEs, according to the FDA AE reporting system.¹⁸ 

Studies indicate repeated exposure to MRI contrast agents can lead to permanent gadolinium retention in the brain and other vital organs. Intravenous (IV) contrast agents cross the blood-brain barrier rapidly, while intrathecal administration has been linked to significant and lasting neurologic effects.¹⁸ 

Gadolinium is chemically bound to pharmaceutical ligands to enhance renal clearance and reduce toxicity. However, available data from human samples suggest potential ligand exchanges with undefined physiologic substances. This exchange may facilitate gadolinium precipitation and accumulation within cells into spiculated nanoparticles. Transmission electron microscopy reveals the formation of unilamellar bodies associated with mitochondriopathy and cellular damage, particularly in renal proximal tubules.^{2,18,22,26,27} It is proposed that intracellular nanoparticle formation represents a key mechanism driving the systemic symptoms observed in patients.^{1,2,18, 22,26,27} 

Any hypothesis based on free soluble gadolinium—or concept derived from it—should be discarded. The high affinity of pharmaceutical ligands for gadolinium suggests that the cationic rare earth metal remains predominantly in a ligand-bound, soluble form. It is hypothesized that gadolinium undergoes ligand exchange with physiologic substances, directly leading to nanoparticle formation. Current data demonstrate gadolinium precipitation according to the Le Chatelier’s principle. Since precipitated gadolinium does not readily re-equilibrate with pharmaceutical ligands, repeated administration of different contrast agent brands may contribute to nanoparticle growth.²⁶

Meanwhile, a growing number of patients are turning to chelation therapy, a largely untested treatment. The premise of chelation therapy is rooted in several unproven assumptions.^18,21 First, it assumes that clinically significant amounts of gadolinium persist in compartments such as the extracellular space, where they can be effectively chelated and cleared. Second, it presumes that free gadolinium is the primary driver of chronic symptoms, an assertion that remains scientifically unsubstantiated. Finally, chelation proponents overlook the potential harm caused by depleting essential physiological metals during the process, assuming without evidence that the scant removal of gadolinium outweighs the risk of physiological mineral depletion. 

These assumptions underpin an unproven remedy that demands critical scrutiny. Recent findings reveal that gadolinium deposits in the skin and kidney often take the form of intracellular nanoparticles, directly challenging the foundation of chelation therapy. Chelation advocates must demonstrate that these intracellular gadolinium deposits neither trigger cellular toxicity nor initiate a cytokine cascade. Chelation supporters must prove that the systemic response to these foreign particles is unrelated to the symptoms reported by patients. Until then, the validity of chelation therapy remains highly questionable.

The causality of the symptoms, mainly whether IV gadolinium was administered, was examined. The null hypothesis stated that the patient was not exposed to gadolinium. However, this hypothesis was contradicted by the detection of gadolinium in the serum and urine 27 days after the potential exposure. 

Two plausible explanations exist for the nonzero gadolinium levels detected in the serum and urine. The first possibility is that minute quantities of gadolinium were introduced during cannulation, with the amount being sufficient to persist in measurable concentrations 27 days postexposure. The second possibility is that the gadolinium originated from an MRI contrast agent administered 4 years earlier. In this scenario, gadolinium stored in organ reservoirs such as bone, liver, or kidneys may have been mobilized into the extracellular fluid compartment due to the administration of high-dose steroids 20 days after the recent contrast-enhanced MRI procedure attempt. Coyte et al reported elevated gadolinium levels in the serum, cord blood, breast milk, and placenta of pregnant women with prior exposure to MRI contrast agents.²⁸ These findings suggest that gadolinium, stored in organs such as bone may be remobilized by variables affecting bone remodeling (eg, high-dose steroids). 

Significantly, the patient exhibited elevated urinary oxalate levels. Previous research has found that oxalic acid reacts rapidly with MRI contrast agents, forming digadolinium trioxalate. While the gadolinium-rich nanoparticles identified in tissues such as the skin and kidney (including the human kidney) are amorphous, these in vitro findings establish a proof-of-concept: the intracellular environment facilitates gadolinium dissociation from pharmaceutical chelates. 

Furthermore, in vitro experiments show that proteins and lysosomal pH promote this dissociation, underscoring how human metabolic conditions—particularly oxalic acid concentration—may drive intracellular gadolinium deposition.

Patient Perspective

“They put something into my body that they cannot get out.” This stark realization underpins the patient’s profound concern about gadolinium-based contrast agents and their potential long-term effects. Reflecting on his experience, the patient expressed deep fears about the unknown future impacts: “I’m concerned about my kidneys, I’m concerned about my heart, and I’m concerned about my brain. I don’t know how this stuff is going to affect me in the future.”

He drew an unsettling parallel between gadolinium and heavy metals: “Heavy metal is poison. The body does not produce this kind of stuff on its own.” His reaction to the procedure left a lasting impression, prompting him to question the logic of using a substance that cannot be purged: “Why would you put something into someone’s body that you cannot extract? Nobody—nobody—should experience what I went through.”

The patient emphasized the lack of clear research on long-term outcomes, which compounds his anxiety: “If there was research that said, ‘Well, this is only going to affect these organs for this long,’ OK, I might be able to accept that. But there is no research like that. Nobody can tell me what’s going to happen in 5 years.”

Strengths and Limitations

A significant strength of this approach is the ability to track gadolinium elimination and symptom resolution over time, supported by unique access to intermediate and long-term clearance data from our ongoing research protocol. The investigators were equipped to back-extrapolate the exposure, which provided a rare opportunity to correlate gadolinium levels with clinical outcomes. The primary limitation is the lack of a defined clinical case definition for gadolinium toxicity and limited mechanistic understanding of SAGE, which hinders diagnosis and management.

Metabolites, proteins, and lipids rich in Lewis bases could initiate this process as substrates for intracellular gadolinium sedimentation. Future studies should investigate whether metabolic conditions such as oxalate burden or altered parathyroid hormone levels modulate gadolinium compartmentalization and tissue retention. If gadolinium-rich nanoparticle formation and accumulation disrupt cellular equilibrium, it underscores an urgent need to understand the implications of long-term gadolinium retention. The research team continues to gather evidence that the gadolinium cation remains chelated from the moment MRI contrast agents are administered through to the formation of intracellular nanoparticles. Retained gadolinium nanoparticles may act as a nidus, triggering cellular signaling cascades that lead to multisymptomatic illnesses. Intracellular and insoluble retained gadolinium challenges proponents of untested chelation therapies.

Conclusions

This case highlights emerging clinical and ethical concerns surrounding gadolinium-based contrast agent use. Clinicians may benefit from considering gadolinium retention as a contributor to persistent, unexplained symptoms—particularly in patients with recent imaging exposure. As contrast use continues to rise within federal health systems, regulatory and administrative stakeholders would do well to re-examine current safety frameworks. Informed consent should reflect what is known: gadolinium can remain in the body long after administration, potentially indefinitely. The long-term consequences of cumulative exposure remain poorly defined, but the presence of a lanthanide element in human tissue warrants greater attention from researchers and regulators alike. Interest in alternative imaging modalities and long-term safety monitoring would mark progress toward more transparent, accountable care.