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Progression of Symptoms in the Early and Middle Stages of Huntington Disease
Sandra Close Kirkwood, PhD;
Jessica L. Su, MS;
P. Michael Conneally, PhD;
Tatiana Foroud, PhD
Arch Neurol. 2001;58:273-278.
ABSTRACT
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Objective To delineate the progression of symptoms in the early and middle stages
of Huntington disease (HD).
Design A survey of individuals with symptomatic HD completed by a first-degree
relative.
Setting The National Huntington Disease Research Roster for Patients and Families,
Indianapolis, Ind.
Participants The survey included 1238 individuals with a minimum of a 6-year history
of symptomatic HD.
Measures Participating families completed a series of surveys, including the
Affected Individual Questionnaire, which consists of 19 physical, emotional,
and cognitive signs commonly thought to occur during disease progression.
The respondent indicates if each of the symptoms occurred and, if so, at what
time during the course of the disease: (1) within 1 year, (2) within 2 to
5 years, (3) within 6 to 10 years, (4) after more than 10 years, (5) has not
occurred, or (6) "don't know."
Results The symptoms are categorized into 6 onset periods. Involuntary movements
are grouped alone as the earliest reported symptom. The second group is composed
entirely of mental and emotional symptoms, including sadness, depression,
and difficult to get along with. The third group includes clumsiness, sexual
problems, lack of motivation, and suspiciousness/paranoia. As the disease
progresses, a variety of motor, emotional/behavioral, and cognitive symptoms
are experienced, including unsteadiness, trouble holding onto things, trouble
walking, changes in sleeping patterns, delusions and hallucinations, intellectual
decline, and memory loss. With the approach of late-stage HD, affected individuals
begin to experience speech difficulty and weight loss. In the late stage,
patients lose bowel and bladder control.
Conclusions Even though the symptoms of HD are fairly well characterized, their
progression, especially in the early and middle stages, remains uncertain.
Clarification of the disease progression is vital to improved understanding
of the pathogenesis of HD and to the evaluation of therapeutic agents that
are designed to slow the progression of disease. The results of this study
assist in clarifying HD progression from early involuntary movements and emotional
changes to more overt motor symptoms and difficulty with activities of daily
living.
INTRODUCTION
HUNTINGTON disease (HD), an autosomal dominant neurodegenerative disorder,
is caused by an increased number of trinucleotide repeats in the coding region
of the gene for Huntington disease.1 A negative
correlation has been observed between the number of repeats and the age at
onset of disease. Individuals with the largest number of repeats (>50) usually
develop the disease in childhood and have a different presentation from those
with the more common adult onset, resulting in the categorization of HD into
2 phenotypes: juvenile and adult onset. Approximately 7% of individuals with
HD become symptomatic before 20 years of age and are classified as having
juvenile HD.2 The most common presenting symptoms
of juvenile HD are an awkward gait and slowed speech due to abnormalities
of voluntary movement, including bradykinesia and rigidity. In the initial
stages of disease progression, performance on simple cognitive tests is good
unless the task is timed. Later in the progression of juvenile HD, seizures
may develop and the voluntary movement abnormalities and cognitive decline
worsen.
Adult-onset HD is characterized by a triad of progressive motor, cognitive,
and emotional symptoms. Although the course of disease is variable, the sequence
of symptom presentation is quite distinct from that of juvenile-onset HD.
In contrast to juvenile-onset HD that typically presents with voluntary movement
abnormalities, the clinical diagnosis of adult-onset HD is typically made
after the onset of involuntary motor abnormalities, primarily chorea.3, 4 Mild chorea, abnormal extraocular movements,
brisk muscle stretch reflexes, and diminished rapid alternating movements
are the most consistent early findings in manifest disease.5, 6, 7
Throughout the course of disease, these motor symptoms progress to more functionally
limiting chorea, voluntary movement abnormalities, and motor deficits, including
dystonia and athetosis, interfering with the activities of daily living. However,
the sequence of motor impairment is not well characterized, as conflicting
results have been found regarding motor impairment in individuals who do not
experience choreiform movements.8, 9, 10, 11
In addition to motor abnormalities, cognitive decline and personality
changes are part of the HD phenotype, although their sequence in the typical
HD prodrome is uncertain. Although the cumulative evidence suggests that subtle
cognitive changes occur before the onset of motor abnormalities, the literature
contains many conflicting reports regarding the presence of cognitive deficits
preceding the onset of motor deficits.10, 12, 13, 14, 15, 16, 17, 18
Early in the disease process, the cognitive deficits are focal, with relatively
intact language function and deficits in executive system functioning, short-term
memory, and visuospatial functioning. Later in the disease process, the cognitive
deficits progress to more widespread global subcortical dementia.19
Although a change in personality is recognized as one of the cardinal
features of HD, the behavioral abnormalities are heterogeneous and without
clear progression.20 Depression, apathy, irritability,
impulsiveness, and antisocial and suicidal behavior are inconsistently demonstrated
by individuals with HD. Depression and apathy may occur several years before
the motor abnormalities begin,21, 22, 23
indicating that they may be an integral part of the disease process rather
than a response to the debilitation that occurs during disease progression.
Research regarding the relationship between central nervous system deterioration
and the personality changes and the timing of their onset is ambiguous.2, 20
While the symptom presentation in the early and middle stages of disease
progression is variable and not well characterized, HD in the late stages
is fairly well delineated.4, 24
Individuals with late-stage HD are functionally incapacitated, with global
dementia and severe limitations in voluntary movement. The later stages are
characterized by bradykinesia, spasticity, dysarthria, dysphagia, incontinence,
and dependence in the activities of daily living.4, 7, 25
Further characterization of disease progression in the early and middle
stages of HD is vital to improved understanding of the underlying pathogenesis
of disease and may provide important insight regarding mechanistic pathways
through which novel therapeutics might be targeted. Also, delineation of the
typical disease progression may assist in the evaluations of therapeutic agents
during clinical trials. The following analysis was designed to delineate the
progression of the motor, cognitive, and emotional symptoms in the early and
middle stages of the typical HD prodrome using the largest reported sample
of individuals affected with HD to date.
PARTICIPANTS AND METHODS
The sample was obtained through the National Research Roster for Huntington
Disease Patients and Families at Indiana University (HD Roster), Indianapolis.
The HD Roster has been collecting data for more than 20 years and is the largest
available database of detailed information on families affected by HD. Although
DNA analysis has not been completed on the HD Roster families, detailed family
and clinical information is available. Participating HD Roster families are
asked to complete a series of surveys, including the Affected Individual Questionnaire
(AQ). The AQ is typically completed by a close relative of the affected individual,
such as a spouse or child, and provides information on the demographics, age
at onset, initial symptoms, disease progression, treatment, living situation,
and clinical, social, and psychiatric histories. One portion of the AQ includes
2 tables listing a total of 19 physical and mental signs commonly thought
to occur during disease progression (Table
1). The respondent indicates if each of the symptoms occurred and,
if so, how long after the onset of disease the symptoms appeared: (1) within
1 year, (2) within 2 to 5 years, (3) within 6 to 10 years, (4) after more
than 10 years, (5) has not occurred, or (6) "don't know."
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Table 1. Signs of Huntington Disease (HD) as Indicated on Affected
Individual Questionnaire*
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PARTICIPANTS
The HD Roster includes AQ data from 2545 individuals. However, many
of these individuals were diagnosed as having HD very recently and thus have
not experienced the majority of the symptoms that we sought to delineate.
Consequently, to describe the typical HD prodrome, our sample included only
those individuals (1) who had disease onset at least 6 years before questionnaire
completion; (2) who had the typical adult-onset choreic form of HD; and (3)
whose AQ was completed by a first-degree relative or spouse of a first-degree
relative to ensure that the respondent was sufficiently familiar with the
patient's symptoms to accurately delineate disease progression. As the clinical
presentation for juvenile- and adult-onset HD is quite distinct, those individuals
whose disease onset with HD symptoms occurred at younger than 20 years or
whose diagnosis of rigid or juvenile-onset HD was confirmed by medical record
(n = 75) were excluded before analysis. Owing to the known cognitive decline
with manifest HD, particularly among individuals who are at least 6 years
beyond their reported age at onset, participants who completed their own questionnaires
(n = 90) were excluded before analysis. A total of 1238 individuals were included
in the final analysis of the AQ data. These data include 600 individuals whose
disease onset occurred more than 10 years before completion of the AQ.
STATISTICAL ANALYSIS
To delineate the progression of the 19 physical and mental signs of
HD, the proportional odds model,26 a regression
model for ordinal data, was used to analyze the AQ data. For each of the individual
19 signs, the 3 responses were (1) within 1 year, (2) within 2 to 5 years,
and (3) within 6 to 10 years. The goal of these analyses was to delineate
the progression of symptoms in the early and middle stages of HD, as the progression
of symptoms in these stages remains ambiguous, while the disease progression
in the later stages of HD is fairly well characterized. Also, requiring the
participants to have manifest HD for more than 10 years dramatically reduces
the sample size; therefore, the responses for the category of after more than
10 years were not used in the analysis. For each symptom, the model uses the
number of responses in each of the 3 periods to calculate a cumulative probability
of the symptom occurring. A logarithmic function of these cumulative probabilities
is used to calculate slope estimates for each individual symptom, which can
then be compared directly with one another, allowing the ordering of the symptoms.
Larger slope estimates imply an earlier onset, while the symptoms with smaller
slope estimates occur later in disease progression.
Although the results of the analysis order each of the 19 symptoms,
these symptoms may actually occur simultaneously or at about the same time.
Also, variability in symptom onset was observed between individuals. A modified
Bonferroni multiple comparisons test was27
used to determine which of the 19 slope estimates were significantly different
from each other, thereby grouping symptoms that develop at approximately the
same time in disease progression.
RESULTS
The demographics for the 1238 participants are presented in Table 2. The participants were primarily
white (98.1%), with similar numbers of male (n = 607) and female (n = 631)
participants. The mean ± SD age at onset reported by the participants
(41.4 ± 10.2 years) is similar to the average age at onset reported
in the literature for adult-onset HD.2
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Table 2. Demographics for the 1238 Participants With HD*
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The individual responses for each category of the AQ are presented in Table 3. As described in the "Participants
and Methods" section, the results are based on the cumulative probabilities
for 3 response groups according to when the symptoms occurred during the course
of the disease: (1) within 1 year, (2) within 2 to 5 years, and (3) within
6 to 10 years. The data were found to be consistent with the use of a proportional
odds model ( 2 = 22.95, df = 18, P = .19) and were therefore entered into a proportional
odds model. ß Estimates were calculated, and based on these estimates,
the symptoms were ordered. After the use of the proportional odds model, the
modified Bonferroni multiple comparisons test was used to categorize the symptoms
into 6 onset periods termed initial, early, early-middle, middle, middle-late, and late (Figure 1).
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Table 3. Percentage of Responses by Category for Each Symptom on the
Affected Individual Questionnaire*
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Mean and 1 SD of ß estimates for 19 symptoms of Huntington disease.
Vertical bars represent proposed divisions based on clustering of ß estimates
into 6 onset periods.
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Involuntary movements were grouped alone as the earliest reported symptom.
The second group of symptoms, which occur early in disease progression, after
involuntary movements, consists of a group of clinical findings that are composed
entirely of mental and emotional symptoms, including sadness, depression,
and difficult to get along with. The majority of individuals in the sample
reported these symptoms as occurring less than 5 years into disease progression,
equally represented between the within-1-year category and the 2-to-5-year
category. The early-middle symptoms include clumsiness, lack of motivation,
sexual problems, and suspiciousness/paranoia. A larger percentage of individuals
reported these symptoms as occurring 2 to 5 years after HD onset. As the disease
progresses, a variety of motor, emotional/behavioral, and cognitive symptoms
are experienced. These middle-disease symptoms include motor difficulties
that interfere with functional activities, such as unsteadiness, trouble holding
onto things, and trouble walking. In addition to the motor symptoms, affected
individuals experience changes in sleeping patterns and delusions or hallucinations.
Cognition also begins to deteriorate, leading to intellectual decline and
memory loss. The symptoms in this middle-disease range were reported to develop
in the 2- to 5-year and 6- to 10-year range in approximately equal percentages.
In the middle- to late-disease stage, affected individuals begin to experience
speech difficulty and weight loss. These symptoms typically occurred 6 to
10 years after disease onset, but in many individuals were delayed until more
than 10 years after onset. Late in the disease, individuals lose bowel and
bladder control (Table 3).
COMMENT
Even though the symptoms that occur with HD are fairly well characterized,
the progression of symptoms, especially in the early and middle stages, remains
uncertain. Clarification of the sequence of symptom presentation is useful
in determining the efficacy of therapeutic agents that are designed to delay
the progression of symptoms and helpful when counseling families and mildly
affected individuals. The literature contains conflicting reports indicating
that, in some instances, emotional and cognitive symptoms precede the onset
of motor symptoms, while others report chorea as the presenting symptom.4, 7 The current sample, the largest reported
sample of individuals affected with HD, helps to clarify the typical progression
of symptoms. According to our analyses, involuntary movements and behavioral
symptoms such as sadness, depression, and irritability characterize the first
year after disease onset in some individuals, while others begin experiencing
these symptoms 2 to 5 years after onset. Following these initial personality
changes, approximately 2 to 5 years after the onset of HD, the affected individuals
experience additional emotional symptoms, such as suspicion, lack of motivation,
changes in sleeping patterns, and sexual problems, along with worsening motor
control, leading to clumsiness. The cognitive decline in this sample is reported
to occur after these personality changes and concomitant with further motor
decline in the middle stage of disease progression. The symptoms that occur
later in disease progression are, as expected, speech difficulty, weight loss,
and incontinence.
Previous studies have suggested that HD presentation may not be homogeneous
and that although the majority of cases may begin with motor disturbance,
a subset of individuals may have a period of cognitive or emotional difficulties
before the onset of motor abnormalities. To determine if our sample was heterogeneous,
the data reported by individuals who stated that they had experienced cognitive
or emotional symptoms in the first year were examined. In addition to the
examination of frequency data, the proportional odds model was rerun. Similar
patterns in symptom presentation were observed for all subgroups, and there
was no evidence supporting heterogeneous disease progression early in HD.
In our previous analyses of presymptomatic gene carriers, subtle cognitive
deficits were found before the onset of obvious motor abnormalities on clinical
examination.12, 14 This finding
of involuntary movements as the initial symptom is not necessarily contradictory
to these previous findings.12, 14
The cognitive deficits we observed were subtle using senstive neuropsychological
tests and thus may not be obvious to affected individuals or family members.
Thus, cognitive deficits might be reported only in the later stages of disease
as global dementia worsens and the deficits interfere with daily activities.
The response rate was good for all symptoms except the more personal
ones: sexual problems, change in sleeping patterns, and delusions and hallucinations
(Table 3). The response rate for
these more personal symptoms would be expected to be lower, as relatives rather
than the participants completed the surveys. Also, since the participants
were required to be a minimum of 6 years from disease onset, some symptoms
that are expected to begin very late in the disease, such as weight loss,
speech difficulty, and bowel and bladder problems, have not yet been observed
by many participants. Therefore, the data collected on these late-onset symptoms
show a large percentage of responses indicating that the affected individual
does not have the symptom, when the symptom simply may not have developed
yet. These factors could lead to a misleading representation of disease progression
through our questionnaire method. However, by collecting these data from a
variety of relatives, most with intimate association with the patient's disease,
we hope to have reduced the impact of nonresponsiveness and lack of awareness
of particular symptoms.
In addition, greater variability in the response data was introduced
through the collection method, since the sequence of symptom appearance was
obtained through family report and not through direct clinical examination.
Data collected through repeated examinations presymptomatically and throughout
disease progression would result in more accurate data. However, longitudinal
data on such a large sample of individuals with HD are not currently available,
and our sample has provided important clinical information. The size of the
sample allows us to make generalizations regarding the typical HD prodrome.
The progression of HD reported herein provides the clinician with the general
disease progression as observed by individuals affected with HD and their
family members. This information can be used when counseling individuals and
families regarding the expected progression of HD. Also, this sample confirms
the importance of careful assessment by the clinician to fully evaluate disease
symptom and progression. To evaluate the efficacy of therapeutic agents that
are designed to delay or prevent HD progression, measures that are sensitive
to motor and cognitive function and behavior abnormalities that are specific
to HD must be used in the clinical setting.
AUTHOR INFORMATION
Accepted for publication September 6, 2000.
This study was supported in part by grants R01-AG-08918, M01-RR-750,
and PHS N01-NS-2326 from the Public Health Service, Washington, DC, and by
Medical Genetics Training Grant Fellowship NICHD-T32-HD07373 from the National
Institute of Child Health and Human Development, Bethesda, Md (Dr Kirkwood).
We thank all participants and members of the Huntington Disease Roster
(Indiana University School of Medicine), Indianapolis, for their efforts.
We thank Jacqueline Gray for insightful comments and assistance with the manuscript.
From the Department of Medical and Molecular Genetics, Indiana University
School of Medicine, Indianapolis.
Corresponding author and reprints: Sandra Close Kirkwood, PhD, Department
of Medical and Molecular Genetics, Indiana University School of Medicine,
975 W Walnut St IB 130, Indianapolis, IN 46202 (e-mail: scloseki{at}iupui.edu).
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