Advance Care Planning and Health-Related Quality of Life in Huntington Disease: Results from a Multicenter National Study

Abstract

Objective:

With Huntington disease (HD), a fatal neurodegenerative disease where the prevalence of suicidal thoughts and behavior (STB) remains elevated as compared to other neurological disorders, it is unknown whether STB and health-related quality of life (HRQoL) affect plans for the end of life or more broadly, advance care planning (ACP). Conversely, it is unknown whether ACP would provoke future changes to STB and HRQoL. Therefore, we sought to evaluate whether STB and HRQoL patient-reported outcomes (PROs) contribute to ACP and whether ACP relates to changes in STB and HRQoL at 24 months.

Methods:

HD-validated clinician- and patient-assessments (i.e., HRQoL PROs) were obtained at baseline enrollment, 12 and 24 months through our multi-center study (HDQLIFE™) throughout the United States among people with premanifest, early-stage, and late-stage manifest HD. We used linear mixed-effects models to determine the relationships between STB and HRQoL at baseline and HDQLIFE End of Life Planning at follow-up. Separate linear mixed-effects models were used to assess the relationship between HDQLIFE End of Life Planning at baseline, and HRQoL and STB at 12 and 24 months. False discovery rate adjustments were used to account for multiple comparisons.

Results:

At baseline enrollment, STB and HRQoL were not related to HDQLIFE End of Life Planning at 12 or 24 months. Similarly, at baseline, HDQLIFE End of Life Planning demonstrated no association with STB or HRQoL at 12 or 24 months.

Interpretation:

STB and HRQoL PROs do not significantly affect patient engagement with ACP. Most importantly, engaging in ACP does not cause untoward effects on HRQoL or STB for this rare neurodegenerative disease where the lifetime prevalence of STB approaches 30%.

Introduction

Advance care planning (ACP) is defined as “a process that consists of many behaviors, such as choosing a surrogate decision-maker, defining values and preferences for medical care, and communicating those wishes to others.”¹ In Huntington disease (HD), a hereditary and ultimately fatal neurodegenerative disease affecting 7 in 100,000 people worldwide,^2,3 the literature on ACP is sparse.^4,5 Our group previously determined that people with HD do not engage in ACP at a rate higher than the general adult population.⁴ We also identified that higher education, older age, and late-stage HD were associated with completing advance directives.⁴

Despite knowledge of these associated factors with advanced directive completion in HD, clinicians who care for people with HD and their families may nonetheless shy away from ACP discussions, believing that broaching discussion about the end of life may increase patient discomfort. However, among other serious illnesses, ACP discussion has not shown adverse psychosocial outcomes.⁶ Yet, whether those findings apply to HD remains unclear, as people with HD differ in their burden of psychiatric and existential symptoms and the capacity to cope, given progressive cognitive and psychiatric dysfunction.

Specifically, people with all stages of HD exhibit elevated rates of hopelessness,⁷ existential distress,⁸ and death anxiety.^9,10 Further, HD has one of the highest rates of suicidal thoughts and behavior (STB) among all neurological disorders, and suicide is a major cause of death.¹¹ Indeed, a comprehensive assessment surrounding the association among ACP, STB, and health-related quality of life (HRQoL) has been lacking in HD.

Data relating ACP with STB and HRQoL might help frame ACP discussions with stakeholders who are fearful of provoking adverse emotional outcomes by engaging in these discussions. Similar concerns pervaded the field of suicidology, where some practitioners falsely presumed that talking about suicide among those with suicidal thoughts might precipitate worsening future STB. Yet, research has not corroborated that hypothesis.¹²

Understanding how STB and HRQoL may affect the engagement of ACP and conversely, how engaging in ACP activities may affect future changes to STB and HRQoL within HD could guide clinician's practices through understanding actual risks of ACP for this vulnerable population. Such knowledge would be vital to clinical care, provider–patient communication, and long-term planning for patients, clinicians, and other family members.

We evaluate the following two objectives: whether baseline enrollment levels of STB and mental, physical, or social aspects of HRQoL were associated with ACP and how ACP engagement effects STB and HRQoL at 12- and 24-month follow-ups. We hypothesized that mental and social HRQoL would predict ACP engagement and that, consistent with past literature among chronic diseases,¹³ ACP would have modest improvements in mental and social HRQoL patient-reported outcomes (PROs) at 12 and 24 months without worsening STB.

Methods

Participants

HDQLIFE™ was an observational, longitudinal study dedicated to creating and validating HRQoL PROs specific to people with the HD genetic mutation (prodromal, n = 50; early-stage, n = 171, and late-stage manifest HD, n = 101). This study was conducted from 2012 to 2016 across several academic medical centers in diverse geographic regions within the United States. A portion of the HDQLIFE study sample was collected concurrently with the PREDICT-HD study, a study designed to identify the earliest clinical features of HD before phenoconersion.¹⁴

Eligibility criteria included those whose primary language was English, 18 years or older, or who had documented HTT gene mutation with ≥36 CAG repeats (additional inclusion/exclusion criteria may be found here¹⁵). Recruitment occurred through advertisements, the national HD roster obtained through Indiana University, skilled nursing facilities, and academic neurology clinics. Each study site received approval from its respective Institutional Review Board. All participants provided informed consent at baseline enrollment, excluding those with cognitive impairment unable to provide consent.

Procedure

Participants completed clinician- and patient-rated assessments at baseline, 12 and 24 months (details surrounding the psychometric validation of the HD clinician-rated assessments and patient-rated Neuro-QoL/PROMIS^®/HDQLIFE PROs may be found elsewhere^15–25). PROs were administered as computer adaptive tests, when available, plus short forms (SFs), either in a clinical setting or remotely via the Internet (Note. HDQLIFE End of Life Planning and HDQLIFE Meaning and Purpose are only available as SFs).

Clinician-rated assessments

The HDQLIFE assessment battery included clinician-rated assessments at each visit. These involved HD-trained clinicians, who administered the Unified Huntington Disease Rating Scale (UHDRS^®)²⁶ and short Problem Behavior Assessment (PBA-s) forms.²⁷

We examined components of the motor scale and the Total Functional Capacity (TFC) from the UHDRS. The “diagnostic confidence level” (DCL) item from the motor scale was examined. The DCL is a single clinician-rated item on a 5-point Likert scale (range from 0 to 4), representing the confidence that the motor signs reflect manifest HD. Ratings of 4 indicate a 98%–100% chance of manifesting HD, defined as “unequivocal.”

Values <4 on the DCL signify prodromal HD. We also examined the TFC from the UHDRS, which scored from 0 to 13 (higher scores indicate greater independence across a range of activities of daily living). The TFC was used to determine the HD stage for individuals with manifest HD (i.e., those with a DCL of 4). Early-stage manifest HD is defined as a TFC score ranging from 7 to 13, and a TFC score <7 indicates late-stage manifest HD.²⁸

The PBA-s comprises 11 different behavioral/cognitive/psychiatric items (including an item on suicidality) within HD, rated by the clinician, including patient and collateral support (e.g., care partner) when available. Each question inquires about the (1) frequency and the (2) severity of the symptom/domain within the last three weeks. The frequency and severity are scored on a 5-point Likert scale, ranging from 0 (complete absence) to 4 (present every day). Each of the 11 items on the PBA-s is computed by multiplying the frequency by the severity. For our study, we examined scores on the PBA-suicide item.

Patient-rated assessments

Our study categorized assessments into four HRQoL categories: physical, mental, social, and cognitive. The physical domain included five PROs: (1) HDQLIFE Chorea, (2) HDQLIFE Swallowing difficulties, (3) HDQLIFE Speech difficulties, (4) Neuro-QoL Upper Extremity Function, and (5) Neuro-QoL Lower Extremity Function. The mental HRQoL category included seven PROs and one clinician-rated assessment: (1) PROMIS Anger, (2) HDQLIFE Meaning and Purpose, (3) HDQLIFE Concern with Death and Dying, (4) Neuro-QoL Anxiety, (5) Neuro-QoL Depression, (6) Neuro-QoL Emotional and Behavioral Dyscontrol, (7) Neuro-QoL Positive Affect and Well-being, and (8) the clinician-rated (PBA-s) item on suicide (PBA-suicide). The social HRQoL domain included three PROs: (1) Neuro-QoL Ability to Participate in Social Roles and Activities; (2) Neuro-QoL Satisfaction with Social Roles and Activities; and (3) Neuro-QoL Stigma. The cognitive HRQoL domain includes two PROs: (1) Neuro-QoL Applied Cognition—Executive Function; and (2) Neuro-QoL Applied Cognition—General Concerns.

HDQLIFE End of Life Planning includes 16 questions on a 3- to 4-point Likert scale.^9,29 This PRO measures the range of health behaviors, communication, and thoughts around ACP. Four subdomains exist (1) “Legal Planning,” (2) “Preferences for Care,” (3) “Death and Dying Preferences,” and (4) “Financial Planning.” Responses are framed around the participant's continuum for the ACP process, ranging from not thinking about a given behavior/communication/topic/action to engaging in said item. The “Legal Planning” subdomain (n = 3 questions) asks about advance directives, living wills, and the health care power of attorney.

“Preferences for Care” (n = 3 questions) discuss skilled nursing facility care and palliative and hospice care. “Death and Dying Preferences” (n = 5 questions) explore conversations about the dying/death process, location of death, and preferences about death, resuscitation (i.e., intubation/cardiopulmonary resuscitation), and funeral arrangements. “Financial Planning” (n = 4 questions) concerns one's insurance, estate, finances, and assistance with helping to make medical decisions if/when the capacity is lost. One question that is not part of any subdomain (but is computed within the total score) and to which a participant may opt out of answering (lack of applicability) concerns preparation for child care.

All PROs are scored using the T score metric (mean = 50; standard deviation = 10) according to the reference population under study (e.g., HD for the HDQLIFE measures and the general neurological or adult populations for the Neuro-QoL or PROMIS assessments, respectively). Higher T scores reflect more of the assessed domain (e.g., higher HDQLIFE End of Life Planning suggests more engagement with ACP activities; and a higher Neuro-QoL Anxiety reflects more anxiety).

Statistical analysis

Demographic and clinical data (age, sex, ethnicity, education, CAG repeats) were described using means and standard deviations for continuous variables and frequencies and percentages for categorical variables. HDQLIFE End-of-Life Planning Total Scores were stratified using the baseline data into three separate groups: low (T score ≤40) versus medium (40 < T score <60) versus high levels of planning (T score ≥60). Comparisons were made using Kruskal–Wallis and Chi-square tests.

Linear mixed-effects models were used to assess the relationships between (1) baseline HRQoL/STB and ACP at follow-up and (2) baseline ACP and HRQoL/STB at follow-up. Random effects for participant were used to address the interdependence of the months 12 and 24 assessments within a participant. When assessing the if HRQoL/STB predicts ACP, 18 linear mixed-effects models (1 for each HRQoL/STB variable) were run with ACP as the outcome (assessed at months 12 and 24) with the following predictors: baseline ACP, an HRQoL/STB variable assessed at baseline (e.g., Chorea), as well as age, education, sex, stage, and baseline depression and anxiety. The same approach was used to assess the relationship between baseline ACP and symptoms at follow-up—this time with HRQoL/STB as the outcome.

We also performed an exploratory analysis because previous data suggested an association of advance directive completion with the sense of meaning and purpose, age, education, and HD stage.⁴ For this analysis, we used the multivariable model we developed that included physical, mental, social, and cognitive PROs/Assessments to test for an interaction between HDQLIFE Meaning and Purpose and each predictor variable. We also tested for an interaction between HDQLIFE Meaning and Purpose and each predictor variable for all linear-mixed effects models.

Two-sided α = 0.05 was used to assess for statistical significance. False-discovery rate-adjusted p-values accounted for multiple comparisons.³¹ Analyses were executed using SAS V9.4 (SAS Institute Inc., Cary, NC).

Results

Participant characteristics

Demographic and clinical differences existed across levels (low, medium, and high) of HDQLIFE End of Life Planning. Compared with the group with low engagement with the end-of-life planning, those with high engagement were, on average, 12.9 years older. On average, those with high engagement in planning had 2.4 more years of education than the low group. Higher physical symptom burden (i.e., HDQLIFE Swallowing difficulties and Neuro-QoL Upper Extremity Function) correlated with higher engagement with the end-of-life planning. No differences existed within ethnicity, race, marital status, or sex among the three groups (Table 1).

Table 1.

Demographic Data by Advance Care Planning

Characteristic	Baseline advance care planning			Overall	p
Characteristic	Low (≤40)	Medium (40–60)	High (≥60)	Overall	p
Demographics	(N = 43)	(N = 227)	(N = 52)	(N = 322)
Age (years)^a	44.0 (15.46)	51.8 (11.95)	56.9 (10.54)	51.6 (12.72)	<0.0001
Female^b	21 (49)	105 (46)	21 (40)	147 (46)	0.67
Hispanic of Latino^b	1 (2)	5 (2)	3 (6)	9 (3)	0.48
Race^b					0.17
African American	4 (9)	5 (2)	1 (2)	10 (3)
Caucasian	37 (86)	218 (96)	50 (96)	305 (95)
Other	2 (5)	3 (1)	1 (2)	6 (2)
Unknown	0 (0)	1 (0)	0 (0)	1 (0)
Education (years)^a	13.2 (2.54)	14.8 (2.57)	15.6 (3.10)	14.7 (2.72)	0.0003
Marital status^b					0.06
Single, never married	13 (30)	28 (12)	3 (6)	44 (14)
Married	22 (51)	134 (59)	31 (60)	187 (58)
Separated/divorced	6 (14)	53 (23)	14 (27)	73 (23)
Living with partner	1 (2)	6 (3)	3 (6)	10 (3)
Widowed	1 (2)	6 (3)	1 (2)	8 (2)
CAG repeats^a	45.4 (7.25)	42.8 (3.32)	43.2 (6.63)	43.3 (4.71)	0.06
HDQLIFE End of Life Planning^a	34.8 (4.27)	50.0 (5.43)	65.4 (4.70)	50.5 (9.78)	<0.0001
Legal	35.6 (4.04)	50.6 (6.70)	60.4 (2.70)	50.2 (8.96)	<0.0001
Preferences for care	43.6 (5.40)	50.0 (6.97)	57.8 (8.54)	50.4 (8.05)	<0.0001
Death and dying preferences	39.7 (5.59)	49.6 (7.44)	61.5 (5.57)	50.2 (9.13)	<0.0001
Financial	41.2 (6.52)	48.9 (7.37)	57.1 (5.40)	49.2 (8.20)	<0.0001
Physical
HDQLIFE Chorea^a	50.5 (9.51)	52.9 (8.35)	54.3 (8.67)	52.8 (8.60)	0.17
HDQLIFE Speech Difficulties^a	48.8 (8.97)	51.2 (7.88)	53.8 (8.36)	51.3 (8.19)	0.05
HDQLIFE Swallowing Difficulties^a	48.8 (8.28)	52.0 (8.20)	55.6 (8.58)	52.1 (8.45)	0.0004
Neuro-QoL Upper Extremity Function^a	43.8 (10.08)	41.1 (9.91)	36.8 (11.28)	40.8 (10.32)	0.0042
Neuro-QoL Lower Extremity Function^a	46.8 (9.72)	45.3 (10.06)	42.7 (9.84)	45.1 (10.02)	0.18
Mental
PROMIS Anger^a	46.9 (12.46)	48.3 (12.49)	47.4 (12.11)	48.0 (12.40)	0.59
HDQLIFE Meaning and Purpose^a	49.5 (9.08)	48.9 (9.69)	53.0 (7.42)	49.6 (9.38)	0.02
HDQLIFE Concern with Death and Dying^a	48.4 (8.73)	51.0 (10.42)	48.7 (8.57)	50.3 (9.96)	0.17
PROMIS Anxiety^a	52.1 (10.04)	53.8 (10.22)	53.2 (11.51)	53.5 (10.39)	0.45
PROMIS Depression^a	51.0 (11.05)	51.1 (10.71)	50.6 (10.90)	51.0 (10.75)	0.90
Neuro-QoL Emotional^a and Behavioral Dyscontrol^a	45.2 (9.07)	47.2 (11.15)	47.7 (10.90)	47.0 (10.86)	0.47
Neuro-QoL Positive Affect and Well-Being^a	54.7 (7.81)	54.7 (8.68)	55.1 (8.48)	54.8 (8.51)	0.82
Problem Behavior Assessment—Suicide^a	0.0 (0.00)	0.0 (0.22)	0.0 (0.14)	0.0 (0.19)	0.22
Social
Neuro-QoL Ability to Participate in Social Roles and Activities^a	46.8 (8.74)	46.3 (8.26)	45.7 (8.43)	46.3 (8.33)	0.67
Neuro-QoL Satisfaction with Social Roles and Activities^a	50.3 (8.36)	46.9 (7.85)	47.3 (9.66)	47.4 (8.28)	0.05
Neuro-QoL Stigma^a	49.0 (8.81)	51.4 (8.83)	52.5 (8.41)	51.3 (8.78)	0.14
Cognitive
Neuro-QoL Applied Cognition—Executive Function^a	39.8 (10.68)	36.4 (10.26)	33.0 (10.22)	36.3 (10.43)	0.01
Neuro-QoL Applied Cognition—General Concerns^a	41.6 (7.68)	39.8 (9.58)	38.2 (8.67)	39.8 (9.24)	0.16

Mean (SD).

Frequency (%).

QoL, quality of life; SD, standard deviation.

HRQoL and STB at baseline do not associate with HDQLIFE End of Life Planning in the future, and HDQLIFE End of Life Planning at baseline does not associate with changes to STB and HRQoL at follow-up

None of the HRQoL/STB measures at baseline predicted ACP at follow-up (Table 2). Similarly, after accounting for multiple comparisons, HDQLIFE End of Life Planning was not associated with 12- or 24-month reports of suicide or any of the physical, mental, social, and cognitive HRQoL PROs (Table 3). In addition, none of the models demonstrated a significant interaction with HDQLIFE Meaning and Purpose.

Table 2.

Mixed Model Results of Baseline Health-Related Quality of Life Predicting HDQLIFE End of Life Planning at Follow-Up

Outcome	β [95% CI]	p
Physical
HDQLIFE Chorea	0.09 [−0.09 to 0.26]	0.32
HDQLIFE Speech Difficulties	0.00 [−0.14 to 0.14]	0.99
HDQLIFE Swallowing Difficulties	−0.04 [−0.18 to 0.10]	0.59
Neuro-QoL Upper Extremity Function	−0.08 [−0.22 to 0.07]	0.30
Neuro-QoL Lower Extremity Function	−0.04 [−0.18 to 0.10]	0.55
Mental
PROMIS Anger	−0.05 [−0.19 to 0.09]	0.51
HDQLIFE Meaning and Purpose	−0.02 [−0.14 to 0.09]	0.68
HDQLIFE Concern with Death and Dying	−0.01 [−0.14 to 0.13]	0.89
NQ/PROMIS Anxiety	−0.10 [−0.27 to 0.08]	0.28
NQ/PROMIS Depression	0.09 [−0.09 to 0.27]	0.31
Neuro-QoL Emotional and Behavioral Dyscontrol	0.03 [−0.13 to 0.18]	0.74
Neuro-QoL Positive Affect and Well-Being	0.03 [−0.13 to 0.19]	0.68
Problem Behavior Assessment—Suicide	−4.69 [−9.86 to 0.49]	0.07
Social
Neuro-QoL Ability to Participate in Social Roles and Activities	−0.05 [−0.19 to 0.08]	0.44
Neuro-QoL Satisfaction with Social Roles and Activities	0.02 [−0.13 to 0.17]	0.80
Neuro-QoL Stigma	0.07 [−0.10 to 0.23]	0.43
Cognitive
Neuro-QoL Applied Cognition—Executive Function	−0.02 [−0.16 to 0.11]	0.73
Neuro-QoL Applied Cognition—General Concerns	−0.08 [−0.21 to 0.06]	0.25

Adjusted for baseline levels of HDQLIFE End of Life Planning and age, education, sex, stage, depression, and anxiety.

CI, confidence interval.

Table 3.

Mixed Model Results of Baseline HDQLIFE End of Life Planning Predicting Symptoms at Follow-Up

Outcome	β [95% CI]	p	q
Physical
HDQLIFE Chorea	0.04 [−0.04 to 0.12]	0.35	0.75
HDQLIFE Speech Difficulties	0.08 [−0.01 to 0.18]	0.07	0.25
HDQLIFE Swallowing Difficulties	0.04 [−0.06 to 0.14]	0.43	0.75
Neuro-QoL Upper Extremity Function	−0.03 [−0.13 to 0.07]	0.56	0.75
Neuro-QoL Lower Extremity Function	−0.03 [−0.13 to 0.07]	0.58	0.75
Mental
PROMIS Anger	0.18 [0.03 to 0.32]	0.02^a	0.11^a
HDQLIFE Meaning and Purpose	0.04 [−0.08 to 0.15]	0.51	0.75
HDQLIFE Concern with Death and Dying	0.02 [−0.10 to 0.13]	0.79	0.86
NQ/PROMIS Anxiety	0.01 [−0.13 to 0.14]	0.94	0.94
NQ/PROMIS Depression	0.13 [−0.00 to 0.25]	0.05	0.23
Neuro-QoL Emotional and Behavioral Dyscontrol	0.11 [−0.02 to 0.24]	0.08	0.25
Neuro-QoL Positive Affect and Well-Being	0.01 [−0.10 to 0.11]	0.87	0.92
Problem Behavior Assessment—Suicide	0.00 [−0.00 to 0.01]	0.20	0.51
Social
Neuro-QoL Ability to Participate in Social Roles and Activities	−0.03 [−0.14 to 0.09]	0.66	0.79
Neuro-QoL Satisfaction with Social Roles and Activities	−0.13 [−0.23 to −0.02]	0.02^a	0.11^a
Neuro-QoL Stigma	0.14 [0.03 to 0.25]	0.01^a	0.11^a
Cognitive
Neuro-QoL Applied Cognition—Executive Function	−0.05 [−0.17 to 0.08]	0.46	0.75
Neuro-QoL Applied Cognition—General Concerns	−0.05 [−0.16 to 0.06]	0.39	0.75

Adjusted for baseline levels of outcome and age, education, sex, stage, depression, and anxiety.

Not significant after false-discovery rate adjustments.

Discussion

Before our study, no information was available on whether ACP relates to changes in HRQoL over a 12- and 24-month time frame in people with HD. This study contributes two key findings that are important for palliative neurology. First, STB and HRQoL PROs do not significantly contribute to patient engagement with ACP. Second, participating in ACP discussions does not cause untoward effects as we observed no changes to STB and physical, mental, social, and cognitive HRQoL in HD over the subsequent 12 and 24 months.

Overall, navigating ACP discussion is an essential role for clinicians caring for patients with HD. Our study shows that these discussions do not worsen STB or HRQoL and further research on ACP is warranted to see how ACP may lead to improved care in patients with fatal neurodegenerative disease like HD.

A priori, we had hypothesized that HRQoL PROs would contribute modestly to ACP. However, our findings suggest otherwise. Other factors may more substantially contribute to ACP engagement in HD. Previous studies in other serious illnesses suggest coping behaviors,³² personalities, self-esteem, illness-specific factors (e.g., stage, age), care partner involvement, behavioral change knowledge, prognostic awareness, readiness to talk about the future, and the attitudes of health care professionals.¹³

Our study is not without its limitations. We analyzed data retrospectively from a longitudinal multi-center observational study dedicated to creating PROs responsive to the HRQoL needs of people with the HD mutation. However, additional insights to understand our findings are notably lacking. Our approach unfortunately does not provide qualitative insights into understanding ACP at each visit and its interpretation with HRQoL for each person with HD and their loved ones.

Indeed, we would foresee that a mixed-methods approach would allow for a greater understanding of our quantitative findings. Another limitation of our findings includes that our dataset did not record who initiated ACP. That is, uncertainty surrounds as to who initiated the process (i.e., the patient, care partner, health care professional, or another third party) or the reasons behind engaging in various forms of ACP (i.e., poor health from other non-HD causes, progression of HD, recent hospitalizations, or falls).³³

Therefore, we recommend that future work within this area should use mixed methods to explore the framing of ACP discussions in HD, their essential components, and barriers to the occurrence.

Reassuringly, and in agreement with prior research, we found that preparing for the end of life does not relate to increases in STB or decreases in HRQoL at 12 and 24 months. While we did observe marginal worsening in mental and social HRQoL at follow-up, specifically in anger, depression, satisfaction with social activities, and stigma, these did not reach significance after correction for multiple comparisons.³⁰ Nevertheless, this warrants further study in the ACP context.

Interestingly, depression and anger comprise stages of grief, per the “stage theory of grief” model.³⁴ We hypothesize that people with the HD mutation who engage in ACP may concurrently engage in “grief work” while experiencing the loss of independence and respect (hence the trend toward worsening stigma) and thus progressing through these different grief stages (e.g., depression and anger). Corroborating such a hypothesis in the future would perhaps recapitulate a recently published longitudinal observation among people with advanced cancer: those who completed a living will or resuscitation preference predicted negative mental HRQoL at two months—specifically increased grief.³⁵

Future work should clarify if an association exists between ACP engagement and measurements of grief within HD, and assess for markers of grief within an HD care partner while incorporating the care partner's HRQoL. If psychosocial distress appears during the ACP process in this population, then the consideration of integrating ACP within an adapted psychotherapeutic neuropalliative intervention might also be warranted.³⁶

Our data suggest that STB and HRQoL are not significantly related to ACP practices within the HD population. Thus, our data should comfort stakeholders that engagement in ACP does not provoke emergent STB, especially within a disease where STB's lifetime prevalence nears 20% to 30% and suicide leads as a cause of death.¹¹ Our findings suggest the importance of future investigation into the non-significant worsening signals observed in mental and social HRQoL, especially in stigma, depression, anger, and satisfaction with social roles and activities.

We conjecture that an unmeasured personality or psychiatric (co-morbid) factor may contribute to residual confounding—and one's predisposition to engage in ACP in this population, especially since our observational study neither promoted nor eschewed ACP. In the interim, our study can help tailor HD-specific neuropalliative interventions that meet the ACP needs of this unique and complex patient population.

Footnotes

Authors' Contributions

All authors contributed to the conception, organization, execution of the project, and revising and critiquing the manuscript for important intellectual content. 1. Research project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review, and Critique; 3. Manuscript Preparation: A. Writing of the first draft, B. Review, and Critique. L.L.S.: 1A, 1B, 1C, 2A, 2C, 3A, 3B. J.P.T.: 1B, 1C, 2A, 2B, 2C, 3B. N.E.C.: 1A, 1B, 1C, 2A, 2B, 2C, 3B. All other authors: 1A, 1B, 1C, 2C, 3B.

L.L.S. conceived the project, wrote the first draft, devised the research questions, interpreted the work, revised the manuscript for valuable intellectual content, and approved the final draft. All other authors oversaw the work, conception, and design, drafted the work for important intellectual content, and approved the final draft.

Ethics Approval

The Institutional Review Boards of HDQLIFE sites approved data collection.

Funding Information

Data reported in this manuscript were collected with support from the National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS) (R01NS077946: PI Carlozzi; R01NS0400068: PI Paulsen), and the National Center for Advancing Translational Sciences (NCATS) (UL1TR000433). J.P.T. was supported in part by the NCATS for the Michigan Institute for Clinical and Health Research (UL1TR002240). Dr. Sokol's work on this study is supported in part extramurally by the Huntington's Disease Society of America (HDSA), SP0070054.

Author Disclosure Statement

L.L.S. receives financial support as a paid consultant from the HDSA, American Film Institute, University of Texas Houston (McGovern School), and Tikvah for Parkinson; he has received research support from the Memorial Sloan Kettering Meaning Centered Psychotherapy (MCP) National Cancer Institute (NCI) R25 Training, and Northwestern Physician Scientist Training program. J.P.T. owns stocks in Procter and Gamble and General Electric, and has received research funding through the University of Michigan with Complexa Inc., Retrophin Inc., and Goldfinch Bio, and the University of Michigan with Vertex Pharmaceuticals and Pfizer Inc. D.B. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Speaker: Teva Pharmaceuticals, Acorda Therapeutics, Neurocrine Biosciences, Adamas Pharmaceuticals Consulting: Biogen Pharmaceuticals, Amgen Pharmaceuticals, Acadia Pharmaceuticals, Genentech, Inc., GE Healthcare, Gerson Lehrman Group, Guidepoint, L.E.K. C., and has received personal compensation in an editorial capacity for Editor: Annals of Clinical and Translational Neurology. B.M.K. received research grant support from the National Institute of Aging (NIA), National Institute of Nursing Research, and Patient-Centered Outcomes Research Institute; he has received speaker honoraria from the Parkinson's Foundation. H.G.P. receives funding from the NIH (CA197730; AG049666; MH121886; NR018693; CA218313). M.N. has received personal compensation in the range of $5,000–$9,999 for serving as a Consultant for Voyager. M.N. has received personal compensation in the range of $500–$4,999 for serving as a Consultant for Roche. M.N. has received personal compensation in the range of $5,000–$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. M.N. has received personal compensation in the range of $500–$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Uniqure. An immediate family member of M.N. has received stock or an ownership interest from Fresca. The institution of M.N. has received research support from HDSA. The institution of M.N. has received research support from Parkinson Foundation. M.N. has received research support from Parkinson Foundation. The institution of M.N. has received research support from Neuraly. M.N. has received personal compensation in the range of $500–$4,999 for serving as a speaker with American Academy of Neurology (AAN). S.F. has received personal compensation in the range of $500–$4,999 for serving as a Consultant for Oscine Therapeutics. S.F. has received personal compensation in the range of $500–$4,999 for serving as a Consultant for uniQure. S.F. has received personal compensation in the range of $500–$4,999 for serving as a Consultant for MCG Health. The institution of S.F. has received research support from HDSA. The institution of S.F. has received research support from Michael J Fox Foundation. The institution of S.F. has received research support from Roche/Genentech. The institution of Dr. Frank has received research support from CHDI Foundation. The institution of S.F. has received research support from Huntington Study Group (HSG). The institution of S.F. has received research support from Triplet Therapeutics. J{has received research funding from the NIH (NS075321, NS103957, NS107281, NS092865, U10NS077384, NS097437, U54NS116025, U19 NS110456, AG050263, AG-64937, NS097799, NS075527, ES029524, NS109487, R61 AT010753 [NCATS, NINDS, NIA], RO1NS118146, R01AG065214), Department of Defense (W81XWH-217-1-0393), Michael J Fox Foundation, Barnes-Jewish Hospital Foundation (Elliot Stein Family Fund and Parkinson disease research fund), American Parkinson Disease Association (APDA) Advanced Research Center at Washington University, Greater St. Louis Chapter of the APDA, Paula and Rodger Riney Fund, Jo Oertli Fund, HDSA, Murphy Fund, and CHDI; has received honoraria from CHDI, Huntington Disease Study Group, Parkinson Study Group, Beth Israel Hospital (Harvard group), University of Pennsylvania, and Stanford University; is co-director for the Dystonia Coalition, which has received the majority of its support through the NIH (grants NS116025, NS065701 from the NINDS and TR 001456 from the Office of Rare Diseases Research at the NCATS); serves as Director of Medical and Scientific Advisory Committee of the Dystonia Medical Research Foundation, Chair of the Scientific Advisory Committee of the Parkinson Study Group, Chair of the Interim Executive Membership Committee of the HSG, Chair of the Nominating Committee of the HSG; Chair of the Standards Committee of the HSG, member of the Scientific Advisory Board of the APDA, Chair of the Scientific and Publication Committee for ENROLL-HD, and member of the Education Committee of the HSG; and has provided medical legal consultation to Wood, Cooper and Peterson, LLC, and Simmons and Simmons LLP. P.D. reports receiving funding from Vaccinex, Inc., Neurocrine Biosciences Inc., and UniQure, for his role as Site Investigator for clinical trials in Huntington Disease. D.C. reports consultant fees from AbbVie, Bristol Myers Squibb (BMS), Exelixis, Merck, Novartis, and Pfizer; reports licensing fees from FACIT.org; research grants (institutional) from AbbVie, Astellas, Aveo, BMS, GlaxoSmithKline, Merck, Novartis, and Pfizer; and is an officer of . N.E.C. reports research grants from the NIH, the Neilsen Foundation, and CHDI, as well as a contract from Teva Pharmaceuticals. She is also supported by research funding from the Alzheimer's Association, the Food and Drug Administration (FDA), as well as the Department of Health and Human Services—Centers for Medicare and Medicaid Services. She receives honoraria for her role on the CHDI scientific advisory board and is a consultant on the Traumatic Brain Injury (TBI) Congressionally mandated study.

Abbreviations Used

References

Sudore

, Heyland

, Lum

, et al. Outcomes that define successful advance care planning: A Delphi Panel Consensus. J Pain Symptom Manag, 2018; 55(2):245.e8–255.e8.

Ross

, Aylward

, Wild

, et al. Huntington disease: Natural history, biomarkers and prospects for therapeutics. Nat Rev Neurol, 2014; 10(4):204–216.

McColgan

, Tabrizi

. Huntington's disease: A clinical review. Eur J Neurol, 2018; 25(1):24–34.

Downing

, Goodnight

, Chae

, et al. Factors associated with end-of-life planning in Huntington disease. Am J Hosp Palliat Med, 2018; 35(3):440–447.

Booij

, Tibben

, Engberts

, et al. Thinking about the end of life: A common issue for patients with Huntington's disease. J Neurol, 2014; 261(11):2184–2191.

Wright

, Zhang

, Ray

, et al. Associations between end-of-life discussions, patient mental health, medical care near death, and caregiver bereavement adjustment. JAMA, 2008; 300(14):1665–1673.

Fiedorowicz

, Mills

, Ruggle

, et al. Suicidal behavior in prodromal Huntington disease. Neurodegener Dis, 2011; 8(6):483–490.

Sokol

, Troost

, Kluger

, et al. Meaning and purpose in Huntington's disease: A longitudinal study of its impact on quality of life. Ann Clin Transl Neur, 2021; 8(8):1668–1679; doi: 10.1002/acn3.51424

Carlozzi

, Boileau

, Paulsen

, et al. End-of-life measures in Huntington disease: HDQLIFE Meaning and Purpose, Concern with Death and Dying, and End of Life Planning. J Neurol, 2019; 266(10):2406–2422.

10.

Carlozzi

, Downing

, McCormack

, et al. New measures to capture end of life concerns in Huntington disease: Meaning and Purpose and Concern with Death and Dying from HDQLIFE (a patient-reported outcomes measurement system). Qual Life Res, 2016; 25(10):2403–2415.

11.

Kachian

, Cohen-Zimerman

, Bega

, et al. Suicidal ideation and behavior in Huntington's disease: Systematic review and recommendations. J Affect Disord, 2019; 250:319–329.

12.

Dazzi

, Gribble

, Wessely

, Fear

. Does asking about suicide and related behaviours induce suicidal ideation? What is the evidence?. Psychol Med, 2014; 44(16):3361–3363.

13.

McMahan

, Tellez

, Sudore

. Deconstructing the complexities of advance care planning outcomes: What do we know and where do we go? A scoping review. J Am Geriatr Soc, 2021; 69(1):234–244.

14.

Paulsen

, Langbehn

, Stout

, et al. Detection of Huntington's disease decades before diagnosis: The Predict-HD study. J Neurol Neurosurg Psychiatry, 2008; 79(8):874–880.

15.

Carlozzi

, Schilling

, Lai

J-S

, et al. HDQLIFE: Development and assessment of health-related quality of life in Huntington disease (HD). Qual Life Res, 2016; 25(10):2441–2455.

16.

Carlozzi

, Goodnight

, Kratz

, et al. Validation of Neuro-QoL and PROMIS mental health patient reported outcome measures in persons with huntington disease. J Huntingtons Dis, 2019; 8(4):467–482.

17.

Carlozzi

, Boileau

, Roché

, et al. Responsiveness to change over time and test-retest reliability of the PROMIS and Neuro-QoL mental health measures in persons with Huntington disease (HD). Qual Life Res, 2020; 29(12):3419–3439.

18.

Mestre

, Carlozzi

, Ho

, et al. Quality of life in Huntington's disease: Critique and recommendations for measures assessing patient health-related quality of life and caregiver quality of life. Movement Disord, 2018; 33(5):742–749.

19.

Carlozzi

, Boileau

, Paulsen

, et al. Psychometric properties and responsiveness of Neuro-QoL Cognitive Function in persons with Huntington disease (HD). Qual Life Res, 2020; 29(5):1393–1403.

20.

Victorson

, Carlozzi

, Frank

, et al. Identifying motor, emotional–behavioral, and cognitive deficits that comprise the Triad of HD Symptoms from patient, caregiver, and provider perspectives. Tremor Other Hyperkinet Mov, 2014; 4(0):224.

21.

Carlozzi

, Tulsky

. Identification of health-related quality of life (HRQOL) issues relevant to individuals with Huntington disease. J Health Psychol, 2013; 18(2):212–225.

22.

Carlozzi

, Schilling

, Lai

J-S

, et al. HDQLIFE: The development of two new computer adaptive tests for use in Huntington disease, Speech Difficulties, and Swallowing Difficulties. Qual Life Res, 2016; 25(10):2417–2427.

23.

Carlozzi

, Boileau

, Chou

, et al. HDQLIFE and Neuro-QoL physical function measures: Responsiveness in persons with Huntington's disease. Movement Disord, 2020; 35(2):326–336.

24.

Salsman

, Victorson

, Choi

, et al. Development and validation of the positive affect and well-being scale for the neurology quality of life (Neuro-QOL) measurement system. Qual Life Res, 2013; 22(9):2569–2580.

25.

Lai

J-S

, Goodnight

, Downing

, et al. Evaluating cognition in individuals with Huntington disease: Neuro-QoL cognitive functioning measures. Qual Life Res, 2018; 27(3):811–822.

26.

Unified Huntington's Disease Rating Scale: Reliability and consistency. Movement Disord, 1996; 11(2):136–142.

27.

Callaghan

, Stopford

, Arran

, et al. Reliability and factor structure of the short problem behaviors assessment for Huntington's disease (PBA-s) in the TRACK-HD and REGISTRY studies. J Neuropsychiatry Clin Neurosci, 2015; 27(1):59–64.

28.

Shoulson

, Kurlan

, Rubin

, et al. Assessment of functional capacity in neurodegenerative movement disorders: Huntington's disease as a prototype. In: Quantification of Neurologic Deficit. ( Munsat

ed.) Butterworths: Boston, MA, USA; 1989; pp. 271–283.

29.

Coordinators

HSI and

, Carlozzi

, Hahn

, et al. A new measure for end of life planning, preparation, and preferences in Huntington disease: HDQLIFE end of life planning. J Neurol, 2018; 265(1):98–107.

30.

Boileau

, Paulsen

, Ready

, et al. Understanding domains that influence perceived stigma in individuals with Huntington disease. Rehabil Psychol, 2020; 65(2):113–121.

31.

Benjamini

, Hochberg

. Controlling the false discovery rate: A practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol, 1995; 57(1):289–300.

32.

Sokol

, Jordan

, Applebaum

, et al. Social media perceptions of legacy-making: A qualitative analysis. Palliat Med Rep, 2020; 1(1):326–330.

33.

Sokol

, Bega

, Yeh

, et al. Disparities in palliative care utilization among hospitalized people with Huntington disease: A National Cross-Sectional Study. Am J Hosp Palliat Med, 2022; 39(5):516–522.

34.

Maciejewski

, Zhang

, Block

, Prigerson

. An empirical examination of the stage theory of grief. JAMA, 2007; 297(7):716–723.

35.

Falzarano

, Prigerson

, Maciejewski

. The role of advance care planning in cancer patient and caregiver grief resolution: Helpful or harmful?. Cancers, 2021; 13(8):1977.

36.

Sokol

, Lum

, Creutzfeldt

, et al. Meaning and dignity therapies for psychoneurology in neuropalliative care: A vision for the future. J Palliat Med, 2020; 23(9):1155–1156.