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

Case Presentation

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

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

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

Discussion

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

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

Conclusions

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

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

Case Presentation

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

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

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

Discussion

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

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

Conclusions

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

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

Case Presentation

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

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

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

Discussion

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

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

Conclusions

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

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

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

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

Case Presentation

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

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

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

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

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

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

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

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

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

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

Discussion

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

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

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

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

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

Conclusions

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

Acknowledgments

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

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

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

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

Case Presentation

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

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

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

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

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

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

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

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

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

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

Discussion

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

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

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

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

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

Conclusions

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

Acknowledgments

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

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

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

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

Case Presentation

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

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

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

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

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

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

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

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

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

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

Discussion

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

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

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

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

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

Conclusions

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

Acknowledgments

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

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.

Hospital leaders report the most common aim of peer review (PR) is to improve quality and patient safety, thus it is a potentially powerful quality improvement (QI) driver.¹ “When conducted systematically and credibly, peer review for quality management can result in both short-term and long-term improvements in patient care by revealing areas for improvement in the provision of care,” Veterans Health Administration (VHA) Directive 1190 states. “This ultimately contributes to organizational improvements.” At the same time, there are anecdotal concerns that PR may be used punitively and driven by case outcomes rather than by accepted best practices supporting QI.

Studies of the PR process suggest these concerns are valid. A key tenet of QI is standardization. PR is problematic in that regard; studies show poor interrater reliability for judgments on care, as well as hindsight bias—the fact that raters are strongly influenced by the outcome of care, not the process of care.^2-5 There are concerns that case selection or review process when not standardized may be wielded as punitive too.⁶ In this study, we sought to identify the relationship between PR findings and subsequent institution quality metrics. If PR does lead to an improvement in quality, or if quality concerns are managed within the PR committee, it should be possible to identify a measurable relationship between the PR process and a facility’s subsequent quality measures.

A handful of studies describe the association between PR and quality of care. Itri and colleagues noted that random, not standardized PR in radiology does not achieve reductions in diagnostic error rate.⁷ However, adoption of just culture principles in PR resulted in a significant improvement in facility leaders’ self-reports of quality measures at surveyed institutions.⁸ The same author reported that increases in PR standardization and integration with performance improvement activities could explain up to 18% of objective quality measure variation.⁹

We sought to determine whether a specific aspect of the PR process, the PR committee judgment of quality of care by clinicians, was related to medical center quality in a cross-sectional study of 136 Veterans Health Administration (VHA) medical centers. The VHA is a good source of study because there are standardized PR processes and training for committee members and reviewers. Our hypothesis was that medical centers with a higher number of Level 2 (“most experienced and competent clinicians might have managed the case differently”) and Level 3 (“most experienced and competent providers would have managed the case differently”) PR findings would also have lower quality metric scores for processes and outcomes of care.

Methods

We used PR data from fiscal year 2018 and 2019. VHA PR data are available quarterly and are self-reported by each facility to the VHA Office of Clinical Risk Management. These data are broken down by facility. The following data, when available in both fiscal years 2018 and 2019, were used for this analysis: percent and number of PR that are ranked as level 1, 2, or 3; medical center group (MCG) acuity measure assigned by the VHA (1 is highest, 3 is lowest); and number of PR per 100,000 unique veteran encounters in 2019. Measures of facility quality are drawn from Strategic Analytics for Improvement and Learning (SAIL) data from 2019, which are available quarterly by facility and are rolling for 12 months. SAIL measures processes and outcomes of care. Table 1 indicates which measures are focused on outcomes vs quality processes.

SAS Version 9.2 was used to perform statistical analyses. We used Spearman correlation to estimate the PR and quality relationship.

Results

There were 136 facilities with 2 years of PR data available. The majority of these facilities (89) were highest complexity MCG 1 facilities; 19 were MCG 2, and 28 were MCG 3. Of 13,515 PRs, most of the 9555 PR findings were level 1 (70.7%). The between-facility range of level 2 and 3 findings was large, varying from 3.5% to nearly 70% in 2019 (Table 2). Findings were similar in 2018; facilities level 2 and 3 ratings ranged from 3.6% to 73.5% of all PR findings.

There was no correlation between most quality measures and facility PR findings (Table 3). The only exception was for Global Measures (GM90), an inpatient process of care measure. Unexpectedly, the correlation was positive—facilities with a higher percentage of level 2 and 3 PR findings had better inpatient processes of care SAIL score. The strongest correlation was between 2018 and 2019 PR findings.

Discussion

We hypothesized that a high percentage of level 2 and 3 PR findings would be negatively associated with objective facility measures of care processes in SAIL but we did not see this association. The only quality measure associated with PR findings was GM90, a score of inpatient care processes. However, the association was positive, with better performance associated with more level 2 and 3 PR findings.

The best predictor of the proportion of a facility’s PR findings is the previous year’s PR findings. With an R = 0.59, the previous year findings explain about 35% of the variability in level assignment. Our analysis may describe a new bias in PR, in which committees consistently assign either low or high proportions of level 2 and 3 findings. This correlation could be due to individual PR committee culture or composition, but it does not relate to objective quality measures.

Strengths

For this study we use objective measures of PR processes, the assignment of levels of care. PR findings should reflect not only outcomes, but also the quality of the care, reflected by adherence to evidence-based processes, such as angiotensin-converting enzyme inhibitor prescription in heart failure. Therefore, we used SAIL scores, an objective and standardized process and outcome quality measures. Additionally, VHA is likely a national leader in the standardization of PR: VHA mandates as well as provides training for reviewers and PR committee members, has a standardized case-referral process, and mandates the documentation of feedback to health care professionals when care did not meet standards. While other publications show that PR has poor interrater reliability, VHA provides an outside contract to perform a second review on a percentage of cases to improve the validity of PR level assignments.

Limitations

Facilities self-report PR outcomes, so there could be errors in reporting. In addition, this study was cross sectional and not longitudinal and it is possible that change in quality measures over time are correlated with PR findings. Future studies using the VHA PR and SAIL data could evaluate whether changes over time, and perhaps in response to level 2 and 3 findings, would be a more sensitive indicator of the impact of the PR process on quality metrics. Future studies could incorporate the relationship between findings from the All Employee Survey, which is conducted annually, such as psychologic safety, as well as the distance the facility has gone on the high reliability organization journey, with PR findings and SAIL metrics. Finally, PR is focused on the practice of an individual clinician, while SAIL quality metrics reflect facility performance. Interventions possibly stay at the clinician level and do not drive subsequent QI processes. This is a missed opportunity, and future studies could evaluate practices by the PR coordinators to determine whether differences in these processes are associated with quality measures.

What does this mean for PR? Since the early 1990s, there have been exhortations from experts to improve PR, by adopting a QI model, or for a deeper integration of PR and QI.^1,2,10 Just culture tools, which include QI, are promoted as a means to improve PR.^8,11,12 Other studies show PR remains problematic in terms of standardization, incorporation of best practices, redesigning systems of care, or demonstrable improvements to facility safety and care quality.^1,4,6,8 Several publications have described interventions to improve PR. Deyo-Svedson discussed a program with standardized training and triggers, much like VHA.¹³ Itri and colleagues standardized PR in radiology to target areas of known diagnostic error, as well as use the issues assessed in PR to perform QI and education. One example of a successful QI effort involved changing the radiology reporting template to make sure areas that are prone to diagnostic error are addressed.⁷

Conclusions

Since 35% of PR level variance is correlated with prior year’s results, PR committees should look at increased standardization in reviews and findings. We endorse a strong focus on standardization, application of just culture tools to case reviews, and tighter linkage between process and outcome metrics measured by SAIL and PR case finding. Studies should be performed to pilot interventions to improve the linkage between PR and quality, so that greater and faster gains can be made in quality processes and, leading from this, outcomes. Additionally, future research should investigate why some facilities consistently choose higher or lower PR ratings.

Acknowledgments

We acknowledge Dr. George “Web” Ross for his helpful edits.

Hospital leaders report the most common aim of peer review (PR) is to improve quality and patient safety, thus it is a potentially powerful quality improvement (QI) driver.¹ “When conducted systematically and credibly, peer review for quality management can result in both short-term and long-term improvements in patient care by revealing areas for improvement in the provision of care,” Veterans Health Administration (VHA) Directive 1190 states. “This ultimately contributes to organizational improvements.” At the same time, there are anecdotal concerns that PR may be used punitively and driven by case outcomes rather than by accepted best practices supporting QI.

Studies of the PR process suggest these concerns are valid. A key tenet of QI is standardization. PR is problematic in that regard; studies show poor interrater reliability for judgments on care, as well as hindsight bias—the fact that raters are strongly influenced by the outcome of care, not the process of care.^2-5 There are concerns that case selection or review process when not standardized may be wielded as punitive too.⁶ In this study, we sought to identify the relationship between PR findings and subsequent institution quality metrics. If PR does lead to an improvement in quality, or if quality concerns are managed within the PR committee, it should be possible to identify a measurable relationship between the PR process and a facility’s subsequent quality measures.

A handful of studies describe the association between PR and quality of care. Itri and colleagues noted that random, not standardized PR in radiology does not achieve reductions in diagnostic error rate.⁷ However, adoption of just culture principles in PR resulted in a significant improvement in facility leaders’ self-reports of quality measures at surveyed institutions.⁸ The same author reported that increases in PR standardization and integration with performance improvement activities could explain up to 18% of objective quality measure variation.⁹

We sought to determine whether a specific aspect of the PR process, the PR committee judgment of quality of care by clinicians, was related to medical center quality in a cross-sectional study of 136 Veterans Health Administration (VHA) medical centers. The VHA is a good source of study because there are standardized PR processes and training for committee members and reviewers. Our hypothesis was that medical centers with a higher number of Level 2 (“most experienced and competent clinicians might have managed the case differently”) and Level 3 (“most experienced and competent providers would have managed the case differently”) PR findings would also have lower quality metric scores for processes and outcomes of care.

Methods

We used PR data from fiscal year 2018 and 2019. VHA PR data are available quarterly and are self-reported by each facility to the VHA Office of Clinical Risk Management. These data are broken down by facility. The following data, when available in both fiscal years 2018 and 2019, were used for this analysis: percent and number of PR that are ranked as level 1, 2, or 3; medical center group (MCG) acuity measure assigned by the VHA (1 is highest, 3 is lowest); and number of PR per 100,000 unique veteran encounters in 2019. Measures of facility quality are drawn from Strategic Analytics for Improvement and Learning (SAIL) data from 2019, which are available quarterly by facility and are rolling for 12 months. SAIL measures processes and outcomes of care. Table 1 indicates which measures are focused on outcomes vs quality processes.

SAS Version 9.2 was used to perform statistical analyses. We used Spearman correlation to estimate the PR and quality relationship.

Results

There were 136 facilities with 2 years of PR data available. The majority of these facilities (89) were highest complexity MCG 1 facilities; 19 were MCG 2, and 28 were MCG 3. Of 13,515 PRs, most of the 9555 PR findings were level 1 (70.7%). The between-facility range of level 2 and 3 findings was large, varying from 3.5% to nearly 70% in 2019 (Table 2). Findings were similar in 2018; facilities level 2 and 3 ratings ranged from 3.6% to 73.5% of all PR findings.

There was no correlation between most quality measures and facility PR findings (Table 3). The only exception was for Global Measures (GM90), an inpatient process of care measure. Unexpectedly, the correlation was positive—facilities with a higher percentage of level 2 and 3 PR findings had better inpatient processes of care SAIL score. The strongest correlation was between 2018 and 2019 PR findings.

Discussion

We hypothesized that a high percentage of level 2 and 3 PR findings would be negatively associated with objective facility measures of care processes in SAIL but we did not see this association. The only quality measure associated with PR findings was GM90, a score of inpatient care processes. However, the association was positive, with better performance associated with more level 2 and 3 PR findings.

The best predictor of the proportion of a facility’s PR findings is the previous year’s PR findings. With an R = 0.59, the previous year findings explain about 35% of the variability in level assignment. Our analysis may describe a new bias in PR, in which committees consistently assign either low or high proportions of level 2 and 3 findings. This correlation could be due to individual PR committee culture or composition, but it does not relate to objective quality measures.

Strengths

For this study we use objective measures of PR processes, the assignment of levels of care. PR findings should reflect not only outcomes, but also the quality of the care, reflected by adherence to evidence-based processes, such as angiotensin-converting enzyme inhibitor prescription in heart failure. Therefore, we used SAIL scores, an objective and standardized process and outcome quality measures. Additionally, VHA is likely a national leader in the standardization of PR: VHA mandates as well as provides training for reviewers and PR committee members, has a standardized case-referral process, and mandates the documentation of feedback to health care professionals when care did not meet standards. While other publications show that PR has poor interrater reliability, VHA provides an outside contract to perform a second review on a percentage of cases to improve the validity of PR level assignments.

Limitations

Facilities self-report PR outcomes, so there could be errors in reporting. In addition, this study was cross sectional and not longitudinal and it is possible that change in quality measures over time are correlated with PR findings. Future studies using the VHA PR and SAIL data could evaluate whether changes over time, and perhaps in response to level 2 and 3 findings, would be a more sensitive indicator of the impact of the PR process on quality metrics. Future studies could incorporate the relationship between findings from the All Employee Survey, which is conducted annually, such as psychologic safety, as well as the distance the facility has gone on the high reliability organization journey, with PR findings and SAIL metrics. Finally, PR is focused on the practice of an individual clinician, while SAIL quality metrics reflect facility performance. Interventions possibly stay at the clinician level and do not drive subsequent QI processes. This is a missed opportunity, and future studies could evaluate practices by the PR coordinators to determine whether differences in these processes are associated with quality measures.

What does this mean for PR? Since the early 1990s, there have been exhortations from experts to improve PR, by adopting a QI model, or for a deeper integration of PR and QI.^1,2,10 Just culture tools, which include QI, are promoted as a means to improve PR.^8,11,12 Other studies show PR remains problematic in terms of standardization, incorporation of best practices, redesigning systems of care, or demonstrable improvements to facility safety and care quality.^1,4,6,8 Several publications have described interventions to improve PR. Deyo-Svedson discussed a program with standardized training and triggers, much like VHA.¹³ Itri and colleagues standardized PR in radiology to target areas of known diagnostic error, as well as use the issues assessed in PR to perform QI and education. One example of a successful QI effort involved changing the radiology reporting template to make sure areas that are prone to diagnostic error are addressed.⁷

Conclusions

Since 35% of PR level variance is correlated with prior year’s results, PR committees should look at increased standardization in reviews and findings. We endorse a strong focus on standardization, application of just culture tools to case reviews, and tighter linkage between process and outcome metrics measured by SAIL and PR case finding. Studies should be performed to pilot interventions to improve the linkage between PR and quality, so that greater and faster gains can be made in quality processes and, leading from this, outcomes. Additionally, future research should investigate why some facilities consistently choose higher or lower PR ratings.

Acknowledgments

We acknowledge Dr. George “Web” Ross for his helpful edits.

Hospital leaders report the most common aim of peer review (PR) is to improve quality and patient safety, thus it is a potentially powerful quality improvement (QI) driver.¹ “When conducted systematically and credibly, peer review for quality management can result in both short-term and long-term improvements in patient care by revealing areas for improvement in the provision of care,” Veterans Health Administration (VHA) Directive 1190 states. “This ultimately contributes to organizational improvements.” At the same time, there are anecdotal concerns that PR may be used punitively and driven by case outcomes rather than by accepted best practices supporting QI.

Studies of the PR process suggest these concerns are valid. A key tenet of QI is standardization. PR is problematic in that regard; studies show poor interrater reliability for judgments on care, as well as hindsight bias—the fact that raters are strongly influenced by the outcome of care, not the process of care.^2-5 There are concerns that case selection or review process when not standardized may be wielded as punitive too.⁶ In this study, we sought to identify the relationship between PR findings and subsequent institution quality metrics. If PR does lead to an improvement in quality, or if quality concerns are managed within the PR committee, it should be possible to identify a measurable relationship between the PR process and a facility’s subsequent quality measures.

A handful of studies describe the association between PR and quality of care. Itri and colleagues noted that random, not standardized PR in radiology does not achieve reductions in diagnostic error rate.⁷ However, adoption of just culture principles in PR resulted in a significant improvement in facility leaders’ self-reports of quality measures at surveyed institutions.⁸ The same author reported that increases in PR standardization and integration with performance improvement activities could explain up to 18% of objective quality measure variation.⁹

We sought to determine whether a specific aspect of the PR process, the PR committee judgment of quality of care by clinicians, was related to medical center quality in a cross-sectional study of 136 Veterans Health Administration (VHA) medical centers. The VHA is a good source of study because there are standardized PR processes and training for committee members and reviewers. Our hypothesis was that medical centers with a higher number of Level 2 (“most experienced and competent clinicians might have managed the case differently”) and Level 3 (“most experienced and competent providers would have managed the case differently”) PR findings would also have lower quality metric scores for processes and outcomes of care.

Methods

We used PR data from fiscal year 2018 and 2019. VHA PR data are available quarterly and are self-reported by each facility to the VHA Office of Clinical Risk Management. These data are broken down by facility. The following data, when available in both fiscal years 2018 and 2019, were used for this analysis: percent and number of PR that are ranked as level 1, 2, or 3; medical center group (MCG) acuity measure assigned by the VHA (1 is highest, 3 is lowest); and number of PR per 100,000 unique veteran encounters in 2019. Measures of facility quality are drawn from Strategic Analytics for Improvement and Learning (SAIL) data from 2019, which are available quarterly by facility and are rolling for 12 months. SAIL measures processes and outcomes of care. Table 1 indicates which measures are focused on outcomes vs quality processes.

SAS Version 9.2 was used to perform statistical analyses. We used Spearman correlation to estimate the PR and quality relationship.

Results

There were 136 facilities with 2 years of PR data available. The majority of these facilities (89) were highest complexity MCG 1 facilities; 19 were MCG 2, and 28 were MCG 3. Of 13,515 PRs, most of the 9555 PR findings were level 1 (70.7%). The between-facility range of level 2 and 3 findings was large, varying from 3.5% to nearly 70% in 2019 (Table 2). Findings were similar in 2018; facilities level 2 and 3 ratings ranged from 3.6% to 73.5% of all PR findings.

There was no correlation between most quality measures and facility PR findings (Table 3). The only exception was for Global Measures (GM90), an inpatient process of care measure. Unexpectedly, the correlation was positive—facilities with a higher percentage of level 2 and 3 PR findings had better inpatient processes of care SAIL score. The strongest correlation was between 2018 and 2019 PR findings.

Discussion

We hypothesized that a high percentage of level 2 and 3 PR findings would be negatively associated with objective facility measures of care processes in SAIL but we did not see this association. The only quality measure associated with PR findings was GM90, a score of inpatient care processes. However, the association was positive, with better performance associated with more level 2 and 3 PR findings.

The best predictor of the proportion of a facility’s PR findings is the previous year’s PR findings. With an R = 0.59, the previous year findings explain about 35% of the variability in level assignment. Our analysis may describe a new bias in PR, in which committees consistently assign either low or high proportions of level 2 and 3 findings. This correlation could be due to individual PR committee culture or composition, but it does not relate to objective quality measures.

Strengths

For this study we use objective measures of PR processes, the assignment of levels of care. PR findings should reflect not only outcomes, but also the quality of the care, reflected by adherence to evidence-based processes, such as angiotensin-converting enzyme inhibitor prescription in heart failure. Therefore, we used SAIL scores, an objective and standardized process and outcome quality measures. Additionally, VHA is likely a national leader in the standardization of PR: VHA mandates as well as provides training for reviewers and PR committee members, has a standardized case-referral process, and mandates the documentation of feedback to health care professionals when care did not meet standards. While other publications show that PR has poor interrater reliability, VHA provides an outside contract to perform a second review on a percentage of cases to improve the validity of PR level assignments.

Limitations

Facilities self-report PR outcomes, so there could be errors in reporting. In addition, this study was cross sectional and not longitudinal and it is possible that change in quality measures over time are correlated with PR findings. Future studies using the VHA PR and SAIL data could evaluate whether changes over time, and perhaps in response to level 2 and 3 findings, would be a more sensitive indicator of the impact of the PR process on quality metrics. Future studies could incorporate the relationship between findings from the All Employee Survey, which is conducted annually, such as psychologic safety, as well as the distance the facility has gone on the high reliability organization journey, with PR findings and SAIL metrics. Finally, PR is focused on the practice of an individual clinician, while SAIL quality metrics reflect facility performance. Interventions possibly stay at the clinician level and do not drive subsequent QI processes. This is a missed opportunity, and future studies could evaluate practices by the PR coordinators to determine whether differences in these processes are associated with quality measures.

What does this mean for PR? Since the early 1990s, there have been exhortations from experts to improve PR, by adopting a QI model, or for a deeper integration of PR and QI.^1,2,10 Just culture tools, which include QI, are promoted as a means to improve PR.^8,11,12 Other studies show PR remains problematic in terms of standardization, incorporation of best practices, redesigning systems of care, or demonstrable improvements to facility safety and care quality.^1,4,6,8 Several publications have described interventions to improve PR. Deyo-Svedson discussed a program with standardized training and triggers, much like VHA.¹³ Itri and colleagues standardized PR in radiology to target areas of known diagnostic error, as well as use the issues assessed in PR to perform QI and education. One example of a successful QI effort involved changing the radiology reporting template to make sure areas that are prone to diagnostic error are addressed.⁷

Conclusions

Since 35% of PR level variance is correlated with prior year’s results, PR committees should look at increased standardization in reviews and findings. We endorse a strong focus on standardization, application of just culture tools to case reviews, and tighter linkage between process and outcome metrics measured by SAIL and PR case finding. Studies should be performed to pilot interventions to improve the linkage between PR and quality, so that greater and faster gains can be made in quality processes and, leading from this, outcomes. Additionally, future research should investigate why some facilities consistently choose higher or lower PR ratings.

Acknowledgments

We acknowledge Dr. George “Web” Ross for his helpful edits.

Contemporary critiques of Memorial and Veterans Day celebrations have emphasized that while ceremonies and celebrations are culturally requisite means of demonstrating a society’s respect and gratitude for those who gave their lives and health in the country’s cause—it is not enough. These holidays have immense symbolic significance to remind the nation of the sacrifice of those who bore arms in its service. An enduring and substantive impact on veterans will require real work done on their behalf. Through its representative institutions, such as the US Departments of Defense (DoD) and Veterans Affairs (VA) and citizens’ voluntary efforts, the public must provide practical assistance to veterans and their families.²

Memorial Day honors our sacred dead who lost their lives defending freedom. In federal practice and the larger community, we are duty-bound to try and restore the things war took from these wounded warriors and in whatever measure is possible to return them to the land of the fully living. Except in memory, we cannot bring back the dead. And while life is the most precious gift, those who survived the battlefield too often lose much that matters to a meaningful human life—friends, family, livelihood, housing, self-worth, peace of heart, soundness of mind, and health of the body.

One such recent initiative of reclamation is the Green Alert. Readers are likely familiar with Amber alerts for abducted children and Silver Alerts for older adults often with cognitive impairment who are lost. The Green Alert is a similar program deploying media and law enforcement to search for missing veterans believed to be vulnerable to harm because of a medical or psychiatric illness related to their service.

In 2017 Wisconsin became the first state to pass Green Alert legislation. The Missing Veterans at Risk Act lists 2 criteria that trigger a Green Alert: There is a reason to believe that the veteran at risk is missing due to a physical or mental health condition or that the veteran at risk is missing due to a physical or mental health condition. Relevant to the readers of Federal Practitioner, in Wisconsin, Green Alerts can be issued on behalf of missing veterans, and active-duty guard and reserve members and thus cover almost all the ranks of US military service.³ When law enforcement receives a report of a missing veteran as defined in the act within 72 hours of their disappearance, a Green Alert is issued. The statute directs the US Department of Justice to permit law enforcement to access the crime notification network to notify the media to broadcast pertinent information about the missing veteran.

As of this writing, Delaware, Kentucky, Connecticut, and Texas have passed similar laws, and legislatures in other states are considering bills, as is Congress.⁴ The sponsorship of the National Green Alert Act is bipartisan. Its stated purpose is: to develop interagency Green Alert systems that would be used when a veteran “goes missing” and “for other purposes.”⁵

The program’s potential to reduce the number of veterans who die by suicide every day has understandably attracted the attention of legislators and the public.⁶ The Cost of War project disclosed the terrible irony that at least 4 times as many post-9/11 service members died by suicide as perished in the combat that Memorial Day traditionally commemorates.⁷ As with many veteran-related laws, the initial Green Alert in Wisconsin was borne out of tragedy and passed through the heroic advocacy of bereaved and outraged family members.⁸ The DoD and VA, Congress, veterans service organizations, and the loved ones of servicemembers desperately want to turn this devastating tide of self-destruction through any means possible.

It seems almost a blasphemous betrayal of our public trust to raise ethical questions about Green Alerts. Yet that must happen if we ensure that these laws achieve their intended aims of preventing harm. For many veterans, these laws may indeed be lifesaving. However, a 2019 National Public Radio report suggested that these laws may, in some cases, result in several unintended harms.⁹ On first reading, it is worthy, even our duty, to extend the public health safety net for children who are victims of abduction and individuals with dementia to vulnerable veterans secondary to the mental and physical wounds of service.

When the service member is located, the alert is canceled. Nevertheless, their data remains in all the protean forms of media now available. In these searches for service members thought to be lost, there is a risk of violating their privacy if too much protected health information is made widely public. These breaches of confidentiality can further exacerbate the already too prevalent stigmatization of mental illness in the military, which has been a formidable obstacle to persuading those in uniform to seek treatment.¹⁰ As J.R.R. Tolkien has noted, not every person who “wanders” is lost.¹ A veteran may leave his home for some period, even without notifying anyone, without being in grave and imminent danger. The diagnoses we health care professionals assign to patients are wide conceptual nets full of empirical holes: they are poorly predictive and protective mechanisms.¹¹ A broadly written or vague law leaves latitude for bias, discrimination, liability, and fear to drive decisions that to be ethically justifiable require consistency, transparency, equity, and expertise. Much more research is needed to develop situational awareness, scientific accuracy, and clinical reliability to understand when, how, and for whom Green Alerts are genuinely beneficial.

These are not insurmountable questions. The experts and stakeholders appointed to the interagency committee the national Green Alert proposes will work to address these problems. Yet, unless they and we look bravely at the thorny issues these laudable laws present, it will be challenging to achieve their purpose to safeguard the dignity, safety, as well as autonomy and well-being of service members.

Contemporary critiques of Memorial and Veterans Day celebrations have emphasized that while ceremonies and celebrations are culturally requisite means of demonstrating a society’s respect and gratitude for those who gave their lives and health in the country’s cause—it is not enough. These holidays have immense symbolic significance to remind the nation of the sacrifice of those who bore arms in its service. An enduring and substantive impact on veterans will require real work done on their behalf. Through its representative institutions, such as the US Departments of Defense (DoD) and Veterans Affairs (VA) and citizens’ voluntary efforts, the public must provide practical assistance to veterans and their families.²

Memorial Day honors our sacred dead who lost their lives defending freedom. In federal practice and the larger community, we are duty-bound to try and restore the things war took from these wounded warriors and in whatever measure is possible to return them to the land of the fully living. Except in memory, we cannot bring back the dead. And while life is the most precious gift, those who survived the battlefield too often lose much that matters to a meaningful human life—friends, family, livelihood, housing, self-worth, peace of heart, soundness of mind, and health of the body.

One such recent initiative of reclamation is the Green Alert. Readers are likely familiar with Amber alerts for abducted children and Silver Alerts for older adults often with cognitive impairment who are lost. The Green Alert is a similar program deploying media and law enforcement to search for missing veterans believed to be vulnerable to harm because of a medical or psychiatric illness related to their service.

In 2017 Wisconsin became the first state to pass Green Alert legislation. The Missing Veterans at Risk Act lists 2 criteria that trigger a Green Alert: There is a reason to believe that the veteran at risk is missing due to a physical or mental health condition or that the veteran at risk is missing due to a physical or mental health condition. Relevant to the readers of Federal Practitioner, in Wisconsin, Green Alerts can be issued on behalf of missing veterans, and active-duty guard and reserve members and thus cover almost all the ranks of US military service.³ When law enforcement receives a report of a missing veteran as defined in the act within 72 hours of their disappearance, a Green Alert is issued. The statute directs the US Department of Justice to permit law enforcement to access the crime notification network to notify the media to broadcast pertinent information about the missing veteran.

As of this writing, Delaware, Kentucky, Connecticut, and Texas have passed similar laws, and legislatures in other states are considering bills, as is Congress.⁴ The sponsorship of the National Green Alert Act is bipartisan. Its stated purpose is: to develop interagency Green Alert systems that would be used when a veteran “goes missing” and “for other purposes.”⁵

The program’s potential to reduce the number of veterans who die by suicide every day has understandably attracted the attention of legislators and the public.⁶ The Cost of War project disclosed the terrible irony that at least 4 times as many post-9/11 service members died by suicide as perished in the combat that Memorial Day traditionally commemorates.⁷ As with many veteran-related laws, the initial Green Alert in Wisconsin was borne out of tragedy and passed through the heroic advocacy of bereaved and outraged family members.⁸ The DoD and VA, Congress, veterans service organizations, and the loved ones of servicemembers desperately want to turn this devastating tide of self-destruction through any means possible.

It seems almost a blasphemous betrayal of our public trust to raise ethical questions about Green Alerts. Yet that must happen if we ensure that these laws achieve their intended aims of preventing harm. For many veterans, these laws may indeed be lifesaving. However, a 2019 National Public Radio report suggested that these laws may, in some cases, result in several unintended harms.⁹ On first reading, it is worthy, even our duty, to extend the public health safety net for children who are victims of abduction and individuals with dementia to vulnerable veterans secondary to the mental and physical wounds of service.

When the service member is located, the alert is canceled. Nevertheless, their data remains in all the protean forms of media now available. In these searches for service members thought to be lost, there is a risk of violating their privacy if too much protected health information is made widely public. These breaches of confidentiality can further exacerbate the already too prevalent stigmatization of mental illness in the military, which has been a formidable obstacle to persuading those in uniform to seek treatment.¹⁰ As J.R.R. Tolkien has noted, not every person who “wanders” is lost.¹ A veteran may leave his home for some period, even without notifying anyone, without being in grave and imminent danger. The diagnoses we health care professionals assign to patients are wide conceptual nets full of empirical holes: they are poorly predictive and protective mechanisms.¹¹ A broadly written or vague law leaves latitude for bias, discrimination, liability, and fear to drive decisions that to be ethically justifiable require consistency, transparency, equity, and expertise. Much more research is needed to develop situational awareness, scientific accuracy, and clinical reliability to understand when, how, and for whom Green Alerts are genuinely beneficial.

These are not insurmountable questions. The experts and stakeholders appointed to the interagency committee the national Green Alert proposes will work to address these problems. Yet, unless they and we look bravely at the thorny issues these laudable laws present, it will be challenging to achieve their purpose to safeguard the dignity, safety, as well as autonomy and well-being of service members.

Contemporary critiques of Memorial and Veterans Day celebrations have emphasized that while ceremonies and celebrations are culturally requisite means of demonstrating a society’s respect and gratitude for those who gave their lives and health in the country’s cause—it is not enough. These holidays have immense symbolic significance to remind the nation of the sacrifice of those who bore arms in its service. An enduring and substantive impact on veterans will require real work done on their behalf. Through its representative institutions, such as the US Departments of Defense (DoD) and Veterans Affairs (VA) and citizens’ voluntary efforts, the public must provide practical assistance to veterans and their families.²

Memorial Day honors our sacred dead who lost their lives defending freedom. In federal practice and the larger community, we are duty-bound to try and restore the things war took from these wounded warriors and in whatever measure is possible to return them to the land of the fully living. Except in memory, we cannot bring back the dead. And while life is the most precious gift, those who survived the battlefield too often lose much that matters to a meaningful human life—friends, family, livelihood, housing, self-worth, peace of heart, soundness of mind, and health of the body.

One such recent initiative of reclamation is the Green Alert. Readers are likely familiar with Amber alerts for abducted children and Silver Alerts for older adults often with cognitive impairment who are lost. The Green Alert is a similar program deploying media and law enforcement to search for missing veterans believed to be vulnerable to harm because of a medical or psychiatric illness related to their service.

In 2017 Wisconsin became the first state to pass Green Alert legislation. The Missing Veterans at Risk Act lists 2 criteria that trigger a Green Alert: There is a reason to believe that the veteran at risk is missing due to a physical or mental health condition or that the veteran at risk is missing due to a physical or mental health condition. Relevant to the readers of Federal Practitioner, in Wisconsin, Green Alerts can be issued on behalf of missing veterans, and active-duty guard and reserve members and thus cover almost all the ranks of US military service.³ When law enforcement receives a report of a missing veteran as defined in the act within 72 hours of their disappearance, a Green Alert is issued. The statute directs the US Department of Justice to permit law enforcement to access the crime notification network to notify the media to broadcast pertinent information about the missing veteran.

As of this writing, Delaware, Kentucky, Connecticut, and Texas have passed similar laws, and legislatures in other states are considering bills, as is Congress.⁴ The sponsorship of the National Green Alert Act is bipartisan. Its stated purpose is: to develop interagency Green Alert systems that would be used when a veteran “goes missing” and “for other purposes.”⁵

The program’s potential to reduce the number of veterans who die by suicide every day has understandably attracted the attention of legislators and the public.⁶ The Cost of War project disclosed the terrible irony that at least 4 times as many post-9/11 service members died by suicide as perished in the combat that Memorial Day traditionally commemorates.⁷ As with many veteran-related laws, the initial Green Alert in Wisconsin was borne out of tragedy and passed through the heroic advocacy of bereaved and outraged family members.⁸ The DoD and VA, Congress, veterans service organizations, and the loved ones of servicemembers desperately want to turn this devastating tide of self-destruction through any means possible.

It seems almost a blasphemous betrayal of our public trust to raise ethical questions about Green Alerts. Yet that must happen if we ensure that these laws achieve their intended aims of preventing harm. For many veterans, these laws may indeed be lifesaving. However, a 2019 National Public Radio report suggested that these laws may, in some cases, result in several unintended harms.⁹ On first reading, it is worthy, even our duty, to extend the public health safety net for children who are victims of abduction and individuals with dementia to vulnerable veterans secondary to the mental and physical wounds of service.

When the service member is located, the alert is canceled. Nevertheless, their data remains in all the protean forms of media now available. In these searches for service members thought to be lost, there is a risk of violating their privacy if too much protected health information is made widely public. These breaches of confidentiality can further exacerbate the already too prevalent stigmatization of mental illness in the military, which has been a formidable obstacle to persuading those in uniform to seek treatment.¹⁰ As J.R.R. Tolkien has noted, not every person who “wanders” is lost.¹ A veteran may leave his home for some period, even without notifying anyone, without being in grave and imminent danger. The diagnoses we health care professionals assign to patients are wide conceptual nets full of empirical holes: they are poorly predictive and protective mechanisms.¹¹ A broadly written or vague law leaves latitude for bias, discrimination, liability, and fear to drive decisions that to be ethically justifiable require consistency, transparency, equity, and expertise. Much more research is needed to develop situational awareness, scientific accuracy, and clinical reliability to understand when, how, and for whom Green Alerts are genuinely beneficial.

These are not insurmountable questions. The experts and stakeholders appointed to the interagency committee the national Green Alert proposes will work to address these problems. Yet, unless they and we look bravely at the thorny issues these laudable laws present, it will be challenging to achieve their purpose to safeguard the dignity, safety, as well as autonomy and well-being of service members.

While previous research suggests that dietary supplementation with L-serine may be beneficial for patients with Alzheimer’s disease (AD), a new study cast doubt on the potential efficacy, and even the safety, of this treatment.

When given to patients with AD, L-serine supplements could be driving abnormally increased serine levels in the brain even higher, potentially accelerating neuronal death, according to study author Xu Chen, PhD, of the University of California, San Diego, and colleagues.

This conclusion conflicts with a 2020 study by Juliette Le Douce, PhD, and colleagues, who reported that oral L-serine supplementation may act as a “ready-to-use therapy” for AD, based on their findings that patients with AD had low levels of PHGDH, an enzyme necessary for synthesizing serine, and AD-like mice had low levels of serine.

Writing in Cell Metabolism, Dr. Chen and colleagues framed the present study, and their findings, in this context.

“In contrast to the work of Le Douce et al., here we report that PHGDH mRNA and protein levels are increased in the brains of two mouse models of AD and/or tauopathy, and are also progressively increased in human brains with no, early, and late AD pathology, as well as in people with no, asymptomatic, and symptomatic AD,” they wrote.

They suggested adjusting clinical recommendations for L-serine, the form of the amino acid commonly found in supplements. In the body, L-serine is converted to D-serine, which acts on the NMDA receptor (NMDAR).

‘Long-term use of D-serine contributes to neuronal death’ suggests research

“We feel oral L-serine as a ready-to-use therapy to AD warrants precaution,” Dr. Chen and colleagues wrote. “This is because despite being a cognitive enhancer, some [research] suggests that long-term use of D-serine contributes to neuronal death in AD through excitotoxicity. Furthermore, D-serine, as a co-agonist of NMDAR, would be expected to oppose NMDAR antagonists, which have proven clinical benefits in treating AD.”

According to principal author Sheng Zhong, PhD, of the University of California, San Diego, “Research is needed to test if targeting PHGDH can ameliorate cognitive decline in AD.”

Dr. Zhong also noted that the present findings support the “promise of using a specific RNA in blood as a biomarker for early detection of Alzheimer’s disease.” This approach is currently being validated at UCSD Shiley-Marcos Alzheimer’s Disease Research Center, he added.

Roles of PHGDH and serine in Alzheimer’s disease require further study

Commenting on both studies, Steve W. Barger, PhD, of the University of Arkansas for Medical Sciences, Little Rock, suggested that more work is needed to better understand the roles of PHGDH and serine in AD before clinical applications can be considered.

“In the end, these two studies fail to provide the clarity we need in designing evidence-based therapeutic hypotheses,” Dr. Barger said in an interview. “We still do not have a firm grasp on the role that D-serine plays in AD. Indeed, the evidence regarding even a single enzyme contributing to its levels is ambiguous.”

Dr. Barger, who has published extensively on the topic of neuronal death, with a particular focus on Alzheimer’s disease, noted that “determination of what happens to D-serine levels in AD has been of interest for decades,” but levels of the amino acid have been notoriously challenging to measure because “D-serine can disappear rapidly from the brain and its fluids after death.”

While Dr. Le Douce and colleagues did measure levels of serine in mice, Dr. Barger noted that the study by Dr. Chen and colleagues was conducted with more “quantitatively rigorous methods.” Even though Dr. Chen and colleagues “did not assay the levels of D-serine itself ... the implication of their findings is that PHGDH is poised to elevate this critical neurotransmitter,” leading to their conclusion that serine supplementation is “potentially dangerous.”

At this point, it may be too early to tell, according to Dr. Barger.

He suggested that conclusions drawn from PHGDH levels alone are “always limited,” and conclusions based on serine levels may be equally dubious, considering that the activities and effects of serine “are quite complex,” and may be influenced by other physiologic processes, including the effects of gut bacteria.

Instead, Dr. Barger suggested that changes in PHGDH and serine may be interpreted as signals coming from a more relevant process upstream: glucose metabolism.

“What we can say confidently is that the glucose metabolism that PHGDH connects to D-serine is most definitely a factor in AD,” he said. “Countless studies have documented what now appears to be a universal decline in glucose delivery to the cerebral cortex, even before frank dementia sets in.”

Dr. Barger noted that declining glucose delivery coincides with some of the earliest events in the development of AD, perhaps “linking accumulation of amyloid β-peptide to subsequent neurofibrillary tangles and tissue atrophy.”

Dr. Barger’s own work recently demonstrated that AD is associated with “an irregularity in the insertion of a specific glucose transporter (GLUT1) into the cell surface” of astrocytes.

“It could be more effective to direct therapeutic interventions at these events lying upstream of PHGDH or serine,” he concluded.

The study was partly supported by a Kreuger v. Wyeth research award. The investigators and Dr. Barger reported no conflicts of interest.

While previous research suggests that dietary supplementation with L-serine may be beneficial for patients with Alzheimer’s disease (AD), a new study cast doubt on the potential efficacy, and even the safety, of this treatment.

When given to patients with AD, L-serine supplements could be driving abnormally increased serine levels in the brain even higher, potentially accelerating neuronal death, according to study author Xu Chen, PhD, of the University of California, San Diego, and colleagues.

This conclusion conflicts with a 2020 study by Juliette Le Douce, PhD, and colleagues, who reported that oral L-serine supplementation may act as a “ready-to-use therapy” for AD, based on their findings that patients with AD had low levels of PHGDH, an enzyme necessary for synthesizing serine, and AD-like mice had low levels of serine.

Writing in Cell Metabolism, Dr. Chen and colleagues framed the present study, and their findings, in this context.

“In contrast to the work of Le Douce et al., here we report that PHGDH mRNA and protein levels are increased in the brains of two mouse models of AD and/or tauopathy, and are also progressively increased in human brains with no, early, and late AD pathology, as well as in people with no, asymptomatic, and symptomatic AD,” they wrote.

They suggested adjusting clinical recommendations for L-serine, the form of the amino acid commonly found in supplements. In the body, L-serine is converted to D-serine, which acts on the NMDA receptor (NMDAR).

‘Long-term use of D-serine contributes to neuronal death’ suggests research

“We feel oral L-serine as a ready-to-use therapy to AD warrants precaution,” Dr. Chen and colleagues wrote. “This is because despite being a cognitive enhancer, some [research] suggests that long-term use of D-serine contributes to neuronal death in AD through excitotoxicity. Furthermore, D-serine, as a co-agonist of NMDAR, would be expected to oppose NMDAR antagonists, which have proven clinical benefits in treating AD.”

According to principal author Sheng Zhong, PhD, of the University of California, San Diego, “Research is needed to test if targeting PHGDH can ameliorate cognitive decline in AD.”

Dr. Zhong also noted that the present findings support the “promise of using a specific RNA in blood as a biomarker for early detection of Alzheimer’s disease.” This approach is currently being validated at UCSD Shiley-Marcos Alzheimer’s Disease Research Center, he added.

Roles of PHGDH and serine in Alzheimer’s disease require further study

Commenting on both studies, Steve W. Barger, PhD, of the University of Arkansas for Medical Sciences, Little Rock, suggested that more work is needed to better understand the roles of PHGDH and serine in AD before clinical applications can be considered.

“In the end, these two studies fail to provide the clarity we need in designing evidence-based therapeutic hypotheses,” Dr. Barger said in an interview. “We still do not have a firm grasp on the role that D-serine plays in AD. Indeed, the evidence regarding even a single enzyme contributing to its levels is ambiguous.”

Dr. Barger, who has published extensively on the topic of neuronal death, with a particular focus on Alzheimer’s disease, noted that “determination of what happens to D-serine levels in AD has been of interest for decades,” but levels of the amino acid have been notoriously challenging to measure because “D-serine can disappear rapidly from the brain and its fluids after death.”

While Dr. Le Douce and colleagues did measure levels of serine in mice, Dr. Barger noted that the study by Dr. Chen and colleagues was conducted with more “quantitatively rigorous methods.” Even though Dr. Chen and colleagues “did not assay the levels of D-serine itself ... the implication of their findings is that PHGDH is poised to elevate this critical neurotransmitter,” leading to their conclusion that serine supplementation is “potentially dangerous.”

At this point, it may be too early to tell, according to Dr. Barger.

He suggested that conclusions drawn from PHGDH levels alone are “always limited,” and conclusions based on serine levels may be equally dubious, considering that the activities and effects of serine “are quite complex,” and may be influenced by other physiologic processes, including the effects of gut bacteria.

Instead, Dr. Barger suggested that changes in PHGDH and serine may be interpreted as signals coming from a more relevant process upstream: glucose metabolism.

“What we can say confidently is that the glucose metabolism that PHGDH connects to D-serine is most definitely a factor in AD,” he said. “Countless studies have documented what now appears to be a universal decline in glucose delivery to the cerebral cortex, even before frank dementia sets in.”

Dr. Barger noted that declining glucose delivery coincides with some of the earliest events in the development of AD, perhaps “linking accumulation of amyloid β-peptide to subsequent neurofibrillary tangles and tissue atrophy.”

Dr. Barger’s own work recently demonstrated that AD is associated with “an irregularity in the insertion of a specific glucose transporter (GLUT1) into the cell surface” of astrocytes.

“It could be more effective to direct therapeutic interventions at these events lying upstream of PHGDH or serine,” he concluded.

The study was partly supported by a Kreuger v. Wyeth research award. The investigators and Dr. Barger reported no conflicts of interest.

While previous research suggests that dietary supplementation with L-serine may be beneficial for patients with Alzheimer’s disease (AD), a new study cast doubt on the potential efficacy, and even the safety, of this treatment.

When given to patients with AD, L-serine supplements could be driving abnormally increased serine levels in the brain even higher, potentially accelerating neuronal death, according to study author Xu Chen, PhD, of the University of California, San Diego, and colleagues.

This conclusion conflicts with a 2020 study by Juliette Le Douce, PhD, and colleagues, who reported that oral L-serine supplementation may act as a “ready-to-use therapy” for AD, based on their findings that patients with AD had low levels of PHGDH, an enzyme necessary for synthesizing serine, and AD-like mice had low levels of serine.

Writing in Cell Metabolism, Dr. Chen and colleagues framed the present study, and their findings, in this context.

“In contrast to the work of Le Douce et al., here we report that PHGDH mRNA and protein levels are increased in the brains of two mouse models of AD and/or tauopathy, and are also progressively increased in human brains with no, early, and late AD pathology, as well as in people with no, asymptomatic, and symptomatic AD,” they wrote.

They suggested adjusting clinical recommendations for L-serine, the form of the amino acid commonly found in supplements. In the body, L-serine is converted to D-serine, which acts on the NMDA receptor (NMDAR).

‘Long-term use of D-serine contributes to neuronal death’ suggests research

“We feel oral L-serine as a ready-to-use therapy to AD warrants precaution,” Dr. Chen and colleagues wrote. “This is because despite being a cognitive enhancer, some [research] suggests that long-term use of D-serine contributes to neuronal death in AD through excitotoxicity. Furthermore, D-serine, as a co-agonist of NMDAR, would be expected to oppose NMDAR antagonists, which have proven clinical benefits in treating AD.”

According to principal author Sheng Zhong, PhD, of the University of California, San Diego, “Research is needed to test if targeting PHGDH can ameliorate cognitive decline in AD.”

Dr. Zhong also noted that the present findings support the “promise of using a specific RNA in blood as a biomarker for early detection of Alzheimer’s disease.” This approach is currently being validated at UCSD Shiley-Marcos Alzheimer’s Disease Research Center, he added.

Roles of PHGDH and serine in Alzheimer’s disease require further study

Commenting on both studies, Steve W. Barger, PhD, of the University of Arkansas for Medical Sciences, Little Rock, suggested that more work is needed to better understand the roles of PHGDH and serine in AD before clinical applications can be considered.

“In the end, these two studies fail to provide the clarity we need in designing evidence-based therapeutic hypotheses,” Dr. Barger said in an interview. “We still do not have a firm grasp on the role that D-serine plays in AD. Indeed, the evidence regarding even a single enzyme contributing to its levels is ambiguous.”

Dr. Barger, who has published extensively on the topic of neuronal death, with a particular focus on Alzheimer’s disease, noted that “determination of what happens to D-serine levels in AD has been of interest for decades,” but levels of the amino acid have been notoriously challenging to measure because “D-serine can disappear rapidly from the brain and its fluids after death.”

While Dr. Le Douce and colleagues did measure levels of serine in mice, Dr. Barger noted that the study by Dr. Chen and colleagues was conducted with more “quantitatively rigorous methods.” Even though Dr. Chen and colleagues “did not assay the levels of D-serine itself ... the implication of their findings is that PHGDH is poised to elevate this critical neurotransmitter,” leading to their conclusion that serine supplementation is “potentially dangerous.”

At this point, it may be too early to tell, according to Dr. Barger.

He suggested that conclusions drawn from PHGDH levels alone are “always limited,” and conclusions based on serine levels may be equally dubious, considering that the activities and effects of serine “are quite complex,” and may be influenced by other physiologic processes, including the effects of gut bacteria.

Instead, Dr. Barger suggested that changes in PHGDH and serine may be interpreted as signals coming from a more relevant process upstream: glucose metabolism.

“What we can say confidently is that the glucose metabolism that PHGDH connects to D-serine is most definitely a factor in AD,” he said. “Countless studies have documented what now appears to be a universal decline in glucose delivery to the cerebral cortex, even before frank dementia sets in.”

Dr. Barger noted that declining glucose delivery coincides with some of the earliest events in the development of AD, perhaps “linking accumulation of amyloid β-peptide to subsequent neurofibrillary tangles and tissue atrophy.”

Dr. Barger’s own work recently demonstrated that AD is associated with “an irregularity in the insertion of a specific glucose transporter (GLUT1) into the cell surface” of astrocytes.

“It could be more effective to direct therapeutic interventions at these events lying upstream of PHGDH or serine,” he concluded.

The study was partly supported by a Kreuger v. Wyeth research award. The investigators and Dr. Barger reported no conflicts of interest.

Children with juvenile idiopathic arthritis (JIA) who need a tumor necrosis factor (TNF) inhibitor after failing conventional disease-modifying antirheumatic drug (DMARD) treatment often experience insurance delays before beginning the new drug because of prior authorization denials, according to research presented at the 2022 annual meeting of the Childhood Arthritis and Rheumatology Research Alliance (CARRA). The findings were also published  as a research letter in JAMA Network Open.

“Prompt escalation to TNF inhibitors is recommended for children with JIA refractory to DMARDs,” author Jordan Roberts, MD, a clinical fellow of the Harvard Medical School Rheumatology Program, Boston, told CARRA attendees. TNF inhibitors are increasingly used as first-line treatment in JIA since growing evidence suggests better outcomes from early treatment with biologics. “Prior authorization requirements that delay TNF inhibitor initiation among children with JIA are common in clinical practice,” Dr. Roberts said, but little evidence exists to understand the extent of this problem and its causes.

The researchers therefore conducted a retrospective cohort study using a search of electronic health records from January 2018 to December 2019 to find all children at a single center with a new diagnosis of nonsystemic JIA. Then the authors pulled the timing of prior authorization requests, approvals, denials, and first TNF inhibitor dose from the medical notes. They also sought out any children who had been recommended a TNF inhibitor but never started one.

The total population included 54 children with an average age of 10 years, about two-thirds of whom had private insurance (63%). The group was predominantly White (63%), although 13% declined to provide race, and 7% were Hispanic. Most subtypes of disease were represented: oligoarticular persistent (28%), oligoarticular extended (2%), polyarticular rheumatoid factor-negative (15%), polyarticular rheumatoid factor-positive (15%), psoriatic arthritis (26%), enthesitis-related arthritis (12%), and undifferentiated arthritis (2%).

The 44 participants with private insurance had an average of two joints with active disease, while the 10 patients with public insurance had an average of four involved joints. Nearly all the patients (91%) had previously taken or were currently taking DMARDs when the prior authorization was submitted, and 61% had received NSAIDs.

All but one of the patients’ insurance plans required a prior authorization. The first prior authorization was denied for about one-third of the public insurance patients (30%) and a quarter of the private insurance patients. About 1 in 5 patients overall (22%) required a written appeal to override the denial, and 4% required peer-to-peer review. Meanwhile, 7% of patients began another medication because of the denial.

It took a median of 3 days for prior authorizations to be approved and a median of 24 days from the time the TNF inhibitor was recommended to the patient receiving the first dose. However, 22% of patients waited at least 2 weeks before the prior authorization was approved, and more than a quarter of the requests took over 30 days before the patient could begin the medication. In the public insurance group in particular, a quarter of children waited at least 19 days for approval and at least 44 days before starting the medication.

In fact, when the researchers looked at the difference in approval time between those who did and did not receive an initial denial, the difference was stark. Median approval time was 16 days when the prior authorization was denied, compared with a median of 5 days when the first prior authorization was approved. Similarly, time to initiation of the drug after recommendation was a median of 35 days for those whose prior authorization was first denied and 17 days for those with an initial approval.

The most common reason for an initial denial was the insurance company requiring a different TNF inhibitor than the one the rheumatologist wanted to prescribe. “These were all children whose rheumatologist has recommended either infliximab or etanercept that were required to use adalimumab instead,” Dr. Roberts said.

The other reasons for initial denial were similarly familiar ones:

• Required submission to another insurer
• Additional documentation required
• Lack of medical necessity
• Prescription was for an indication not approved by the Food and Drug Administration
• Age of patient
• Nonbiologic DMARD required
• NSAID required for step therapy

Only three children who were advised to begin a TNF inhibitor did not do so, including one who was lost to follow-up, one who had injection-related anxiety, and one who had safety concerns about the medication.

“Several children were required to use alternative TNF inhibitors than the one that was recommended due to restricted formularies, which may reduce shared decisionmaking between physicians and families and may not be the optimal clinical choice for an individual child,” Dr. Roberts said in her conclusion. Most children, however, were able to get approval for the TNF inhibitor originally requested, “suggesting that utilization management strategies present barriers to timely care despite appropriate specialty medication requests,” she said. “Therefore, it’s important for us to advocate for access to medications for children with JIA.”

Findings are not surprising

“I have these same experiences at my institution – often insurance will dictate clinical practice, and step therapy is the only option, causing a delay to initiation of TNFi even if we think, as the pediatric rheumatologist, that a child needs this medicine to be initiated on presentation to our clinic,” Nayimisha Balmuri, MD, assistant professor of pediatrics in the division of allergy, immunology, and rheumatology at the Johns Hopkins School of Medicine, Baltimore, told this news organization.

Dr. Balmuri, who was not involved in the study, noted that in her clinic at Johns Hopkins, it is hit or miss if an appeal to insurance companies or to the state (if it is Medicaid coverage) will be successful. “Unfortunately, [we are] mostly unsuccessful, and we have to try another DMARD for 8 to 12 weeks first before trying to get TNFi,” she said.

Dr. Balmuri called for bringing these issues to the attention of state and federal legislators. “It’s so important for us to continue to advocate for our patients at the state and national level! We are the advocates for our patients, and we are uniquely trained to know the best medications to initiate to help patients maximize their chance to reach remission of arthritis. Insurance companies need to hear our voices!”

Dr. Roberts reported grants from CARRA, the Lupus Foundation of America, and the National Institute of Allergy and Infectious Diseases during the conduct of the study.

A version of this article first appeared on Medscape.com.

Children with juvenile idiopathic arthritis (JIA) who need a tumor necrosis factor (TNF) inhibitor after failing conventional disease-modifying antirheumatic drug (DMARD) treatment often experience insurance delays before beginning the new drug because of prior authorization denials, according to research presented at the 2022 annual meeting of the Childhood Arthritis and Rheumatology Research Alliance (CARRA). The findings were also published  as a research letter in JAMA Network Open.

“Prompt escalation to TNF inhibitors is recommended for children with JIA refractory to DMARDs,” author Jordan Roberts, MD, a clinical fellow of the Harvard Medical School Rheumatology Program, Boston, told CARRA attendees. TNF inhibitors are increasingly used as first-line treatment in JIA since growing evidence suggests better outcomes from early treatment with biologics. “Prior authorization requirements that delay TNF inhibitor initiation among children with JIA are common in clinical practice,” Dr. Roberts said, but little evidence exists to understand the extent of this problem and its causes.

The researchers therefore conducted a retrospective cohort study using a search of electronic health records from January 2018 to December 2019 to find all children at a single center with a new diagnosis of nonsystemic JIA. Then the authors pulled the timing of prior authorization requests, approvals, denials, and first TNF inhibitor dose from the medical notes. They also sought out any children who had been recommended a TNF inhibitor but never started one.

The total population included 54 children with an average age of 10 years, about two-thirds of whom had private insurance (63%). The group was predominantly White (63%), although 13% declined to provide race, and 7% were Hispanic. Most subtypes of disease were represented: oligoarticular persistent (28%), oligoarticular extended (2%), polyarticular rheumatoid factor-negative (15%), polyarticular rheumatoid factor-positive (15%), psoriatic arthritis (26%), enthesitis-related arthritis (12%), and undifferentiated arthritis (2%).

The 44 participants with private insurance had an average of two joints with active disease, while the 10 patients with public insurance had an average of four involved joints. Nearly all the patients (91%) had previously taken or were currently taking DMARDs when the prior authorization was submitted, and 61% had received NSAIDs.

All but one of the patients’ insurance plans required a prior authorization. The first prior authorization was denied for about one-third of the public insurance patients (30%) and a quarter of the private insurance patients. About 1 in 5 patients overall (22%) required a written appeal to override the denial, and 4% required peer-to-peer review. Meanwhile, 7% of patients began another medication because of the denial.

It took a median of 3 days for prior authorizations to be approved and a median of 24 days from the time the TNF inhibitor was recommended to the patient receiving the first dose. However, 22% of patients waited at least 2 weeks before the prior authorization was approved, and more than a quarter of the requests took over 30 days before the patient could begin the medication. In the public insurance group in particular, a quarter of children waited at least 19 days for approval and at least 44 days before starting the medication.

In fact, when the researchers looked at the difference in approval time between those who did and did not receive an initial denial, the difference was stark. Median approval time was 16 days when the prior authorization was denied, compared with a median of 5 days when the first prior authorization was approved. Similarly, time to initiation of the drug after recommendation was a median of 35 days for those whose prior authorization was first denied and 17 days for those with an initial approval.

The most common reason for an initial denial was the insurance company requiring a different TNF inhibitor than the one the rheumatologist wanted to prescribe. “These were all children whose rheumatologist has recommended either infliximab or etanercept that were required to use adalimumab instead,” Dr. Roberts said.

The other reasons for initial denial were similarly familiar ones:

• Required submission to another insurer
• Additional documentation required
• Lack of medical necessity
• Prescription was for an indication not approved by the Food and Drug Administration
• Age of patient
• Nonbiologic DMARD required
• NSAID required for step therapy

Only three children who were advised to begin a TNF inhibitor did not do so, including one who was lost to follow-up, one who had injection-related anxiety, and one who had safety concerns about the medication.

“Several children were required to use alternative TNF inhibitors than the one that was recommended due to restricted formularies, which may reduce shared decisionmaking between physicians and families and may not be the optimal clinical choice for an individual child,” Dr. Roberts said in her conclusion. Most children, however, were able to get approval for the TNF inhibitor originally requested, “suggesting that utilization management strategies present barriers to timely care despite appropriate specialty medication requests,” she said. “Therefore, it’s important for us to advocate for access to medications for children with JIA.”

Findings are not surprising

“I have these same experiences at my institution – often insurance will dictate clinical practice, and step therapy is the only option, causing a delay to initiation of TNFi even if we think, as the pediatric rheumatologist, that a child needs this medicine to be initiated on presentation to our clinic,” Nayimisha Balmuri, MD, assistant professor of pediatrics in the division of allergy, immunology, and rheumatology at the Johns Hopkins School of Medicine, Baltimore, told this news organization.

Dr. Balmuri, who was not involved in the study, noted that in her clinic at Johns Hopkins, it is hit or miss if an appeal to insurance companies or to the state (if it is Medicaid coverage) will be successful. “Unfortunately, [we are] mostly unsuccessful, and we have to try another DMARD for 8 to 12 weeks first before trying to get TNFi,” she said.

Dr. Balmuri called for bringing these issues to the attention of state and federal legislators. “It’s so important for us to continue to advocate for our patients at the state and national level! We are the advocates for our patients, and we are uniquely trained to know the best medications to initiate to help patients maximize their chance to reach remission of arthritis. Insurance companies need to hear our voices!”

Dr. Roberts reported grants from CARRA, the Lupus Foundation of America, and the National Institute of Allergy and Infectious Diseases during the conduct of the study.

A version of this article first appeared on Medscape.com.

Children with juvenile idiopathic arthritis (JIA) who need a tumor necrosis factor (TNF) inhibitor after failing conventional disease-modifying antirheumatic drug (DMARD) treatment often experience insurance delays before beginning the new drug because of prior authorization denials, according to research presented at the 2022 annual meeting of the Childhood Arthritis and Rheumatology Research Alliance (CARRA). The findings were also published  as a research letter in JAMA Network Open.

“Prompt escalation to TNF inhibitors is recommended for children with JIA refractory to DMARDs,” author Jordan Roberts, MD, a clinical fellow of the Harvard Medical School Rheumatology Program, Boston, told CARRA attendees. TNF inhibitors are increasingly used as first-line treatment in JIA since growing evidence suggests better outcomes from early treatment with biologics. “Prior authorization requirements that delay TNF inhibitor initiation among children with JIA are common in clinical practice,” Dr. Roberts said, but little evidence exists to understand the extent of this problem and its causes.

The researchers therefore conducted a retrospective cohort study using a search of electronic health records from January 2018 to December 2019 to find all children at a single center with a new diagnosis of nonsystemic JIA. Then the authors pulled the timing of prior authorization requests, approvals, denials, and first TNF inhibitor dose from the medical notes. They also sought out any children who had been recommended a TNF inhibitor but never started one.

The total population included 54 children with an average age of 10 years, about two-thirds of whom had private insurance (63%). The group was predominantly White (63%), although 13% declined to provide race, and 7% were Hispanic. Most subtypes of disease were represented: oligoarticular persistent (28%), oligoarticular extended (2%), polyarticular rheumatoid factor-negative (15%), polyarticular rheumatoid factor-positive (15%), psoriatic arthritis (26%), enthesitis-related arthritis (12%), and undifferentiated arthritis (2%).

The 44 participants with private insurance had an average of two joints with active disease, while the 10 patients with public insurance had an average of four involved joints. Nearly all the patients (91%) had previously taken or were currently taking DMARDs when the prior authorization was submitted, and 61% had received NSAIDs.

All but one of the patients’ insurance plans required a prior authorization. The first prior authorization was denied for about one-third of the public insurance patients (30%) and a quarter of the private insurance patients. About 1 in 5 patients overall (22%) required a written appeal to override the denial, and 4% required peer-to-peer review. Meanwhile, 7% of patients began another medication because of the denial.

It took a median of 3 days for prior authorizations to be approved and a median of 24 days from the time the TNF inhibitor was recommended to the patient receiving the first dose. However, 22% of patients waited at least 2 weeks before the prior authorization was approved, and more than a quarter of the requests took over 30 days before the patient could begin the medication. In the public insurance group in particular, a quarter of children waited at least 19 days for approval and at least 44 days before starting the medication.

In fact, when the researchers looked at the difference in approval time between those who did and did not receive an initial denial, the difference was stark. Median approval time was 16 days when the prior authorization was denied, compared with a median of 5 days when the first prior authorization was approved. Similarly, time to initiation of the drug after recommendation was a median of 35 days for those whose prior authorization was first denied and 17 days for those with an initial approval.

The most common reason for an initial denial was the insurance company requiring a different TNF inhibitor than the one the rheumatologist wanted to prescribe. “These were all children whose rheumatologist has recommended either infliximab or etanercept that were required to use adalimumab instead,” Dr. Roberts said.

The other reasons for initial denial were similarly familiar ones:

• Required submission to another insurer
• Additional documentation required
• Lack of medical necessity
• Prescription was for an indication not approved by the Food and Drug Administration
• Age of patient
• Nonbiologic DMARD required
• NSAID required for step therapy

Only three children who were advised to begin a TNF inhibitor did not do so, including one who was lost to follow-up, one who had injection-related anxiety, and one who had safety concerns about the medication.

“Several children were required to use alternative TNF inhibitors than the one that was recommended due to restricted formularies, which may reduce shared decisionmaking between physicians and families and may not be the optimal clinical choice for an individual child,” Dr. Roberts said in her conclusion. Most children, however, were able to get approval for the TNF inhibitor originally requested, “suggesting that utilization management strategies present barriers to timely care despite appropriate specialty medication requests,” she said. “Therefore, it’s important for us to advocate for access to medications for children with JIA.”

Findings are not surprising

“I have these same experiences at my institution – often insurance will dictate clinical practice, and step therapy is the only option, causing a delay to initiation of TNFi even if we think, as the pediatric rheumatologist, that a child needs this medicine to be initiated on presentation to our clinic,” Nayimisha Balmuri, MD, assistant professor of pediatrics in the division of allergy, immunology, and rheumatology at the Johns Hopkins School of Medicine, Baltimore, told this news organization.

Dr. Balmuri, who was not involved in the study, noted that in her clinic at Johns Hopkins, it is hit or miss if an appeal to insurance companies or to the state (if it is Medicaid coverage) will be successful. “Unfortunately, [we are] mostly unsuccessful, and we have to try another DMARD for 8 to 12 weeks first before trying to get TNFi,” she said.

Dr. Balmuri called for bringing these issues to the attention of state and federal legislators. “It’s so important for us to continue to advocate for our patients at the state and national level! We are the advocates for our patients, and we are uniquely trained to know the best medications to initiate to help patients maximize their chance to reach remission of arthritis. Insurance companies need to hear our voices!”

Dr. Roberts reported grants from CARRA, the Lupus Foundation of America, and the National Institute of Allergy and Infectious Diseases during the conduct of the study.

A version of this article first appeared on Medscape.com.

SAN DIEGO – If a medical professional is trying to figure out the best medical treatment for a pregnant woman with headache, it may be helpful to review data from randomized clinical trials (RCTs). Well, make that data from the RCT. There’s just been one, Northwestern Medicine obstetrician-gynecologist Catherine Stika, MD, told colleagues at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

Only a single efficacy RCT has examined headache in pregnancy, said Dr. Stika. “Overall, we have very limited data in pregnancy to tell us exactly what to do,” she added.

But ob.gyns. aren’t entirely in the dark, according to medical specialists who spoke at the session. Expert opinion and fetal safety data offer insight into the best treatments, as does a new ACOG clinical practice guideline on headaches during pregnancy and post partum that was coauthored by the speakers.

And there’s some good news: Pregnancy itself is often a good treatment for headaches.

Pregnant women often find relief from one kind of headache – migraine – as their estradiol levels rise, said Laura Mercer, MD, an ob.gyn. at the University of Arizona, Phoenix. “About half of patients will report that migraines are getting better as early as the first trimester, and upwards of 83% will say that their migraines are better by the time they’re in their third trimester,” she said. “What this means for us as obstetricians is that oftentimes we can actually discontinue preventative therapies for patients during pregnancy.”

But simply discontinuing every headache treatment during pregnancy may not be the right approach, Dr. Mercer said. Instead, she said, consider the benefits and risks.

Divalproex sodium (Depakote) and topiramate (Topamax) must be avoided because of fetal risk, she said. “In fact, we will prefer that people stop these medications before they discontinue their contraception if they’re planning on getting pregnant,” she said.

Other medications, such as ACE inhibitors and the herbal remedy feverfew, should not be used at any time during pregnancy, she said.

On the other hand, calcium channel blockers and antihistamines are alright to use in pregnancy, she said. “These two should be considered first-line because there’s no known risks for them.”

Beta-blockers also may be used “with some consideration to the known risks that we’re familiar with when we use them for other indications,” she said.

There are questions about the safety of oral magnesium in pregnancy, although it’s generally considered safe, she added, and “nerve blocks and nerve stimulators seem very promising and have little known risks.”

Dr. Mercer recommended gradually tapering most medications prior to conception. But it’s crucial to stop higher-risk drugs immediately once pregnancy is confirmed, she said.

In regard to acute headache, Dr. Stika urged caution if a patient reports taking a headache medication more than twice a week. “All the medications we use for the treatment of migraine, both in and outside of pregnancy, carry the risk of what’s called medication overuse” that can lead to rebound headaches, she said.

Excedrin Tension Headache may be used for headaches in pregnancy, she said, but not Excedrin Migraine since it includes aspirin. Triptans are not recommended as first-line therapy, she added, and they “should absolutely not be used in any pregnant patient with a history of known cardiac disease or hypertension.”

Dr. Stika added that ACOG advises against the use of drugs that contain butalbital, a barbiturate that’s combined with other agents to treat headache. “Butalbital is the drug that’s most closely associated with getting people into this medication overuse headache,” she said. “It’s even worse than opioids.”

Unlike multiple other countries and the entire European Union, the United States has not banned compounds that contain butalbital, she said.

In some cases, she said, patients may present to triage with vomiting, an inability to keep food down, and persistent headache despite treatment. “This is a really classic presentation.”

The ACOG clinical practice guideline offers a flow chart about what to do, she said. Hydration is key, she said, and various treatment options can help. A referral to neurology may be needed in extreme cases, she said. But “most of the time, you’re able to get rid of her headache.”

Dr. Mercer and Dr. Stika report no disclosures.

SAN DIEGO – If a medical professional is trying to figure out the best medical treatment for a pregnant woman with headache, it may be helpful to review data from randomized clinical trials (RCTs). Well, make that data from the RCT. There’s just been one, Northwestern Medicine obstetrician-gynecologist Catherine Stika, MD, told colleagues at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

Only a single efficacy RCT has examined headache in pregnancy, said Dr. Stika. “Overall, we have very limited data in pregnancy to tell us exactly what to do,” she added.

But ob.gyns. aren’t entirely in the dark, according to medical specialists who spoke at the session. Expert opinion and fetal safety data offer insight into the best treatments, as does a new ACOG clinical practice guideline on headaches during pregnancy and post partum that was coauthored by the speakers.

And there’s some good news: Pregnancy itself is often a good treatment for headaches.

Pregnant women often find relief from one kind of headache – migraine – as their estradiol levels rise, said Laura Mercer, MD, an ob.gyn. at the University of Arizona, Phoenix. “About half of patients will report that migraines are getting better as early as the first trimester, and upwards of 83% will say that their migraines are better by the time they’re in their third trimester,” she said. “What this means for us as obstetricians is that oftentimes we can actually discontinue preventative therapies for patients during pregnancy.”

But simply discontinuing every headache treatment during pregnancy may not be the right approach, Dr. Mercer said. Instead, she said, consider the benefits and risks.

Divalproex sodium (Depakote) and topiramate (Topamax) must be avoided because of fetal risk, she said. “In fact, we will prefer that people stop these medications before they discontinue their contraception if they’re planning on getting pregnant,” she said.

Other medications, such as ACE inhibitors and the herbal remedy feverfew, should not be used at any time during pregnancy, she said.

On the other hand, calcium channel blockers and antihistamines are alright to use in pregnancy, she said. “These two should be considered first-line because there’s no known risks for them.”

Beta-blockers also may be used “with some consideration to the known risks that we’re familiar with when we use them for other indications,” she said.

There are questions about the safety of oral magnesium in pregnancy, although it’s generally considered safe, she added, and “nerve blocks and nerve stimulators seem very promising and have little known risks.”

Dr. Mercer recommended gradually tapering most medications prior to conception. But it’s crucial to stop higher-risk drugs immediately once pregnancy is confirmed, she said.

In regard to acute headache, Dr. Stika urged caution if a patient reports taking a headache medication more than twice a week. “All the medications we use for the treatment of migraine, both in and outside of pregnancy, carry the risk of what’s called medication overuse” that can lead to rebound headaches, she said.

Excedrin Tension Headache may be used for headaches in pregnancy, she said, but not Excedrin Migraine since it includes aspirin. Triptans are not recommended as first-line therapy, she added, and they “should absolutely not be used in any pregnant patient with a history of known cardiac disease or hypertension.”

Dr. Stika added that ACOG advises against the use of drugs that contain butalbital, a barbiturate that’s combined with other agents to treat headache. “Butalbital is the drug that’s most closely associated with getting people into this medication overuse headache,” she said. “It’s even worse than opioids.”

Unlike multiple other countries and the entire European Union, the United States has not banned compounds that contain butalbital, she said.

In some cases, she said, patients may present to triage with vomiting, an inability to keep food down, and persistent headache despite treatment. “This is a really classic presentation.”

The ACOG clinical practice guideline offers a flow chart about what to do, she said. Hydration is key, she said, and various treatment options can help. A referral to neurology may be needed in extreme cases, she said. But “most of the time, you’re able to get rid of her headache.”

Dr. Mercer and Dr. Stika report no disclosures.

SAN DIEGO – If a medical professional is trying to figure out the best medical treatment for a pregnant woman with headache, it may be helpful to review data from randomized clinical trials (RCTs). Well, make that data from the RCT. There’s just been one, Northwestern Medicine obstetrician-gynecologist Catherine Stika, MD, told colleagues at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

Only a single efficacy RCT has examined headache in pregnancy, said Dr. Stika. “Overall, we have very limited data in pregnancy to tell us exactly what to do,” she added.

But ob.gyns. aren’t entirely in the dark, according to medical specialists who spoke at the session. Expert opinion and fetal safety data offer insight into the best treatments, as does a new ACOG clinical practice guideline on headaches during pregnancy and post partum that was coauthored by the speakers.

And there’s some good news: Pregnancy itself is often a good treatment for headaches.

Pregnant women often find relief from one kind of headache – migraine – as their estradiol levels rise, said Laura Mercer, MD, an ob.gyn. at the University of Arizona, Phoenix. “About half of patients will report that migraines are getting better as early as the first trimester, and upwards of 83% will say that their migraines are better by the time they’re in their third trimester,” she said. “What this means for us as obstetricians is that oftentimes we can actually discontinue preventative therapies for patients during pregnancy.”

But simply discontinuing every headache treatment during pregnancy may not be the right approach, Dr. Mercer said. Instead, she said, consider the benefits and risks.

Divalproex sodium (Depakote) and topiramate (Topamax) must be avoided because of fetal risk, she said. “In fact, we will prefer that people stop these medications before they discontinue their contraception if they’re planning on getting pregnant,” she said.

Other medications, such as ACE inhibitors and the herbal remedy feverfew, should not be used at any time during pregnancy, she said.

On the other hand, calcium channel blockers and antihistamines are alright to use in pregnancy, she said. “These two should be considered first-line because there’s no known risks for them.”

Beta-blockers also may be used “with some consideration to the known risks that we’re familiar with when we use them for other indications,” she said.

There are questions about the safety of oral magnesium in pregnancy, although it’s generally considered safe, she added, and “nerve blocks and nerve stimulators seem very promising and have little known risks.”

Dr. Mercer recommended gradually tapering most medications prior to conception. But it’s crucial to stop higher-risk drugs immediately once pregnancy is confirmed, she said.

In regard to acute headache, Dr. Stika urged caution if a patient reports taking a headache medication more than twice a week. “All the medications we use for the treatment of migraine, both in and outside of pregnancy, carry the risk of what’s called medication overuse” that can lead to rebound headaches, she said.

Excedrin Tension Headache may be used for headaches in pregnancy, she said, but not Excedrin Migraine since it includes aspirin. Triptans are not recommended as first-line therapy, she added, and they “should absolutely not be used in any pregnant patient with a history of known cardiac disease or hypertension.”

Dr. Stika added that ACOG advises against the use of drugs that contain butalbital, a barbiturate that’s combined with other agents to treat headache. “Butalbital is the drug that’s most closely associated with getting people into this medication overuse headache,” she said. “It’s even worse than opioids.”

Unlike multiple other countries and the entire European Union, the United States has not banned compounds that contain butalbital, she said.

In some cases, she said, patients may present to triage with vomiting, an inability to keep food down, and persistent headache despite treatment. “This is a really classic presentation.”

The ACOG clinical practice guideline offers a flow chart about what to do, she said. Hydration is key, she said, and various treatment options can help. A referral to neurology may be needed in extreme cases, she said. But “most of the time, you’re able to get rid of her headache.”

Dr. Mercer and Dr. Stika report no disclosures.

Bronchoscopic lung volume reduction significantly increased survival in patients with severe chronic obstructive pulmonary disease, based on data from more than 1,400 individuals.

Previous studies have shown that patients with severe chronic obstructive pulmonary disease (COPD) can benefit from treatment with bronchoscopic lung volume reduction (BLVR) involving lung volume reduction coils or endobronchial valves (EBVs) in terms of improved pulmonary function, lung volume, exercise capacity, and quality of life.

However, data on the impact of the procedure on patient survival are limited, and most previous studies have been small, wrote Jorine E. Hartman, MD, of the University of Groningen, the Netherlands, and colleagues.

In a study published in Respiratory Medicine, the researchers reviewed data from 1,471 patients with severe COPD who had consultations for BLVR at a single center between June 2006 and July 2019. Of these, 483 (33%) underwent a BLVR treatment.

The follow-up period ranged from 633 days to 5,401 days. During this time, 531 patients died (35%); 165 of these (34%) were in the BLVR group.

Overall, the median survival of BLVR patients was significantly longer, compared with those who did not have the procedure, for a difference of approximately 1.7 years (3,133 days vs. 2,503 days, P < .001). No significant differences in survival were noted in BLVR patients treated with coils or EBVs.

The average age of the study population at baseline was 61 years, and 63% were women. Overall, patients treated with BLVR were more likely to be younger and female, with fewer COPD exacerbations but worse pulmonary function, as well as lower body mass index and more evidence of emphysema than the untreated patients, the researchers noted. Patients treated with BLVR also were more likely than untreated patients to have a history of myocardial infarction, percutaneous coronary intervention, or stroke.

However, BLVR was a significant independent predictor of survival after controlling for multiple variables, including age, sex, and disease severity, the researchers noted.

The current study supports existing literature on the value of BLVR for severe COPD but stands out from previous studies by comparing patients who underwent BLVR with those who did not, the researchers noted in their discussion of the findings.

The study findings were limited by several factors, including the fact that the non-treated patients were not eligible for treatment for various reasons that might have impacted survival, the researchers noted. Another limitation was the lack of data on cause of death and other medical events and treatments during the follow-up period, they said.

However, the results were strengthened by the large sample size and long-term follow-up and suggest that “reducing lung volume in patients with COPD and severe hyperinflation and reduced life expectancy may lead to a survival benefit,” they concluded.

The study received no outside funding. Dr. Hartman had no financial conflicts to disclose.

Bronchoscopic lung volume reduction significantly increased survival in patients with severe chronic obstructive pulmonary disease, based on data from more than 1,400 individuals.

Previous studies have shown that patients with severe chronic obstructive pulmonary disease (COPD) can benefit from treatment with bronchoscopic lung volume reduction (BLVR) involving lung volume reduction coils or endobronchial valves (EBVs) in terms of improved pulmonary function, lung volume, exercise capacity, and quality of life.

However, data on the impact of the procedure on patient survival are limited, and most previous studies have been small, wrote Jorine E. Hartman, MD, of the University of Groningen, the Netherlands, and colleagues.

In a study published in Respiratory Medicine, the researchers reviewed data from 1,471 patients with severe COPD who had consultations for BLVR at a single center between June 2006 and July 2019. Of these, 483 (33%) underwent a BLVR treatment.

The follow-up period ranged from 633 days to 5,401 days. During this time, 531 patients died (35%); 165 of these (34%) were in the BLVR group.

Overall, the median survival of BLVR patients was significantly longer, compared with those who did not have the procedure, for a difference of approximately 1.7 years (3,133 days vs. 2,503 days, P < .001). No significant differences in survival were noted in BLVR patients treated with coils or EBVs.

The average age of the study population at baseline was 61 years, and 63% were women. Overall, patients treated with BLVR were more likely to be younger and female, with fewer COPD exacerbations but worse pulmonary function, as well as lower body mass index and more evidence of emphysema than the untreated patients, the researchers noted. Patients treated with BLVR also were more likely than untreated patients to have a history of myocardial infarction, percutaneous coronary intervention, or stroke.

However, BLVR was a significant independent predictor of survival after controlling for multiple variables, including age, sex, and disease severity, the researchers noted.

The current study supports existing literature on the value of BLVR for severe COPD but stands out from previous studies by comparing patients who underwent BLVR with those who did not, the researchers noted in their discussion of the findings.

The study findings were limited by several factors, including the fact that the non-treated patients were not eligible for treatment for various reasons that might have impacted survival, the researchers noted. Another limitation was the lack of data on cause of death and other medical events and treatments during the follow-up period, they said.

However, the results were strengthened by the large sample size and long-term follow-up and suggest that “reducing lung volume in patients with COPD and severe hyperinflation and reduced life expectancy may lead to a survival benefit,” they concluded.

The study received no outside funding. Dr. Hartman had no financial conflicts to disclose.

Bronchoscopic lung volume reduction significantly increased survival in patients with severe chronic obstructive pulmonary disease, based on data from more than 1,400 individuals.

Previous studies have shown that patients with severe chronic obstructive pulmonary disease (COPD) can benefit from treatment with bronchoscopic lung volume reduction (BLVR) involving lung volume reduction coils or endobronchial valves (EBVs) in terms of improved pulmonary function, lung volume, exercise capacity, and quality of life.

However, data on the impact of the procedure on patient survival are limited, and most previous studies have been small, wrote Jorine E. Hartman, MD, of the University of Groningen, the Netherlands, and colleagues.

In a study published in Respiratory Medicine, the researchers reviewed data from 1,471 patients with severe COPD who had consultations for BLVR at a single center between June 2006 and July 2019. Of these, 483 (33%) underwent a BLVR treatment.

The follow-up period ranged from 633 days to 5,401 days. During this time, 531 patients died (35%); 165 of these (34%) were in the BLVR group.

Overall, the median survival of BLVR patients was significantly longer, compared with those who did not have the procedure, for a difference of approximately 1.7 years (3,133 days vs. 2,503 days, P < .001). No significant differences in survival were noted in BLVR patients treated with coils or EBVs.

The average age of the study population at baseline was 61 years, and 63% were women. Overall, patients treated with BLVR were more likely to be younger and female, with fewer COPD exacerbations but worse pulmonary function, as well as lower body mass index and more evidence of emphysema than the untreated patients, the researchers noted. Patients treated with BLVR also were more likely than untreated patients to have a history of myocardial infarction, percutaneous coronary intervention, or stroke.

However, BLVR was a significant independent predictor of survival after controlling for multiple variables, including age, sex, and disease severity, the researchers noted.

The current study supports existing literature on the value of BLVR for severe COPD but stands out from previous studies by comparing patients who underwent BLVR with those who did not, the researchers noted in their discussion of the findings.

The study findings were limited by several factors, including the fact that the non-treated patients were not eligible for treatment for various reasons that might have impacted survival, the researchers noted. Another limitation was the lack of data on cause of death and other medical events and treatments during the follow-up period, they said.

However, the results were strengthened by the large sample size and long-term follow-up and suggest that “reducing lung volume in patients with COPD and severe hyperinflation and reduced life expectancy may lead to a survival benefit,” they concluded.

The study received no outside funding. Dr. Hartman had no financial conflicts to disclose.

Advances in Alzheimer disease (AD) genes and biomarkers now allow older adults to undergo testing and learn about their risk for AD.¹ Current routes for doing so include testing in cardiology, screening for enrollment in secondary prevention trials (which use these tests to determine trial eligibility),² and direct-to-consumer (DTC) services that provide these results as part of large panels.³ Patients may also obtain apolipoprotein (APOE) genotype information as part of an assessment of the risks and benefits of treatment with aducanumab (Aduhelm) or other anti-amyloid therapies that have been developed to stop or slow the progression of AD pathologies.

Expanded access to testing, in combination with limited guidance from DTC companies, suggests more older adults may consult their primary care physicians about this testing. In this narrative review, we use a vignette-driven approach to summarize the current scientific knowledge of the topic and to offer guidance on provider-patient discussions and follow-up.

First, a look at APOE genotyping

In cognitively unimpaired older adults, the APOE gene is a known risk factor for mild cognitive impairment (MCI) or AD.³ A person has 2 alleles of the APOE gene, which has 3 variants: ε2, ε3, and ε4. The combination of alleles conveys varying levels of risk for developing clinical symptoms (TABLE 1⁴), with ε4 increasing risk and ε2 decreasing risk compared to the more common ε3; thus the ε4/ε4 genotype conveys the most risk and the ε2/ε2 the least.

The APOE gene differs from other genes that have been identified in early-onset familial AD. These other genes, which include APP, PSEN1, and PSEN2, are deterministic genes that are fully penetrant. The APOE gene is not deterministic, meaning there is no combination of APOE alleles that are necessary or sufficient to cause late-onset AD dementia.

In clinical trials of amyloid-modifying therapies, the APOE gene has been shown to convey a risk of amyloid-related imaging abnormalities (ARIA).⁵ That is, in addition to conveying a risk for AD, the gene also conveys a risk for adverse effects of emerging treatments that can result in serious injury or death. This includes the drug aducanumab that was recently approved by the US Food and Drug Administration (FDA).⁶ In this review, we focus primarily on common clinical scenarios related to APOE. However, in light of the recent controversy over aducanumab and whether the drug should be offered to patients,^7-9 we also describe how a patient’s APOE genotype may factor into drug candidacy decisions.

Testing, in clinic and “at home.” To date, practice guidelines have consistently recommended against APOE genetic testing in routine clinical practice. This is primarily due to low clinical prognostic utility and the lack of actionable results. Furthermore, no lifestyle or pharmaceutical interventions based on APOE genotype currently exist (although trials are underway¹⁰).

In 2017, the FDA approved marketing of DTC testing for the APOE gene.¹¹ While DTC companies tend to issue standardized test result reports, the content and quality can vary widely. In fact, some provide risk estimates that are too high and too definitive and may not reflect the most recent science.¹²

Continue to: 7 clinical scenarios and how to approach them

7 clinical scenarios and how to approach them

Six of the following vignettes describe common clinical scenarios in which patients seek medical advice regarding APOE test results. The seventh vignette describes a patient whose APOE genotype may play a role in possible disease-modifying treatments down the road. Each vignette is designed to guide your approach to patient discussions and follow-up. Recommendations and considerations are also summarized in TABLE 2^13-16.

Vignette 1

Janet W, age 65, comes to the clinic for a new patient visit. She has no concerns about her memory but recently purchased DTC genetic testing to learn about her genetic health risks. Her results showed an APOE ε4/ε4 genotype. She is now concerned about developing AD. Her mother was diagnosed with AD in her 70s.

Several important pieces of information can be conveyed by the primary care physician. First, patients such as Ms. W should be told that the APOE gene is not deterministic; many people, even those with 2 ε4 alleles, never develop dementia. Second, no specific preventive measures or treatments exist based on an individual’s APOE genotype (see Vignette 5 for additional discussion).

In this scenario, patients may ask for numeric quantification of their risk for dementia (see TABLE 1⁴ for estimates). When conveying probabilistic risk, consider using simple percentages or pictographs (eg, out of 100 individuals with an ε4/ε4 genotype, 30 to 55 develop MCI or AD). Additionally, because people tend to exhibit confirmatory bias in thinking about probabilistic risk, providing opposing interpretations of an estimate may help them to consider alternative possibilities.¹⁷ For example, ε4/ε4 individuals have a 30% to 55% risk for MCI or AD. Alternatively, they have a 45% to 70% risk of not developing MCI or AD.

There are important caveats to the interpretation of APOE risk estimates. Because APOE risk estimates are probabilistic and averaged across a broader spectrum of people in large population cohorts,⁴ estimates may not accurately reflect a given individual’s risk. The ranges reflect the uncertainty in the estimates. The uncertainty arises from relatively small samples, the rareness of some genotypes (notably ε4/ε4) even in large samples, and variations in methods and sampling that can lead to differences in estimates beyond statistical variation.

Vignette 2

Eric J, age 85, presents for a new patient visit accompanied by his daughter. He lives independently, volunteers at a senior center several times a week, and exercises regularly, and neither he nor his daughter has any concerns about his memory. As a gift, he recently underwent DTC genetic testing and unexpectedly learned his APOE result, which is ε4/ε4. He wants to know about his chances of developing AD.

Risk conveyed by APOE genotype can be modified by a patient’s age. At age 85, Mr. J is healthy, highly functional, and cognitively unimpaired. Given his age, Mr. J has likely “outlived” much of the risk for dementia attributable to the ε4/ε4 genotype. His risk for dementia remains high, but this risk is likely driven more by age than by his APOE genotype. Data for individuals older than age 80 are limited, and thus risk estimates lack precision. Given Mr. J’s good health and functional status, his physician may want to perform a brief cognitive screening test to serve as a baseline for future evaluations.

Continue to: Vignette 3

Vignette 3

Audrey S is a 60-year-old African American woman who comes to the clinic for her annual visit. Because her father had AD, she recently purchased DTC genetic testing to learn about her APOE genotype and risk for AD. Her results are ε3/ε4. She is wondering what this may mean for her future.

Lack of diversity in research cohorts often limits the generalizability of estimates. For example, both the frequency and impact of APOE ε4 differ across racial groups.¹⁸ But most of the data on APOE lifetime risk estimates are from largely White patient samples. While APOE ε4 seems to confer increased risk for AD across sociocultural groups, these effects may be attenuated in African American and Hispanic populations.^19,20 If Ms. S is interested in numeric risk estimates, the physician can provide the estimate for ε3/ε4 (20%-25% lifetime risk), with the important caveat that this estimate may not be reflective of her individual risk.

Both the frequency and impact of APOE ε4 differ across racial groups, but most of the data on APOE lifetime risk estimates are from largely White patient samples.

It may be prudent to determine whether Ms. S, at age 60, has subjective memory concerns and if she does, to perform a brief cognitive exam to serve as a baseline for future evaluations. Additionally, while the Genetic Information Nondiscrimination Act (GINA, 2008) prohibits health insurers and employers from discriminating based on genetic testing results, no legal provisions exist regarding long-term care, disability, or life insurance. Documented conversations about APOE test results in the medical record may become part of patients’ applications for these insurance products, and physicians should be cautious before documenting such discussions in the medical record.

Vignette 4

Tina L, age 60, comes to the clinic for a routine wellness visit. She recently developed an interest in genealogy and purchased a DNA testing kit to learn more about her family tree. As part of this testing, she unexpectedly learned that she has an APOE ε4/ε4 genotype. She describes feeling distraught and anxious about what the result means for her future.

Ms. L’s reaction to receiving unexpected genetic results highlights a concern of DTC APOE testing. Her experience is quite different from individuals undergoing medically recommended genetic testing or those who are participating in research studies. They receive comprehensive pre-test counseling by licensed genetic counselors. The counseling includes psychological assessment, education, and discussion of expectations.²

In Ms. L’s case, it may be helpful to explain the limits of APOE lifetime risk estimates (see Vignettes 1-3). But it’s also important to address her concerns. There are behavior scales that can aid the assessment and monitoring of an individual’s well-being. The Impact of Genetic Testing for Alzheimer’s Disease (IGT-AD) scale is a tool that assesses psychological impact. It can help physicians to identify, monitor, and address concerns.²¹ Other useful tools include the Patient Health Questionnaire-9 (PHQ-9) and the Geriatric Depression Scale (GDS) for depression, and a suicide or self-harm assessment.^2,22,23 Finally, a follow-up visit at 2 to 4 weeks may be useful to reassess psychological well-being.

Vignette 4 (cont’d)

Ms. L returns to the clinic 2 weeks later, reporting continued anxiety about her APOE test result and feelings of hopelessness and despair.

Continue to: Some patients struggle...

Some patients struggle with knowing their APOE test result. Test result–related distress is often a combination of depression (as with Ms. L), anger, confusion, and grief.²⁴ Cognitions often include worries about uncertainty, stereotyped threat, and internalized stigma.^25,26 These issues can spill over to patient concerns about sharing an APOE test result with others.²⁷

Intolerance of uncertainty is a transdiagnostic risk factor that can influence psychological suffering.²⁸ Brief cognitive behavioral interventions that reinforce routines and encourage healthy and mindful practices may help alleviate patient distress from unexpected genetic test results.²⁹ Interventions that personalize and validate an individual’s experience can help address internalized stigma.³⁰ Referral to a psychologist or psychiatrist could be warranted. Additionally, referral to a genetic counselor may help provide patients with access to added expertise and guidance; useful web-based resources for identifying an appropriate referral include https://medlineplus.gov/genetics/­understanding/consult/findingprofessional/ and https://findageneticcounselor.nsgc.org/.

Vignette 5

Bob K, age 65, comes to the clinic for his annual exam. He is a current smoker and says he’s hoping to be more physically active now that he is retired. He says that his mother and grandmother both had AD. He recently purchased DTC genetic testing to learn more about his risk for AD. His learned his APOE genotype is ε3/ε4 and is wondering what he can do to decrease his chances of developing AD.

Mr. K likely would have benefited from pre-test counseling regarding the lack of current therapies to modify one’s genetic risk for AD. A pre-test counseling session often includes education about APOE testing and a brief evaluation to assess psychological readiness to undergo testing. Posttest educational information may help Mr. K avoid predatory advertising of products claiming—without scientific evidence—to modify risk for cognitive decline or to improve cognitive function.

Emerging evidence from RCTs suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.

There are several important pieces of information that should be communicated to Mr. K. Emerging evidence from randomized controlled trials suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.³¹ It would be prudent to address proper blood pressure control³² and counsel Mr. K on how he may be able to avoid diabetes through exercise and weight maintenance. Lifestyle recommendations for Mr. K could include: smoking cessation, regular aerobic exercise (eg, 150 min/wk), and a brain-healthy diet (eg, the Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet).^13,14 Moreover, dementia prevention also includes appropriately managing depression and chronic illnesses and preventing social isolation and hearing loss.^15,16 This information should be thoughtfully conveyed, as these interventions can improve overall (especially cardiovascular) health, as well as mitigating one’s personal risk for AD.

Vignette 6

Juan L, age 45, comes in for his annual physical exam. He has a strong family history of heart disease. His cardiologist recently ordered lipid disorder genetic testing for familial hypercholesterolemia. This panel included APOE testing and showed Mr. L’s genotype is ε2/ε4. He read that the APOE gene can be associated with an increased AD risk and asks for information about his genotype.

Mr. L received genetic testing results that were ordered by a physician for another health purpose. Current recommendations for genetic testing in cardiology advise pre-test genetic counseling.³³ But this counseling may not include discussion of the relationship of APOE and risk for MCI or AD. This additional information may be unexpected for Mr. L. Moreover, its significance in the context of his present concerns about cardiovascular disease may influence his reaction.

Continue to: The ε2/ε4 genotype...

The ε2/ε4 genotype is rare. One study showed that in healthy adults, the frequency was 7 in 210 (0.02 [0.01-0.04]).³⁴ Given the rarity of the ε2/ε4 genotype, data about it are sparse. However, since the ε4 allele increases risk but the ε2 allele decreases risk, it is likely that any increase in risk is more modest than with ε3/ε4. In addition, it would help Mr. L to know that AD occurs infrequently before age 60.³⁵ Given his relatively young age, he is unlikely to develop AD any time in the near future. In addition, particularly if he starts early, he might be able to mitigate any increased risk through some of the advice provided to Mr. K in Vignette 5.

Vignette 7

Joe J, age 65, comes to the clinic for a new patient visit. He has no concerns about his memory but has a family history of dementia and recently purchased DTC genetic testing to learn about his genetic health risks. His results showed an APOE ε4/ε4 genotype. He is concerned about developing AD. He heard on the news that there is a drug that can treat AD and wants to know if he is a candidate for this treatment.

Mr. J would benefit from the education provided to Ms. W in Vignette 1. Patients such as Mr. J should be advised that while an APOE ε4/ε4 genotype conveys an increased risk for AD, it is not deterministic of the disease. While there are no specific preventive measures or treatments based on APOE genotype, careful medical care and lifestyle factors can offset some of the risk (see Vignette 5 for discussion).

One reason for the aducanumab controversy is that the drug has potenially severe adverse effects.

Recently (and controversially), the FDA approved aducanumab, a drug that targets amyloid.^6,36 Of note, brain amyloid is more common in individuals with the APOE ε4/ε4 genotype, such as Mr. J. However, there would be no point in testing Mr. J for brain amyloid because at present the drug is only indicated in symptomatic individuals—and, even in this setting, it is controversial. One reason for the controversy is that aducanumab has potentially severe adverse effects. Patients with the ε4/ε4 genotype should know that this genotype carries increased risk for the most serious adverse event, ARIA—which can include brain edema and microhemorrhages.

What lies ahead?

More research is needed to explore the impact that greater AD gene and biomarker testing will have on the health system and workforce development. In addition, graduate schools and training programs will need to prepare clinicians to address probabilistic risk estimates for common diseases, such as AD. Finally, health systems and medical groups that employ clinicians may want to offer simulated training—similar to the vignettes in this article—as a practice requirement or as continuing medical education. This may also allow health systems or medical groups to put in place frameworks that support clinicians in proactively answering questions for patients and families about APOE and other emerging markers of disease risk.

CORRESPONDENCE
Shana Stites, University of Pennsylvania, 3615 Chestnut Street, Philadelphia, PA 19104; [email protected]

Advances in Alzheimer disease (AD) genes and biomarkers now allow older adults to undergo testing and learn about their risk for AD.¹ Current routes for doing so include testing in cardiology, screening for enrollment in secondary prevention trials (which use these tests to determine trial eligibility),² and direct-to-consumer (DTC) services that provide these results as part of large panels.³ Patients may also obtain apolipoprotein (APOE) genotype information as part of an assessment of the risks and benefits of treatment with aducanumab (Aduhelm) or other anti-amyloid therapies that have been developed to stop or slow the progression of AD pathologies.

Expanded access to testing, in combination with limited guidance from DTC companies, suggests more older adults may consult their primary care physicians about this testing. In this narrative review, we use a vignette-driven approach to summarize the current scientific knowledge of the topic and to offer guidance on provider-patient discussions and follow-up.

First, a look at APOE genotyping

In cognitively unimpaired older adults, the APOE gene is a known risk factor for mild cognitive impairment (MCI) or AD.³ A person has 2 alleles of the APOE gene, which has 3 variants: ε2, ε3, and ε4. The combination of alleles conveys varying levels of risk for developing clinical symptoms (TABLE 1⁴), with ε4 increasing risk and ε2 decreasing risk compared to the more common ε3; thus the ε4/ε4 genotype conveys the most risk and the ε2/ε2 the least.

The APOE gene differs from other genes that have been identified in early-onset familial AD. These other genes, which include APP, PSEN1, and PSEN2, are deterministic genes that are fully penetrant. The APOE gene is not deterministic, meaning there is no combination of APOE alleles that are necessary or sufficient to cause late-onset AD dementia.

In clinical trials of amyloid-modifying therapies, the APOE gene has been shown to convey a risk of amyloid-related imaging abnormalities (ARIA).⁵ That is, in addition to conveying a risk for AD, the gene also conveys a risk for adverse effects of emerging treatments that can result in serious injury or death. This includes the drug aducanumab that was recently approved by the US Food and Drug Administration (FDA).⁶ In this review, we focus primarily on common clinical scenarios related to APOE. However, in light of the recent controversy over aducanumab and whether the drug should be offered to patients,^7-9 we also describe how a patient’s APOE genotype may factor into drug candidacy decisions.

Testing, in clinic and “at home.” To date, practice guidelines have consistently recommended against APOE genetic testing in routine clinical practice. This is primarily due to low clinical prognostic utility and the lack of actionable results. Furthermore, no lifestyle or pharmaceutical interventions based on APOE genotype currently exist (although trials are underway¹⁰).

In 2017, the FDA approved marketing of DTC testing for the APOE gene.¹¹ While DTC companies tend to issue standardized test result reports, the content and quality can vary widely. In fact, some provide risk estimates that are too high and too definitive and may not reflect the most recent science.¹²

Continue to: 7 clinical scenarios and how to approach them

7 clinical scenarios and how to approach them

Six of the following vignettes describe common clinical scenarios in which patients seek medical advice regarding APOE test results. The seventh vignette describes a patient whose APOE genotype may play a role in possible disease-modifying treatments down the road. Each vignette is designed to guide your approach to patient discussions and follow-up. Recommendations and considerations are also summarized in TABLE 2^13-16.

Vignette 1

Janet W, age 65, comes to the clinic for a new patient visit. She has no concerns about her memory but recently purchased DTC genetic testing to learn about her genetic health risks. Her results showed an APOE ε4/ε4 genotype. She is now concerned about developing AD. Her mother was diagnosed with AD in her 70s.

Several important pieces of information can be conveyed by the primary care physician. First, patients such as Ms. W should be told that the APOE gene is not deterministic; many people, even those with 2 ε4 alleles, never develop dementia. Second, no specific preventive measures or treatments exist based on an individual’s APOE genotype (see Vignette 5 for additional discussion).

In this scenario, patients may ask for numeric quantification of their risk for dementia (see TABLE 1⁴ for estimates). When conveying probabilistic risk, consider using simple percentages or pictographs (eg, out of 100 individuals with an ε4/ε4 genotype, 30 to 55 develop MCI or AD). Additionally, because people tend to exhibit confirmatory bias in thinking about probabilistic risk, providing opposing interpretations of an estimate may help them to consider alternative possibilities.¹⁷ For example, ε4/ε4 individuals have a 30% to 55% risk for MCI or AD. Alternatively, they have a 45% to 70% risk of not developing MCI or AD.

There are important caveats to the interpretation of APOE risk estimates. Because APOE risk estimates are probabilistic and averaged across a broader spectrum of people in large population cohorts,⁴ estimates may not accurately reflect a given individual’s risk. The ranges reflect the uncertainty in the estimates. The uncertainty arises from relatively small samples, the rareness of some genotypes (notably ε4/ε4) even in large samples, and variations in methods and sampling that can lead to differences in estimates beyond statistical variation.

Vignette 2

Eric J, age 85, presents for a new patient visit accompanied by his daughter. He lives independently, volunteers at a senior center several times a week, and exercises regularly, and neither he nor his daughter has any concerns about his memory. As a gift, he recently underwent DTC genetic testing and unexpectedly learned his APOE result, which is ε4/ε4. He wants to know about his chances of developing AD.

Risk conveyed by APOE genotype can be modified by a patient’s age. At age 85, Mr. J is healthy, highly functional, and cognitively unimpaired. Given his age, Mr. J has likely “outlived” much of the risk for dementia attributable to the ε4/ε4 genotype. His risk for dementia remains high, but this risk is likely driven more by age than by his APOE genotype. Data for individuals older than age 80 are limited, and thus risk estimates lack precision. Given Mr. J’s good health and functional status, his physician may want to perform a brief cognitive screening test to serve as a baseline for future evaluations.

Continue to: Vignette 3

Vignette 3

Audrey S is a 60-year-old African American woman who comes to the clinic for her annual visit. Because her father had AD, she recently purchased DTC genetic testing to learn about her APOE genotype and risk for AD. Her results are ε3/ε4. She is wondering what this may mean for her future.

Lack of diversity in research cohorts often limits the generalizability of estimates. For example, both the frequency and impact of APOE ε4 differ across racial groups.¹⁸ But most of the data on APOE lifetime risk estimates are from largely White patient samples. While APOE ε4 seems to confer increased risk for AD across sociocultural groups, these effects may be attenuated in African American and Hispanic populations.^19,20 If Ms. S is interested in numeric risk estimates, the physician can provide the estimate for ε3/ε4 (20%-25% lifetime risk), with the important caveat that this estimate may not be reflective of her individual risk.

Both the frequency and impact of APOE ε4 differ across racial groups, but most of the data on APOE lifetime risk estimates are from largely White patient samples.

It may be prudent to determine whether Ms. S, at age 60, has subjective memory concerns and if she does, to perform a brief cognitive exam to serve as a baseline for future evaluations. Additionally, while the Genetic Information Nondiscrimination Act (GINA, 2008) prohibits health insurers and employers from discriminating based on genetic testing results, no legal provisions exist regarding long-term care, disability, or life insurance. Documented conversations about APOE test results in the medical record may become part of patients’ applications for these insurance products, and physicians should be cautious before documenting such discussions in the medical record.

Vignette 4

Tina L, age 60, comes to the clinic for a routine wellness visit. She recently developed an interest in genealogy and purchased a DNA testing kit to learn more about her family tree. As part of this testing, she unexpectedly learned that she has an APOE ε4/ε4 genotype. She describes feeling distraught and anxious about what the result means for her future.

Ms. L’s reaction to receiving unexpected genetic results highlights a concern of DTC APOE testing. Her experience is quite different from individuals undergoing medically recommended genetic testing or those who are participating in research studies. They receive comprehensive pre-test counseling by licensed genetic counselors. The counseling includes psychological assessment, education, and discussion of expectations.²

In Ms. L’s case, it may be helpful to explain the limits of APOE lifetime risk estimates (see Vignettes 1-3). But it’s also important to address her concerns. There are behavior scales that can aid the assessment and monitoring of an individual’s well-being. The Impact of Genetic Testing for Alzheimer’s Disease (IGT-AD) scale is a tool that assesses psychological impact. It can help physicians to identify, monitor, and address concerns.²¹ Other useful tools include the Patient Health Questionnaire-9 (PHQ-9) and the Geriatric Depression Scale (GDS) for depression, and a suicide or self-harm assessment.^2,22,23 Finally, a follow-up visit at 2 to 4 weeks may be useful to reassess psychological well-being.

Vignette 4 (cont’d)

Ms. L returns to the clinic 2 weeks later, reporting continued anxiety about her APOE test result and feelings of hopelessness and despair.

Continue to: Some patients struggle...

Some patients struggle with knowing their APOE test result. Test result–related distress is often a combination of depression (as with Ms. L), anger, confusion, and grief.²⁴ Cognitions often include worries about uncertainty, stereotyped threat, and internalized stigma.^25,26 These issues can spill over to patient concerns about sharing an APOE test result with others.²⁷

Intolerance of uncertainty is a transdiagnostic risk factor that can influence psychological suffering.²⁸ Brief cognitive behavioral interventions that reinforce routines and encourage healthy and mindful practices may help alleviate patient distress from unexpected genetic test results.²⁹ Interventions that personalize and validate an individual’s experience can help address internalized stigma.³⁰ Referral to a psychologist or psychiatrist could be warranted. Additionally, referral to a genetic counselor may help provide patients with access to added expertise and guidance; useful web-based resources for identifying an appropriate referral include https://medlineplus.gov/genetics/­understanding/consult/findingprofessional/ and https://findageneticcounselor.nsgc.org/.

Vignette 5

Bob K, age 65, comes to the clinic for his annual exam. He is a current smoker and says he’s hoping to be more physically active now that he is retired. He says that his mother and grandmother both had AD. He recently purchased DTC genetic testing to learn more about his risk for AD. His learned his APOE genotype is ε3/ε4 and is wondering what he can do to decrease his chances of developing AD.

Mr. K likely would have benefited from pre-test counseling regarding the lack of current therapies to modify one’s genetic risk for AD. A pre-test counseling session often includes education about APOE testing and a brief evaluation to assess psychological readiness to undergo testing. Posttest educational information may help Mr. K avoid predatory advertising of products claiming—without scientific evidence—to modify risk for cognitive decline or to improve cognitive function.

Emerging evidence from RCTs suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.

There are several important pieces of information that should be communicated to Mr. K. Emerging evidence from randomized controlled trials suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.³¹ It would be prudent to address proper blood pressure control³² and counsel Mr. K on how he may be able to avoid diabetes through exercise and weight maintenance. Lifestyle recommendations for Mr. K could include: smoking cessation, regular aerobic exercise (eg, 150 min/wk), and a brain-healthy diet (eg, the Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet).^13,14 Moreover, dementia prevention also includes appropriately managing depression and chronic illnesses and preventing social isolation and hearing loss.^15,16 This information should be thoughtfully conveyed, as these interventions can improve overall (especially cardiovascular) health, as well as mitigating one’s personal risk for AD.

Vignette 6

Juan L, age 45, comes in for his annual physical exam. He has a strong family history of heart disease. His cardiologist recently ordered lipid disorder genetic testing for familial hypercholesterolemia. This panel included APOE testing and showed Mr. L’s genotype is ε2/ε4. He read that the APOE gene can be associated with an increased AD risk and asks for information about his genotype.

Mr. L received genetic testing results that were ordered by a physician for another health purpose. Current recommendations for genetic testing in cardiology advise pre-test genetic counseling.³³ But this counseling may not include discussion of the relationship of APOE and risk for MCI or AD. This additional information may be unexpected for Mr. L. Moreover, its significance in the context of his present concerns about cardiovascular disease may influence his reaction.

Continue to: The ε2/ε4 genotype...

The ε2/ε4 genotype is rare. One study showed that in healthy adults, the frequency was 7 in 210 (0.02 [0.01-0.04]).³⁴ Given the rarity of the ε2/ε4 genotype, data about it are sparse. However, since the ε4 allele increases risk but the ε2 allele decreases risk, it is likely that any increase in risk is more modest than with ε3/ε4. In addition, it would help Mr. L to know that AD occurs infrequently before age 60.³⁵ Given his relatively young age, he is unlikely to develop AD any time in the near future. In addition, particularly if he starts early, he might be able to mitigate any increased risk through some of the advice provided to Mr. K in Vignette 5.

Vignette 7

Joe J, age 65, comes to the clinic for a new patient visit. He has no concerns about his memory but has a family history of dementia and recently purchased DTC genetic testing to learn about his genetic health risks. His results showed an APOE ε4/ε4 genotype. He is concerned about developing AD. He heard on the news that there is a drug that can treat AD and wants to know if he is a candidate for this treatment.

Mr. J would benefit from the education provided to Ms. W in Vignette 1. Patients such as Mr. J should be advised that while an APOE ε4/ε4 genotype conveys an increased risk for AD, it is not deterministic of the disease. While there are no specific preventive measures or treatments based on APOE genotype, careful medical care and lifestyle factors can offset some of the risk (see Vignette 5 for discussion).

One reason for the aducanumab controversy is that the drug has potenially severe adverse effects.

Recently (and controversially), the FDA approved aducanumab, a drug that targets amyloid.^6,36 Of note, brain amyloid is more common in individuals with the APOE ε4/ε4 genotype, such as Mr. J. However, there would be no point in testing Mr. J for brain amyloid because at present the drug is only indicated in symptomatic individuals—and, even in this setting, it is controversial. One reason for the controversy is that aducanumab has potentially severe adverse effects. Patients with the ε4/ε4 genotype should know that this genotype carries increased risk for the most serious adverse event, ARIA—which can include brain edema and microhemorrhages.

What lies ahead?

More research is needed to explore the impact that greater AD gene and biomarker testing will have on the health system and workforce development. In addition, graduate schools and training programs will need to prepare clinicians to address probabilistic risk estimates for common diseases, such as AD. Finally, health systems and medical groups that employ clinicians may want to offer simulated training—similar to the vignettes in this article—as a practice requirement or as continuing medical education. This may also allow health systems or medical groups to put in place frameworks that support clinicians in proactively answering questions for patients and families about APOE and other emerging markers of disease risk.

CORRESPONDENCE
Shana Stites, University of Pennsylvania, 3615 Chestnut Street, Philadelphia, PA 19104; [email protected]

Advances in Alzheimer disease (AD) genes and biomarkers now allow older adults to undergo testing and learn about their risk for AD.¹ Current routes for doing so include testing in cardiology, screening for enrollment in secondary prevention trials (which use these tests to determine trial eligibility),² and direct-to-consumer (DTC) services that provide these results as part of large panels.³ Patients may also obtain apolipoprotein (APOE) genotype information as part of an assessment of the risks and benefits of treatment with aducanumab (Aduhelm) or other anti-amyloid therapies that have been developed to stop or slow the progression of AD pathologies.

Expanded access to testing, in combination with limited guidance from DTC companies, suggests more older adults may consult their primary care physicians about this testing. In this narrative review, we use a vignette-driven approach to summarize the current scientific knowledge of the topic and to offer guidance on provider-patient discussions and follow-up.

First, a look at APOE genotyping

In cognitively unimpaired older adults, the APOE gene is a known risk factor for mild cognitive impairment (MCI) or AD.³ A person has 2 alleles of the APOE gene, which has 3 variants: ε2, ε3, and ε4. The combination of alleles conveys varying levels of risk for developing clinical symptoms (TABLE 1⁴), with ε4 increasing risk and ε2 decreasing risk compared to the more common ε3; thus the ε4/ε4 genotype conveys the most risk and the ε2/ε2 the least.

The APOE gene differs from other genes that have been identified in early-onset familial AD. These other genes, which include APP, PSEN1, and PSEN2, are deterministic genes that are fully penetrant. The APOE gene is not deterministic, meaning there is no combination of APOE alleles that are necessary or sufficient to cause late-onset AD dementia.

In clinical trials of amyloid-modifying therapies, the APOE gene has been shown to convey a risk of amyloid-related imaging abnormalities (ARIA).⁵ That is, in addition to conveying a risk for AD, the gene also conveys a risk for adverse effects of emerging treatments that can result in serious injury or death. This includes the drug aducanumab that was recently approved by the US Food and Drug Administration (FDA).⁶ In this review, we focus primarily on common clinical scenarios related to APOE. However, in light of the recent controversy over aducanumab and whether the drug should be offered to patients,^7-9 we also describe how a patient’s APOE genotype may factor into drug candidacy decisions.

Testing, in clinic and “at home.” To date, practice guidelines have consistently recommended against APOE genetic testing in routine clinical practice. This is primarily due to low clinical prognostic utility and the lack of actionable results. Furthermore, no lifestyle or pharmaceutical interventions based on APOE genotype currently exist (although trials are underway¹⁰).

In 2017, the FDA approved marketing of DTC testing for the APOE gene.¹¹ While DTC companies tend to issue standardized test result reports, the content and quality can vary widely. In fact, some provide risk estimates that are too high and too definitive and may not reflect the most recent science.¹²

Continue to: 7 clinical scenarios and how to approach them

7 clinical scenarios and how to approach them

Six of the following vignettes describe common clinical scenarios in which patients seek medical advice regarding APOE test results. The seventh vignette describes a patient whose APOE genotype may play a role in possible disease-modifying treatments down the road. Each vignette is designed to guide your approach to patient discussions and follow-up. Recommendations and considerations are also summarized in TABLE 2^13-16.

Vignette 1

Janet W, age 65, comes to the clinic for a new patient visit. She has no concerns about her memory but recently purchased DTC genetic testing to learn about her genetic health risks. Her results showed an APOE ε4/ε4 genotype. She is now concerned about developing AD. Her mother was diagnosed with AD in her 70s.

Several important pieces of information can be conveyed by the primary care physician. First, patients such as Ms. W should be told that the APOE gene is not deterministic; many people, even those with 2 ε4 alleles, never develop dementia. Second, no specific preventive measures or treatments exist based on an individual’s APOE genotype (see Vignette 5 for additional discussion).

In this scenario, patients may ask for numeric quantification of their risk for dementia (see TABLE 1⁴ for estimates). When conveying probabilistic risk, consider using simple percentages or pictographs (eg, out of 100 individuals with an ε4/ε4 genotype, 30 to 55 develop MCI or AD). Additionally, because people tend to exhibit confirmatory bias in thinking about probabilistic risk, providing opposing interpretations of an estimate may help them to consider alternative possibilities.¹⁷ For example, ε4/ε4 individuals have a 30% to 55% risk for MCI or AD. Alternatively, they have a 45% to 70% risk of not developing MCI or AD.

There are important caveats to the interpretation of APOE risk estimates. Because APOE risk estimates are probabilistic and averaged across a broader spectrum of people in large population cohorts,⁴ estimates may not accurately reflect a given individual’s risk. The ranges reflect the uncertainty in the estimates. The uncertainty arises from relatively small samples, the rareness of some genotypes (notably ε4/ε4) even in large samples, and variations in methods and sampling that can lead to differences in estimates beyond statistical variation.

Vignette 2

Eric J, age 85, presents for a new patient visit accompanied by his daughter. He lives independently, volunteers at a senior center several times a week, and exercises regularly, and neither he nor his daughter has any concerns about his memory. As a gift, he recently underwent DTC genetic testing and unexpectedly learned his APOE result, which is ε4/ε4. He wants to know about his chances of developing AD.

Risk conveyed by APOE genotype can be modified by a patient’s age. At age 85, Mr. J is healthy, highly functional, and cognitively unimpaired. Given his age, Mr. J has likely “outlived” much of the risk for dementia attributable to the ε4/ε4 genotype. His risk for dementia remains high, but this risk is likely driven more by age than by his APOE genotype. Data for individuals older than age 80 are limited, and thus risk estimates lack precision. Given Mr. J’s good health and functional status, his physician may want to perform a brief cognitive screening test to serve as a baseline for future evaluations.

Continue to: Vignette 3

Vignette 3

Audrey S is a 60-year-old African American woman who comes to the clinic for her annual visit. Because her father had AD, she recently purchased DTC genetic testing to learn about her APOE genotype and risk for AD. Her results are ε3/ε4. She is wondering what this may mean for her future.

Lack of diversity in research cohorts often limits the generalizability of estimates. For example, both the frequency and impact of APOE ε4 differ across racial groups.¹⁸ But most of the data on APOE lifetime risk estimates are from largely White patient samples. While APOE ε4 seems to confer increased risk for AD across sociocultural groups, these effects may be attenuated in African American and Hispanic populations.^19,20 If Ms. S is interested in numeric risk estimates, the physician can provide the estimate for ε3/ε4 (20%-25% lifetime risk), with the important caveat that this estimate may not be reflective of her individual risk.

Both the frequency and impact of APOE ε4 differ across racial groups, but most of the data on APOE lifetime risk estimates are from largely White patient samples.

It may be prudent to determine whether Ms. S, at age 60, has subjective memory concerns and if she does, to perform a brief cognitive exam to serve as a baseline for future evaluations. Additionally, while the Genetic Information Nondiscrimination Act (GINA, 2008) prohibits health insurers and employers from discriminating based on genetic testing results, no legal provisions exist regarding long-term care, disability, or life insurance. Documented conversations about APOE test results in the medical record may become part of patients’ applications for these insurance products, and physicians should be cautious before documenting such discussions in the medical record.

Vignette 4

Tina L, age 60, comes to the clinic for a routine wellness visit. She recently developed an interest in genealogy and purchased a DNA testing kit to learn more about her family tree. As part of this testing, she unexpectedly learned that she has an APOE ε4/ε4 genotype. She describes feeling distraught and anxious about what the result means for her future.

Ms. L’s reaction to receiving unexpected genetic results highlights a concern of DTC APOE testing. Her experience is quite different from individuals undergoing medically recommended genetic testing or those who are participating in research studies. They receive comprehensive pre-test counseling by licensed genetic counselors. The counseling includes psychological assessment, education, and discussion of expectations.²

In Ms. L’s case, it may be helpful to explain the limits of APOE lifetime risk estimates (see Vignettes 1-3). But it’s also important to address her concerns. There are behavior scales that can aid the assessment and monitoring of an individual’s well-being. The Impact of Genetic Testing for Alzheimer’s Disease (IGT-AD) scale is a tool that assesses psychological impact. It can help physicians to identify, monitor, and address concerns.²¹ Other useful tools include the Patient Health Questionnaire-9 (PHQ-9) and the Geriatric Depression Scale (GDS) for depression, and a suicide or self-harm assessment.^2,22,23 Finally, a follow-up visit at 2 to 4 weeks may be useful to reassess psychological well-being.

Vignette 4 (cont’d)

Ms. L returns to the clinic 2 weeks later, reporting continued anxiety about her APOE test result and feelings of hopelessness and despair.

Continue to: Some patients struggle...

Some patients struggle with knowing their APOE test result. Test result–related distress is often a combination of depression (as with Ms. L), anger, confusion, and grief.²⁴ Cognitions often include worries about uncertainty, stereotyped threat, and internalized stigma.^25,26 These issues can spill over to patient concerns about sharing an APOE test result with others.²⁷

Intolerance of uncertainty is a transdiagnostic risk factor that can influence psychological suffering.²⁸ Brief cognitive behavioral interventions that reinforce routines and encourage healthy and mindful practices may help alleviate patient distress from unexpected genetic test results.²⁹ Interventions that personalize and validate an individual’s experience can help address internalized stigma.³⁰ Referral to a psychologist or psychiatrist could be warranted. Additionally, referral to a genetic counselor may help provide patients with access to added expertise and guidance; useful web-based resources for identifying an appropriate referral include https://medlineplus.gov/genetics/­understanding/consult/findingprofessional/ and https://findageneticcounselor.nsgc.org/.

Vignette 5

Bob K, age 65, comes to the clinic for his annual exam. He is a current smoker and says he’s hoping to be more physically active now that he is retired. He says that his mother and grandmother both had AD. He recently purchased DTC genetic testing to learn more about his risk for AD. His learned his APOE genotype is ε3/ε4 and is wondering what he can do to decrease his chances of developing AD.

Mr. K likely would have benefited from pre-test counseling regarding the lack of current therapies to modify one’s genetic risk for AD. A pre-test counseling session often includes education about APOE testing and a brief evaluation to assess psychological readiness to undergo testing. Posttest educational information may help Mr. K avoid predatory advertising of products claiming—without scientific evidence—to modify risk for cognitive decline or to improve cognitive function.

Emerging evidence from RCTs suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.

There are several important pieces of information that should be communicated to Mr. K. Emerging evidence from randomized controlled trials suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.³¹ It would be prudent to address proper blood pressure control³² and counsel Mr. K on how he may be able to avoid diabetes through exercise and weight maintenance. Lifestyle recommendations for Mr. K could include: smoking cessation, regular aerobic exercise (eg, 150 min/wk), and a brain-healthy diet (eg, the Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet).^13,14 Moreover, dementia prevention also includes appropriately managing depression and chronic illnesses and preventing social isolation and hearing loss.^15,16 This information should be thoughtfully conveyed, as these interventions can improve overall (especially cardiovascular) health, as well as mitigating one’s personal risk for AD.

Vignette 6

Juan L, age 45, comes in for his annual physical exam. He has a strong family history of heart disease. His cardiologist recently ordered lipid disorder genetic testing for familial hypercholesterolemia. This panel included APOE testing and showed Mr. L’s genotype is ε2/ε4. He read that the APOE gene can be associated with an increased AD risk and asks for information about his genotype.

Mr. L received genetic testing results that were ordered by a physician for another health purpose. Current recommendations for genetic testing in cardiology advise pre-test genetic counseling.³³ But this counseling may not include discussion of the relationship of APOE and risk for MCI or AD. This additional information may be unexpected for Mr. L. Moreover, its significance in the context of his present concerns about cardiovascular disease may influence his reaction.

Continue to: The ε2/ε4 genotype...

The ε2/ε4 genotype is rare. One study showed that in healthy adults, the frequency was 7 in 210 (0.02 [0.01-0.04]).³⁴ Given the rarity of the ε2/ε4 genotype, data about it are sparse. However, since the ε4 allele increases risk but the ε2 allele decreases risk, it is likely that any increase in risk is more modest than with ε3/ε4. In addition, it would help Mr. L to know that AD occurs infrequently before age 60.³⁵ Given his relatively young age, he is unlikely to develop AD any time in the near future. In addition, particularly if he starts early, he might be able to mitigate any increased risk through some of the advice provided to Mr. K in Vignette 5.

Vignette 7

Joe J, age 65, comes to the clinic for a new patient visit. He has no concerns about his memory but has a family history of dementia and recently purchased DTC genetic testing to learn about his genetic health risks. His results showed an APOE ε4/ε4 genotype. He is concerned about developing AD. He heard on the news that there is a drug that can treat AD and wants to know if he is a candidate for this treatment.

Mr. J would benefit from the education provided to Ms. W in Vignette 1. Patients such as Mr. J should be advised that while an APOE ε4/ε4 genotype conveys an increased risk for AD, it is not deterministic of the disease. While there are no specific preventive measures or treatments based on APOE genotype, careful medical care and lifestyle factors can offset some of the risk (see Vignette 5 for discussion).

One reason for the aducanumab controversy is that the drug has potenially severe adverse effects.

Recently (and controversially), the FDA approved aducanumab, a drug that targets amyloid.^6,36 Of note, brain amyloid is more common in individuals with the APOE ε4/ε4 genotype, such as Mr. J. However, there would be no point in testing Mr. J for brain amyloid because at present the drug is only indicated in symptomatic individuals—and, even in this setting, it is controversial. One reason for the controversy is that aducanumab has potentially severe adverse effects. Patients with the ε4/ε4 genotype should know that this genotype carries increased risk for the most serious adverse event, ARIA—which can include brain edema and microhemorrhages.

What lies ahead?

More research is needed to explore the impact that greater AD gene and biomarker testing will have on the health system and workforce development. In addition, graduate schools and training programs will need to prepare clinicians to address probabilistic risk estimates for common diseases, such as AD. Finally, health systems and medical groups that employ clinicians may want to offer simulated training—similar to the vignettes in this article—as a practice requirement or as continuing medical education. This may also allow health systems or medical groups to put in place frameworks that support clinicians in proactively answering questions for patients and families about APOE and other emerging markers of disease risk.

CORRESPONDENCE
Shana Stites, University of Pennsylvania, 3615 Chestnut Street, Philadelphia, PA 19104; [email protected]