Case Reports

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

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

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

Case Presentation

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

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

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

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

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

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

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

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

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

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

Discussion

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

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

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

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

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

Conclusions

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

Acknowledgments

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

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

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

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

Case Presentation

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

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

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

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

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

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

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

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

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

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

Discussion

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

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

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

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

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

Conclusions

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

Acknowledgments

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

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

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

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

Case Presentation

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

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

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

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

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

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

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

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

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

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

Discussion

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

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

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

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

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

Conclusions

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

Acknowledgments

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

Gadolinium (Gd)-based contrast agents are frequently used in health care for enhancing magnetic resonance image (MRI) signals at low concentrations. Contrary to popular opinion, this widely used heavy metal is not biologically inert. Once notable for its safety profile, there is mounting evidence for Gd deposition in various organ systems of the body, even in those with normal renal function. A large knowledge gap remains concerning the potential harms of Gd deposition and the factors determining its elimination from the body. However, the findings of deposited Gd throughout various organs and their intracellular compartments even years after the initial exposure have been established. Here, we describe a case of a Vietnam-era veteran whose presentation, clinical, and laboratory findings were consistent within the spectrum of Gd deposition disease. 

Case Presentation

A Vietnam-era veteran aged > 70 years presented for evaluation of Gd-based contrast agent–induced chronic multisymptomatic illness His medical history was significant for chronic low back pain, chronic hypertension, type 2 diabetes mellitus, and hypogonadism. Surgical history was notable for back surgery (24 years prior), laminectomy (2 years prior), shoulder replacement (2 years prior), and an epidural complicated by a hematoma (1 year prior). His presenting concerns included a painful and pruritic rash that worsened with showering, pain originating at the right Achilles tendon with migration to the knee, and shoulder pain. His symptoms started shortly after receiving multiple exposures to Gd-based contrast agents to enhance MRIs during his clinical care (Omniscan 20 mL, Omniscan 20 mL, and Gadovist 10 mL, administered 578, 565, and 496 days prior to the clinic visit, respectively). New onset headaches coincided with the timeline of symptom onset, in addition to hoarseness and liberation of an “oily substance” from the skin. More than one year prior to this clinic visit, he was considered for having polymyalgia rheumatica given the ambiguity of symptoms. Functional status remained impaired despite treatment with prednisone and methotrexate.

The patient’s military service was in the mid-1960s. He was deployed to Japan and had no knowledge of an Agent Orange exposure. His tobacco history was distant, and he reported no tattoos, prior transfusions, or occupational metal exposure (he was never stationed at Camp Lejeune or other bases with potential toxicants in the drinking water). Family history was significant for lung cancer in his mother (smoker) and his father died aged > 90 years. One sister had fibromyalgia. The patient’s children were healthy.

Clinical Findings

The patient was afebrile, normotensive (146/88 mmHg), and normocardic. His weight was 100 kg. He was well nourished and in no acute distress. The thought process was attentive, and his affect pleasant. Ocular examination was notable for arcus senilus. The fundoscopic examination was limited on the left, but there was no neovascularization on the right. Jugular venous pulsation was normal at 8 cm. Right ventricular impulse was slightly hyperdynamic, the rhythm was regular, and there was no abnormal splitting of S2. A soft-grade I/VI crescendo/decrescendo murmur was auscultated along the apex. Radial pulses were 2/2. He was not in respiratory distress, with equally resonant fields bilaterally. Lung sounds were clear bilaterally. A papular, erythematous rash was present in a general distribution over the chest, with few telangiectasias and some varicosity along his left arm. The skin had normal elasticity, although the skin of the hands and legs was papyraceous.

Gd levels were measured in the blood and urine (Table 1). Gd was detectable in the skin (0.2 µg/g) nearly 400 days after the last exposure. Gd was still detectable in the patient’s blood and urine (0.2 ng/mL and 0.5 µg/24 h, respectively) more than 3 years after his last exposure.

Discussion

In the United States, there are 40.44 MRI units per million people and 40 million MRIs are conducted annually. From 30 to 50% of these are enhanced with Gd-based contrast agents. In the past 30 years, there have been > 450 million contrast-enhanced MRI procedures.¹

Gd is a rare earth metal. Among commercially available elements Gd has exceptional properties for enhancing MRI signals at low concentrations.¹ The nonphysiologic metal is detoxified by chelation with proprietary multidentate formulations that enhance (primarily renal) elimination while retaining the paramagnetic and chemical properties for imaging. Gd exposure was found to be associated to iatrogenic nephrogenic systemic fibrosis in 2006 and later confirmed via multiple systematic reviews.² Gd is retained in every vital organ after exposure.³ Gd-based contrast agents stimulate bone marrow–derived fibrocytes in mediating fibrosis, and bone marrow develop a memory of prior contrast exposure (Figure 1).^4-6 Systemic fibrosis is mediated by the monocyte chemoattractant protein 1/C-C chemokine receptor 2.^6,7 Even in the setting of normal renal function, Gd-based contrast induces the formation of Gd-rich nanoparticles in the skin and kidney.^7,8 Far from being inert, Gd-based contrast agents induce systemic metabolic changes such as hypertriglyceridemia, elevations in low-density lipoprotein cholesterol, insulin resistance, and the Warburg effect (glycolytic/energy switching) in the renal cortex concomitant with profound mitochondrial abnormalities.⁸

A, B, and C are the proportions (adding to 100%) that represent each of the compartments: quickly, intermediately, and slowly equilibrated spaces. The rate constants for renal elimination from the plasma (K_P0,) flux from the fast space to plasma (K_FP) and from the slowly equilibrated space to plasma (K_SP) are components of the total Gd elimination from these compartments, respectively (Figure 3). It is improbable that Gd is liberated from the multidentate formulations that constitute MRI contrast agents given the relatively high affinities for the toxic lanthanide metal, the low volume of distribution, and the rapid—essentially entirely renal—elimination rates (Figure 4). Nonetheless, Gd is retained long-term in subjects with normal renal function, in symptomatic patients, permanently in the brains of patients, and in every organ we have tested with our animal models.^3,7,8,10-12 Patients with normal renal function continue to report symptoms attributed to Gd-based contrast agents concomitant with retarded elimination.

Numerous patients with normal renal function developed similar or novel symptoms that have been attributed to Gd concomitant with detectable urinary Gd years after exposure.¹¹ Gd-based contrast agents are increasingly associated with cutaneous abnormalities even outside of nephrogenic systemic fibrosis. Gd-associated plaques develop in patients without kidney disease—these range from asymptomatic, pruritic, to burning.¹³ Histologic specimens reveal CD68 and factor XIIIa–positive spindle-shaped myeloid cells (the same mediators of iatrogenic systemic fibrosis) or CD34-positive cells. CD68 and factor XIIIa are distinctive for histologic specimens from patients with systemic fibrosis, and these markers have been detected in our preclinical models that demonstrated that bone marrow–derived cells are involved in mediating fibrosis.^3,4,14-19 Similarly, CD34-positive cells have been historically associated with systemic fibrosis lesions.^15,16,18-23 Plump osteocyte-appearing cells have also been noted (note that extraosseous metaplasia makes the histologic diagnosis of systemic fibrosis).¹⁴ Nephrogenic systemic fibrosis is an iatrogenic disease that can manifest years after exposure to Gd.⁵ Gd induces the recruitment of bone marrow–derived cells to the affected sites.⁴

The VA Health Service Research and Development Evidence Synthesis Program reviewed the safety of Gd-based contrast agents in patients with impaired kidney function.^24,25 The group found only a single study of Gd and veterans. “Awareness and concern are growing about the long-term deposition of gadolinium in [the] brain and other tissues among patients with normal kidney function,” according to Lunyera and colleagues.²⁵ The largest knowledge gap was that a comprehensive review “of all potential harms associated with gadolinium exposure” was not addressed. Furthermore, the group advised “caution in the use of [Gd-based contrast agents] in patients with severely impaired kidney function and acute kidney injury remains prudent, because the exact clinical factors contributing to [nephrogenic systemic fibrosis] risk in these subpopulations are still unknown.”²⁵

Gd-based contrast agents—contrary to a widely held misconception—are not biologically inert.¹ Gd-based contrast agents have a long history of association with acute renal injury. We have demonstrated that systemic treatment with MRI contrast agents leads to vacuolization of the proximal tubule and tubular injury.^7,8 Kidney injury may be mediated by the generation of reactive oxygen species from NADPH oxidase 4 (Nox4).²⁶

Gd retention, Gd-induced multisymptomatic illnesses, Gd-associated plaques, Gd-induced neurotoxicity, and nephrogenic systemic fibrosis are part of a continuum (with Gd as the common thread)—a theme of the September 8, 2017, US Food and Drug Administration (FDA) Medical Imaging Drugs Advisory Committee meeting.²⁷ Patients, patient advocacy groups, and regulating agencies are concerned about long-term retention of a nonphysiologic rare earth element such as Gd.^28-30 A patient advocacy group, The Lighthouse Project, collected information from patients linking the last date of Gd-based contrast agent exposure and urinary Gd.¹¹ Data from their report suggest that the rate constants (valuable for the elimination equation above) are obtainable from 24-hour urine collections. Conceptually, Gd-induced diseases may represent a continuum that results from the retention of a nonphysiologic, toxic heavy rare earth metal.

As a heavy metal, Gd is not a natural physiologic trace element. Similar to numerous nonphysiologic metals, Gd is toxic. Inhaled Gd oxide (Gd₂O₃) dust leads to a number of time-dependent pathologies. Animal lung studies demonstrate reduced elasticity, enlarged cells, thickened lung walls, and recruitment of immune cells.³¹ Symptoms of acute IV Gd toxicity include decreased respiration, lethargy, abdominal cramps, and diarrhea.³² Pharmacologically, Gd concentrates in the liver and kidney and accumulates in the bone.³² Animals demonstrate intestinal depression and low blood pressure in response to Gd and, with higher doses, cardiovascular collapse.³² IV Gd chloride leads to metal deposition in the small blood vessels diffusely throughout the body, particularly in the lung and kidney and the metal is absorbed by the scavenging white blood cells.³³ Gd chloride induces severe damage to the liver, spleen, and the digestive tract.³³ Furthermore, this form of the toxicant metal markedly impacted functions associated with bleeding and clotting, ie, decreased platelet numbers and an increase in the laboratory-measured coagulation parameters.³³ Semelka and colleagues have characterized chronic symptoms attributed to Gd-based contrast agents (not limited to chronic pain, headache, bone pain, skin thickening, and clouded mentation).^34,35 Because Gd-induced conditions are underrecognized and ill-defined, disinherited patients often resort to untested (and potentially dangerous) chelation therapies.³⁶

This patient presented with numerous symptoms that arose after Gd exposure. It is well established that Gd-based contrast agents (of any class) are retained in multiple organs (including the brain), for months to years. Gd-based contrast agents enter the cerebrospinal fluid within minutes of IV administration.³⁷ Gd was found in the cerebrospinal fluid 9 months after administration in a case presented to the FDA Medical Imaging Drugs Advisory Committee.³⁸ We know from intentional and accidental intrathecal administrations that Gd-based contrast agents are neurotoxic.³⁹ Runge and colleagues demonstrated that Gd-based contrast agents exert mitochondrial toxicity in cultured neurons in vitro.⁴⁰ McDonald and his team found Gd-rich nanoparticles within the brain neurons (cytoplasm and nuclei) from patients exposed to MRI contrast in the normal course of care.⁴¹ These nanoparticles are similar to what we have found in rodent models of Gd-induced disease.^7,8,42

Patient Perspective

“Seems like it’s one thing after another. My family doctor said that once I had the gadolinium exposures, I have had problems ever since that I don’t recover from.” This includes chronic numbness from the rectum to the bilateral lower extremities and an indolent worsening kidney function; “I have already developed stage 3B chronic kidney disease.” Similar to many suffering with gadolinium retention, the patient was concerned about the long-term consequences. Gadolinium “is a toxic metal that is going through my body for 4 years. That has to be a problem. How come we don’t have that answer?” Clinician ignorance of Gd-induced complications and long-term retention is frustrating. “Not one of my doctors has taken gadolinium retention seriously. Where else are patients supposed to go?”

Conclusions

Health care professionals should be considering subclinical manifestations of nephrogenic systemic fibrosis or open to considering that intracellular neuronal retention of Gd may correlate with symptoms arising after MRI contrast exposures. The science concerning the mechanisms of how Gd exerts its pathologic effects is lagging behind the commercialization of enhancing Gd elimination (ie, chelation therapies) and other untested remedies. Practitioners need to acknowledge the unknown potential consequences of Gd and listen to patients who suspect chronic adverse effects.

Gadolinium (Gd)-based contrast agents are frequently used in health care for enhancing magnetic resonance image (MRI) signals at low concentrations. Contrary to popular opinion, this widely used heavy metal is not biologically inert. Once notable for its safety profile, there is mounting evidence for Gd deposition in various organ systems of the body, even in those with normal renal function. A large knowledge gap remains concerning the potential harms of Gd deposition and the factors determining its elimination from the body. However, the findings of deposited Gd throughout various organs and their intracellular compartments even years after the initial exposure have been established. Here, we describe a case of a Vietnam-era veteran whose presentation, clinical, and laboratory findings were consistent within the spectrum of Gd deposition disease. 

Case Presentation

A Vietnam-era veteran aged > 70 years presented for evaluation of Gd-based contrast agent–induced chronic multisymptomatic illness His medical history was significant for chronic low back pain, chronic hypertension, type 2 diabetes mellitus, and hypogonadism. Surgical history was notable for back surgery (24 years prior), laminectomy (2 years prior), shoulder replacement (2 years prior), and an epidural complicated by a hematoma (1 year prior). His presenting concerns included a painful and pruritic rash that worsened with showering, pain originating at the right Achilles tendon with migration to the knee, and shoulder pain. His symptoms started shortly after receiving multiple exposures to Gd-based contrast agents to enhance MRIs during his clinical care (Omniscan 20 mL, Omniscan 20 mL, and Gadovist 10 mL, administered 578, 565, and 496 days prior to the clinic visit, respectively). New onset headaches coincided with the timeline of symptom onset, in addition to hoarseness and liberation of an “oily substance” from the skin. More than one year prior to this clinic visit, he was considered for having polymyalgia rheumatica given the ambiguity of symptoms. Functional status remained impaired despite treatment with prednisone and methotrexate.

The patient’s military service was in the mid-1960s. He was deployed to Japan and had no knowledge of an Agent Orange exposure. His tobacco history was distant, and he reported no tattoos, prior transfusions, or occupational metal exposure (he was never stationed at Camp Lejeune or other bases with potential toxicants in the drinking water). Family history was significant for lung cancer in his mother (smoker) and his father died aged > 90 years. One sister had fibromyalgia. The patient’s children were healthy.

Clinical Findings

The patient was afebrile, normotensive (146/88 mmHg), and normocardic. His weight was 100 kg. He was well nourished and in no acute distress. The thought process was attentive, and his affect pleasant. Ocular examination was notable for arcus senilus. The fundoscopic examination was limited on the left, but there was no neovascularization on the right. Jugular venous pulsation was normal at 8 cm. Right ventricular impulse was slightly hyperdynamic, the rhythm was regular, and there was no abnormal splitting of S2. A soft-grade I/VI crescendo/decrescendo murmur was auscultated along the apex. Radial pulses were 2/2. He was not in respiratory distress, with equally resonant fields bilaterally. Lung sounds were clear bilaterally. A papular, erythematous rash was present in a general distribution over the chest, with few telangiectasias and some varicosity along his left arm. The skin had normal elasticity, although the skin of the hands and legs was papyraceous.

Gd levels were measured in the blood and urine (Table 1). Gd was detectable in the skin (0.2 µg/g) nearly 400 days after the last exposure. Gd was still detectable in the patient’s blood and urine (0.2 ng/mL and 0.5 µg/24 h, respectively) more than 3 years after his last exposure.

Discussion

In the United States, there are 40.44 MRI units per million people and 40 million MRIs are conducted annually. From 30 to 50% of these are enhanced with Gd-based contrast agents. In the past 30 years, there have been > 450 million contrast-enhanced MRI procedures.¹

Gd is a rare earth metal. Among commercially available elements Gd has exceptional properties for enhancing MRI signals at low concentrations.¹ The nonphysiologic metal is detoxified by chelation with proprietary multidentate formulations that enhance (primarily renal) elimination while retaining the paramagnetic and chemical properties for imaging. Gd exposure was found to be associated to iatrogenic nephrogenic systemic fibrosis in 2006 and later confirmed via multiple systematic reviews.² Gd is retained in every vital organ after exposure.³ Gd-based contrast agents stimulate bone marrow–derived fibrocytes in mediating fibrosis, and bone marrow develop a memory of prior contrast exposure (Figure 1).^4-6 Systemic fibrosis is mediated by the monocyte chemoattractant protein 1/C-C chemokine receptor 2.^6,7 Even in the setting of normal renal function, Gd-based contrast induces the formation of Gd-rich nanoparticles in the skin and kidney.^7,8 Far from being inert, Gd-based contrast agents induce systemic metabolic changes such as hypertriglyceridemia, elevations in low-density lipoprotein cholesterol, insulin resistance, and the Warburg effect (glycolytic/energy switching) in the renal cortex concomitant with profound mitochondrial abnormalities.⁸

A, B, and C are the proportions (adding to 100%) that represent each of the compartments: quickly, intermediately, and slowly equilibrated spaces. The rate constants for renal elimination from the plasma (K_P0,) flux from the fast space to plasma (K_FP) and from the slowly equilibrated space to plasma (K_SP) are components of the total Gd elimination from these compartments, respectively (Figure 3). It is improbable that Gd is liberated from the multidentate formulations that constitute MRI contrast agents given the relatively high affinities for the toxic lanthanide metal, the low volume of distribution, and the rapid—essentially entirely renal—elimination rates (Figure 4). Nonetheless, Gd is retained long-term in subjects with normal renal function, in symptomatic patients, permanently in the brains of patients, and in every organ we have tested with our animal models.^3,7,8,10-12 Patients with normal renal function continue to report symptoms attributed to Gd-based contrast agents concomitant with retarded elimination.

Numerous patients with normal renal function developed similar or novel symptoms that have been attributed to Gd concomitant with detectable urinary Gd years after exposure.¹¹ Gd-based contrast agents are increasingly associated with cutaneous abnormalities even outside of nephrogenic systemic fibrosis. Gd-associated plaques develop in patients without kidney disease—these range from asymptomatic, pruritic, to burning.¹³ Histologic specimens reveal CD68 and factor XIIIa–positive spindle-shaped myeloid cells (the same mediators of iatrogenic systemic fibrosis) or CD34-positive cells. CD68 and factor XIIIa are distinctive for histologic specimens from patients with systemic fibrosis, and these markers have been detected in our preclinical models that demonstrated that bone marrow–derived cells are involved in mediating fibrosis.^3,4,14-19 Similarly, CD34-positive cells have been historically associated with systemic fibrosis lesions.^15,16,18-23 Plump osteocyte-appearing cells have also been noted (note that extraosseous metaplasia makes the histologic diagnosis of systemic fibrosis).¹⁴ Nephrogenic systemic fibrosis is an iatrogenic disease that can manifest years after exposure to Gd.⁵ Gd induces the recruitment of bone marrow–derived cells to the affected sites.⁴

The VA Health Service Research and Development Evidence Synthesis Program reviewed the safety of Gd-based contrast agents in patients with impaired kidney function.^24,25 The group found only a single study of Gd and veterans. “Awareness and concern are growing about the long-term deposition of gadolinium in [the] brain and other tissues among patients with normal kidney function,” according to Lunyera and colleagues.²⁵ The largest knowledge gap was that a comprehensive review “of all potential harms associated with gadolinium exposure” was not addressed. Furthermore, the group advised “caution in the use of [Gd-based contrast agents] in patients with severely impaired kidney function and acute kidney injury remains prudent, because the exact clinical factors contributing to [nephrogenic systemic fibrosis] risk in these subpopulations are still unknown.”²⁵

Gd-based contrast agents—contrary to a widely held misconception—are not biologically inert.¹ Gd-based contrast agents have a long history of association with acute renal injury. We have demonstrated that systemic treatment with MRI contrast agents leads to vacuolization of the proximal tubule and tubular injury.^7,8 Kidney injury may be mediated by the generation of reactive oxygen species from NADPH oxidase 4 (Nox4).²⁶

Gd retention, Gd-induced multisymptomatic illnesses, Gd-associated plaques, Gd-induced neurotoxicity, and nephrogenic systemic fibrosis are part of a continuum (with Gd as the common thread)—a theme of the September 8, 2017, US Food and Drug Administration (FDA) Medical Imaging Drugs Advisory Committee meeting.²⁷ Patients, patient advocacy groups, and regulating agencies are concerned about long-term retention of a nonphysiologic rare earth element such as Gd.^28-30 A patient advocacy group, The Lighthouse Project, collected information from patients linking the last date of Gd-based contrast agent exposure and urinary Gd.¹¹ Data from their report suggest that the rate constants (valuable for the elimination equation above) are obtainable from 24-hour urine collections. Conceptually, Gd-induced diseases may represent a continuum that results from the retention of a nonphysiologic, toxic heavy rare earth metal.

As a heavy metal, Gd is not a natural physiologic trace element. Similar to numerous nonphysiologic metals, Gd is toxic. Inhaled Gd oxide (Gd₂O₃) dust leads to a number of time-dependent pathologies. Animal lung studies demonstrate reduced elasticity, enlarged cells, thickened lung walls, and recruitment of immune cells.³¹ Symptoms of acute IV Gd toxicity include decreased respiration, lethargy, abdominal cramps, and diarrhea.³² Pharmacologically, Gd concentrates in the liver and kidney and accumulates in the bone.³² Animals demonstrate intestinal depression and low blood pressure in response to Gd and, with higher doses, cardiovascular collapse.³² IV Gd chloride leads to metal deposition in the small blood vessels diffusely throughout the body, particularly in the lung and kidney and the metal is absorbed by the scavenging white blood cells.³³ Gd chloride induces severe damage to the liver, spleen, and the digestive tract.³³ Furthermore, this form of the toxicant metal markedly impacted functions associated with bleeding and clotting, ie, decreased platelet numbers and an increase in the laboratory-measured coagulation parameters.³³ Semelka and colleagues have characterized chronic symptoms attributed to Gd-based contrast agents (not limited to chronic pain, headache, bone pain, skin thickening, and clouded mentation).^34,35 Because Gd-induced conditions are underrecognized and ill-defined, disinherited patients often resort to untested (and potentially dangerous) chelation therapies.³⁶

This patient presented with numerous symptoms that arose after Gd exposure. It is well established that Gd-based contrast agents (of any class) are retained in multiple organs (including the brain), for months to years. Gd-based contrast agents enter the cerebrospinal fluid within minutes of IV administration.³⁷ Gd was found in the cerebrospinal fluid 9 months after administration in a case presented to the FDA Medical Imaging Drugs Advisory Committee.³⁸ We know from intentional and accidental intrathecal administrations that Gd-based contrast agents are neurotoxic.³⁹ Runge and colleagues demonstrated that Gd-based contrast agents exert mitochondrial toxicity in cultured neurons in vitro.⁴⁰ McDonald and his team found Gd-rich nanoparticles within the brain neurons (cytoplasm and nuclei) from patients exposed to MRI contrast in the normal course of care.⁴¹ These nanoparticles are similar to what we have found in rodent models of Gd-induced disease.^7,8,42

Patient Perspective

“Seems like it’s one thing after another. My family doctor said that once I had the gadolinium exposures, I have had problems ever since that I don’t recover from.” This includes chronic numbness from the rectum to the bilateral lower extremities and an indolent worsening kidney function; “I have already developed stage 3B chronic kidney disease.” Similar to many suffering with gadolinium retention, the patient was concerned about the long-term consequences. Gadolinium “is a toxic metal that is going through my body for 4 years. That has to be a problem. How come we don’t have that answer?” Clinician ignorance of Gd-induced complications and long-term retention is frustrating. “Not one of my doctors has taken gadolinium retention seriously. Where else are patients supposed to go?”

Conclusions

Health care professionals should be considering subclinical manifestations of nephrogenic systemic fibrosis or open to considering that intracellular neuronal retention of Gd may correlate with symptoms arising after MRI contrast exposures. The science concerning the mechanisms of how Gd exerts its pathologic effects is lagging behind the commercialization of enhancing Gd elimination (ie, chelation therapies) and other untested remedies. Practitioners need to acknowledge the unknown potential consequences of Gd and listen to patients who suspect chronic adverse effects.

Gadolinium (Gd)-based contrast agents are frequently used in health care for enhancing magnetic resonance image (MRI) signals at low concentrations. Contrary to popular opinion, this widely used heavy metal is not biologically inert. Once notable for its safety profile, there is mounting evidence for Gd deposition in various organ systems of the body, even in those with normal renal function. A large knowledge gap remains concerning the potential harms of Gd deposition and the factors determining its elimination from the body. However, the findings of deposited Gd throughout various organs and their intracellular compartments even years after the initial exposure have been established. Here, we describe a case of a Vietnam-era veteran whose presentation, clinical, and laboratory findings were consistent within the spectrum of Gd deposition disease. 

Case Presentation

A Vietnam-era veteran aged > 70 years presented for evaluation of Gd-based contrast agent–induced chronic multisymptomatic illness His medical history was significant for chronic low back pain, chronic hypertension, type 2 diabetes mellitus, and hypogonadism. Surgical history was notable for back surgery (24 years prior), laminectomy (2 years prior), shoulder replacement (2 years prior), and an epidural complicated by a hematoma (1 year prior). His presenting concerns included a painful and pruritic rash that worsened with showering, pain originating at the right Achilles tendon with migration to the knee, and shoulder pain. His symptoms started shortly after receiving multiple exposures to Gd-based contrast agents to enhance MRIs during his clinical care (Omniscan 20 mL, Omniscan 20 mL, and Gadovist 10 mL, administered 578, 565, and 496 days prior to the clinic visit, respectively). New onset headaches coincided with the timeline of symptom onset, in addition to hoarseness and liberation of an “oily substance” from the skin. More than one year prior to this clinic visit, he was considered for having polymyalgia rheumatica given the ambiguity of symptoms. Functional status remained impaired despite treatment with prednisone and methotrexate.

The patient’s military service was in the mid-1960s. He was deployed to Japan and had no knowledge of an Agent Orange exposure. His tobacco history was distant, and he reported no tattoos, prior transfusions, or occupational metal exposure (he was never stationed at Camp Lejeune or other bases with potential toxicants in the drinking water). Family history was significant for lung cancer in his mother (smoker) and his father died aged > 90 years. One sister had fibromyalgia. The patient’s children were healthy.

Clinical Findings

The patient was afebrile, normotensive (146/88 mmHg), and normocardic. His weight was 100 kg. He was well nourished and in no acute distress. The thought process was attentive, and his affect pleasant. Ocular examination was notable for arcus senilus. The fundoscopic examination was limited on the left, but there was no neovascularization on the right. Jugular venous pulsation was normal at 8 cm. Right ventricular impulse was slightly hyperdynamic, the rhythm was regular, and there was no abnormal splitting of S2. A soft-grade I/VI crescendo/decrescendo murmur was auscultated along the apex. Radial pulses were 2/2. He was not in respiratory distress, with equally resonant fields bilaterally. Lung sounds were clear bilaterally. A papular, erythematous rash was present in a general distribution over the chest, with few telangiectasias and some varicosity along his left arm. The skin had normal elasticity, although the skin of the hands and legs was papyraceous.

Gd levels were measured in the blood and urine (Table 1). Gd was detectable in the skin (0.2 µg/g) nearly 400 days after the last exposure. Gd was still detectable in the patient’s blood and urine (0.2 ng/mL and 0.5 µg/24 h, respectively) more than 3 years after his last exposure.

Discussion

In the United States, there are 40.44 MRI units per million people and 40 million MRIs are conducted annually. From 30 to 50% of these are enhanced with Gd-based contrast agents. In the past 30 years, there have been > 450 million contrast-enhanced MRI procedures.¹

Gd is a rare earth metal. Among commercially available elements Gd has exceptional properties for enhancing MRI signals at low concentrations.¹ The nonphysiologic metal is detoxified by chelation with proprietary multidentate formulations that enhance (primarily renal) elimination while retaining the paramagnetic and chemical properties for imaging. Gd exposure was found to be associated to iatrogenic nephrogenic systemic fibrosis in 2006 and later confirmed via multiple systematic reviews.² Gd is retained in every vital organ after exposure.³ Gd-based contrast agents stimulate bone marrow–derived fibrocytes in mediating fibrosis, and bone marrow develop a memory of prior contrast exposure (Figure 1).^4-6 Systemic fibrosis is mediated by the monocyte chemoattractant protein 1/C-C chemokine receptor 2.^6,7 Even in the setting of normal renal function, Gd-based contrast induces the formation of Gd-rich nanoparticles in the skin and kidney.^7,8 Far from being inert, Gd-based contrast agents induce systemic metabolic changes such as hypertriglyceridemia, elevations in low-density lipoprotein cholesterol, insulin resistance, and the Warburg effect (glycolytic/energy switching) in the renal cortex concomitant with profound mitochondrial abnormalities.⁸

A, B, and C are the proportions (adding to 100%) that represent each of the compartments: quickly, intermediately, and slowly equilibrated spaces. The rate constants for renal elimination from the plasma (K_P0,) flux from the fast space to plasma (K_FP) and from the slowly equilibrated space to plasma (K_SP) are components of the total Gd elimination from these compartments, respectively (Figure 3). It is improbable that Gd is liberated from the multidentate formulations that constitute MRI contrast agents given the relatively high affinities for the toxic lanthanide metal, the low volume of distribution, and the rapid—essentially entirely renal—elimination rates (Figure 4). Nonetheless, Gd is retained long-term in subjects with normal renal function, in symptomatic patients, permanently in the brains of patients, and in every organ we have tested with our animal models.^3,7,8,10-12 Patients with normal renal function continue to report symptoms attributed to Gd-based contrast agents concomitant with retarded elimination.

Numerous patients with normal renal function developed similar or novel symptoms that have been attributed to Gd concomitant with detectable urinary Gd years after exposure.¹¹ Gd-based contrast agents are increasingly associated with cutaneous abnormalities even outside of nephrogenic systemic fibrosis. Gd-associated plaques develop in patients without kidney disease—these range from asymptomatic, pruritic, to burning.¹³ Histologic specimens reveal CD68 and factor XIIIa–positive spindle-shaped myeloid cells (the same mediators of iatrogenic systemic fibrosis) or CD34-positive cells. CD68 and factor XIIIa are distinctive for histologic specimens from patients with systemic fibrosis, and these markers have been detected in our preclinical models that demonstrated that bone marrow–derived cells are involved in mediating fibrosis.^3,4,14-19 Similarly, CD34-positive cells have been historically associated with systemic fibrosis lesions.^15,16,18-23 Plump osteocyte-appearing cells have also been noted (note that extraosseous metaplasia makes the histologic diagnosis of systemic fibrosis).¹⁴ Nephrogenic systemic fibrosis is an iatrogenic disease that can manifest years after exposure to Gd.⁵ Gd induces the recruitment of bone marrow–derived cells to the affected sites.⁴

The VA Health Service Research and Development Evidence Synthesis Program reviewed the safety of Gd-based contrast agents in patients with impaired kidney function.^24,25 The group found only a single study of Gd and veterans. “Awareness and concern are growing about the long-term deposition of gadolinium in [the] brain and other tissues among patients with normal kidney function,” according to Lunyera and colleagues.²⁵ The largest knowledge gap was that a comprehensive review “of all potential harms associated with gadolinium exposure” was not addressed. Furthermore, the group advised “caution in the use of [Gd-based contrast agents] in patients with severely impaired kidney function and acute kidney injury remains prudent, because the exact clinical factors contributing to [nephrogenic systemic fibrosis] risk in these subpopulations are still unknown.”²⁵

Gd-based contrast agents—contrary to a widely held misconception—are not biologically inert.¹ Gd-based contrast agents have a long history of association with acute renal injury. We have demonstrated that systemic treatment with MRI contrast agents leads to vacuolization of the proximal tubule and tubular injury.^7,8 Kidney injury may be mediated by the generation of reactive oxygen species from NADPH oxidase 4 (Nox4).²⁶

Gd retention, Gd-induced multisymptomatic illnesses, Gd-associated plaques, Gd-induced neurotoxicity, and nephrogenic systemic fibrosis are part of a continuum (with Gd as the common thread)—a theme of the September 8, 2017, US Food and Drug Administration (FDA) Medical Imaging Drugs Advisory Committee meeting.²⁷ Patients, patient advocacy groups, and regulating agencies are concerned about long-term retention of a nonphysiologic rare earth element such as Gd.^28-30 A patient advocacy group, The Lighthouse Project, collected information from patients linking the last date of Gd-based contrast agent exposure and urinary Gd.¹¹ Data from their report suggest that the rate constants (valuable for the elimination equation above) are obtainable from 24-hour urine collections. Conceptually, Gd-induced diseases may represent a continuum that results from the retention of a nonphysiologic, toxic heavy rare earth metal.

As a heavy metal, Gd is not a natural physiologic trace element. Similar to numerous nonphysiologic metals, Gd is toxic. Inhaled Gd oxide (Gd₂O₃) dust leads to a number of time-dependent pathologies. Animal lung studies demonstrate reduced elasticity, enlarged cells, thickened lung walls, and recruitment of immune cells.³¹ Symptoms of acute IV Gd toxicity include decreased respiration, lethargy, abdominal cramps, and diarrhea.³² Pharmacologically, Gd concentrates in the liver and kidney and accumulates in the bone.³² Animals demonstrate intestinal depression and low blood pressure in response to Gd and, with higher doses, cardiovascular collapse.³² IV Gd chloride leads to metal deposition in the small blood vessels diffusely throughout the body, particularly in the lung and kidney and the metal is absorbed by the scavenging white blood cells.³³ Gd chloride induces severe damage to the liver, spleen, and the digestive tract.³³ Furthermore, this form of the toxicant metal markedly impacted functions associated with bleeding and clotting, ie, decreased platelet numbers and an increase in the laboratory-measured coagulation parameters.³³ Semelka and colleagues have characterized chronic symptoms attributed to Gd-based contrast agents (not limited to chronic pain, headache, bone pain, skin thickening, and clouded mentation).^34,35 Because Gd-induced conditions are underrecognized and ill-defined, disinherited patients often resort to untested (and potentially dangerous) chelation therapies.³⁶

This patient presented with numerous symptoms that arose after Gd exposure. It is well established that Gd-based contrast agents (of any class) are retained in multiple organs (including the brain), for months to years. Gd-based contrast agents enter the cerebrospinal fluid within minutes of IV administration.³⁷ Gd was found in the cerebrospinal fluid 9 months after administration in a case presented to the FDA Medical Imaging Drugs Advisory Committee.³⁸ We know from intentional and accidental intrathecal administrations that Gd-based contrast agents are neurotoxic.³⁹ Runge and colleagues demonstrated that Gd-based contrast agents exert mitochondrial toxicity in cultured neurons in vitro.⁴⁰ McDonald and his team found Gd-rich nanoparticles within the brain neurons (cytoplasm and nuclei) from patients exposed to MRI contrast in the normal course of care.⁴¹ These nanoparticles are similar to what we have found in rodent models of Gd-induced disease.^7,8,42

Patient Perspective

“Seems like it’s one thing after another. My family doctor said that once I had the gadolinium exposures, I have had problems ever since that I don’t recover from.” This includes chronic numbness from the rectum to the bilateral lower extremities and an indolent worsening kidney function; “I have already developed stage 3B chronic kidney disease.” Similar to many suffering with gadolinium retention, the patient was concerned about the long-term consequences. Gadolinium “is a toxic metal that is going through my body for 4 years. That has to be a problem. How come we don’t have that answer?” Clinician ignorance of Gd-induced complications and long-term retention is frustrating. “Not one of my doctors has taken gadolinium retention seriously. Where else are patients supposed to go?”

Conclusions

Health care professionals should be considering subclinical manifestations of nephrogenic systemic fibrosis or open to considering that intracellular neuronal retention of Gd may correlate with symptoms arising after MRI contrast exposures. The science concerning the mechanisms of how Gd exerts its pathologic effects is lagging behind the commercialization of enhancing Gd elimination (ie, chelation therapies) and other untested remedies. Practitioners need to acknowledge the unknown potential consequences of Gd and listen to patients who suspect chronic adverse effects.

Nasopharyngeal carcinoma (NPC) differs from other head and neck (H&N) cancers in its epidemiology and treatment. Unlike other H&N cancers, NPC has a distinct geographical distribution with a much higher incidence in endemic areas, such as southern China, than in areas where it is relatively uncommon, such as the United States.¹ The etiology of NPC varies based on the geographical distribution, with Epstein-Barr virus (EBV) thought to be the primary etiologic agent in endemic areas. On the other hand, in North America 2 additional subsets of NPC have been identified: human papillomavirus (HPV)–positive/EBV-negative and HPV-negative/EBV-negative.^2,3 NPC arises from the epithelial lining of the nasopharynx, often in the fossa of Rosenmuller, and is the most seen tumor in the nasopharynx.⁴ NPC is less surgically accessible than other H&N cancers, and surgery to the nasopharynx poses more risks given the proximity of critical surrounding structures. NPC is radiosensitive, and therefore radiotherapy (RT), in combination with chemotherapy for locally advanced tumors, has become the mainstay of treatment for nonmetastatic NPC.⁴

NPC often presents with an asymptomatic neck mass or with symptoms of epistaxis, nasal obstruction, and otitis media.⁵ Advanced cases of NPC can present with direct extension into the skull base, paranasal sinuses, and orbit, as well as involvement of cranial nerves. Radiation planning for tumors of the nasopharynx is complicated by the need to deliver an adequate dose to the tumor while limiting dose and toxicity to nearby critical structures such as the brainstem, optic chiasm, eyes, spinal cord (SC), temporal lobes, and cochleae. Achieving an adequate dose to nasopharyngeal primary tumors is especially complicated for T4 tumors invading the skull base with intracranial extension, in direct contact with these critical structures (Table 1).

Case Presentation

A 34-year-old male patient with no previous medical history presented to the emergency department with worsening diplopia, nasal obstruction, facial pain, and neck stiffness. The patient reported a 3 pack-year smoking history with recent smoking cessation. His physical examination was notable for a right abducens nerve palsy and an ulcerated nasopharyngeal mass on endoscopy.

Computed tomography (CT) scan revealed a 7-cm mass in the nasopharynx, eroding through the skull base with destruction and replacement of the clivus by tumor. Also noted was erosion of the petrous apices, carotid canals, sella turcica, dens, and the bilateral occipital condyles. There was intracranial extension with replacement of portions of the cavernous sinuses as well as mass effect on the prepontine cistern. Additional brain imaging studies, including magnetic resonance imaging (MRI) and positron emission tomography (PET) scans, were obtained for completion of the staging workup. The MRI correlated with the findings noted on CT and demonstrated involvement of Meckel cave, foramen ovale, foramen rotundum, Dorello canal, and the hypoglossal canals. No cervical lymphadenopathy or distant metastases were noted on imaging. Pathology from biopsy revealed poorly differentiated squamous cell carcinoma, EBV-negative, strongly p16-positive, HPV-16 positive, and P53-negative.

RT planning was complicated by the tumor’s contact with the brainstem and upper cervical SC, as well as proximity of the tumor to the optic apparatus. The patient underwent 2 replanning CT scans at 26 Gy and 44 Gy to evaluate for tumor shrinkage. These CT scans demonstrated shrinkage of the tumor away from critical neural structures, allowing the treatment volume to be reduced away from these structures in order to achieve required dose tolerances (brainstem < 54 Gy, optic nerves and chiasm < 50 Gy, SC < 45 Gy for this case). The replanning CT scan at 44 Gy, 5 weeks after treatment initiation, demonstrated that dramatic tumor shrinkage had occurred early in treatment, with separation of the remaining tumor from the area of the SC and brainstem with which it was initially in contact (Figure 1). This improvement allowed for shrinkage of the high-dose radiation field away from these critical neural structures.

Discussion

RT for NPC is complicated by the proximity of these tumors to critical surrounding neural structures. It is challenging to achieve the required dose constraints to surrounding neural tissues while delivering the usual 70-Gy dose to the gross tumor, especially when the tumor comes into direct contact with these structures.

This case provides an example of response-adapted RT using imaging during treatment to shrink the high-dose target as the tumor shrinks away from critical surrounding structures.⁷ This strategy permits delivery of the maximum dose to the tumor while minimizing radiation dose, and therefore risk of toxicity, to normal surrounding structures. While it is typical to deliver 70 Gy to the full extent of tumor involvement for H&N tumors, this was not possible in this case as the tumor was in contact with the brainstem and upper cervical SC. Delivering the full 70 Gy to these areas of tumor would have placed this patient at substantial risk of brainstem and/or SC toxicity. This report demonstrates that response-adapted RT with shrinking fields can allow for tumor control while avoiding toxicity to critical neural structures for cases of locally advanced NPC in which tumor is abutting these structures.

Bony regeneration of the skull base following RT has been reported in the literature, but in limited reviews. Early reports used plain radiography to follow changes. Unger and colleagues demonstrated the regeneration of bone using skull radiographs 4 to 6 months after completion of RT for NPC.⁸ More recent literature details the ability of bone to regenerate after RT based on CT findings. Fang and colleagues reported on 90 cases of NPC with skull base destruction, with 63% having bony regeneration on posttreatment CT.⁹ Most of the patients in Fang’s report had bony regeneration within 1 year of treatment, and in general, bony regeneration became more evident on imaging with longer follow-up. Of note, local control was significantly greater in patients with regeneration vs persistent destruction (77% vs 21%, P < .001). On multivariate analysis, complete tumor response was significantly associated with bony regeneration; other factors such as age, sex, radiation dose, and chemotherapy were not significantly associated with the likelihood of bony regeneration.

Our report details a nasopharyngeal tumor that destroyed the skull base with no intact bony barrier. In such cases, concern arises regarding craniospinal instability with tumor regression if there is not simultaneous bone regeneration. Tumor invasion of the skull base and C1-2 vertebral bodies and complications from treatment of such tumor extent can lead to symptoms of craniospinal instability, including pain, difficulty with neck range of motion, and loss of strength and sensation in the upper and lower extremities.¹⁰ A case report of a woman treated with chemoradiation for a plasmacytoma of the skull base detailed her posttreatment presentation with quadriparesis resulting from craniospinal instability after tumor regression.¹¹ Such instability is generally treated surgically, and during this woman’s surgery, there was an injury to the right vertebral artery, although this did not cause any additional neurologic deficits.

Conclusions

There is a paucity of literature on bony regeneration in patients with skull base destruction from advanced NPC, and in particular, the ability of skull base regeneration to occur during treatment simultaneous with tumor regression. Our patient had HPV-positive/EBV-negative NPC, but it is unclear how this subtype affected his prognosis. Factors such as tumor histology, radiosensitivity with rapid tumor regression, and young age may have all contributed to the rapidity of bone regeneration in our patient. This case report demonstrates that an impressive tumor response to chemoradiation with simultaneous bony regeneration is possible among patients presenting with tumor destruction of the skull base, precluding the need for neurosurgical intervention.

Nasopharyngeal carcinoma (NPC) differs from other head and neck (H&N) cancers in its epidemiology and treatment. Unlike other H&N cancers, NPC has a distinct geographical distribution with a much higher incidence in endemic areas, such as southern China, than in areas where it is relatively uncommon, such as the United States.¹ The etiology of NPC varies based on the geographical distribution, with Epstein-Barr virus (EBV) thought to be the primary etiologic agent in endemic areas. On the other hand, in North America 2 additional subsets of NPC have been identified: human papillomavirus (HPV)–positive/EBV-negative and HPV-negative/EBV-negative.^2,3 NPC arises from the epithelial lining of the nasopharynx, often in the fossa of Rosenmuller, and is the most seen tumor in the nasopharynx.⁴ NPC is less surgically accessible than other H&N cancers, and surgery to the nasopharynx poses more risks given the proximity of critical surrounding structures. NPC is radiosensitive, and therefore radiotherapy (RT), in combination with chemotherapy for locally advanced tumors, has become the mainstay of treatment for nonmetastatic NPC.⁴

NPC often presents with an asymptomatic neck mass or with symptoms of epistaxis, nasal obstruction, and otitis media.⁵ Advanced cases of NPC can present with direct extension into the skull base, paranasal sinuses, and orbit, as well as involvement of cranial nerves. Radiation planning for tumors of the nasopharynx is complicated by the need to deliver an adequate dose to the tumor while limiting dose and toxicity to nearby critical structures such as the brainstem, optic chiasm, eyes, spinal cord (SC), temporal lobes, and cochleae. Achieving an adequate dose to nasopharyngeal primary tumors is especially complicated for T4 tumors invading the skull base with intracranial extension, in direct contact with these critical structures (Table 1).

Case Presentation

A 34-year-old male patient with no previous medical history presented to the emergency department with worsening diplopia, nasal obstruction, facial pain, and neck stiffness. The patient reported a 3 pack-year smoking history with recent smoking cessation. His physical examination was notable for a right abducens nerve palsy and an ulcerated nasopharyngeal mass on endoscopy.

Computed tomography (CT) scan revealed a 7-cm mass in the nasopharynx, eroding through the skull base with destruction and replacement of the clivus by tumor. Also noted was erosion of the petrous apices, carotid canals, sella turcica, dens, and the bilateral occipital condyles. There was intracranial extension with replacement of portions of the cavernous sinuses as well as mass effect on the prepontine cistern. Additional brain imaging studies, including magnetic resonance imaging (MRI) and positron emission tomography (PET) scans, were obtained for completion of the staging workup. The MRI correlated with the findings noted on CT and demonstrated involvement of Meckel cave, foramen ovale, foramen rotundum, Dorello canal, and the hypoglossal canals. No cervical lymphadenopathy or distant metastases were noted on imaging. Pathology from biopsy revealed poorly differentiated squamous cell carcinoma, EBV-negative, strongly p16-positive, HPV-16 positive, and P53-negative.

RT planning was complicated by the tumor’s contact with the brainstem and upper cervical SC, as well as proximity of the tumor to the optic apparatus. The patient underwent 2 replanning CT scans at 26 Gy and 44 Gy to evaluate for tumor shrinkage. These CT scans demonstrated shrinkage of the tumor away from critical neural structures, allowing the treatment volume to be reduced away from these structures in order to achieve required dose tolerances (brainstem < 54 Gy, optic nerves and chiasm < 50 Gy, SC < 45 Gy for this case). The replanning CT scan at 44 Gy, 5 weeks after treatment initiation, demonstrated that dramatic tumor shrinkage had occurred early in treatment, with separation of the remaining tumor from the area of the SC and brainstem with which it was initially in contact (Figure 1). This improvement allowed for shrinkage of the high-dose radiation field away from these critical neural structures.

Discussion

RT for NPC is complicated by the proximity of these tumors to critical surrounding neural structures. It is challenging to achieve the required dose constraints to surrounding neural tissues while delivering the usual 70-Gy dose to the gross tumor, especially when the tumor comes into direct contact with these structures.

This case provides an example of response-adapted RT using imaging during treatment to shrink the high-dose target as the tumor shrinks away from critical surrounding structures.⁷ This strategy permits delivery of the maximum dose to the tumor while minimizing radiation dose, and therefore risk of toxicity, to normal surrounding structures. While it is typical to deliver 70 Gy to the full extent of tumor involvement for H&N tumors, this was not possible in this case as the tumor was in contact with the brainstem and upper cervical SC. Delivering the full 70 Gy to these areas of tumor would have placed this patient at substantial risk of brainstem and/or SC toxicity. This report demonstrates that response-adapted RT with shrinking fields can allow for tumor control while avoiding toxicity to critical neural structures for cases of locally advanced NPC in which tumor is abutting these structures.

Bony regeneration of the skull base following RT has been reported in the literature, but in limited reviews. Early reports used plain radiography to follow changes. Unger and colleagues demonstrated the regeneration of bone using skull radiographs 4 to 6 months after completion of RT for NPC.⁸ More recent literature details the ability of bone to regenerate after RT based on CT findings. Fang and colleagues reported on 90 cases of NPC with skull base destruction, with 63% having bony regeneration on posttreatment CT.⁹ Most of the patients in Fang’s report had bony regeneration within 1 year of treatment, and in general, bony regeneration became more evident on imaging with longer follow-up. Of note, local control was significantly greater in patients with regeneration vs persistent destruction (77% vs 21%, P < .001). On multivariate analysis, complete tumor response was significantly associated with bony regeneration; other factors such as age, sex, radiation dose, and chemotherapy were not significantly associated with the likelihood of bony regeneration.

Our report details a nasopharyngeal tumor that destroyed the skull base with no intact bony barrier. In such cases, concern arises regarding craniospinal instability with tumor regression if there is not simultaneous bone regeneration. Tumor invasion of the skull base and C1-2 vertebral bodies and complications from treatment of such tumor extent can lead to symptoms of craniospinal instability, including pain, difficulty with neck range of motion, and loss of strength and sensation in the upper and lower extremities.¹⁰ A case report of a woman treated with chemoradiation for a plasmacytoma of the skull base detailed her posttreatment presentation with quadriparesis resulting from craniospinal instability after tumor regression.¹¹ Such instability is generally treated surgically, and during this woman’s surgery, there was an injury to the right vertebral artery, although this did not cause any additional neurologic deficits.

Conclusions

There is a paucity of literature on bony regeneration in patients with skull base destruction from advanced NPC, and in particular, the ability of skull base regeneration to occur during treatment simultaneous with tumor regression. Our patient had HPV-positive/EBV-negative NPC, but it is unclear how this subtype affected his prognosis. Factors such as tumor histology, radiosensitivity with rapid tumor regression, and young age may have all contributed to the rapidity of bone regeneration in our patient. This case report demonstrates that an impressive tumor response to chemoradiation with simultaneous bony regeneration is possible among patients presenting with tumor destruction of the skull base, precluding the need for neurosurgical intervention.

Nasopharyngeal carcinoma (NPC) differs from other head and neck (H&N) cancers in its epidemiology and treatment. Unlike other H&N cancers, NPC has a distinct geographical distribution with a much higher incidence in endemic areas, such as southern China, than in areas where it is relatively uncommon, such as the United States.¹ The etiology of NPC varies based on the geographical distribution, with Epstein-Barr virus (EBV) thought to be the primary etiologic agent in endemic areas. On the other hand, in North America 2 additional subsets of NPC have been identified: human papillomavirus (HPV)–positive/EBV-negative and HPV-negative/EBV-negative.^2,3 NPC arises from the epithelial lining of the nasopharynx, often in the fossa of Rosenmuller, and is the most seen tumor in the nasopharynx.⁴ NPC is less surgically accessible than other H&N cancers, and surgery to the nasopharynx poses more risks given the proximity of critical surrounding structures. NPC is radiosensitive, and therefore radiotherapy (RT), in combination with chemotherapy for locally advanced tumors, has become the mainstay of treatment for nonmetastatic NPC.⁴

NPC often presents with an asymptomatic neck mass or with symptoms of epistaxis, nasal obstruction, and otitis media.⁵ Advanced cases of NPC can present with direct extension into the skull base, paranasal sinuses, and orbit, as well as involvement of cranial nerves. Radiation planning for tumors of the nasopharynx is complicated by the need to deliver an adequate dose to the tumor while limiting dose and toxicity to nearby critical structures such as the brainstem, optic chiasm, eyes, spinal cord (SC), temporal lobes, and cochleae. Achieving an adequate dose to nasopharyngeal primary tumors is especially complicated for T4 tumors invading the skull base with intracranial extension, in direct contact with these critical structures (Table 1).

Case Presentation

A 34-year-old male patient with no previous medical history presented to the emergency department with worsening diplopia, nasal obstruction, facial pain, and neck stiffness. The patient reported a 3 pack-year smoking history with recent smoking cessation. His physical examination was notable for a right abducens nerve palsy and an ulcerated nasopharyngeal mass on endoscopy.

Computed tomography (CT) scan revealed a 7-cm mass in the nasopharynx, eroding through the skull base with destruction and replacement of the clivus by tumor. Also noted was erosion of the petrous apices, carotid canals, sella turcica, dens, and the bilateral occipital condyles. There was intracranial extension with replacement of portions of the cavernous sinuses as well as mass effect on the prepontine cistern. Additional brain imaging studies, including magnetic resonance imaging (MRI) and positron emission tomography (PET) scans, were obtained for completion of the staging workup. The MRI correlated with the findings noted on CT and demonstrated involvement of Meckel cave, foramen ovale, foramen rotundum, Dorello canal, and the hypoglossal canals. No cervical lymphadenopathy or distant metastases were noted on imaging. Pathology from biopsy revealed poorly differentiated squamous cell carcinoma, EBV-negative, strongly p16-positive, HPV-16 positive, and P53-negative.

RT planning was complicated by the tumor’s contact with the brainstem and upper cervical SC, as well as proximity of the tumor to the optic apparatus. The patient underwent 2 replanning CT scans at 26 Gy and 44 Gy to evaluate for tumor shrinkage. These CT scans demonstrated shrinkage of the tumor away from critical neural structures, allowing the treatment volume to be reduced away from these structures in order to achieve required dose tolerances (brainstem < 54 Gy, optic nerves and chiasm < 50 Gy, SC < 45 Gy for this case). The replanning CT scan at 44 Gy, 5 weeks after treatment initiation, demonstrated that dramatic tumor shrinkage had occurred early in treatment, with separation of the remaining tumor from the area of the SC and brainstem with which it was initially in contact (Figure 1). This improvement allowed for shrinkage of the high-dose radiation field away from these critical neural structures.

Discussion

RT for NPC is complicated by the proximity of these tumors to critical surrounding neural structures. It is challenging to achieve the required dose constraints to surrounding neural tissues while delivering the usual 70-Gy dose to the gross tumor, especially when the tumor comes into direct contact with these structures.

This case provides an example of response-adapted RT using imaging during treatment to shrink the high-dose target as the tumor shrinks away from critical surrounding structures.⁷ This strategy permits delivery of the maximum dose to the tumor while minimizing radiation dose, and therefore risk of toxicity, to normal surrounding structures. While it is typical to deliver 70 Gy to the full extent of tumor involvement for H&N tumors, this was not possible in this case as the tumor was in contact with the brainstem and upper cervical SC. Delivering the full 70 Gy to these areas of tumor would have placed this patient at substantial risk of brainstem and/or SC toxicity. This report demonstrates that response-adapted RT with shrinking fields can allow for tumor control while avoiding toxicity to critical neural structures for cases of locally advanced NPC in which tumor is abutting these structures.

Bony regeneration of the skull base following RT has been reported in the literature, but in limited reviews. Early reports used plain radiography to follow changes. Unger and colleagues demonstrated the regeneration of bone using skull radiographs 4 to 6 months after completion of RT for NPC.⁸ More recent literature details the ability of bone to regenerate after RT based on CT findings. Fang and colleagues reported on 90 cases of NPC with skull base destruction, with 63% having bony regeneration on posttreatment CT.⁹ Most of the patients in Fang’s report had bony regeneration within 1 year of treatment, and in general, bony regeneration became more evident on imaging with longer follow-up. Of note, local control was significantly greater in patients with regeneration vs persistent destruction (77% vs 21%, P < .001). On multivariate analysis, complete tumor response was significantly associated with bony regeneration; other factors such as age, sex, radiation dose, and chemotherapy were not significantly associated with the likelihood of bony regeneration.

Our report details a nasopharyngeal tumor that destroyed the skull base with no intact bony barrier. In such cases, concern arises regarding craniospinal instability with tumor regression if there is not simultaneous bone regeneration. Tumor invasion of the skull base and C1-2 vertebral bodies and complications from treatment of such tumor extent can lead to symptoms of craniospinal instability, including pain, difficulty with neck range of motion, and loss of strength and sensation in the upper and lower extremities.¹⁰ A case report of a woman treated with chemoradiation for a plasmacytoma of the skull base detailed her posttreatment presentation with quadriparesis resulting from craniospinal instability after tumor regression.¹¹ Such instability is generally treated surgically, and during this woman’s surgery, there was an injury to the right vertebral artery, although this did not cause any additional neurologic deficits.

Conclusions

There is a paucity of literature on bony regeneration in patients with skull base destruction from advanced NPC, and in particular, the ability of skull base regeneration to occur during treatment simultaneous with tumor regression. Our patient had HPV-positive/EBV-negative NPC, but it is unclear how this subtype affected his prognosis. Factors such as tumor histology, radiosensitivity with rapid tumor regression, and young age may have all contributed to the rapidity of bone regeneration in our patient. This case report demonstrates that an impressive tumor response to chemoradiation with simultaneous bony regeneration is possible among patients presenting with tumor destruction of the skull base, precluding the need for neurosurgical intervention.

THE CASE

A 43-year-old Black male presented to his primary care physician with an 8-month history of progressive fatigue, weakness, and unintentional weight loss. The patient’s history also included antiphospholipid antibody syndrome (APS) with prior deep venous thrombosis/­pulmonary embolism for which he was taking warfarin.

At the time of presentation, he reported profound dyspnea on exertion, lightheadedness, dry mouth, low back pain, and worsening nocturia. The remainder of the review of systems was negative. He denied tobacco, alcohol, or illicit drug use or recent travel. His personal and family histories were negative for cancer.

Laboratory data collected during the outpatient visit were notable for a white blood cell count of 2300/mcL (reference range, 4000-11,000/mcL); hemoglobin, 8.6 g/dL (13.5-17.5 g/dL); and platelets, 44,000/mcL (150,000-400,000/mcL). Proteinuria was indicated by a measurement > 500 mg/dL on urine dipstick.

The patient was admitted to the hospital for further work-up of new pancytopenia. His vital signs on admission were notable for tachycardia and a weight of 237 lbs, decreased from 283 lbs 8 months prior. His physical exam revealed dry mucous membranes, bruising of fingertips, and marked lower extremity weakness with preserved sensation. No lymphadenopathy was noted on the admission physical exam.

THE DIAGNOSIS

Inpatient laboratory studies showed elevated inflammatory markers and a positive Coombs test with low haptoglobin. There was no evidence of bacterial or viral infection. Computed tomography of the chest, abdomen, and pelvis revealed axillary, subpectoral, and pelvic lymphadenopathy (see FIGURE). A work-up for multiple myeloma was negative, and a bone marrow biopsy was nondiagnostic.

Autoimmune laboratory data included a positive antiphospholipid antibody (ANA) test (1:10,240, diffuse; reference < 1:160), an elevated dsDNA antibody level (800 IU/mL; reference range, 0-99 IU/mL), low complement levels, and antibody titers consistent with the patient’s known APS. Based on these findings, the patient was given a diagnosis of systemic lupus erythematosus (SLE).

DISCUSSION

Lymphadenopathy, revealed by exam or by imaging, in combination with systemic symptoms such as weight loss and fatigue, elicits an extensive differential diagnosis. In the absence of recent exposures, travel, or risk factors for infectious causes, our patient’s work-up was appropriately narrowed to noninfectious etiologies of pancytopenia and lymphadenopathy. At the top of this differential are malignancies—in particular, multiple myeloma and lymphoma—and rheumatologic processes, such as sarcoidosis, connective tissue disease, and SLE.^1,2 Ultimately, the combination of autoimmune markers with the pancytopenia and a negative work-up for malignancy confirmed a diagnosis of SLE.

Continue to: SLE classification and generalized lymphadenopathy

SLE classification and generalized lymphadenopathy. SLE is a multisystem inflammatory process with a wide spectrum of clinical presentations. The American College of Rheumatology (ACR) has established validated criteria to aid in the diagnosis of SLE,³ which were most recently updated in 2012 to improve clinical utility. For a diagnosis to be made, at least 1 clinical and 1 immunologic criterion must be present or a renal biopsy must show lupus nephritis.³

Notably, lymphadenopathy is not included in this validated model, despite its occurrence in 25% to 50% of patients with SLE.^1,3,4 With this in mind, SLE should be considered in the work-up of generalized lymphadenopathy.

ANA and SLE. Although it is estimated that 30% to 40% of patients with SLE test positive for ANA,⁵ the presence of ANA also is not part of the diagnostic criteria for SLE. Interestingly, the co-occurrence of the 2 has clinical implications for patients. In particular, patients with SLE and a positive ANA have higher prevalence of thrombosis, valvular disease, thrombocytopenia, and hemolytic anemia, among other complications.⁵ Although our patient’s presentation of thrombocytopenia and hemolysis clouded the initial work-up, such a combination is consistent with co-presentation of SLE and APS.

Differences in sex, age, and race. SLE is more common in women than in men, with a prevalence ratio of 7:1.⁶ It is estimated that 65% of patients with SLE experience disease onset between the ages of 16 and 55 years.⁷

The median age of diagnosis also differs based on sex and race: According to Rus et al,⁸ the typical age ranges are 37 to 50 years for White women; 50 to 59 for White men; 15 to 44 for Black women; and 45 to 64 for Black men. These estimates of incidence stratified by race, sex, and age can be helpful when evaluating patients with confusing clinical presentations. Our patient’s age was consistent with the median for his sex and race.

Continue to: Our patient

Our patient was started on oral prednisone 60 mg/d with plans for a prolonged taper over 6 months under the close supervision of Rheumatology. His weakness and polyuria began to improve within a month, and lupus-­related symptoms resolved within 3 months. His cytopenia also significantly improved, with the exception of refractory thrombocytopenia.

THE TAKEAWAY

SLE is a common diagnosis with multiple presentations. Although lymphadenopathy is not part of the clinical criteria for the diagnosis of SLE, multiple case studies have highlighted its prevalence among affected patients.^1,2,4,9-17 APS and antiphospholipid antibodies are also absent in the diagnostic criteria despite being highly associated with SLE. Thus, co-­presentation (as well as age and sex) can be helpful with both disease stratification and risk assessment once a diagnosis is made.

CORRESPONDENCE
Isabella Buzzo Bellon Brout, MD, 409 West Broadway, Boston, MA 02127; [email protected]

THE CASE

A 43-year-old Black male presented to his primary care physician with an 8-month history of progressive fatigue, weakness, and unintentional weight loss. The patient’s history also included antiphospholipid antibody syndrome (APS) with prior deep venous thrombosis/­pulmonary embolism for which he was taking warfarin.

At the time of presentation, he reported profound dyspnea on exertion, lightheadedness, dry mouth, low back pain, and worsening nocturia. The remainder of the review of systems was negative. He denied tobacco, alcohol, or illicit drug use or recent travel. His personal and family histories were negative for cancer.

Laboratory data collected during the outpatient visit were notable for a white blood cell count of 2300/mcL (reference range, 4000-11,000/mcL); hemoglobin, 8.6 g/dL (13.5-17.5 g/dL); and platelets, 44,000/mcL (150,000-400,000/mcL). Proteinuria was indicated by a measurement > 500 mg/dL on urine dipstick.

The patient was admitted to the hospital for further work-up of new pancytopenia. His vital signs on admission were notable for tachycardia and a weight of 237 lbs, decreased from 283 lbs 8 months prior. His physical exam revealed dry mucous membranes, bruising of fingertips, and marked lower extremity weakness with preserved sensation. No lymphadenopathy was noted on the admission physical exam.

THE DIAGNOSIS

Inpatient laboratory studies showed elevated inflammatory markers and a positive Coombs test with low haptoglobin. There was no evidence of bacterial or viral infection. Computed tomography of the chest, abdomen, and pelvis revealed axillary, subpectoral, and pelvic lymphadenopathy (see FIGURE). A work-up for multiple myeloma was negative, and a bone marrow biopsy was nondiagnostic.

Autoimmune laboratory data included a positive antiphospholipid antibody (ANA) test (1:10,240, diffuse; reference < 1:160), an elevated dsDNA antibody level (800 IU/mL; reference range, 0-99 IU/mL), low complement levels, and antibody titers consistent with the patient’s known APS. Based on these findings, the patient was given a diagnosis of systemic lupus erythematosus (SLE).

DISCUSSION

Lymphadenopathy, revealed by exam or by imaging, in combination with systemic symptoms such as weight loss and fatigue, elicits an extensive differential diagnosis. In the absence of recent exposures, travel, or risk factors for infectious causes, our patient’s work-up was appropriately narrowed to noninfectious etiologies of pancytopenia and lymphadenopathy. At the top of this differential are malignancies—in particular, multiple myeloma and lymphoma—and rheumatologic processes, such as sarcoidosis, connective tissue disease, and SLE.^1,2 Ultimately, the combination of autoimmune markers with the pancytopenia and a negative work-up for malignancy confirmed a diagnosis of SLE.

Continue to: SLE classification and generalized lymphadenopathy

SLE classification and generalized lymphadenopathy. SLE is a multisystem inflammatory process with a wide spectrum of clinical presentations. The American College of Rheumatology (ACR) has established validated criteria to aid in the diagnosis of SLE,³ which were most recently updated in 2012 to improve clinical utility. For a diagnosis to be made, at least 1 clinical and 1 immunologic criterion must be present or a renal biopsy must show lupus nephritis.³

Notably, lymphadenopathy is not included in this validated model, despite its occurrence in 25% to 50% of patients with SLE.^1,3,4 With this in mind, SLE should be considered in the work-up of generalized lymphadenopathy.

ANA and SLE. Although it is estimated that 30% to 40% of patients with SLE test positive for ANA,⁵ the presence of ANA also is not part of the diagnostic criteria for SLE. Interestingly, the co-occurrence of the 2 has clinical implications for patients. In particular, patients with SLE and a positive ANA have higher prevalence of thrombosis, valvular disease, thrombocytopenia, and hemolytic anemia, among other complications.⁵ Although our patient’s presentation of thrombocytopenia and hemolysis clouded the initial work-up, such a combination is consistent with co-presentation of SLE and APS.

Differences in sex, age, and race. SLE is more common in women than in men, with a prevalence ratio of 7:1.⁶ It is estimated that 65% of patients with SLE experience disease onset between the ages of 16 and 55 years.⁷

The median age of diagnosis also differs based on sex and race: According to Rus et al,⁸ the typical age ranges are 37 to 50 years for White women; 50 to 59 for White men; 15 to 44 for Black women; and 45 to 64 for Black men. These estimates of incidence stratified by race, sex, and age can be helpful when evaluating patients with confusing clinical presentations. Our patient’s age was consistent with the median for his sex and race.

Continue to: Our patient

Our patient was started on oral prednisone 60 mg/d with plans for a prolonged taper over 6 months under the close supervision of Rheumatology. His weakness and polyuria began to improve within a month, and lupus-­related symptoms resolved within 3 months. His cytopenia also significantly improved, with the exception of refractory thrombocytopenia.

THE TAKEAWAY

SLE is a common diagnosis with multiple presentations. Although lymphadenopathy is not part of the clinical criteria for the diagnosis of SLE, multiple case studies have highlighted its prevalence among affected patients.^1,2,4,9-17 APS and antiphospholipid antibodies are also absent in the diagnostic criteria despite being highly associated with SLE. Thus, co-­presentation (as well as age and sex) can be helpful with both disease stratification and risk assessment once a diagnosis is made.

CORRESPONDENCE
Isabella Buzzo Bellon Brout, MD, 409 West Broadway, Boston, MA 02127; [email protected]

THE CASE

A 43-year-old Black male presented to his primary care physician with an 8-month history of progressive fatigue, weakness, and unintentional weight loss. The patient’s history also included antiphospholipid antibody syndrome (APS) with prior deep venous thrombosis/­pulmonary embolism for which he was taking warfarin.

At the time of presentation, he reported profound dyspnea on exertion, lightheadedness, dry mouth, low back pain, and worsening nocturia. The remainder of the review of systems was negative. He denied tobacco, alcohol, or illicit drug use or recent travel. His personal and family histories were negative for cancer.

Laboratory data collected during the outpatient visit were notable for a white blood cell count of 2300/mcL (reference range, 4000-11,000/mcL); hemoglobin, 8.6 g/dL (13.5-17.5 g/dL); and platelets, 44,000/mcL (150,000-400,000/mcL). Proteinuria was indicated by a measurement > 500 mg/dL on urine dipstick.

The patient was admitted to the hospital for further work-up of new pancytopenia. His vital signs on admission were notable for tachycardia and a weight of 237 lbs, decreased from 283 lbs 8 months prior. His physical exam revealed dry mucous membranes, bruising of fingertips, and marked lower extremity weakness with preserved sensation. No lymphadenopathy was noted on the admission physical exam.

THE DIAGNOSIS

Inpatient laboratory studies showed elevated inflammatory markers and a positive Coombs test with low haptoglobin. There was no evidence of bacterial or viral infection. Computed tomography of the chest, abdomen, and pelvis revealed axillary, subpectoral, and pelvic lymphadenopathy (see FIGURE). A work-up for multiple myeloma was negative, and a bone marrow biopsy was nondiagnostic.

Autoimmune laboratory data included a positive antiphospholipid antibody (ANA) test (1:10,240, diffuse; reference < 1:160), an elevated dsDNA antibody level (800 IU/mL; reference range, 0-99 IU/mL), low complement levels, and antibody titers consistent with the patient’s known APS. Based on these findings, the patient was given a diagnosis of systemic lupus erythematosus (SLE).

DISCUSSION

Lymphadenopathy, revealed by exam or by imaging, in combination with systemic symptoms such as weight loss and fatigue, elicits an extensive differential diagnosis. In the absence of recent exposures, travel, or risk factors for infectious causes, our patient’s work-up was appropriately narrowed to noninfectious etiologies of pancytopenia and lymphadenopathy. At the top of this differential are malignancies—in particular, multiple myeloma and lymphoma—and rheumatologic processes, such as sarcoidosis, connective tissue disease, and SLE.^1,2 Ultimately, the combination of autoimmune markers with the pancytopenia and a negative work-up for malignancy confirmed a diagnosis of SLE.

Continue to: SLE classification and generalized lymphadenopathy

SLE classification and generalized lymphadenopathy. SLE is a multisystem inflammatory process with a wide spectrum of clinical presentations. The American College of Rheumatology (ACR) has established validated criteria to aid in the diagnosis of SLE,³ which were most recently updated in 2012 to improve clinical utility. For a diagnosis to be made, at least 1 clinical and 1 immunologic criterion must be present or a renal biopsy must show lupus nephritis.³

Notably, lymphadenopathy is not included in this validated model, despite its occurrence in 25% to 50% of patients with SLE.^1,3,4 With this in mind, SLE should be considered in the work-up of generalized lymphadenopathy.

ANA and SLE. Although it is estimated that 30% to 40% of patients with SLE test positive for ANA,⁵ the presence of ANA also is not part of the diagnostic criteria for SLE. Interestingly, the co-occurrence of the 2 has clinical implications for patients. In particular, patients with SLE and a positive ANA have higher prevalence of thrombosis, valvular disease, thrombocytopenia, and hemolytic anemia, among other complications.⁵ Although our patient’s presentation of thrombocytopenia and hemolysis clouded the initial work-up, such a combination is consistent with co-presentation of SLE and APS.

Differences in sex, age, and race. SLE is more common in women than in men, with a prevalence ratio of 7:1.⁶ It is estimated that 65% of patients with SLE experience disease onset between the ages of 16 and 55 years.⁷

The median age of diagnosis also differs based on sex and race: According to Rus et al,⁸ the typical age ranges are 37 to 50 years for White women; 50 to 59 for White men; 15 to 44 for Black women; and 45 to 64 for Black men. These estimates of incidence stratified by race, sex, and age can be helpful when evaluating patients with confusing clinical presentations. Our patient’s age was consistent with the median for his sex and race.

Continue to: Our patient

Our patient was started on oral prednisone 60 mg/d with plans for a prolonged taper over 6 months under the close supervision of Rheumatology. His weakness and polyuria began to improve within a month, and lupus-­related symptoms resolved within 3 months. His cytopenia also significantly improved, with the exception of refractory thrombocytopenia.

THE TAKEAWAY

SLE is a common diagnosis with multiple presentations. Although lymphadenopathy is not part of the clinical criteria for the diagnosis of SLE, multiple case studies have highlighted its prevalence among affected patients.^1,2,4,9-17 APS and antiphospholipid antibodies are also absent in the diagnostic criteria despite being highly associated with SLE. Thus, co-­presentation (as well as age and sex) can be helpful with both disease stratification and risk assessment once a diagnosis is made.

CORRESPONDENCE
Isabella Buzzo Bellon Brout, MD, 409 West Broadway, Boston, MA 02127; [email protected]

Mohs micrographic surgery (MMS) frequently is used in surgical removal of cancerous cutaneous lesions on cosmetically sensitive areas and anatomically challenging sites, including the ears. The vascular supply of the ear is complex and includes several watershed regions that are susceptible to injury during surgical resection or operative closure.

Case Reports

Patient 1—An 82-year-old woman with a 100-pack-year smoking history and no known history of diabetes mellitus or coronary artery disease presented with a superficial and micronodular basal cell carcinoma (BCC) of the left postauricular skin of approximately 18 months’ duration. Mohs micrographic surgery was performed for lesion removal. The BCC was noted to be deeply penetrating and by the second stage was to the depth of the deep subcutaneous tissue (Figure 1A [inset]). Frozen section histopathology revealed a micronodular and superficial BCC. A 2.1×2.0-cm postoperative defect including the posterior surface of the ear, postauricular sulcus, and postauricular scalp remained. To minimize the area left to heal via secondary intention, partial layered closure was performed by placing four 4-0 polyglactin sutures from the scalp side of the defect on the postauricular skin to the postauricular sulcus (Figure 1A).

The patient presented to the clinic on postoperative day (POD) 4, noting pain and redness since the evening of the surgery on the anterior surface of the ear, specifically the cavum concha. Physical examination revealed that the incision site appeared to be healing as expected, but the cavum concha demonstrated erosions and ecchymosis (Figure 1B). A fluid culture was collected, and the patient was started on doxycycline 100 mg twice daily for 10 days. The patient returned to the clinic at POD 10 with skin sloughing and a small border of dark purple discoloration, consistent with early necrosis.

At the 1-month postsurgery follow-up visit, the wound had persistent anterior sloughing and discoloration with adherent debris suggestive of vascular compromise. At the 5-month wound check, the left conchal bowl had a 1-cm through-and-through defect of the concha cavum (Figure 1B [inset]). The favored etiology was occlusion of the posterior auricular artery during the patient’s MMS and reconstruction. Once healed, options including reconstruction, prosthesis, and no treatment were discussed with the patient. The patient decided to pursue partial closure of the defect.

Patient 2—A 71-year-old man with coronary artery disease and no known smoking or diabetes mellitus history presented with a 0.7×0.6-cm cutaneous squamous cell carcinoma of the left helix (Figure 2A [inset]). Mohs micrographic surgery was completed, resulting in a 1.1×1.0-cm defect that extended to the perichondrium. Given the location and size, a linear closure was performed with a deep layer of 5-0 polyglactin sutures and a cutaneous layer of 6-0 polypropylene sutures. The final closure length was 2.1 cm (Figure 2A).

On POD 14, the patient presented for suture removal and reported the onset of brown discoloration of the ear on POD 3. Physical examination revealed the left ear appeared dusky around the mid helix with extension onto the antihelix (Figure 2B). Because one of the main concerns was necrosis, a thin layer of nitropaste ointment 2% was prescribed to be applied twice daily to the affected area, in addition to liberal application of petroleum jelly. On POD 21, the left mid helix demonstrated a well-defined area of necrosis on the helical rim extending to the antihelix, and conservative treatment was continued. Four weeks later, the left ear had a prominent eschar, which was debrided. On follow-up 6 weeks later, the area was well healed with an obvious notched defect of the helix and scaphoid fossa (Figure 2B [inset]). The favored etiology was occlusion of the middle helical arcade during the patient’s MMS and reconstruction. Reconstructive options were discussed with the patient; however, he declined any further reconstructive intervention.

Comment

Auricular Vasculature—In our patients, the auricular vascular supply was compromised during routine MMS followed by reconstruction, resulting in tissue necrosis. Given the relative frequency of these procedures and the risk for tissue necrosis, a review of the auricular vasculature with special attention to the conchal bowl and helical rim was warranted (Figure 3).

The auricle is supplied by 2 main arterial sources arising from the external carotid artery: the superficial temporal artery (STA) supplying the anterior auricle and the posterior auricular artery (PAA) supplying the posterior auricle and the concha.¹ Anastomoses between these 2 blood supplies occur through perforating arteries and vascular arcades.

As the STA courses cranially, it moves from a deep position—deep to the parotidomasseteric fascia—to the superficial temporal fascia approximately 1 cm anterior and superior to the tragus. In approximately 80% of patients, 3 perpendicular branches stem from the STA—the upper, middle, and lower anterior branches—which supply the ascending helix, tragus, and lower margin of the earlobe, respectively.² The upper anterior branch of the STA joins other branches to form 2 dominant arcades: the first with the nonperforating branches of the PAA forming the upper third of the helical arcade, and the second with the lower anterior branch of the STA forming the middle portion of the helical arcade.^3,4 In 75% of patients, the middle helical arcade was identified as a single connecting artery, whereas in the remaining 25% of patients, a robust capillary network was formed.² In patient 2, the middle helical arcade was likely disrupted during closure, resulting in the helical necrosis seen postoperatively.

The second main blood supply of the auricle is the PAA, which enters in a more superficial position after traversing superiorly from the meatal cartilage, between the mastoid process and the posterior surface of the concha. From this point, the PAA runs in the deep subcutaneous tissue in the groove formed by the conchal cartilage and the mastoid process. Near the midpoint of the postauricular groove, it passes inferior to the postauricular muscle. The PAA has multiple radial branches that anastomose with helical branches; it also sends perforating branches (there were 2–4 branches in a recent study²) through the cartilage to the anterior surface of the concha. The 2 primary perforating arteries most commonly are located at the level of the antihelix and the antitragus.⁵ These arteries transverse through a vascular foramen located approximately 11 mm from the tragus in the horizontal plane and supply blood to the conchal bowl.⁶ In patient 1, the PAA itself, or the perforating arteries that course anteriorly through the vascular foramen, was likely disrupted, resulting in the conchal defect.

Special Considerations Before Surgery—As evidenced by these cases, special attention is needed during operative planning to account for the external ear vascular arcades. Damage to the helical arcades (patient 2) or the perforating arteries within the conchal bowl (patient 1) can lead to unintended consequences such as postoperative tissue necrosis. Tissue manipulation in these areas should be approached cautiously and with the least invasive treatment and closure options available. In doing so, blood flow and tissue integrity can be maintained, resulting in improved postoperative outcomes. Further research is warranted to identify the best intervention in cases involving these watershed regions.

Mohs micrographic surgery (MMS) frequently is used in surgical removal of cancerous cutaneous lesions on cosmetically sensitive areas and anatomically challenging sites, including the ears. The vascular supply of the ear is complex and includes several watershed regions that are susceptible to injury during surgical resection or operative closure.

Case Reports

Patient 1—An 82-year-old woman with a 100-pack-year smoking history and no known history of diabetes mellitus or coronary artery disease presented with a superficial and micronodular basal cell carcinoma (BCC) of the left postauricular skin of approximately 18 months’ duration. Mohs micrographic surgery was performed for lesion removal. The BCC was noted to be deeply penetrating and by the second stage was to the depth of the deep subcutaneous tissue (Figure 1A [inset]). Frozen section histopathology revealed a micronodular and superficial BCC. A 2.1×2.0-cm postoperative defect including the posterior surface of the ear, postauricular sulcus, and postauricular scalp remained. To minimize the area left to heal via secondary intention, partial layered closure was performed by placing four 4-0 polyglactin sutures from the scalp side of the defect on the postauricular skin to the postauricular sulcus (Figure 1A).

The patient presented to the clinic on postoperative day (POD) 4, noting pain and redness since the evening of the surgery on the anterior surface of the ear, specifically the cavum concha. Physical examination revealed that the incision site appeared to be healing as expected, but the cavum concha demonstrated erosions and ecchymosis (Figure 1B). A fluid culture was collected, and the patient was started on doxycycline 100 mg twice daily for 10 days. The patient returned to the clinic at POD 10 with skin sloughing and a small border of dark purple discoloration, consistent with early necrosis.

At the 1-month postsurgery follow-up visit, the wound had persistent anterior sloughing and discoloration with adherent debris suggestive of vascular compromise. At the 5-month wound check, the left conchal bowl had a 1-cm through-and-through defect of the concha cavum (Figure 1B [inset]). The favored etiology was occlusion of the posterior auricular artery during the patient’s MMS and reconstruction. Once healed, options including reconstruction, prosthesis, and no treatment were discussed with the patient. The patient decided to pursue partial closure of the defect.

Patient 2—A 71-year-old man with coronary artery disease and no known smoking or diabetes mellitus history presented with a 0.7×0.6-cm cutaneous squamous cell carcinoma of the left helix (Figure 2A [inset]). Mohs micrographic surgery was completed, resulting in a 1.1×1.0-cm defect that extended to the perichondrium. Given the location and size, a linear closure was performed with a deep layer of 5-0 polyglactin sutures and a cutaneous layer of 6-0 polypropylene sutures. The final closure length was 2.1 cm (Figure 2A).

On POD 14, the patient presented for suture removal and reported the onset of brown discoloration of the ear on POD 3. Physical examination revealed the left ear appeared dusky around the mid helix with extension onto the antihelix (Figure 2B). Because one of the main concerns was necrosis, a thin layer of nitropaste ointment 2% was prescribed to be applied twice daily to the affected area, in addition to liberal application of petroleum jelly. On POD 21, the left mid helix demonstrated a well-defined area of necrosis on the helical rim extending to the antihelix, and conservative treatment was continued. Four weeks later, the left ear had a prominent eschar, which was debrided. On follow-up 6 weeks later, the area was well healed with an obvious notched defect of the helix and scaphoid fossa (Figure 2B [inset]). The favored etiology was occlusion of the middle helical arcade during the patient’s MMS and reconstruction. Reconstructive options were discussed with the patient; however, he declined any further reconstructive intervention.

Comment

Auricular Vasculature—In our patients, the auricular vascular supply was compromised during routine MMS followed by reconstruction, resulting in tissue necrosis. Given the relative frequency of these procedures and the risk for tissue necrosis, a review of the auricular vasculature with special attention to the conchal bowl and helical rim was warranted (Figure 3).

The auricle is supplied by 2 main arterial sources arising from the external carotid artery: the superficial temporal artery (STA) supplying the anterior auricle and the posterior auricular artery (PAA) supplying the posterior auricle and the concha.¹ Anastomoses between these 2 blood supplies occur through perforating arteries and vascular arcades.

As the STA courses cranially, it moves from a deep position—deep to the parotidomasseteric fascia—to the superficial temporal fascia approximately 1 cm anterior and superior to the tragus. In approximately 80% of patients, 3 perpendicular branches stem from the STA—the upper, middle, and lower anterior branches—which supply the ascending helix, tragus, and lower margin of the earlobe, respectively.² The upper anterior branch of the STA joins other branches to form 2 dominant arcades: the first with the nonperforating branches of the PAA forming the upper third of the helical arcade, and the second with the lower anterior branch of the STA forming the middle portion of the helical arcade.^3,4 In 75% of patients, the middle helical arcade was identified as a single connecting artery, whereas in the remaining 25% of patients, a robust capillary network was formed.² In patient 2, the middle helical arcade was likely disrupted during closure, resulting in the helical necrosis seen postoperatively.

The second main blood supply of the auricle is the PAA, which enters in a more superficial position after traversing superiorly from the meatal cartilage, between the mastoid process and the posterior surface of the concha. From this point, the PAA runs in the deep subcutaneous tissue in the groove formed by the conchal cartilage and the mastoid process. Near the midpoint of the postauricular groove, it passes inferior to the postauricular muscle. The PAA has multiple radial branches that anastomose with helical branches; it also sends perforating branches (there were 2–4 branches in a recent study²) through the cartilage to the anterior surface of the concha. The 2 primary perforating arteries most commonly are located at the level of the antihelix and the antitragus.⁵ These arteries transverse through a vascular foramen located approximately 11 mm from the tragus in the horizontal plane and supply blood to the conchal bowl.⁶ In patient 1, the PAA itself, or the perforating arteries that course anteriorly through the vascular foramen, was likely disrupted, resulting in the conchal defect.

Special Considerations Before Surgery—As evidenced by these cases, special attention is needed during operative planning to account for the external ear vascular arcades. Damage to the helical arcades (patient 2) or the perforating arteries within the conchal bowl (patient 1) can lead to unintended consequences such as postoperative tissue necrosis. Tissue manipulation in these areas should be approached cautiously and with the least invasive treatment and closure options available. In doing so, blood flow and tissue integrity can be maintained, resulting in improved postoperative outcomes. Further research is warranted to identify the best intervention in cases involving these watershed regions.

Mohs micrographic surgery (MMS) frequently is used in surgical removal of cancerous cutaneous lesions on cosmetically sensitive areas and anatomically challenging sites, including the ears. The vascular supply of the ear is complex and includes several watershed regions that are susceptible to injury during surgical resection or operative closure.

Case Reports

Patient 1—An 82-year-old woman with a 100-pack-year smoking history and no known history of diabetes mellitus or coronary artery disease presented with a superficial and micronodular basal cell carcinoma (BCC) of the left postauricular skin of approximately 18 months’ duration. Mohs micrographic surgery was performed for lesion removal. The BCC was noted to be deeply penetrating and by the second stage was to the depth of the deep subcutaneous tissue (Figure 1A [inset]). Frozen section histopathology revealed a micronodular and superficial BCC. A 2.1×2.0-cm postoperative defect including the posterior surface of the ear, postauricular sulcus, and postauricular scalp remained. To minimize the area left to heal via secondary intention, partial layered closure was performed by placing four 4-0 polyglactin sutures from the scalp side of the defect on the postauricular skin to the postauricular sulcus (Figure 1A).

The patient presented to the clinic on postoperative day (POD) 4, noting pain and redness since the evening of the surgery on the anterior surface of the ear, specifically the cavum concha. Physical examination revealed that the incision site appeared to be healing as expected, but the cavum concha demonstrated erosions and ecchymosis (Figure 1B). A fluid culture was collected, and the patient was started on doxycycline 100 mg twice daily for 10 days. The patient returned to the clinic at POD 10 with skin sloughing and a small border of dark purple discoloration, consistent with early necrosis.

At the 1-month postsurgery follow-up visit, the wound had persistent anterior sloughing and discoloration with adherent debris suggestive of vascular compromise. At the 5-month wound check, the left conchal bowl had a 1-cm through-and-through defect of the concha cavum (Figure 1B [inset]). The favored etiology was occlusion of the posterior auricular artery during the patient’s MMS and reconstruction. Once healed, options including reconstruction, prosthesis, and no treatment were discussed with the patient. The patient decided to pursue partial closure of the defect.

Patient 2—A 71-year-old man with coronary artery disease and no known smoking or diabetes mellitus history presented with a 0.7×0.6-cm cutaneous squamous cell carcinoma of the left helix (Figure 2A [inset]). Mohs micrographic surgery was completed, resulting in a 1.1×1.0-cm defect that extended to the perichondrium. Given the location and size, a linear closure was performed with a deep layer of 5-0 polyglactin sutures and a cutaneous layer of 6-0 polypropylene sutures. The final closure length was 2.1 cm (Figure 2A).

On POD 14, the patient presented for suture removal and reported the onset of brown discoloration of the ear on POD 3. Physical examination revealed the left ear appeared dusky around the mid helix with extension onto the antihelix (Figure 2B). Because one of the main concerns was necrosis, a thin layer of nitropaste ointment 2% was prescribed to be applied twice daily to the affected area, in addition to liberal application of petroleum jelly. On POD 21, the left mid helix demonstrated a well-defined area of necrosis on the helical rim extending to the antihelix, and conservative treatment was continued. Four weeks later, the left ear had a prominent eschar, which was debrided. On follow-up 6 weeks later, the area was well healed with an obvious notched defect of the helix and scaphoid fossa (Figure 2B [inset]). The favored etiology was occlusion of the middle helical arcade during the patient’s MMS and reconstruction. Reconstructive options were discussed with the patient; however, he declined any further reconstructive intervention.

Comment

Auricular Vasculature—In our patients, the auricular vascular supply was compromised during routine MMS followed by reconstruction, resulting in tissue necrosis. Given the relative frequency of these procedures and the risk for tissue necrosis, a review of the auricular vasculature with special attention to the conchal bowl and helical rim was warranted (Figure 3).

The auricle is supplied by 2 main arterial sources arising from the external carotid artery: the superficial temporal artery (STA) supplying the anterior auricle and the posterior auricular artery (PAA) supplying the posterior auricle and the concha.¹ Anastomoses between these 2 blood supplies occur through perforating arteries and vascular arcades.

As the STA courses cranially, it moves from a deep position—deep to the parotidomasseteric fascia—to the superficial temporal fascia approximately 1 cm anterior and superior to the tragus. In approximately 80% of patients, 3 perpendicular branches stem from the STA—the upper, middle, and lower anterior branches—which supply the ascending helix, tragus, and lower margin of the earlobe, respectively.² The upper anterior branch of the STA joins other branches to form 2 dominant arcades: the first with the nonperforating branches of the PAA forming the upper third of the helical arcade, and the second with the lower anterior branch of the STA forming the middle portion of the helical arcade.^3,4 In 75% of patients, the middle helical arcade was identified as a single connecting artery, whereas in the remaining 25% of patients, a robust capillary network was formed.² In patient 2, the middle helical arcade was likely disrupted during closure, resulting in the helical necrosis seen postoperatively.

The second main blood supply of the auricle is the PAA, which enters in a more superficial position after traversing superiorly from the meatal cartilage, between the mastoid process and the posterior surface of the concha. From this point, the PAA runs in the deep subcutaneous tissue in the groove formed by the conchal cartilage and the mastoid process. Near the midpoint of the postauricular groove, it passes inferior to the postauricular muscle. The PAA has multiple radial branches that anastomose with helical branches; it also sends perforating branches (there were 2–4 branches in a recent study²) through the cartilage to the anterior surface of the concha. The 2 primary perforating arteries most commonly are located at the level of the antihelix and the antitragus.⁵ These arteries transverse through a vascular foramen located approximately 11 mm from the tragus in the horizontal plane and supply blood to the conchal bowl.⁶ In patient 1, the PAA itself, or the perforating arteries that course anteriorly through the vascular foramen, was likely disrupted, resulting in the conchal defect.

Special Considerations Before Surgery—As evidenced by these cases, special attention is needed during operative planning to account for the external ear vascular arcades. Damage to the helical arcades (patient 2) or the perforating arteries within the conchal bowl (patient 1) can lead to unintended consequences such as postoperative tissue necrosis. Tissue manipulation in these areas should be approached cautiously and with the least invasive treatment and closure options available. In doing so, blood flow and tissue integrity can be maintained, resulting in improved postoperative outcomes. Further research is warranted to identify the best intervention in cases involving these watershed regions.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome is the most common monogenic inherited cause of stroke. CADASIL syndrome is a nonsclerotic angiopathy resulting from a mutation of the NOTCH3 gene on chromosome 19p13, encoding a receptor expressed by vascular smooth muscle cells.¹ This mutation results in migraine, recurrent ischemic stroke, affective disorders, and dementia, with migraine often manifesting earliest.^2,3

The onset of stroke symptoms occurs typically in ages ≥ 60 years with some patients experiencing stroke as early as in their 30s.^1,4 Presentation varies among patients even within the same family.⁵ CADASIL syndrome is frequently mistaken for other more common neurologic conditions due to the low prevalence of CADASIL syndrome, reported to be between 2 and 5 per 100,000.^3,6 The cumulative nature of multiple ischemic episodes seen in 85% of symptomatic individuals leads to disability. Dementia is often hallmarked as one of the features of end-stage CADASIL syndrome.⁷ Extent and severity of brain tissue damage are shown to be the most critical factors of clinical symptoms.⁸ There is no specific treatment for CADASIL syndrome other than addressing risk factors.⁹

Symptoms are traditionally described to be limited to the central nervous system (CNS); however, reports of other organ system effects exist. Twenty-six percent of premature mortality relating to CADASIL syndrome is sudden unexpected death, which several authors have postulated could be attributed to cardiac events.^10,11

The NOTCH3 gene encodes a protein expressed during gastrulation and in the CNS during embryological development. The expression of this protein decreases with time and has limited expression in adulthood.¹² The pathophysiology of CADASIL syndrome includes myriad changes, including cerebral vessels narrowed by intimal thickening due to expansion of the extracellular matrix, degeneration of smooth muscle cells of the cerebral vessel walls, and osmiophilic material deposition in patients with CADASIL syndrome.¹³ Granular osmiophilic material in the vascular basal lamina can be observed on electron microscopy of patients with CADASIL syndrome and are used for diagnostic purposes.¹⁴

CADASIL syndrome often presents a diagnostic dilemma for physicians and is easy to misdiagnose in the early stages. The diagnostic dilemma arises given the subacute onset of CADASIL syndrome with vague early presenting symptoms, such as headache, prior to more specific findings (ie, multiple early strokes or transient ischemic attacks [TIA]). Patients presenting with CADASIL syndrome may be misdiagnosed with other neurologic conditions, including migraine or multiple sclerosis (MS).¹⁵ Especially in the case of MS, lesions visible on magnetic resonance imaging (MRI) may be differentiated by the higher rates of temporo polar lesions seen in CADASIL syndrome in comparison with those in MS.³

It is important to consider CADASIL syndrome in patients presenting at a young age with stroke due to the compounding effects of multiple ischemic episodes and subsequent motor/sensory and neuropsychologic deficits. This necessitates increasing awareness of CADASIL syndrome in the neurologic and radiologic community and the importance of educating families of patients on the importance of being evaluated. This diagnostic dilemma can lead to delay in appropriate therapy and control of related modifiable risk factors, including hypertension, hyperlipidemia, etc. Delays in initiation of anti-stroke pharmacotherapy can lead to additional morbidity and mortality in these patients.

The radiology of CADASIL syndrome is unique and particularly important due to the possible confusion with MS. MRI is an important tool in the evaluation of the cerebral pathology of CADASIL syndrome, revealing white matter and microangiopathic signal abnormalities, indicative of ischemic infarcts, lacunar strokes, and diffuse leukoencephalopathy.^13,16 MRI lesions are often seen in the basal ganglia, thalamus, external capsule, and pons.⁷ The lesions also are seen in the periventricular region, explaining its misperception as MS.¹⁷ In addition, cerebral microhemorrhages have been seen. To further differentiate these lesions, the anterior temporal lobe should be observed for gliosis or hyperintensities, which correlates with CADASIL syndrome.¹⁸ Location of hyperintensity in the temporal lobes, relative sparing of the occipital/orbitofrontal white matter, corpus callosum, subcortical u-fibers, and cortex is helpful in differentiating from other etiologies, such as microvascular white matter ischemic disease, MS, and mitochondrial encephalopathy with lactic acidosis and strokelike symptoms (MELAS).

Case Presentation

A patient aged > 50 years presented to the emergency department (ED) due to numbness of the right perioral area, gait difficulties, difficulty speaking, and increasing right lower extremity weakness with no numbness or paresthesia. The patient’s medical history is relevant for CADASIL syndrome, hypertension, prior cerebrovascular accident, recurrent TIAs, multinodular goiter with a history of radioactive iodine treatment, and neurogenic bladder controlled with oxybutynin since age 30 years. The patient had a significant stroke history: the first stroke occurred at age 36 years and 3 more strokes at ages 38, 44, and 53 years and 4 TIAs over that period. This patient reported no recent headache or memory changes and had no history of smoking, alcohol, or recreational drug use. Family history was pertinent for the mother’s death secondary to stroke, with a history of multiple strokes beginning at a young, undetermined age and no major motor, sensory, or neuropsychologic deficits prior to her death. A sister and first cousin had been diagnosed with MS.

On triage in the ED, stroke alert was called but tissue plasminogen activator was not given due to time eligibility. The patient’s numbness and weakness were improved within 7 hours, but she continued to have difficulty with dysarthric speech and unsteady gait following this incident. Antihypertensive medications were discontinued on admission to allow for permissive hypertension to improve cerebral blood flow. A brain MRI revealed bilateral increased T2 fluid-attenuated inversion recovery (FLAIR) signal in the anterior temporal lobes, confluent increased T2 FLAIR signal in the periventricular/deep white matter, bilateral basal ganglia chronic lacunar infarcts, and several chronic microbleeds (Figure 1). There was no evidence for an acute infarct on the MRI. Recrudescence of prior stroke symptoms secondary to CADASIL syndrome was suspected as a primary diagnosis with a differential of TIA.

Discussion

This patient with CADASIL syndrome and significant stroke history with cardiac symptoms demonstrates 3 important discussion points: the difficulty of early diagnosis, high rates of morbidity/mortality, and the need for further research into the cardiac effects of CADASIL syndrome. Due to this patient’s bradycardic episodes while being monitored on telemetry, it is possible that the cause of the strokelike symptoms was a TIA, secondary to decreased perfusion pressure, explaining the lack of acute ischemia on imaging. With regards to the history of thyroid dysfunction, this particular episode of bradycardia was unlikely to be related as the thyroid-stimulating hormone was reflective of subclinical hyperthyroidism with T4 levels within normal limits.

This case demonstrates a potential link between CADASIL syndrome and autonomic dysfunction. Similar to general stroke patients, patients with CADASIL syndrome are at an increased risk of hypoperfusion injury secondary to cardiovascular and autonomic dysfunction. This raises a question of initial and surveillance screening tests on diagnosis of CADASIL syndrome. It may be appropriate to obtain routine echocardiogram and ECG and other arrhythmia screening tests in these patients, especially during or following an ischemic episode. However, more evidence is required to support creation of a formal recommendation.

In a study of cardiac rhythm abnormalities in a half-million adults, 1.57% of women aged 55 to 64 years were found to have rhythm abnormality with 0.27% having a bradyarrhythmia.¹⁹ In the setting of neurologic disease, ECG changes such as arrhythmias and repolarization changes are regularly noted.²⁰ However, it is unlikely that the bradycardia would be causing the brain lesions. In CADASIL syndrome, there is relative sparing of the occipital, orbitofrontal subcortical white matter, subcortical fibers, and cortex. Specifically, within CADASIL syndrome, a study of 23 patients showed no ECG changes regarding infarction/ischemia, conduction disturbances, or arrhythmias compared with that of controls.²¹

Further research into the cardiac effects of CADASIL syndrome is needed. As CADASIL syndrome is primarily a disorder of the vasculature, the disease has potential to affect the heart in addition to the brain.¹ This theory is well supported by the embryologic effects of the NOTCH3 receptor pathways, which are responsible for the development of the cardiovascular system.²² Anecdotal evidence supports this theory as few case reports have been published that describe various cardiac abnormalities in patients with CADASIL syndrome, including myocardial infarction (MI), conduction abnormalities, and arrhythmias.^{2, 23-25}

There have only been 2 published studies regarding investigations into CADASIL syndrome and cardiac disease. The first paper was a case-control study that investigated ECG changes in the setting of CADASIL syndrome. The study found no evidence for MI, ischemia, conduction disorder, or arrhythmias in patients with CADASIL syndrome.²¹ Unfortunately, this study was underpowered and limited in scope, only investigating a single ECG recording from 23 patients with CADASIL syndrome in a single clinic.²¹ Other cardiac markers, such as echocardiogram, stress test, and contractility, and longitudinal cardiac outcomes were not investigated in this study.²¹ The second paper was also a case-control study by Rufa and colleagues that investigated HR variability and other ECG changes during a 10-minute rest recording on 23 patients with CADASIL syndrome and compared the results to 22 age- and gender-matched patients in good health.¹¹

This study found reduced HR variability and an increased ratio of low-frequency to high-frequency variability, which the authors claimed demonstrates autonomic dysfunction in patients with CADASIL syndrome.¹¹ Rufa and colleagues concluded that patients with CADASIL syndrome are at higher risk for cardiac arrhythmias.¹¹ This study also found no evidence for MI, ischemia, conduction disorder, or arrhythmias in the patients with CADASIL syndrome compared with that of age-matched controls.¹¹ Similar to the first paper, this study is underpowered, only looks at a single timepoint recording, and uses incomplete and indirect measurements of cardiac function.

There is a need for a longitudinal review of cardiac outcomes in the CADASIL syndrome population to determine whether these patients require additional surveillance or prophylaxis. While the variability in HR of our patient cannot be definitively attributed solely to CADASIL syndrome, the subsequent admissions demonstrate that long-term monitoring may be warranted.

Conclusions

CADASIL syndrome is an autosomal dominant NOTCH3 signaling disease that affects the small vessel vasculature and leads to early ischemic events, headache, dementia, and death. CADASIL syndrome is frequently misdiagnosed due to insidious onset and vague presenting symptoms. Delay in diagnosis often results in nonoptimized medical management. Current guidelines recommend following poststroke protocol and minimizing individual risk factors by using antiplatelet, antihypertensive, and dyslipidemia medications. This case demonstrates a classic presentation of CADASIL syndrome with lesser described cardiac symptoms. Few cases of unusual cardiac symptoms in the setting of CADASIL syndrome have been reported. The relationship between cardiovascular disease and CADASIL syndrome is not well described. Further research is needed to elucidate any links between CADASIL syndrome and cardiovascular disease and to optimize management for these patients.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome is the most common monogenic inherited cause of stroke. CADASIL syndrome is a nonsclerotic angiopathy resulting from a mutation of the NOTCH3 gene on chromosome 19p13, encoding a receptor expressed by vascular smooth muscle cells.¹ This mutation results in migraine, recurrent ischemic stroke, affective disorders, and dementia, with migraine often manifesting earliest.^2,3

The onset of stroke symptoms occurs typically in ages ≥ 60 years with some patients experiencing stroke as early as in their 30s.^1,4 Presentation varies among patients even within the same family.⁵ CADASIL syndrome is frequently mistaken for other more common neurologic conditions due to the low prevalence of CADASIL syndrome, reported to be between 2 and 5 per 100,000.^3,6 The cumulative nature of multiple ischemic episodes seen in 85% of symptomatic individuals leads to disability. Dementia is often hallmarked as one of the features of end-stage CADASIL syndrome.⁷ Extent and severity of brain tissue damage are shown to be the most critical factors of clinical symptoms.⁸ There is no specific treatment for CADASIL syndrome other than addressing risk factors.⁹

Symptoms are traditionally described to be limited to the central nervous system (CNS); however, reports of other organ system effects exist. Twenty-six percent of premature mortality relating to CADASIL syndrome is sudden unexpected death, which several authors have postulated could be attributed to cardiac events.^10,11

The NOTCH3 gene encodes a protein expressed during gastrulation and in the CNS during embryological development. The expression of this protein decreases with time and has limited expression in adulthood.¹² The pathophysiology of CADASIL syndrome includes myriad changes, including cerebral vessels narrowed by intimal thickening due to expansion of the extracellular matrix, degeneration of smooth muscle cells of the cerebral vessel walls, and osmiophilic material deposition in patients with CADASIL syndrome.¹³ Granular osmiophilic material in the vascular basal lamina can be observed on electron microscopy of patients with CADASIL syndrome and are used for diagnostic purposes.¹⁴

CADASIL syndrome often presents a diagnostic dilemma for physicians and is easy to misdiagnose in the early stages. The diagnostic dilemma arises given the subacute onset of CADASIL syndrome with vague early presenting symptoms, such as headache, prior to more specific findings (ie, multiple early strokes or transient ischemic attacks [TIA]). Patients presenting with CADASIL syndrome may be misdiagnosed with other neurologic conditions, including migraine or multiple sclerosis (MS).¹⁵ Especially in the case of MS, lesions visible on magnetic resonance imaging (MRI) may be differentiated by the higher rates of temporo polar lesions seen in CADASIL syndrome in comparison with those in MS.³

It is important to consider CADASIL syndrome in patients presenting at a young age with stroke due to the compounding effects of multiple ischemic episodes and subsequent motor/sensory and neuropsychologic deficits. This necessitates increasing awareness of CADASIL syndrome in the neurologic and radiologic community and the importance of educating families of patients on the importance of being evaluated. This diagnostic dilemma can lead to delay in appropriate therapy and control of related modifiable risk factors, including hypertension, hyperlipidemia, etc. Delays in initiation of anti-stroke pharmacotherapy can lead to additional morbidity and mortality in these patients.

The radiology of CADASIL syndrome is unique and particularly important due to the possible confusion with MS. MRI is an important tool in the evaluation of the cerebral pathology of CADASIL syndrome, revealing white matter and microangiopathic signal abnormalities, indicative of ischemic infarcts, lacunar strokes, and diffuse leukoencephalopathy.^13,16 MRI lesions are often seen in the basal ganglia, thalamus, external capsule, and pons.⁷ The lesions also are seen in the periventricular region, explaining its misperception as MS.¹⁷ In addition, cerebral microhemorrhages have been seen. To further differentiate these lesions, the anterior temporal lobe should be observed for gliosis or hyperintensities, which correlates with CADASIL syndrome.¹⁸ Location of hyperintensity in the temporal lobes, relative sparing of the occipital/orbitofrontal white matter, corpus callosum, subcortical u-fibers, and cortex is helpful in differentiating from other etiologies, such as microvascular white matter ischemic disease, MS, and mitochondrial encephalopathy with lactic acidosis and strokelike symptoms (MELAS).

Case Presentation

A patient aged > 50 years presented to the emergency department (ED) due to numbness of the right perioral area, gait difficulties, difficulty speaking, and increasing right lower extremity weakness with no numbness or paresthesia. The patient’s medical history is relevant for CADASIL syndrome, hypertension, prior cerebrovascular accident, recurrent TIAs, multinodular goiter with a history of radioactive iodine treatment, and neurogenic bladder controlled with oxybutynin since age 30 years. The patient had a significant stroke history: the first stroke occurred at age 36 years and 3 more strokes at ages 38, 44, and 53 years and 4 TIAs over that period. This patient reported no recent headache or memory changes and had no history of smoking, alcohol, or recreational drug use. Family history was pertinent for the mother’s death secondary to stroke, with a history of multiple strokes beginning at a young, undetermined age and no major motor, sensory, or neuropsychologic deficits prior to her death. A sister and first cousin had been diagnosed with MS.

On triage in the ED, stroke alert was called but tissue plasminogen activator was not given due to time eligibility. The patient’s numbness and weakness were improved within 7 hours, but she continued to have difficulty with dysarthric speech and unsteady gait following this incident. Antihypertensive medications were discontinued on admission to allow for permissive hypertension to improve cerebral blood flow. A brain MRI revealed bilateral increased T2 fluid-attenuated inversion recovery (FLAIR) signal in the anterior temporal lobes, confluent increased T2 FLAIR signal in the periventricular/deep white matter, bilateral basal ganglia chronic lacunar infarcts, and several chronic microbleeds (Figure 1). There was no evidence for an acute infarct on the MRI. Recrudescence of prior stroke symptoms secondary to CADASIL syndrome was suspected as a primary diagnosis with a differential of TIA.

Discussion

This patient with CADASIL syndrome and significant stroke history with cardiac symptoms demonstrates 3 important discussion points: the difficulty of early diagnosis, high rates of morbidity/mortality, and the need for further research into the cardiac effects of CADASIL syndrome. Due to this patient’s bradycardic episodes while being monitored on telemetry, it is possible that the cause of the strokelike symptoms was a TIA, secondary to decreased perfusion pressure, explaining the lack of acute ischemia on imaging. With regards to the history of thyroid dysfunction, this particular episode of bradycardia was unlikely to be related as the thyroid-stimulating hormone was reflective of subclinical hyperthyroidism with T4 levels within normal limits.

This case demonstrates a potential link between CADASIL syndrome and autonomic dysfunction. Similar to general stroke patients, patients with CADASIL syndrome are at an increased risk of hypoperfusion injury secondary to cardiovascular and autonomic dysfunction. This raises a question of initial and surveillance screening tests on diagnosis of CADASIL syndrome. It may be appropriate to obtain routine echocardiogram and ECG and other arrhythmia screening tests in these patients, especially during or following an ischemic episode. However, more evidence is required to support creation of a formal recommendation.

In a study of cardiac rhythm abnormalities in a half-million adults, 1.57% of women aged 55 to 64 years were found to have rhythm abnormality with 0.27% having a bradyarrhythmia.¹⁹ In the setting of neurologic disease, ECG changes such as arrhythmias and repolarization changes are regularly noted.²⁰ However, it is unlikely that the bradycardia would be causing the brain lesions. In CADASIL syndrome, there is relative sparing of the occipital, orbitofrontal subcortical white matter, subcortical fibers, and cortex. Specifically, within CADASIL syndrome, a study of 23 patients showed no ECG changes regarding infarction/ischemia, conduction disturbances, or arrhythmias compared with that of controls.²¹

Further research into the cardiac effects of CADASIL syndrome is needed. As CADASIL syndrome is primarily a disorder of the vasculature, the disease has potential to affect the heart in addition to the brain.¹ This theory is well supported by the embryologic effects of the NOTCH3 receptor pathways, which are responsible for the development of the cardiovascular system.²² Anecdotal evidence supports this theory as few case reports have been published that describe various cardiac abnormalities in patients with CADASIL syndrome, including myocardial infarction (MI), conduction abnormalities, and arrhythmias.^{2, 23-25}

There have only been 2 published studies regarding investigations into CADASIL syndrome and cardiac disease. The first paper was a case-control study that investigated ECG changes in the setting of CADASIL syndrome. The study found no evidence for MI, ischemia, conduction disorder, or arrhythmias in patients with CADASIL syndrome.²¹ Unfortunately, this study was underpowered and limited in scope, only investigating a single ECG recording from 23 patients with CADASIL syndrome in a single clinic.²¹ Other cardiac markers, such as echocardiogram, stress test, and contractility, and longitudinal cardiac outcomes were not investigated in this study.²¹ The second paper was also a case-control study by Rufa and colleagues that investigated HR variability and other ECG changes during a 10-minute rest recording on 23 patients with CADASIL syndrome and compared the results to 22 age- and gender-matched patients in good health.¹¹

This study found reduced HR variability and an increased ratio of low-frequency to high-frequency variability, which the authors claimed demonstrates autonomic dysfunction in patients with CADASIL syndrome.¹¹ Rufa and colleagues concluded that patients with CADASIL syndrome are at higher risk for cardiac arrhythmias.¹¹ This study also found no evidence for MI, ischemia, conduction disorder, or arrhythmias in the patients with CADASIL syndrome compared with that of age-matched controls.¹¹ Similar to the first paper, this study is underpowered, only looks at a single timepoint recording, and uses incomplete and indirect measurements of cardiac function.

There is a need for a longitudinal review of cardiac outcomes in the CADASIL syndrome population to determine whether these patients require additional surveillance or prophylaxis. While the variability in HR of our patient cannot be definitively attributed solely to CADASIL syndrome, the subsequent admissions demonstrate that long-term monitoring may be warranted.

Conclusions

CADASIL syndrome is an autosomal dominant NOTCH3 signaling disease that affects the small vessel vasculature and leads to early ischemic events, headache, dementia, and death. CADASIL syndrome is frequently misdiagnosed due to insidious onset and vague presenting symptoms. Delay in diagnosis often results in nonoptimized medical management. Current guidelines recommend following poststroke protocol and minimizing individual risk factors by using antiplatelet, antihypertensive, and dyslipidemia medications. This case demonstrates a classic presentation of CADASIL syndrome with lesser described cardiac symptoms. Few cases of unusual cardiac symptoms in the setting of CADASIL syndrome have been reported. The relationship between cardiovascular disease and CADASIL syndrome is not well described. Further research is needed to elucidate any links between CADASIL syndrome and cardiovascular disease and to optimize management for these patients.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome is the most common monogenic inherited cause of stroke. CADASIL syndrome is a nonsclerotic angiopathy resulting from a mutation of the NOTCH3 gene on chromosome 19p13, encoding a receptor expressed by vascular smooth muscle cells.¹ This mutation results in migraine, recurrent ischemic stroke, affective disorders, and dementia, with migraine often manifesting earliest.^2,3

The onset of stroke symptoms occurs typically in ages ≥ 60 years with some patients experiencing stroke as early as in their 30s.^1,4 Presentation varies among patients even within the same family.⁵ CADASIL syndrome is frequently mistaken for other more common neurologic conditions due to the low prevalence of CADASIL syndrome, reported to be between 2 and 5 per 100,000.^3,6 The cumulative nature of multiple ischemic episodes seen in 85% of symptomatic individuals leads to disability. Dementia is often hallmarked as one of the features of end-stage CADASIL syndrome.⁷ Extent and severity of brain tissue damage are shown to be the most critical factors of clinical symptoms.⁸ There is no specific treatment for CADASIL syndrome other than addressing risk factors.⁹

Symptoms are traditionally described to be limited to the central nervous system (CNS); however, reports of other organ system effects exist. Twenty-six percent of premature mortality relating to CADASIL syndrome is sudden unexpected death, which several authors have postulated could be attributed to cardiac events.^10,11

The NOTCH3 gene encodes a protein expressed during gastrulation and in the CNS during embryological development. The expression of this protein decreases with time and has limited expression in adulthood.¹² The pathophysiology of CADASIL syndrome includes myriad changes, including cerebral vessels narrowed by intimal thickening due to expansion of the extracellular matrix, degeneration of smooth muscle cells of the cerebral vessel walls, and osmiophilic material deposition in patients with CADASIL syndrome.¹³ Granular osmiophilic material in the vascular basal lamina can be observed on electron microscopy of patients with CADASIL syndrome and are used for diagnostic purposes.¹⁴

CADASIL syndrome often presents a diagnostic dilemma for physicians and is easy to misdiagnose in the early stages. The diagnostic dilemma arises given the subacute onset of CADASIL syndrome with vague early presenting symptoms, such as headache, prior to more specific findings (ie, multiple early strokes or transient ischemic attacks [TIA]). Patients presenting with CADASIL syndrome may be misdiagnosed with other neurologic conditions, including migraine or multiple sclerosis (MS).¹⁵ Especially in the case of MS, lesions visible on magnetic resonance imaging (MRI) may be differentiated by the higher rates of temporo polar lesions seen in CADASIL syndrome in comparison with those in MS.³

It is important to consider CADASIL syndrome in patients presenting at a young age with stroke due to the compounding effects of multiple ischemic episodes and subsequent motor/sensory and neuropsychologic deficits. This necessitates increasing awareness of CADASIL syndrome in the neurologic and radiologic community and the importance of educating families of patients on the importance of being evaluated. This diagnostic dilemma can lead to delay in appropriate therapy and control of related modifiable risk factors, including hypertension, hyperlipidemia, etc. Delays in initiation of anti-stroke pharmacotherapy can lead to additional morbidity and mortality in these patients.

The radiology of CADASIL syndrome is unique and particularly important due to the possible confusion with MS. MRI is an important tool in the evaluation of the cerebral pathology of CADASIL syndrome, revealing white matter and microangiopathic signal abnormalities, indicative of ischemic infarcts, lacunar strokes, and diffuse leukoencephalopathy.^13,16 MRI lesions are often seen in the basal ganglia, thalamus, external capsule, and pons.⁷ The lesions also are seen in the periventricular region, explaining its misperception as MS.¹⁷ In addition, cerebral microhemorrhages have been seen. To further differentiate these lesions, the anterior temporal lobe should be observed for gliosis or hyperintensities, which correlates with CADASIL syndrome.¹⁸ Location of hyperintensity in the temporal lobes, relative sparing of the occipital/orbitofrontal white matter, corpus callosum, subcortical u-fibers, and cortex is helpful in differentiating from other etiologies, such as microvascular white matter ischemic disease, MS, and mitochondrial encephalopathy with lactic acidosis and strokelike symptoms (MELAS).

Case Presentation

A patient aged > 50 years presented to the emergency department (ED) due to numbness of the right perioral area, gait difficulties, difficulty speaking, and increasing right lower extremity weakness with no numbness or paresthesia. The patient’s medical history is relevant for CADASIL syndrome, hypertension, prior cerebrovascular accident, recurrent TIAs, multinodular goiter with a history of radioactive iodine treatment, and neurogenic bladder controlled with oxybutynin since age 30 years. The patient had a significant stroke history: the first stroke occurred at age 36 years and 3 more strokes at ages 38, 44, and 53 years and 4 TIAs over that period. This patient reported no recent headache or memory changes and had no history of smoking, alcohol, or recreational drug use. Family history was pertinent for the mother’s death secondary to stroke, with a history of multiple strokes beginning at a young, undetermined age and no major motor, sensory, or neuropsychologic deficits prior to her death. A sister and first cousin had been diagnosed with MS.

On triage in the ED, stroke alert was called but tissue plasminogen activator was not given due to time eligibility. The patient’s numbness and weakness were improved within 7 hours, but she continued to have difficulty with dysarthric speech and unsteady gait following this incident. Antihypertensive medications were discontinued on admission to allow for permissive hypertension to improve cerebral blood flow. A brain MRI revealed bilateral increased T2 fluid-attenuated inversion recovery (FLAIR) signal in the anterior temporal lobes, confluent increased T2 FLAIR signal in the periventricular/deep white matter, bilateral basal ganglia chronic lacunar infarcts, and several chronic microbleeds (Figure 1). There was no evidence for an acute infarct on the MRI. Recrudescence of prior stroke symptoms secondary to CADASIL syndrome was suspected as a primary diagnosis with a differential of TIA.

Discussion

This patient with CADASIL syndrome and significant stroke history with cardiac symptoms demonstrates 3 important discussion points: the difficulty of early diagnosis, high rates of morbidity/mortality, and the need for further research into the cardiac effects of CADASIL syndrome. Due to this patient’s bradycardic episodes while being monitored on telemetry, it is possible that the cause of the strokelike symptoms was a TIA, secondary to decreased perfusion pressure, explaining the lack of acute ischemia on imaging. With regards to the history of thyroid dysfunction, this particular episode of bradycardia was unlikely to be related as the thyroid-stimulating hormone was reflective of subclinical hyperthyroidism with T4 levels within normal limits.

This case demonstrates a potential link between CADASIL syndrome and autonomic dysfunction. Similar to general stroke patients, patients with CADASIL syndrome are at an increased risk of hypoperfusion injury secondary to cardiovascular and autonomic dysfunction. This raises a question of initial and surveillance screening tests on diagnosis of CADASIL syndrome. It may be appropriate to obtain routine echocardiogram and ECG and other arrhythmia screening tests in these patients, especially during or following an ischemic episode. However, more evidence is required to support creation of a formal recommendation.

In a study of cardiac rhythm abnormalities in a half-million adults, 1.57% of women aged 55 to 64 years were found to have rhythm abnormality with 0.27% having a bradyarrhythmia.¹⁹ In the setting of neurologic disease, ECG changes such as arrhythmias and repolarization changes are regularly noted.²⁰ However, it is unlikely that the bradycardia would be causing the brain lesions. In CADASIL syndrome, there is relative sparing of the occipital, orbitofrontal subcortical white matter, subcortical fibers, and cortex. Specifically, within CADASIL syndrome, a study of 23 patients showed no ECG changes regarding infarction/ischemia, conduction disturbances, or arrhythmias compared with that of controls.²¹

Further research into the cardiac effects of CADASIL syndrome is needed. As CADASIL syndrome is primarily a disorder of the vasculature, the disease has potential to affect the heart in addition to the brain.¹ This theory is well supported by the embryologic effects of the NOTCH3 receptor pathways, which are responsible for the development of the cardiovascular system.²² Anecdotal evidence supports this theory as few case reports have been published that describe various cardiac abnormalities in patients with CADASIL syndrome, including myocardial infarction (MI), conduction abnormalities, and arrhythmias.^{2, 23-25}

There have only been 2 published studies regarding investigations into CADASIL syndrome and cardiac disease. The first paper was a case-control study that investigated ECG changes in the setting of CADASIL syndrome. The study found no evidence for MI, ischemia, conduction disorder, or arrhythmias in patients with CADASIL syndrome.²¹ Unfortunately, this study was underpowered and limited in scope, only investigating a single ECG recording from 23 patients with CADASIL syndrome in a single clinic.²¹ Other cardiac markers, such as echocardiogram, stress test, and contractility, and longitudinal cardiac outcomes were not investigated in this study.²¹ The second paper was also a case-control study by Rufa and colleagues that investigated HR variability and other ECG changes during a 10-minute rest recording on 23 patients with CADASIL syndrome and compared the results to 22 age- and gender-matched patients in good health.¹¹

This study found reduced HR variability and an increased ratio of low-frequency to high-frequency variability, which the authors claimed demonstrates autonomic dysfunction in patients with CADASIL syndrome.¹¹ Rufa and colleagues concluded that patients with CADASIL syndrome are at higher risk for cardiac arrhythmias.¹¹ This study also found no evidence for MI, ischemia, conduction disorder, or arrhythmias in the patients with CADASIL syndrome compared with that of age-matched controls.¹¹ Similar to the first paper, this study is underpowered, only looks at a single timepoint recording, and uses incomplete and indirect measurements of cardiac function.

There is a need for a longitudinal review of cardiac outcomes in the CADASIL syndrome population to determine whether these patients require additional surveillance or prophylaxis. While the variability in HR of our patient cannot be definitively attributed solely to CADASIL syndrome, the subsequent admissions demonstrate that long-term monitoring may be warranted.

Conclusions

CADASIL syndrome is an autosomal dominant NOTCH3 signaling disease that affects the small vessel vasculature and leads to early ischemic events, headache, dementia, and death. CADASIL syndrome is frequently misdiagnosed due to insidious onset and vague presenting symptoms. Delay in diagnosis often results in nonoptimized medical management. Current guidelines recommend following poststroke protocol and minimizing individual risk factors by using antiplatelet, antihypertensive, and dyslipidemia medications. This case demonstrates a classic presentation of CADASIL syndrome with lesser described cardiac symptoms. Few cases of unusual cardiac symptoms in the setting of CADASIL syndrome have been reported. The relationship between cardiovascular disease and CADASIL syndrome is not well described. Further research is needed to elucidate any links between CADASIL syndrome and cardiovascular disease and to optimize management for these patients.

THE CASE

A 52-year-old man presented to the emergency department after vomiting a large volume of blood and was admitted to the intensive care unit. His past medical history was remarkable for untreated chronic hepatitis C resulting from injection drug use and cirrhosis without prior history of esophageal varices.

Due to ongoing hematemesis, he was intubated for airway protection and underwent esophagogastroduodenoscopy with banding of large esophageal varices on hospital day (HD) 1. He was extubated on HD 2 after clinical stability was achieved; however, he became encephalopathic over the subsequent days despite treatment with lactulose. On HD 4, the patient required re-intubation for progressive respiratory failure. Chest imaging revealed a large, simple-appearing right pleural effusion and extensive bilateral patchy ground-glass opacities (FIGURE 1).

Thoracentesis was ordered and revealed transudative pleural fluid; this finding, along with negative infectious studies, was consistent with hepatic hydrothorax. In the setting of initial decompensation, empiric treatment with vancomycin and meropenem was started for suspected hospital-acquired pneumonia.

The patient had persistent fevers that had developed during his hospital stay and pulmonary opacities, despite 72 hours of treatment with broad-spectrum antibiotics. Thus, a diagnostic bronchoscopy with bronchoalveolar lavage (BAL) was performed. BAL cell count and differential revealed 363 nucleated cells/µL, with profound eosinophilia (42% eosinophils, 44% macrophages, 14% neutrophils).

Bacterial and fungal cultures and a viral polymerase chain reaction panel were negative. HIV antibody-antigen and RNA testing were also negative. The patient had no evidence or history of underlying malignancy, autoimmune disease, or recent immunosuppressive therapy, including corticosteroids. Due to consistent imaging findings and lack of improvement with appropriate treatment for bacterial pneumonia, further work-up was pursued.

THE DIAGNOSIS

Given the consistent radiographic pattern, the differential diagnosis for this patient included pneumocystis pneumonia (PCP), a potentially life-threatening opportunistic infection. Work-up therefore included direct fluorescent antibody testing, which was positive for Pneumocystis jirovecii, a fungus that can cause PCP.

Of note, the patient’s white blood cell count was elevated on admission (11.44 × 10³/µL) but low for much of his hospital stay (nadir = 1.97 × 10³/µL), with associated lymphopenia (nadir = 0.22 × 10³/µl). No peripheral eosinophilia was noted.

Continue to: DISCUSSION

PCP typically occurs in immunocompromised individuals and may be related to HIV infection, malignancy, or exposure to immunosuppressive therapies.^1,2 While rare cases of PCP have been described in adults without predisposing factors, many of these cases occurred at the beginning of the AIDS epidemic, prior to reliable HIV testing.^3-5

Uncharted territory. We were confident in our diagnosis because immunofluorescence testing has very few false-positives and a high specificity.^6-8 But there were informational gaps. The eosinophilia recorded on BAL is poorly described in HIV-negative patients with PCP but well-described in HIV-positive patients, with the level of eosinophilia associated with disease severity.^9,10 Eosinophils are thought to contribute to pulmonary inflammation, which may explain the severity of our patient’s course.¹⁰

A first of its kind case?

To our knowledge, this is the first report of PCP in a patient with cirrhosis from chronic hepatitis C virus infection and no other predisposing conditions or preceding immunosuppressive therapy. We suspect that his lymphopenia, which was noted during his critical illness, predisposed him to PCP.

Individuals with lymphopenia and low CD4+ T-cell counts have been shown to be at increased risk of pneumocystis pneumonia.

Lymphocytes (in particular CD4+ T cells) have been shown to play an important role, along with alveolar macrophages and neutrophils, in directing the host defense against P jirovecii infection.^1,3,11 Individuals with lymphopenia and low CD4+ T-cell counts have been shown to be at increased risk of PCP; risk increases markedly with CD4+ T cells below 200 cells/µL.^11-13

Typical risk factors for lymphopenia had not been observed in this patient. However, cirrhosis has been associated with low CD4+ T-cell counts and disruption of cell-mediated immunity, even in HIV-­seronegative patients.^14,15 There are several postulated mechanisms for low CD4+ T-cell counts in cirrhosis, including splenic sequestration, impaired T-cell production (due to impaired thymopoiesis), increased T-cell consumption, and apoptosis (due to persistent immune system activation from bacterial translocation and an overall pro-infl­ammatory state).^16,17

Continue to: Predisposing factors guide treatment

Routine treatment for PCP in patients without HIV is a 21-day course of trimethoprim/­sulfamethoxazole (Bactrim). Dosing for patients with normal renal function is 15 to 20 mg/kg orally or intravenously per day. Patients with allergy to trimethoprim/sulfamethoxazole should ideally undergo desensitization, given its effectiveness against PCP.

Due to a sulfonamide allergy, our patient was started on primaquine 30 mg/d, clindamycin 600 mg tid, and prednisone 40 mg bid. (The corticosteroid was added because of the severity of the disease.) Three days after starting treatment—and 10 days into his hospital stay—the patient had significant improvement in his respiratory status and was successfully extubated. He underwent trimethoprim/sulfamethoxazole desensitization and completed a 21-day course of treatment for PCP with complete resolution of respiratory symptoms. Follow-up chest radiograph 2 months later (FIGURE 2) confirmed clearance of opacities.

THE TAKEAWAY

PCP remains a rare disease in patients without the typical immunosuppressive risk factors. However, it should be considered in patients with cirrhosis who develop respiratory failure, especially those with compatible radiographic findings and negative microbiologic evaluation for other, more typical, organisms.

CORRESPONDENCE
Tyler Albert, MD, VA Puget Sound Healthcare System, 1660 South Columbian Way, S-111-Pulm, Seattle, WA 98108; [email protected]

THE CASE

A 52-year-old man presented to the emergency department after vomiting a large volume of blood and was admitted to the intensive care unit. His past medical history was remarkable for untreated chronic hepatitis C resulting from injection drug use and cirrhosis without prior history of esophageal varices.

Due to ongoing hematemesis, he was intubated for airway protection and underwent esophagogastroduodenoscopy with banding of large esophageal varices on hospital day (HD) 1. He was extubated on HD 2 after clinical stability was achieved; however, he became encephalopathic over the subsequent days despite treatment with lactulose. On HD 4, the patient required re-intubation for progressive respiratory failure. Chest imaging revealed a large, simple-appearing right pleural effusion and extensive bilateral patchy ground-glass opacities (FIGURE 1).

Thoracentesis was ordered and revealed transudative pleural fluid; this finding, along with negative infectious studies, was consistent with hepatic hydrothorax. In the setting of initial decompensation, empiric treatment with vancomycin and meropenem was started for suspected hospital-acquired pneumonia.

The patient had persistent fevers that had developed during his hospital stay and pulmonary opacities, despite 72 hours of treatment with broad-spectrum antibiotics. Thus, a diagnostic bronchoscopy with bronchoalveolar lavage (BAL) was performed. BAL cell count and differential revealed 363 nucleated cells/µL, with profound eosinophilia (42% eosinophils, 44% macrophages, 14% neutrophils).

Bacterial and fungal cultures and a viral polymerase chain reaction panel were negative. HIV antibody-antigen and RNA testing were also negative. The patient had no evidence or history of underlying malignancy, autoimmune disease, or recent immunosuppressive therapy, including corticosteroids. Due to consistent imaging findings and lack of improvement with appropriate treatment for bacterial pneumonia, further work-up was pursued.

THE DIAGNOSIS

Given the consistent radiographic pattern, the differential diagnosis for this patient included pneumocystis pneumonia (PCP), a potentially life-threatening opportunistic infection. Work-up therefore included direct fluorescent antibody testing, which was positive for Pneumocystis jirovecii, a fungus that can cause PCP.

Of note, the patient’s white blood cell count was elevated on admission (11.44 × 10³/µL) but low for much of his hospital stay (nadir = 1.97 × 10³/µL), with associated lymphopenia (nadir = 0.22 × 10³/µl). No peripheral eosinophilia was noted.

Continue to: DISCUSSION

PCP typically occurs in immunocompromised individuals and may be related to HIV infection, malignancy, or exposure to immunosuppressive therapies.^1,2 While rare cases of PCP have been described in adults without predisposing factors, many of these cases occurred at the beginning of the AIDS epidemic, prior to reliable HIV testing.^3-5

Uncharted territory. We were confident in our diagnosis because immunofluorescence testing has very few false-positives and a high specificity.^6-8 But there were informational gaps. The eosinophilia recorded on BAL is poorly described in HIV-negative patients with PCP but well-described in HIV-positive patients, with the level of eosinophilia associated with disease severity.^9,10 Eosinophils are thought to contribute to pulmonary inflammation, which may explain the severity of our patient’s course.¹⁰

A first of its kind case?

To our knowledge, this is the first report of PCP in a patient with cirrhosis from chronic hepatitis C virus infection and no other predisposing conditions or preceding immunosuppressive therapy. We suspect that his lymphopenia, which was noted during his critical illness, predisposed him to PCP.

Individuals with lymphopenia and low CD4+ T-cell counts have been shown to be at increased risk of pneumocystis pneumonia.

Lymphocytes (in particular CD4+ T cells) have been shown to play an important role, along with alveolar macrophages and neutrophils, in directing the host defense against P jirovecii infection.^1,3,11 Individuals with lymphopenia and low CD4+ T-cell counts have been shown to be at increased risk of PCP; risk increases markedly with CD4+ T cells below 200 cells/µL.^11-13

Typical risk factors for lymphopenia had not been observed in this patient. However, cirrhosis has been associated with low CD4+ T-cell counts and disruption of cell-mediated immunity, even in HIV-­seronegative patients.^14,15 There are several postulated mechanisms for low CD4+ T-cell counts in cirrhosis, including splenic sequestration, impaired T-cell production (due to impaired thymopoiesis), increased T-cell consumption, and apoptosis (due to persistent immune system activation from bacterial translocation and an overall pro-infl­ammatory state).^16,17

Continue to: Predisposing factors guide treatment

Routine treatment for PCP in patients without HIV is a 21-day course of trimethoprim/­sulfamethoxazole (Bactrim). Dosing for patients with normal renal function is 15 to 20 mg/kg orally or intravenously per day. Patients with allergy to trimethoprim/sulfamethoxazole should ideally undergo desensitization, given its effectiveness against PCP.

Due to a sulfonamide allergy, our patient was started on primaquine 30 mg/d, clindamycin 600 mg tid, and prednisone 40 mg bid. (The corticosteroid was added because of the severity of the disease.) Three days after starting treatment—and 10 days into his hospital stay—the patient had significant improvement in his respiratory status and was successfully extubated. He underwent trimethoprim/sulfamethoxazole desensitization and completed a 21-day course of treatment for PCP with complete resolution of respiratory symptoms. Follow-up chest radiograph 2 months later (FIGURE 2) confirmed clearance of opacities.

THE TAKEAWAY

PCP remains a rare disease in patients without the typical immunosuppressive risk factors. However, it should be considered in patients with cirrhosis who develop respiratory failure, especially those with compatible radiographic findings and negative microbiologic evaluation for other, more typical, organisms.

CORRESPONDENCE
Tyler Albert, MD, VA Puget Sound Healthcare System, 1660 South Columbian Way, S-111-Pulm, Seattle, WA 98108; [email protected]

THE CASE

A 52-year-old man presented to the emergency department after vomiting a large volume of blood and was admitted to the intensive care unit. His past medical history was remarkable for untreated chronic hepatitis C resulting from injection drug use and cirrhosis without prior history of esophageal varices.

Due to ongoing hematemesis, he was intubated for airway protection and underwent esophagogastroduodenoscopy with banding of large esophageal varices on hospital day (HD) 1. He was extubated on HD 2 after clinical stability was achieved; however, he became encephalopathic over the subsequent days despite treatment with lactulose. On HD 4, the patient required re-intubation for progressive respiratory failure. Chest imaging revealed a large, simple-appearing right pleural effusion and extensive bilateral patchy ground-glass opacities (FIGURE 1).

Thoracentesis was ordered and revealed transudative pleural fluid; this finding, along with negative infectious studies, was consistent with hepatic hydrothorax. In the setting of initial decompensation, empiric treatment with vancomycin and meropenem was started for suspected hospital-acquired pneumonia.

The patient had persistent fevers that had developed during his hospital stay and pulmonary opacities, despite 72 hours of treatment with broad-spectrum antibiotics. Thus, a diagnostic bronchoscopy with bronchoalveolar lavage (BAL) was performed. BAL cell count and differential revealed 363 nucleated cells/µL, with profound eosinophilia (42% eosinophils, 44% macrophages, 14% neutrophils).

Bacterial and fungal cultures and a viral polymerase chain reaction panel were negative. HIV antibody-antigen and RNA testing were also negative. The patient had no evidence or history of underlying malignancy, autoimmune disease, or recent immunosuppressive therapy, including corticosteroids. Due to consistent imaging findings and lack of improvement with appropriate treatment for bacterial pneumonia, further work-up was pursued.

THE DIAGNOSIS

Given the consistent radiographic pattern, the differential diagnosis for this patient included pneumocystis pneumonia (PCP), a potentially life-threatening opportunistic infection. Work-up therefore included direct fluorescent antibody testing, which was positive for Pneumocystis jirovecii, a fungus that can cause PCP.

Of note, the patient’s white blood cell count was elevated on admission (11.44 × 10³/µL) but low for much of his hospital stay (nadir = 1.97 × 10³/µL), with associated lymphopenia (nadir = 0.22 × 10³/µl). No peripheral eosinophilia was noted.

Continue to: DISCUSSION

PCP typically occurs in immunocompromised individuals and may be related to HIV infection, malignancy, or exposure to immunosuppressive therapies.^1,2 While rare cases of PCP have been described in adults without predisposing factors, many of these cases occurred at the beginning of the AIDS epidemic, prior to reliable HIV testing.^3-5

Uncharted territory. We were confident in our diagnosis because immunofluorescence testing has very few false-positives and a high specificity.^6-8 But there were informational gaps. The eosinophilia recorded on BAL is poorly described in HIV-negative patients with PCP but well-described in HIV-positive patients, with the level of eosinophilia associated with disease severity.^9,10 Eosinophils are thought to contribute to pulmonary inflammation, which may explain the severity of our patient’s course.¹⁰

A first of its kind case?

To our knowledge, this is the first report of PCP in a patient with cirrhosis from chronic hepatitis C virus infection and no other predisposing conditions or preceding immunosuppressive therapy. We suspect that his lymphopenia, which was noted during his critical illness, predisposed him to PCP.

Individuals with lymphopenia and low CD4+ T-cell counts have been shown to be at increased risk of pneumocystis pneumonia.

Lymphocytes (in particular CD4+ T cells) have been shown to play an important role, along with alveolar macrophages and neutrophils, in directing the host defense against P jirovecii infection.^1,3,11 Individuals with lymphopenia and low CD4+ T-cell counts have been shown to be at increased risk of PCP; risk increases markedly with CD4+ T cells below 200 cells/µL.^11-13

Typical risk factors for lymphopenia had not been observed in this patient. However, cirrhosis has been associated with low CD4+ T-cell counts and disruption of cell-mediated immunity, even in HIV-­seronegative patients.^14,15 There are several postulated mechanisms for low CD4+ T-cell counts in cirrhosis, including splenic sequestration, impaired T-cell production (due to impaired thymopoiesis), increased T-cell consumption, and apoptosis (due to persistent immune system activation from bacterial translocation and an overall pro-infl­ammatory state).^16,17

Continue to: Predisposing factors guide treatment

Routine treatment for PCP in patients without HIV is a 21-day course of trimethoprim/­sulfamethoxazole (Bactrim). Dosing for patients with normal renal function is 15 to 20 mg/kg orally or intravenously per day. Patients with allergy to trimethoprim/sulfamethoxazole should ideally undergo desensitization, given its effectiveness against PCP.

Due to a sulfonamide allergy, our patient was started on primaquine 30 mg/d, clindamycin 600 mg tid, and prednisone 40 mg bid. (The corticosteroid was added because of the severity of the disease.) Three days after starting treatment—and 10 days into his hospital stay—the patient had significant improvement in his respiratory status and was successfully extubated. He underwent trimethoprim/sulfamethoxazole desensitization and completed a 21-day course of treatment for PCP with complete resolution of respiratory symptoms. Follow-up chest radiograph 2 months later (FIGURE 2) confirmed clearance of opacities.

THE TAKEAWAY

PCP remains a rare disease in patients without the typical immunosuppressive risk factors. However, it should be considered in patients with cirrhosis who develop respiratory failure, especially those with compatible radiographic findings and negative microbiologic evaluation for other, more typical, organisms.

CORRESPONDENCE
Tyler Albert, MD, VA Puget Sound Healthcare System, 1660 South Columbian Way, S-111-Pulm, Seattle, WA 98108; [email protected]

THE CASE 

An active 61-year-old woman (140 lbs) in good health became ill during a sailing holiday in the Virgin Islands. During the trip, she ate various fish in local restaurants; after one lunch, she developed nausea, diarrhea, dizziness, headache, and light-headedness. In the following days, she suffered “intense itching” in the ears, dizziness, malaise, a “fluttering feeling” throughout her body, genitourinary sensitivity, and a “rhythmic buzzing sensation near the rectum.”

She said that cold objects and beverages felt uncomfortably hot (cold allodynia). She noted heightened senses of smell and taste, as well as paresthesia down her spine, and described feeling “moody.” She reduced her workload, took many days off from work, and ceased consuming meat and alcohol because these items seemed to aggravate her symptoms.

The paresthesia persisted, and she consulted her family physician one month later. Laboratory tests—including a complete blood count, hematocrit, thyroid-stimulating hormone, antinuclear antibodies, and titers for Ehrlichia chaffeensis, Lyme disease, and Anaplasma phagocytophila—all yielded normal results. Her symptoms continued for 3 more months before referral to Medical Toxicology.

THE DIAGNOSIS

The patient’s symptoms and history were consistent with ciguatera poisoning. Features supporting this diagnosis included an acute gastrointestinal illness after eating fish caught in tropical waters and subsequent persistent paresthesia, including cold allodynia.¹ Laboratory testing excluded acute infection, anemia, thyroid dysfunction, vitamin B12 deficiency, lupus, rheumatoid arthritis, Lyme disease, ehrlichiosis, and anaplasmosis.

DISCUSSION

Ciguatera results from ciguatoxin, a class of heat-stable polycyclic toxins produced in warm tropical waters by microscopic dinoflagellates (most often Gambierdiscus toxicus).^2,3 Small variations exist in the Caribbean, Pacific, and Indian Ocean forms. Ciguatoxin bio-­accumulates in the food chain, and humans most often ingest it by eating larger fish (typically barracuda, snapper, grouper, or amberjack).⁴ Because ciguatoxin confers no characteristic taste or smell to the fish, people who prepare or eat contaminated seafood have no reliable means to detect and avoid it.

Ciguatoxin opens neuronal voltage-gated sodium channels and blocks delayed-­rectifier potassium channels.⁵ These cause repetitive, spontaneous action potentials that explain the paresthesia. Sodium influx triggers an increase in intracellular calcium concentrations. Increased intracellular sodium and calcium concentrations draw water into the intracellular space and cause neuronal edema.

Death is rarely associated with ciguatera (< 0.1% in the largest observational study).¹ Even without treatment (discussed shortly), symptoms of ciguatera will gradually resolve over several weeks to several months in most cases.^1,4,5 However, after recovery, patients often briefly experience milder symptoms after consuming fish, alcohol, or nuts.⁶

Continue to: Treatment of ciguatera

Treatment of ciguatera may include intravenous (IV) mannitol infusion. Other treatments, such as amitriptyline, gabapentin, pregabalin, and tocainide, have been used, but there is limited supporting evidence and they appear variably effective.⁷

Mannitol reverses the effects of ciguatoxin, with suppression of spontaneous action potentials and reversal of neuronal edema.^8,9 It is reasonable to offer mannitol for acute or persistent symptoms of ciguatera fish poisoning even after a delay of several weeks.

Ciguatoxin confers no characteristic taste or smell to the fish. Thus, people who prepare or eat contaminated seafood have no reliable means to detect and avoid it.

A recent systematic review found that mannitol has the largest body of evidence supporting its use, although that evidence is generally of low quality (case reports and large case series).⁷ While these reports^10-13 describe beneficial effects of mannitol, a single randomized trial suggested that mannitol is no more effective than normal saline.¹⁴ However, this study was underpowered and had inadequate treatment concealment; twice as many saline control patients as mannitol-treated patients requested a rescue dose of mannitol.¹⁴

Mannitol may be most effective when given early in the course of ciguatera but has shown some success when given later.^5,12,13 In 1 large case series, the longest interval from symptom onset to successful treatment was 70 days, although most patients with satisfactory results received mannitol in the first few days.⁵

Our patient was administered an IV infusion of 100 g of 20% mannitol over 1 hour. She received the infusion 140 days after the onset of her symptoms and experienced rapid symptom relief.

Continue to: At a follow-up visit...

At a follow-up visit 2 weeks later, she described increased energy and further improvement in her paresthesia. She returned to a full work schedule and resumed all of her daily activities. However, she continued to avoid alcohol and proteins, as she had experienced a mild recurrence that she temporally related to eating meat and drinking alcohol.

At the 2-month follow-up, the patient reported continued improvement in her paresthesia but continued to experience occasional gastrointestinal symptoms and fatigue associated with meat and alcohol consumption.

The Takeaway 

Ciguatera fish poisoning is largely a clinical diagnosis. It is based on early gastrointestinal symptoms followed by persistent paresthesia and cold allodynia after consumption of fish caught in tropical waters. Family physicians may see ciguatera in returning travelers or people who have consumed certain fish imported from endemic areas. Untreated symptoms may last for many weeks or months. IV mannitol may relieve symptoms of ciguatera poisoning even when administered several months after symptom onset.

Acknowledgement
We are grateful to our patient, who allowed us to share her story in the hope of helping other travelers.

CORRESPONDENCE
Michael E. Mullins, MD, Division of Medical Toxicology, Department of Emergency Medicine, Washington University School of Medicine, Campus Box 8072, 660 South Euclid Avenue, Saint Louis, MO 63110; [email protected]

THE CASE 

An active 61-year-old woman (140 lbs) in good health became ill during a sailing holiday in the Virgin Islands. During the trip, she ate various fish in local restaurants; after one lunch, she developed nausea, diarrhea, dizziness, headache, and light-headedness. In the following days, she suffered “intense itching” in the ears, dizziness, malaise, a “fluttering feeling” throughout her body, genitourinary sensitivity, and a “rhythmic buzzing sensation near the rectum.”

She said that cold objects and beverages felt uncomfortably hot (cold allodynia). She noted heightened senses of smell and taste, as well as paresthesia down her spine, and described feeling “moody.” She reduced her workload, took many days off from work, and ceased consuming meat and alcohol because these items seemed to aggravate her symptoms.

The paresthesia persisted, and she consulted her family physician one month later. Laboratory tests—including a complete blood count, hematocrit, thyroid-stimulating hormone, antinuclear antibodies, and titers for Ehrlichia chaffeensis, Lyme disease, and Anaplasma phagocytophila—all yielded normal results. Her symptoms continued for 3 more months before referral to Medical Toxicology.

THE DIAGNOSIS

The patient’s symptoms and history were consistent with ciguatera poisoning. Features supporting this diagnosis included an acute gastrointestinal illness after eating fish caught in tropical waters and subsequent persistent paresthesia, including cold allodynia.¹ Laboratory testing excluded acute infection, anemia, thyroid dysfunction, vitamin B12 deficiency, lupus, rheumatoid arthritis, Lyme disease, ehrlichiosis, and anaplasmosis.

DISCUSSION

Ciguatera results from ciguatoxin, a class of heat-stable polycyclic toxins produced in warm tropical waters by microscopic dinoflagellates (most often Gambierdiscus toxicus).^2,3 Small variations exist in the Caribbean, Pacific, and Indian Ocean forms. Ciguatoxin bio-­accumulates in the food chain, and humans most often ingest it by eating larger fish (typically barracuda, snapper, grouper, or amberjack).⁴ Because ciguatoxin confers no characteristic taste or smell to the fish, people who prepare or eat contaminated seafood have no reliable means to detect and avoid it.

Ciguatoxin opens neuronal voltage-gated sodium channels and blocks delayed-­rectifier potassium channels.⁵ These cause repetitive, spontaneous action potentials that explain the paresthesia. Sodium influx triggers an increase in intracellular calcium concentrations. Increased intracellular sodium and calcium concentrations draw water into the intracellular space and cause neuronal edema.

Death is rarely associated with ciguatera (< 0.1% in the largest observational study).¹ Even without treatment (discussed shortly), symptoms of ciguatera will gradually resolve over several weeks to several months in most cases.^1,4,5 However, after recovery, patients often briefly experience milder symptoms after consuming fish, alcohol, or nuts.⁶

Continue to: Treatment of ciguatera

Treatment of ciguatera may include intravenous (IV) mannitol infusion. Other treatments, such as amitriptyline, gabapentin, pregabalin, and tocainide, have been used, but there is limited supporting evidence and they appear variably effective.⁷

Mannitol reverses the effects of ciguatoxin, with suppression of spontaneous action potentials and reversal of neuronal edema.^8,9 It is reasonable to offer mannitol for acute or persistent symptoms of ciguatera fish poisoning even after a delay of several weeks.

Ciguatoxin confers no characteristic taste or smell to the fish. Thus, people who prepare or eat contaminated seafood have no reliable means to detect and avoid it.

A recent systematic review found that mannitol has the largest body of evidence supporting its use, although that evidence is generally of low quality (case reports and large case series).⁷ While these reports^10-13 describe beneficial effects of mannitol, a single randomized trial suggested that mannitol is no more effective than normal saline.¹⁴ However, this study was underpowered and had inadequate treatment concealment; twice as many saline control patients as mannitol-treated patients requested a rescue dose of mannitol.¹⁴

Mannitol may be most effective when given early in the course of ciguatera but has shown some success when given later.^5,12,13 In 1 large case series, the longest interval from symptom onset to successful treatment was 70 days, although most patients with satisfactory results received mannitol in the first few days.⁵

Our patient was administered an IV infusion of 100 g of 20% mannitol over 1 hour. She received the infusion 140 days after the onset of her symptoms and experienced rapid symptom relief.

Continue to: At a follow-up visit...

At a follow-up visit 2 weeks later, she described increased energy and further improvement in her paresthesia. She returned to a full work schedule and resumed all of her daily activities. However, she continued to avoid alcohol and proteins, as she had experienced a mild recurrence that she temporally related to eating meat and drinking alcohol.

At the 2-month follow-up, the patient reported continued improvement in her paresthesia but continued to experience occasional gastrointestinal symptoms and fatigue associated with meat and alcohol consumption.

The Takeaway 

Ciguatera fish poisoning is largely a clinical diagnosis. It is based on early gastrointestinal symptoms followed by persistent paresthesia and cold allodynia after consumption of fish caught in tropical waters. Family physicians may see ciguatera in returning travelers or people who have consumed certain fish imported from endemic areas. Untreated symptoms may last for many weeks or months. IV mannitol may relieve symptoms of ciguatera poisoning even when administered several months after symptom onset.

Acknowledgement
We are grateful to our patient, who allowed us to share her story in the hope of helping other travelers.

CORRESPONDENCE
Michael E. Mullins, MD, Division of Medical Toxicology, Department of Emergency Medicine, Washington University School of Medicine, Campus Box 8072, 660 South Euclid Avenue, Saint Louis, MO 63110; [email protected]

THE CASE 

An active 61-year-old woman (140 lbs) in good health became ill during a sailing holiday in the Virgin Islands. During the trip, she ate various fish in local restaurants; after one lunch, she developed nausea, diarrhea, dizziness, headache, and light-headedness. In the following days, she suffered “intense itching” in the ears, dizziness, malaise, a “fluttering feeling” throughout her body, genitourinary sensitivity, and a “rhythmic buzzing sensation near the rectum.”

She said that cold objects and beverages felt uncomfortably hot (cold allodynia). She noted heightened senses of smell and taste, as well as paresthesia down her spine, and described feeling “moody.” She reduced her workload, took many days off from work, and ceased consuming meat and alcohol because these items seemed to aggravate her symptoms.

The paresthesia persisted, and she consulted her family physician one month later. Laboratory tests—including a complete blood count, hematocrit, thyroid-stimulating hormone, antinuclear antibodies, and titers for Ehrlichia chaffeensis, Lyme disease, and Anaplasma phagocytophila—all yielded normal results. Her symptoms continued for 3 more months before referral to Medical Toxicology.

THE DIAGNOSIS

The patient’s symptoms and history were consistent with ciguatera poisoning. Features supporting this diagnosis included an acute gastrointestinal illness after eating fish caught in tropical waters and subsequent persistent paresthesia, including cold allodynia.¹ Laboratory testing excluded acute infection, anemia, thyroid dysfunction, vitamin B12 deficiency, lupus, rheumatoid arthritis, Lyme disease, ehrlichiosis, and anaplasmosis.

DISCUSSION

Ciguatera results from ciguatoxin, a class of heat-stable polycyclic toxins produced in warm tropical waters by microscopic dinoflagellates (most often Gambierdiscus toxicus).^2,3 Small variations exist in the Caribbean, Pacific, and Indian Ocean forms. Ciguatoxin bio-­accumulates in the food chain, and humans most often ingest it by eating larger fish (typically barracuda, snapper, grouper, or amberjack).⁴ Because ciguatoxin confers no characteristic taste or smell to the fish, people who prepare or eat contaminated seafood have no reliable means to detect and avoid it.

Ciguatoxin opens neuronal voltage-gated sodium channels and blocks delayed-­rectifier potassium channels.⁵ These cause repetitive, spontaneous action potentials that explain the paresthesia. Sodium influx triggers an increase in intracellular calcium concentrations. Increased intracellular sodium and calcium concentrations draw water into the intracellular space and cause neuronal edema.

Death is rarely associated with ciguatera (< 0.1% in the largest observational study).¹ Even without treatment (discussed shortly), symptoms of ciguatera will gradually resolve over several weeks to several months in most cases.^1,4,5 However, after recovery, patients often briefly experience milder symptoms after consuming fish, alcohol, or nuts.⁶

Continue to: Treatment of ciguatera

Treatment of ciguatera may include intravenous (IV) mannitol infusion. Other treatments, such as amitriptyline, gabapentin, pregabalin, and tocainide, have been used, but there is limited supporting evidence and they appear variably effective.⁷

Mannitol reverses the effects of ciguatoxin, with suppression of spontaneous action potentials and reversal of neuronal edema.^8,9 It is reasonable to offer mannitol for acute or persistent symptoms of ciguatera fish poisoning even after a delay of several weeks.

Ciguatoxin confers no characteristic taste or smell to the fish. Thus, people who prepare or eat contaminated seafood have no reliable means to detect and avoid it.

A recent systematic review found that mannitol has the largest body of evidence supporting its use, although that evidence is generally of low quality (case reports and large case series).⁷ While these reports^10-13 describe beneficial effects of mannitol, a single randomized trial suggested that mannitol is no more effective than normal saline.¹⁴ However, this study was underpowered and had inadequate treatment concealment; twice as many saline control patients as mannitol-treated patients requested a rescue dose of mannitol.¹⁴

Mannitol may be most effective when given early in the course of ciguatera but has shown some success when given later.^5,12,13 In 1 large case series, the longest interval from symptom onset to successful treatment was 70 days, although most patients with satisfactory results received mannitol in the first few days.⁵

Our patient was administered an IV infusion of 100 g of 20% mannitol over 1 hour. She received the infusion 140 days after the onset of her symptoms and experienced rapid symptom relief.

Continue to: At a follow-up visit...

At a follow-up visit 2 weeks later, she described increased energy and further improvement in her paresthesia. She returned to a full work schedule and resumed all of her daily activities. However, she continued to avoid alcohol and proteins, as she had experienced a mild recurrence that she temporally related to eating meat and drinking alcohol.

At the 2-month follow-up, the patient reported continued improvement in her paresthesia but continued to experience occasional gastrointestinal symptoms and fatigue associated with meat and alcohol consumption.

The Takeaway 

Ciguatera fish poisoning is largely a clinical diagnosis. It is based on early gastrointestinal symptoms followed by persistent paresthesia and cold allodynia after consumption of fish caught in tropical waters. Family physicians may see ciguatera in returning travelers or people who have consumed certain fish imported from endemic areas. Untreated symptoms may last for many weeks or months. IV mannitol may relieve symptoms of ciguatera poisoning even when administered several months after symptom onset.

Acknowledgement
We are grateful to our patient, who allowed us to share her story in the hope of helping other travelers.

CORRESPONDENCE
Michael E. Mullins, MD, Division of Medical Toxicology, Department of Emergency Medicine, Washington University School of Medicine, Campus Box 8072, 660 South Euclid Avenue, Saint Louis, MO 63110; [email protected]