OVERVIEW AND OBJECTIVES

The workshop brought together researchers, clinicians, and people who are living with genetic disorders to discuss issues related to end of life in genetic diseases. Specifically, the participants evaluated whether end-of-life issues in people with genetic disorders are different from these issues in other populations. The participants then identified directions for research about this important topic. As an operating framework, the discussions were organized around four trajectories of dying as depicted in Figure 1: sudden death, terminal illness, organ system failure, and frailty.1 The workshop was co-sponsored by the National Institute of Nursing Research (NINR), the Office of Rare Diseases, and the National Human Genome Research Institute (NHGRI).

Fig. 1
figure 1

The graphs depict four functional trajectories of dying identified in elderly people receiving Medicare benefits. Reprinted with permission from the Journal of the American Geriatrics Society, Blackwell Publishing.1

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WORKSHOP FORMAT

Dr. Patricia A. Grady, the director of NINR, provided opening remarks that summarized the work NIH and NINR have sponsored to develop the science of end of life. To focus the discussions on the end-of-life trajectories, Dr. June Lunney provided an overview of these trajectories. Experts then presented information about specific genetic disorders that might illustrate each trajectory. After each presentation, two panel members commented about the presentations and whether the trajectories were a useful approach to conceptualizing end of life in people with genetic disorders. The workgroup members then discussed the utility of the end-of-life trajectories. After the discussions, the nominal group technique was used to generate questions for future research as outlined in Table 1.

Table 1 Summary of potential research topic areas for EOL in genetic diseases
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INTRODUCTION

This workshop represents an evolution of NINR’s involvement with end-of-life research since 1997 when the pivotal report, “Approaching Death: Improving Care at the End of Life,” was released by the Institute of Medicine.2 That report found that Americans are dissatisfied with the care they receive at the end of life. Research, care, and community involvement were subjects of criticism in the report. This is an important area for research and the issue, as it pertains to those with genetic disorders, is currently understudied.

THE TRAJECTORIES

The end-of-life movement has roots in the hospice movement with cancer patients. However, there is a growing realization that the manner in which cancer patients die may differ from the way others die. Dr. June Lunney, formerly with the RAND Center to Improve Care of the Dying and now a postdoctoral fellow with NINR and the National Institute on Aging, discussed four functional trajectories of dying that were evaluated through a retrospective study of Medicare beneficiaries between 1993 and 1998.1 The data from a random sample of beneficiaries were analyzed. In the sudden death trajectory, decedents were older and primarily male, with this group having a slightly higher representation of people from ethnic minority backgrounds. The vast majority of people in this trajectory died outside of the hospital. Most of the decedents in the terminal illness trajectory were cancer patients. This group was slightly younger; almost half received hospice care, and they had the highest physician bills. The group with organ systems failure included those who had had an inpatient hospitalization or an emergency room visit in the last year of life. The discharge diagnoses for this group were primarily congestive heart failure or chronic obstructive pulmonary disease. The frailty group included mostly older females who had conditions such as dementia, stroke, pneumonia, and leg cellulitis.

PRESENTATIONS AND PANEL RESPONSES

Sudden death trajectory

Genetic cardiac diseases were chosen to represent this trajectory. Dr. Clair Francomano, Section Chief of the Human Genetics and Integrative Medicine Section of the National Institute on Aging, presented information on patients with these types of conditions. Approximately 72 cardiac diseases are classified as genetic; they include Marfan syndrome, long QT syndrome, and Ehlers-Danlos syndrome.3 Both Ehlers-Danlos syndrome and Marfan syndrome have autosomal dominant inheritance, but the manifestations of these disorders vary. The cardiac manifestations of Ehlers-Danlos syndrome are mild and no specific treatment is necessary, whereas with Marfan syndrome complications are potentially lethal and anticipatory treatment can prolong life. With Marfan syndrome aortic dissection and/or rupture is a common cause of sudden death, and clinically it is difficult if not impossible to judge who will die suddenly and who will not. However, prospective routine echocardiography can identify those at highest risk.4 Many times the diagnosis of a genetic cardiac condition is not made until there has been at least one death in the family.

One of the issues associated with this trajectory is the idea of foreknowledge. The majority of patients with genetic disorders know they are at risk for a shortened lifespan. A person who has a familial arrhythmia like long QT syndrome knows death can come suddenly and unexpectedly and there may be no treatment to prevent or allay such an outcome. The experience can be likened to “sitting atop a volcano.” Therefore, it is critical to help the patient keep on living, adhering to treatments and not despairing. “Reasons for Living Inventories” that measure adaptive, life-maintaining characteristics can be useful in these situations.5–8

Other issues faced at the end of life in genetic disorders are remorse, fear, and guilt. Guilt about having passed on the disease can affect the end-of-life decisions that parents make. There are also reproductive issues. Family members’ reproductive decisions may be influenced by the sudden death of a close relative. Patients with genetic disorders who manifest a sudden death trajectory are subject to depression that can further exacerbate the underlying condition. Often, medical interventions such as β-blockers and exercise restrictions cause greater depression, which can increase the risk of death in cardiac disease. To know death is imminent obviously increases the risk of depression.

There is not an exact match in terms of the trajectories for genetic diseases and nongenetic diseases if age is considered. The trajectories used to frame this discussion are based on an older Medicare population. Genetic disorders often afflict a much younger population of children, adolescents, and young adults, and therefore the trajectory approach may not apply.

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 presentations on this trajectory. Hereditary cancers and cancer risk include, 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 nonpolyposis colorectal cancer, usually manifests later in adult life.

Generally, genetic cancer deaths 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 genetic diseases, including inheritance, guilt and anxiety about 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 others may also be at risk. Intergenerational care issues may also arise. Dealing with these patients and the families in terms of the genetic risk raises many issues such as how to give news of a gene mutation in the family in a constructive way. Death may mean not only loss of a loved one but also a personal increased risk for developing cancer. There may be a special issue in genetic cancers, that is, shame due to the genetic stigma of inherited cancer risk. Families may perceive themselves as flawed or “damaged goods,” and they may also worry about their vulnerability for losing insurance or even employment as a result of their risk.9

It may not be possible to cleanly separate the trajectories. For example, a family member’s death may seem like “sudden death” even if there has been a terminal illness. Another genetic disease that could fit into the category of a terminal illness is Huntington disease. People with this disease may have a different view of end of life compared with patients with cancer. Many patients with colon cancer view the condition as treatable and less threatening, whereas patients with Huntington disease (which cannot be treated or prevented) come for testing with great fear and view it as a life-changing event. Even in a family with one single gene mutation, there can be one family member who has a trajectory very different from that of another who is affected. End-of-life care in cancer is generally based on the hospice model, whereas people with genetic cancers may require a different end-of-life approach.

Organ system failure trajectory

Genetic pulmonary diseases were used to represent the organ system failure trajectory. Dr. Ben Wilfond, Head of the Bioethics Research Section, Medical Genetics Branch at the NHGRI, presented data on pulmonary disease, specifically cystic fibrosis (CF). In CF, as with other genetic diseases, advances in treatment have changed the nature of the disease.10 There are many 20- to 30-year-old patients today who were told they would die before they reached adulthood. This longer life expectancy results from medical advances that have changed not only the nature of the disease, but also complicated end-of-life decision-making. Lung transplant from living donors who may possibly be relatives of the patient, noninvasive mechanical ventilation, alternative antibiotics and the use of intravenous antibiotics at home, and increasing ICU survival are examples of medical advances that have extended the lives of these patients.10 This focus on complex, life-sustaining treatments can delay palliative care. Such treatments prolong life and may add to quality of life as measured by the patient, but they also make it more difficult to predict end of life and therefore palliative care may not be provided as soon or as readily. We need to change our thinking that palliative means giving up on life.

The disabilities community can help us in thinking about the end-of-life trajectories. We should not think of people as their disease, and likewise we should not generalize the dying process for a disease into any one particular trajectory. Parents have similar experiences in end-of-life care for their children, regardless of whether the disease is genetic or not. The trajectories are good, but caution should be used in applying them.

Frailty trajectory

Neuromuscular diseases, particularly Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), are the prototypes for the frailty trajectory. Dr. R. Rodney Howell, Professor and Chairman of the Department of Pediatrics at the University of Miami School of Medicine, presented information on neuromuscular diseases. All muscular dystrophies are genetic in origin. DMD is due to a severe deficiency of the protein dystrophin and is inherited in an x-linked fashion. These patients lose the ability to walk between the ages of 7 and 12 years and die of cardiopulmonary complications in their early 20s. The steady downhill course of the disease necessitates many complex decisions such as whether or not to use mechanical ventilation. Some patients have mental retardation that makes decision-making more complex. BMD involves a partial deficiency of dystrophin, and the diagnosis may not be made until adolescence. The muscle degeneration with BMD is much more gradual than in DMD, and many persons with BMD who were told they would be wheelchair-bound by age 7 to 12 are in their 20s before they require one.

With muscular dystrophy the disease proceeds over many years and eventually leads to death following a gradual decline in function, making this disease a paradigm for the frailty trajectory. However, there are some unique issues; the disease can be diagnosed prenatally, which raises ethical issues surrounding termination of the pregnancy and how health care professionals interact with parents. Inheritance issues are particularly important with muscular dystrophy because the mother carries the gene but usually does not have symptoms.11 This issue can complicate not only end-of-life decisions, but also grief following the death of the child. In neuromuscular disorders there may be two family members in wheelchairs, raising issues of family functioning, coping, and caregiving. Some of these neuromuscular diseases may be treatable in the near future, raising some of the same issues discussed with CF.

SUMMARY OF DISCUSSION

There is general consensus that the four trajectories are valid and useful as applied to genetic diseases. However, they should not be applied categorically. It may be helpful to let the patients themselves identify where they see themselves on the trajectories. It is possible a person may identify a different trajectory at different times during the course of the same illness.

The distinction between genetic and nongenetic diseases is a fine one since, on some level, all disease has a genetic component, and many end-of-life issues faced by those with genetic disorders are similar to those in nongenetic diseases. But the hereditary factor does pose some special emotional issues for patients and families, such as foreknowledge of the disease and its prognosis, potential for prenatal diagnosis, parental guilt regarding transmission, and rapidly expanding understanding of genetics that influences treatment options and end-of-life decisions. Many of these diseases are rare, so care is provided at specialized centers over a long period of time; a strong relationship develops between the patient, his/her family, and the health care providers.

There was agreement that the health care community needs to find a way to talk to people about end-of-life issues earlier in the course of their disease. The difficulty of balancing hope with realistic information is particularly acute with genetic diseases. The community needs to find ways to help people accept death as a part of life. A more seamless approach to palliative care—one that avoids unnecessary conflicts between palliative care and life-prolonging treatments—is necessary. We need to help people deal with uncertainty rather than the current model, which tries to eliminate all uncertainty. Involvement of the family is critically important. Parents feel a moral imperative to be the best possible guardians, yet they often feel the medical system deprives them of that role when an infant or child is very sick.

Social, cultural, and environmental contexts influence end of life in genetic diseases. Coping with disease may mean seeking a reason why this has happened to a family. Responses may differ by culture, socioeconomic status, and educational level. For example, Hispanic women who are urged to undergo fetal testing may feel that the medical system is trying to take their baby away. There is a need to support parents prenatally when fetal testing indicates the child has a genetic disorder, whether they elect to maintain the pregnancy or not. The way in which messages are delivered by health care providers requires careful thought because the messages concern highly charged decision areas such as genetic testing or deciding whether or not to use certain technologies.

Using the nominal group technique, Dr. Carole Hudgings, Assistant Director, Division of Extramural Activities, NINR, led the group in generating research questions as outlined in Table 1. In summarizing, Dr. Hudgings emphasized the heterogeneity across the various genetic diseases. Foreknowledge was identified as a key aspect of end of life in genetic diseases, as was the uncertain course of the trajectory. Different trajectories may apply at different times, and there is hesitation in applying the trajectories without further study. The family emerges as a unit, rather than focusing on individuals. Communication and the actual wording of messages can be critical elements in speaking with families, especially regarding decision-making and advance directives. Technology can be viewed positively and negatively. It is important to consider how families evaluate the many implications of technology. Changes in prognosis because of technological advances raise questions about being a survivor. From a nursing perspective, it is interesting to note the struggle to help people make the most of living while at the same time helping them to die with dignity.

CLOSING REMARKS

Rosemary Quigley, Esq., who is a member of the NIH Council of Public Representatives and Assistant Professor at the Center for Medical Ethics and Health Policy at Baylor College of Medicine, ended the workshop with a message of hopefulness. She presented a realistic picture of where gene therapy is today and the mistaken public perception that gene therapy will present cures for most diseases soon. Patients and families need accurate information about gene therapy and other therapies in order to make informed decisions. However, we must not completely crush hope in patients, so they will continue to take the best possible care of themselves and not cross over into despair. Since there is a family element in genetic diseases, there may be some hope for the patient in knowing that even though he/she may die of the disease, some other family member may live as a result of new treatments. Many of these patients may have lived knowing they would die, but they sometimes forget that everybody dies. Holistic attitudes about dying need to be developed. Hope for the best; plan for the worst is the best advice. Research is needed on how some people do that, so others can learn from them.

CONCLUSION

The issues related to end of life in genetic diseases identified in the literature mirror those discussed in the workshop with a couple of exceptions. The literature highlights quality of life and societal attitudes as issues, and these were subsumed within other discussions during the workshop. The literature generally focuses on a broader view of the issues at the end of life in genetic diseases, whereas the workshop dealt with real-life problems, emotions, and decisions, which must be faced at the end of life by these individuals and their families.

Both the literature and the workshop findings suggest that the issues faced at the end of life in genetic diseases can differ from those faced generally at the end of life. Some important areas for research unique to end of life in genetic diseases were highlighted: communication and the wording of messages by health care providers; balancing hope regarding genetic advances with the realities of the genetic diagnosis; guilt, fear, and remorse among the family members at the possibility of having passed on a life-threatening disease; foreknowledge of the disease through genetic testing; difficult reproductive decisions such as whether or not to initiate or terminate a pregnancy; decisions regarding use of rapidly advancing technological interventions within the context of an environment that lacks 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.

More research is needed to ascertain whether or not the four trajectories (or others) are suitable as a framework from which to study the end of life in genetic diseases. If there are identifiable trajectories, additional research is needed to help the health care community develop approaches that correspond to them. It may be, as has been proposed, that different approaches matching different trajectories are needed for different phases of an illness over time. As our understanding of the human genome expands, the science of how to care for people dying from genetic diseases must also expand so that dying can become an accepted part of life.