September/October 2002 ⅐ Vol. 4 ⅐ No. 5 meeting report

End-of-life issues in genetic disorders: Summary of workshop held at the National Institutes of Health on September 26, 2001 Ann R. Knebel, RN, DNSc, FAAN, and Carole Hudgings, PhD, RN, FAAN

OVERVIEW AND OBJECTIVES found that Americans are dissatisfied with the care they receive at the end of life. Research, care, and community involvement The workshop brought together researchers, clinicians, and were subjects of criticism in the report. This is an important people who are living with genetic disorders to discuss issues area for research and the issue, as it pertains to those with related to end of life in genetic diseases. Specifically, the partic- genetic disorders, is currently understudied. ipants evaluated whether end-of-life issues in people with ge- netic disorders are different from these issues in other popula- tions. The participants then identified directions for research THE TRAJECTORIES about this important topic. As an operating framework, the discussions were organized around four trajectories of dying as The end-of-life movement has roots in the hospice move- depicted in Figure 1: sudden , , organ sys- ment with cancer patients. However, there is a growing real- tem failure, and frailty.1 The workshop was co-sponsored by ization that the manner in which cancer patients die may differ the National Institute of Nursing Research (NINR), the Office from the way others die. Dr. June Lunney, formerly with the of Rare Diseases, and the National Human Genome Research RAND Center to Improve Care of the Dying and now a post- Institute (NHGRI). doctoral fellow with NINR and the National Institute on Ag- ing, discussed four functional trajectories of dying that were evaluated through a retrospective study of Medicare beneficia- WORKSHOP FORMAT ries between 1993 and 1998.1 The data from a random sample Dr. Patricia A. Grady, the director of NINR, provided open- of beneficiaries were analyzed. In the sudden death trajectory, ing remarks that summarized the work NIH and NINR have decedents were older and primarily male, with this group hav- sponsored to develop the science of end of life. To focus the ing a slightly higher representation of people from ethnic mi- discussions on the end-of-life trajectories, Dr. June Lunney nority backgrounds. The vast majority of people in this trajec- provided an overview of these trajectories. Experts then pre- tory died outside of the hospital. Most of the decedents in the sented information about specific genetic disorders that might terminal illness trajectory were cancer patients. This group was illustrate each trajectory. After each presentation, two panel slightly younger; almost half received hospice care, and they members commented about the presentations and whether the had the highest physician bills. The group with organ systems trajectories were a useful approach to conceptualizing end of failure included those who had had an inpatient hospitaliza- life in people with genetic disorders. The workgroup members tion or an emergency room visit in the last year of life. The then discussed the utility of the end-of-life trajectories. After discharge diagnoses for this group were primarily congestive the discussions, the nominal group technique was used to gen- heart failure or chronic obstructive pulmonary disease. The erate questions for future research as outlined in Table 1. frailty group included mostly older females who had condi- tions such as dementia, stroke, pneumonia, and leg cellulitis. INTRODUCTION PRESENTATIONS AND PANEL RESPONSES This workshop represents an evolution of NINR’s involve- ment with end-of-life research since 1997 when the pivotal Sudden death trajectory report, “Approaching Death: Improving Care at the End of Genetic cardiac diseases were chosen to represent this tra- Life,” was released by the Institute of Medicine.2 That report jectory. Dr. Clair Francomano, Section Chief of the Human Genetics and Integrative Medicine Section of the National In- From the National Institute of Nursing Research at the National Institutes of Health, stitute on Aging, presented information on patients with these Bethesda, MD. types of conditions. Approximately 72 cardiac diseases are clas- Ann R. Knebel, RN, DNSc, FAAN, 31 Center Drive, MSC 2178, Building 31, Room 5B10, sified as genetic; they include Marfan syndrome, long QT syn- Bethesda, MD 20892-2178. drome, and Ehlers-Danlos syndrome.3 Both Ehlers-Danlos Received: April 4, 2002. syndrome and Marfan syndrome have autosomal dominant Accepted: June 7, 2002. inheritance, but the manifestations of these disorders vary. The DOI: 10.1097/01.GIM.0000031565.77652.AB cardiac manifestations of Ehlers-Danlos syndrome are mild

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Terminal illness trajectory Hereditary cancer syndromes were chosen to exemplify the terminal illness trajectory. Barbara Bowles Biesecker, Associate Investigator, Director, Genetic Counseling Graduate Program, Johns Hopkins University/NHGRI, coordinated the presenta- tions on this trajectory. Hereditary cancers and cancer risk in- clude, among others: breast, colorectal, kidney, brain, and Mendelian disorders such as neurofibromatosis. The age of onset varies among these syndromes. For example, one type of inherited colon cancer, familial polyposis, has an early onset and can affect adolescents and another, hereditary nonpolypo- sis colorectal cancer, usually manifests later in adult life. Generally, genetic cancer occur at a younger age than do deaths from cancer of nongenetic origin. Some of the issues associated with the terminal illness trajectory apply across all Fig. 1 The graphs depict four functional trajectories of dying identified in elderly peo- genetic diseases, including inheritance, guilt and anxiety about ple receiving Medicare benefits. Reprinted with permission from the Journal of the Amer- ican Geriatrics Society, Blackwell Publishing.1 passing on the gene mutation, and risks to close relatives, which may complicate the grieving process following death due to cancer. Families face the potential loss of a relative while and no specific treatment is necessary, whereas with Marfan others may also be at risk. Intergenerational care issues may syndrome complications are potentially lethal and anticipa- also arise. Dealing with these patients and the families in terms tory treatment can prolong life. With Marfan syndrome aortic of the genetic risk raises many issues such as how to give news and/or rupture is a common cause of sudden death, of a gene mutation in the family in a constructive way. Death and clinically it is difficult if not impossible to judge who will may mean not only loss of a loved one but also a personal die suddenly and who will not. However, prospective routine increased risk for developing cancer. There may be a special echocardiography can identify those at highest risk.4 Many issue in genetic cancers, that is, shame due to the genetic stigma times the diagnosis of a genetic cardiac condition is not made of inherited cancer risk. Families may perceive themselves as until there has been at least one death in the family. flawed or “damaged goods,” and they may also worry about One of the issues associated with this trajectory is the idea of their vulnerability for losing insurance or even employment as foreknowledge. The majority of patients with genetic disorders a result of their risk.9 know they are at risk for a shortened lifespan. A person who has a It may not be possible to cleanly separate the trajectories. For familial arrhythmia like long QT syndrome knows death can example, a family member’s death may seem like “sudden come suddenly and unexpectedly and there may be no treatment death” even if there has been a terminal illness. Another genetic to prevent or allay such an outcome. The experience can be lik- disease that could fit into the category of a terminal illness is ened to “sitting atop a volcano.” Therefore, it is critical to help the Huntington disease. People with this disease may have a differ- patient keep on living, adhering to treatments and not despairing. ent view of end of life compared with patients with cancer. “Reasons for Living Inventories” that measure adaptive, life- Many patients with colon cancer view the condition as treat- maintaining characteristics can be useful in these situations.5–8 able and less threatening, whereas patients with Huntington Other issues faced at the end of life in genetic disorders are disease (which cannot be treated or prevented) come for test- remorse, fear, and guilt. Guilt about having passed on the dis- ing with great fear and view it as a life-changing event. Even in ease can affect the end-of-life decisions that parents make. a family with one single gene mutation, there can be one family There are also reproductive issues. Family members’ repro- member who has a trajectory very different from that of an- ductive decisions may be influenced by the sudden death of a other who is affected. End-of-life care in cancer is generally close relative. Patients with genetic disorders who manifest a based on the hospice model, whereas people with genetic can- sudden death trajectory are subject to depression that can fur- cers may require a different end-of-life approach. ther exacerbate the underlying condition. Often, medical in- terventions such as ␤-blockers and exercise restrictions cause greater depression, which can increase the risk of death in car- Organ system failure trajectory diac disease. To know death is imminent obviously increases Genetic pulmonary diseases were used to represent the or- the risk of depression. gan system failure trajectory. Dr. Ben Wilfond, Head of the There is not an exact match in terms of the trajectories for Bioethics Research Section, Medical Genetics Branch at the genetic diseases and nongenetic diseases if age is considered. NHGRI, presented data on pulmonary disease, specifically cys- The trajectories used to frame this discussion are based on an tic fibrosis (CF). In CF, as with other genetic diseases, advances in older Medicare population. Genetic disorders often afflict a treatment have changed the nature of the disease.10 There are much younger population of children, adolescents, and young many 20- to 30-year-old patients today who were told they would adults, and therefore the trajectory approach may not apply. die before they reached adulthood. This longer life expectancy

374 Genetics IN Medicine End-of-life issues in genetics: Workshop results from medical advances that have changed not only the SUMMARY OF DISCUSSION nature of the disease, but also complicated end-of-life decision- There is general consensus that the four trajectories are valid making. Lung transplant from living donors who may possibly be and useful as applied to genetic diseases. However, they should relatives of the patient, noninvasive mechanical ventilation, alter- not be applied categorically. It may be helpful to let the patients native antibiotics and the use of intravenous antibiotics at home, themselves identify where they see themselves on the trajecto- and increasing ICU survival are examples of medical advances ries. It is possible a person may identify a different trajectory at that have extended the lives of these patients.10 This focus on com- plex, life-sustaining treatments can delay . Such different times during the course of the same illness. treatments prolong life and may add to quality of life as measured The distinction between genetic and nongenetic diseases is a by the patient, but they also make it more difficult to predict end fine one since, on some level, all disease has a genetic compo- of life and therefore palliative care may not be provided as soon or nent, and many end-of-life issues faced by those with genetic as readily. We need to change our thinking that palliative means disorders are similar to those in nongenetic diseases. But the giving up on life. hereditary factor does pose some special emotional issues for The disabilities community can help us in thinking about patients and families, such as foreknowledge of the disease and the end-of-life trajectories. We should not think of people as its prognosis, potential for prenatal diagnosis, parental guilt their disease, and likewise we should not generalize the dying regarding transmission, and rapidly expanding understanding process for a disease into any one particular trajectory. Parents of genetics that influences treatment options and end-of-life have similar experiences in end-of-life care for their children, decisions. Many of these diseases are rare, so care is provided at regardless of whether the disease is genetic or not. The trajec- specialized centers over a long period of time; a strong relation- tories are good, but caution should be used in applying them. ship develops between the patient, his/her family, and the health care providers. Frailty trajectory There was agreement that the health care community needs Neuromuscular diseases, particularly Duchenne muscular to find a way to talk to people about end-of-life issues earlier in dystrophy (DMD) and Becker muscular dystrophy (BMD), are the course of their disease. The difficulty of balancing hope the prototypes for the frailty trajectory. Dr. R. Rodney Howell, with realistic information is particularly acute with genetic dis- Professor and Chairman of the Department of Pediatrics at the eases. The community needs to find ways to help people accept University of Miami School of Medicine, presented informa- death as a part of life. A more seamless approach to palliative tion on neuromuscular diseases. All muscular dystrophies are care—one that avoids unnecessary conflicts between palliative genetic in origin. DMD is due to a severe deficiency of the care and life-prolonging treatments—is necessary. We need to protein dystrophin and is inherited in an x-linked fashion. help people deal with uncertainty rather than the current These patients lose the ability to walk between the ages of 7 and model, which tries to eliminate all uncertainty. Involvement of 12 years and die of cardiopulmonary complications in their the family is critically important. Parents feel a moral impera- early 20s. The steady downhill course of the disease necessitates tive to be the best possible guardians, yet they often feel the many complex decisions such as whether or not to use me- medical system deprives them of that role when an infant or chanical ventilation. Some patients have mental retardation child is very sick. that makes decision-making more complex. BMD involves a Social, cultural, and environmental contexts influence end partial deficiency of dystrophin, and the diagnosis may not be of life in genetic diseases. Coping with disease may mean seek- made until adolescence. The muscle degeneration with BMD is ing a reason why this has happened to a family. Responses may much more gradual than in DMD, and many persons with differ by culture, socioeconomic status, and educational level. BMD who were told they would be wheelchair-bound by age 7 For example, Hispanic women who are urged to undergo fetal to 12 are in their 20s before they require one. testing may feel that the medical system is trying to take their With muscular dystrophy the disease proceeds over many baby away. There is a need to support parents prenatally when years and eventually leads to death following a gradual decline fetal testing indicates the child has a genetic disorder, whether in function, making this disease a paradigm for the frailty tra- they elect to maintain the pregnancy or not. The way in which jectory. However, there are some unique issues; the disease can messages are delivered by health care providers requires careful be diagnosed prenatally, which raises ethical issues surround- thought because the messages concern highly charged decision ing termination of the pregnancy and how health care profes- areas such as genetic testing or deciding whether or not to use sionals interact with parents. Inheritance issues are particularly certain technologies. important with muscular dystrophy because the mother car- Using the nominal group technique, Dr. Carole Hudgings, ries the gene but usually does not have symptoms.11 This issue Assistant Director, Division of Extramural Activities, NINR, can complicate not only end-of-life decisions, but also led the group in generating research questions as outlined in Table following the death of the child. In neuromuscular disorders 1. In summarizing, Dr. Hudgings emphasized the heterogeneity there may be two family members in wheelchairs, raising issues across the various genetic diseases. Foreknowledge was identified of family functioning, coping, and caregiving. Some of these as a key aspect of end of life in genetic diseases, as was the uncer- neuromuscular diseases may be treatable in the near future, tain course of the trajectory. Different trajectories may apply at raising some of the same issues discussed with CF. different times, and there is hesitation in applying the trajectories

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Table 1 Summary of potential research topic areas for EOL in genetic diseases Category Topic areas Health care providers and systems 1. In patients with genetic diseases, does the health care they receive help them live the life they wish, or does it impede their quality of life? If it is the latter, is there something that can be done to improve the situation? 2. How can the palliative care team work together with other teams, such as the transplant team, who focus on prolonging life? 3. How can we improve continuity of care as people with genetic diseases move across health care systems and from provider to provider during the end-of-life trajectory? Does authority for decision-making maintain across systems? 4. Examine differences in care providers’ attitudes and behaviors toward use of life-sustaining treatments in patients dying of genetic vs. nongenetic diseases. 5. What is the role of genetic professionals in providing counseling about end-of-life decisions and planning? Coping 1. Can we create better models for balancing hope and uncertainty in those awaiting transplant and/or gene therapy? 2. Does grief differ with a genetic (or type of trajectory)? If so, are there targeted interventions to help people cope with loss, rather than treating all grief the same? 3. Compare differences in end-of-life issues in genetic diseases in families who engage in a support group or receive clerical counseling vs. those who do not have such support. 4. For people who are terminally ill due to genetic diseases, under what circumstances are certain coping mechanisms like denial useful and at what point are they counterproductive? Perception of the end-of-life 1. Are the end-of-life trajectories for persons with genetic diseases the same as the trajectories identified in persons trajectories receiving Medicare? 2. Use qualitative methods to ascertain how people with genetic diseases see their end-of-life trajectory and evaluate the degree of congruency between the person’s and their family’s perception of the trajectory. 3. Test the predictive validity of the trajectories and examine whether there is an effect if the disorder is genetic or not. 4. Define the clinical parameters we are using to describe the trajectories. 5. Study the duration of terminal illness and use of expensive treatments as a function of socioeconomic status. Does the trajectory vary depending of the family’s socioeconomic status? Issues within the community of 1. Study how the community with a genetic disorder is affected by a member’s dying. Can the community relationships people with the genetic diseases provide an opportunity for education and discussion with other ill members of that community about end of life? 2. Investigate how a community member’s perception of the dying process is influenced by what he/she has witnessed within the community. 3. How does a change in a community (e.g., the introduction of a new, dangerous bacteria or the hope of gene therapy) affect end-of-life issues within the community? Cofactors/mediating variables 1. Compare those with genetic diseases who have exhibited characteristics of resilience throughout life with those who have not, to determine whether there are different clinical trajectories, different decision-making patterns, and different perceptions of quality of life at the end of life. 2. Is the patient’s acceptance of death related to the genetic diagnosis and/or spiritual beliefs and practices? 3. Are there characteristics of individuals with a genetic disorder who have a healthy adaptation to an adverse prognosis that differ from those with an unhealthy adaptation? Communication 1. Investigate different models of communicating information and their impact on advance care planning and on emotional, spiritual, and physical outcomes for persons with a genetic diagnosis. 2. Study how language affects perceptions of the end-of-life trajectory and decisions regarding care. 3. Develop and test models of teaching health care professionals skills in communicating with families about palliative care and end-of-life decision-making as a result of a genetic diagnosis. 4. Is there a difference between those with genetic vs. nongenetic cancer in their willingness to discuss palliative care? Impact on family 1. When a genetic disorder is inherited from only one side of the family, how does the death of the child impact the family? 2. What happens to a family that experiences more than one death due to a genetic disease? 3. In end-of-life decision-making with genetic diseases, what is the role of nontraditional family members? 4. Look at psychosocial impact on siblings and other family members as a function of the degree of uncertainty concerning their own risk of death. 5. How does the death of a child from a genetic disease affect the parents’ relationship? —Continued

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Table 1 Continued Category Topic areas Decision-making 1. Compare perceptions of the decision-making process regarding end of life in genetic diseases between the family and the health care providers. 2. Compare decision-making and long-term planning for care in families when the disease is carried by the parent vs. when the disease is a new mutation. 3. Compare decision-making in a group of patients with obvious, visible genetic disease against that of a group of patients with equally lethal but not visible disease. 4. Is a patient’s desire for control of end-of-life decisions related to the attribution of the disease to a genetic etiology? 5. Does a genetic diagnosis (and associated feelings of hopelessness and predetermination) and availability of technical treatments influence desire for control over end-of-life decisions? 6. What role does socioeconomic status play in end-of-life decisions in people with genetic diseases? 7. What interventions can help parents of children who are developmentally disabled, but not necessarily fatally ill, prepare for their own end of life? Foreknowledge 1. In genetic diseases it may be possible to have foreknowledge of the end-of-life trajectory. Do health care providers correctly give predictions, and how do these predictions affect the dying process? 2. Study the effect of being told multiple times that you would die, but death is delayed because of technological advances. Interventions 1. What role do alternative/complementary therapies have during end of life in genetic diseases? 2. What effects do cultural and socioeconomic backgrounds have on interventions used during the end-of-life trajectories? Cultural issues 1. How does an ethnic culture influence end-of-life decisions in genetic diseases, such as whether or not to use technical support systems? 2. Do spiritual and emotional responses to a genetic diagnosis, illness, and prognosis differ by cultural/ethnic group? 3. Examine the views of different ethnic groups on the importance of a genetic etiology of disease. 4. Is there ethnic diversity in response to end of life with genetic disorders? without further study. The family emerges as a unit, rather than despair. Since there is a family element in genetic diseases, focusing on individuals. Communication and the actual wording there may be some hope for the patient in knowing that even of messages can be critical elements in speaking with families, though he/she may die of the disease, some other family mem- especially regarding decision-making and advance directives. ber may live as a result of new treatments. Many of these pa- Technology can be viewed positively and negatively. It is impor- tients may have lived knowing they would die, but they some- tant to consider how families evaluate the many implications of times forget that everybody dies. Holistic attitudes about dying technology. Changes in prognosis because of technological ad- need to be developed. Hope for the best; plan for the worst is vances raise questions about being a survivor. From a nursing the best advice. Research is needed on how some people do perspective, it is interesting to note the struggle to help people that, so others can learn from them. make the most of living while at the same time helping them to die with dignity. CONCLUSION

CLOSING REMARKS The issues related to end of life in genetic diseases identified in the literature mirror those discussed in the workshop with a Rosemary Quigley, Esq., who is a member of the NIH Coun- couple of exceptions. The literature highlights quality of life cil of Public Representatives and Assistant Professor at the and societal attitudes as issues, and these were subsumed Center for Medical Ethics and Health Policy at Baylor College within other discussions during the workshop. The literature of Medicine, ended the workshop with a message of hopeful- generally focuses on a broader view of the issues at the end of ness. She presented a realistic picture of where gene therapy is life in genetic diseases, whereas the workshop dealt with real- today and the mistaken public perception that gene therapy life problems, emotions, and decisions, which must be faced at will present cures for most diseases soon. Patients and families the end of life by these individuals and their families. need accurate information about gene therapy and other ther- Both the literature and the workshop findings suggest that apies in order to make informed decisions. However, we must the issues faced at the end of life in genetic diseases can differ not completely crush hope in patients, so they will continue to from those faced generally at the end of life. Some important take the best possible care of themselves and not cross over into areas for research unique to end of life in genetic diseases were

September/October 2002 ⅐ Vol. 4 ⅐ No. 5 377 Knebel and Hudgings highlighted: communication and the wording of messages by 8. Ivanoff A, Jang SJ, Smyth NF Linehan MM. Fewer reasons for staying alive when you are thinking of killing yourself: the Brief Reasons for Living Inventory. J Psychopath health care providers; balancing hope regarding genetic ad- Behav Assess 1994;16:1–13. vances with the realities of the genetic diagnosis; guilt, fear, and 9. Kessler S. Kessler H, Ward P. Psychological aspects of genetic counseling, III: man- remorse among the family members at the possibility of having agement of guilt and shame. Am J Med Genet 1984;17:673–697. 10. Wilfond B, Taussig LM. Cystic fibrosis: clinical overview. In: Taussig LM, Landau LI, passed on a life-threatening disease; foreknowledge of the dis- editors. Textbook of pediatric pulmonary medicine. St Louis: Mosby Year Book, ease through genetic testing; difficult reproductive decisions 1999:982–990. such as whether or not to initiate or terminate a pregnancy; 11. Hoogerwaard EM, Bakker E, Ippel PF, Oosterwijk JC, Majoor-Krakauer DK, Leschot NJ, Van Essen AJ, Brunner HG, van der Wouz PA, Wilde AA, de Visser M. Signs and decisions regarding use of rapidly advancing technological in- symptoms of Duchenne muscular dystrophy and Becker muscular dystrophy among terventions within the context of an environment that lacks carriers in the Netherlands: a cohort study. Lancet 1999;353:2116–2119. approaches to care that integrate palliative and curative care; and intergenerational care issues when more than one family member is affected by a genetic disease. Appendix: Readings suggested by workshop participants More research is needed to ascertain whether or not the four Albelda SM, Wiewrodt R, Zuckerman JB. Gene therapy for lung disease: hype or hope? 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