Chapter 7 Huntington’s disease
Introduction
Inevitably, a chapter in a physiotherapy textbook will concentrate on the physical aspects of the condition, but for most families and carers a much greater problem is the behavioural change which can lead to irritability, aggression, depression or apathy. Professionals dealing with HD patients need to have an understanding of the neuropsychological and neuro-psychiatric aspects of HD which will help with their management of the patient. Over time the needs of the patient and family change, so professionals need to reassess their management. This chapter will describe the genetic and pathological features before going on to describe the stages of the condition and the associated physiotherapy management. A number of useful texts are available for a wider discussion of the condition including Bates et al. (2002), Quarrell (2009) and Walker (2007).
Prevalence and aspects of natural history
Most UK studies quote a prevalence of 4–10 per 100 000, with similar results from studies from Europe and the US, and low prevalence figures reported from Japan and Finland (Harper, 2002). Whilst HD may be considered a rare disorder it must be remembered that for every affected person there are approximately twice that number who have the mutation and are currently asymptomatic (Conneally, 1984). The median duration of HD is between 16 and 21 years (Foroud et al., 1999; Roos et al., 1993) so this represents a considerable demand on families and carers.
HD can develop at almost any age from under 20 years (and occasionally under 10 years) to over 75 years, but most people develop the condition between the ages of 35 and 55 years, which is after the usual years of reproduction (Harper et al., 1988). One consequence of this is that the 50% risk for an asymptomatic person does not decline appreciably until s/he is going through middle age.
Individuals with an age of onset less than 20 years are described as having the juvenile form of HD. It is difficult to know precisely how many patients have early onset, but 5% is a reasonable estimate. Young people with juvenile HD may develop problems with speech, bradykinesia and dystonic movements earlier in the course in the illness; this topic is reviewed in Quarrell et al. (2009).
Genetics
As HD is a dominant disorder; each cell contains one normal copy and one abnormal copy of the gene. The gene for HD was cloned in 1993 (Huntington’s Disease Collaborative Research Group, 1993) and the protein for which it codes was named huntingtin. The first part of the HD gene has a sequence CAGCAG…CAG which is repeated a number of times. CAG codes for the amino acid glutamine so that the huntingtin protein contains a sequence called a polyglutamine repeat. The mutation causing HD is an expansion of the number of CAG repeats in the gene and therefore of the polyglutamine repeat in the protein. Up to 35 repeats would be considered normal, although there is a possibility that if a person has a repeat size at the upper end of this range it could expand into the pathological range in future generations; a result between 36 and 39 repeats is abnormal, but it is possible that a person may develop the condition late or even live a full life and not develop HD; 40 or more repeats is considered definitely abnormal (ASHG/AMCG statement, 1998). At a mathematical level, there is a correlation between the average age of onset and the CAG repeat size but there is such a wide variation that it is not possible to predict the age of onset for an individual from knowing the CAG repeat size.
An asymptomatic individual with an affected parent has a prior probability of 50% of inheriting the HD gene. Such a person could have a genetic test at this stage. This is called a predictive test. As there is no effective treatment to alter the natural history of HD such tests are used cautiously in conjunction with counselling and according to widely accepted international guidelines drawn up by an ad hoc committee of the International Huntington’s Association/World Federation of Neurology Research Group on Huntington’s chorea (1994). Less than 20% of adults at risk of HD choose to have a predictive test (Tassiker et al., 2009).
Genetics
Pathology
The gene is widely expressed in the cells of the body but some cells within the brain are very sensitive to abnormal huntingtin and there is selective neurodegeneration. An explanation for the selective neurodegeneration characteristic of HD is unclear. The most striking cell loss occurs in the basal ganglia but other areas of the brain including the cortex are also affected. The anatomy of the basal ganglia is shown in Figure 7.1. To emphasize this point it should be noted that the brain of a patient with HD will be smaller and weigh less than that of an age-matched control. The efferent medium spiny neurons within the caudate and putamen nuclei, which are collectively called the striatum, are especially sensitive to the abnormal huntingtin protein (see Figure 7.2).
Implications of pathology for understanding the movement disorder
The striatum receives excitatory inputs from the cortex. The efferent medium spiny neurons contain inhibitory neurotransmitters which project to the internal globus pallidus via direct and indirect pathways (Albin et al., 1989). Figure 7.3 shows a simplified diagram of the process. In broad terms, damage to the indirect pathway leads to overstimulation of the thalamo-cortical feedback and chorea (random purposeless movements), whereas loss of the direct pathway results in increased inhibition of the thalamus and less activity of the thalamo-cortical feedback producing bradykinesia and rigidity. Although both pathways degenerate, the balance between them is disturbed. The medium spiny neurons of both the direct and indirect pathways contain dopamine receptors, which are consistently reduced in Huntington’s disease. Conventionally, excitatory D1 receptors are on the direct and inhibitory D2 receptors are on the indirect pathway. This means that whilst it is possible to control the chorea of patients with dopa blocker and dopa depleting drugs, this may worsen the bradykinesia and dystonia.
Understanding pathology at the level of the cell
HD should be easy to explain because one gene is involved with one mutation that affects a single protein. Unfortunately, this is not the case because huntingtin is involved in many cellular processes. Apart from man, no natural animal develops HD. Following the identification of the gene a tremendous research effort involved developing animal models. The first of these, and most studied, was the R6 mice which contain multiple copies of the first part of the HD gene (Mangiarini et al., 1996). These mice die before they develop significant cell death. One feature of the cells is that they contain aggregates of the first part of the huntintin protein (Davies, et al., 1997). These aggregates are now recognized as occurring in human HD brains (DiFiglia et al., 1997). It is unclear as to whether these aggregates are directly related to the cellular pathology or represent a defence mechanism within the cell. There are a number of different animal models; details of their similarities and differences are not relevant to this chapter, but animal models have enabled an understanding that neuronal cells are dysfunctional (‘sick’) before they die which gives hope for interventions to alter the natural history of the disease. This natural history is modelled in Figure 7.4 with neuronal dysfunction preceding the onset of symptoms. In the absence of serendipity, an understanding of the pathology at the cellular level using animal and cellular models is the way forward for developing and subsequently testing new treatments for HD.
Figure 7.4 Primary physiotherapy aims and the continuum of Huntington’s disease.
(Modified from the Walker et al., Huntington’s Disease. Lancet 2007;369 (9557): 218-28, with permission from Elsevier.)
Pathology
Life history of the disease
If a person has inherited the gene there will be a period of time where she/he is completely asymptomatic. In time, the neurones become dysfunctional. Onset of HD is insidious with non-specific problems such as mood change or being slightly forgetful, which can be attributed easily to other mundane causes. A person in this prodromal stage may become depressed, but a clinical diagnosis cannot be made confidently until motor signs, such as chorea, appear. These may be infrequent, of low amplitude and may not be noticed by the patient, family or clinician with limited experience of the condition. Indeed even at a time when the chorea is quite obvious it may be denied as a problem by the patient (Snowden et al., 1998).
If a patient is seen when there are obvious signs of HD, the CAG repeat size may be measured from a venous blood sample to confirm the clinical diagnosis. It is important to realize that the result of the genetic test will be the same whether the individual is completely asymptomatic, in the prodromal phase, or in the early, middle or later stages of HD. As with any test the interpretationof the test result depends upon the clinical context. This raises an important issue about the genetic test: it is a ‘trait marker’ but says nothing about the state of the illness. There is a significant research effort to determine other laboratory biomarkers (‘state markers’) which can track the development and progression of the disease (Henley et al., 2005). The boundaries between early, middle and late stages are ill defined, but nonetheless they form a useful way of categorizing the impact of HD.
Clinical assessment
The Unified Huntington’s Disease Rating Scale (UHDRS) (Huntington Study Group, 1996) is a rating system that is used to quantify the severity of Huntington’s disease. It was developed as a clinical rating scale to assess four domains of clinical performance and capacity in individuals with HD: motor function, cognitive function, behavioural abnormalities, and functional capacity. These scores can be calculated by summing the various questions of each section. The UHDRS is useful for tracking changes in the clinical features of HD over time, and appears to be appropriate for repeated administration during clinical studies. Stages in Huntington’s disease are traditionally defined by the Total Functional Capacity scale, developed by Shoulson and Fahn (1979), which classifies patients into one of five stages of disease progression (Marder et al., 2000). The staging evaluates patients based on functioning for ADLs, domestic chores, finances, work and overall care level. Mid-stage is typically defined as levels II-III (see Table 7.1).
Stage I (Early stage)
In the early stages of the disease, the person with HD is able to remain functional and independent, retaining their ability to work and drive (HDSA, 2000). Movement disorders include minor involuntary movements, reduced coordination and linearly progressive motor impersistence or inability to maintain a voluntary muscle contraction at a constant level (Walker, 2007). Even at this stage, it may be possible to detect some slowing of saccadic eye movements (rapidly moving the eye to a new target; this is done by asking the patient to move his/her eye to one corner in response to a cue). Voluntary motor tasks (fine and gross motor skills) may become increasingly difficult as the disease progresses (Aubeeluck & Wilson, 2008). Cognitive tasks also become more difficult with reduced ability to sequence and organize information (HDSA, 2000). Deficits in gait have been identified across the spectrum of HD (Churchyard et al., 2001; Grimbergen et al., 2008; Hausdorff et al., 1998; Koller & Trimble, 1985; Rao et al., 2008). Decreased gait velocity, stride length, and increased time in double support compared to healthy controls may occur (Rao et al., 2008). These impairments appear to worsen with increasing disease severity and can be useful markers of disease progression and treatment efficacy.
Stage II and III (Middle stage)
During the middle stages of HD, involuntary movements such as chorea increase. In the early stages of HD, this is typically seen in the fingers, hands and face muscles, but as the disease progresses, it can be seen throughout thebody, including in all four extremities and the trunk. Chorea does not usually result in a direct impairment of motor function, however voluntary motor impairments may have a functional impact (Walker, 2007).
Dystonic postures (abnormal, sustained posturing) in sitting or standing (Louis et al., 1999) and in movements such as shoulder elevation, foot inversion and supination, and trunk extension might be present. People may experience frequent loss of balance and falls, which interfere with their ability to walk and maintain an upright position (Busse et al., 2009). Common tasks during which patients demonstrate balance problems include those where the base of support is decreased; tandem standing and walking, dual tasks, eyes closed and in response to external perturbations (Bilney et al., 2003b; Quinn & Rao, 2002). Falls are frequent in people with HD; 60% of people with early to mid-stage HD in two separate studies (n=45 & n=24) reported two or more falls in the previous 12 months (Busse et al., 2009; Grimbergen et al., 2008). Falls can have physical and psychological consequences (Myers et al., 1996). The fear of future falls may be a more pervasive problem than falls per se, as fear of falls may lead to people restricting their physical activities. Self-imposed restriction of daily activities leads to immobility and consequently osteoporosis, reduced fitness and social isolation (Grimbergen et al., 2004). Individuals with HD have also been found to have lower-limb muscular weakness compared to age-matched controls (Busse et al., 2008a). Strength can be measured clinically by manual muscle testing or by functional observation of strength during task performance (e.g. stair climbing or evidence of gait deviation during walking).
Stage IV and V (Late stage)
In the advanced stages of the disease motor symptoms continue to progress, severely limiting mobility. Choreic and dystonic movement may further increase (see Figure 7.4), but involuntary movements are often overshadowed by Parkinsonian symptoms (Aubeeluck & Wilson, 2008; HDSA, 2000) such as bradykinesia or slowness of movement. People with HD can also experience pain, particularly in the later stage of the disease. The source of this pain can be unknown; however, dystonia or muscle imbalances can often cause musculoskeletal pain. Excessive chorea can cause pain if people injure themselves by hitting their arm or leg into an object or hard surface.
Weight loss can occur in part due to impaired swallowing function (Aubeeluck & Wilson, 2008; HDSA, 2000). People may no longer be able to work or drive and will need assistance when performing some activities of daily living (ADL) (HDSA, 2000).
Even though people with HD appear to be in constant movement, their underlying volitional movements during task performance have been found to be slower than healthy controls for reaching (Quinn et al., 2001) and ambulation (Delval et al., 2006; Delval et al., 2007). Bradykinesia can typically be evaluated by measuring time to complete a task (movement time). Akinesia or delayed initiation of movement is also seen. In research studies, akinesia is typically measured by reaction time. In the clinical setting, it is often difficult to quantitatively evaluate akinesia, but delays in onset of movement for various tasks can be noted. Impaired speech results in difficulties communicating, and cognitive and psychiatric deterioration may continue, but it is thought that patients retain some comprehension (HDSA, 2000). At this stage most people will require assistance in all aspects of daily living, relying fully on nursing care (HDSA, 2000). Despite the severity of the neurological disorder, the primary causes of death in HD are aspiration pneumonia, cardiovascular disease and complications from falls (Sorensen & Fenger, 1992; Walker, 2007).
Physiotherapy assessment
The physiotherapy aims should be both anticipatory and responsive to the disease stage (see Figure 7.4) with interventions to assist HD patients to maintain independence, functional capacity and participation in society (Bilney et al., 2003a).
The World Health Organization International Classification of Functioning, Disability and Health (ICF) (WHO, 2001) is useful as an aid in structuring assessment of a person’s functioning and participation (see Figure 7.5), and in allowing consideration of the triad of motor, cognitive and psychiatric symptoms that are often seen in HD. The ICF can be used for functional status assessment, goal setting and treatment planning, and focuses on aspects of a person’s health and health-related wellbeing in terms of activities and participation, i.e. the description of the tasks (activities) and/or life situations (participation) in which the person wishes to engage, and the impact that impaired body function or structure is having on these aspects. The ICF further takes into consideration the contextual factors (both environmental and personal), which may impact on a person’s life, and the relationships with body function/structure, activities and participation. The specific impairments and associated activities and participations that may need consideration when assessing a person with HD are listed in Table 7.2. Documentation of the impact of the noted impairments on functional abilities, activities and participation is important to help highlight specific factors that contribute to a patient’s functional problems and inform the clinical reasoning process in terms of maximizing functional abilities. Qualifiers of the degree of impairment, and the performance and capacity of activities and participation enable essential documentation of disability and health status.
Table 7.2 Specific impairments and associated activities and participations that may need consideration when assessing a person with Huntington’s disease
| Impairments in Body Structure and Function | |
|---|---|
| B1 Global and specific mental functions B3 Voice and speech functions b 440-449 Functions of the respiratory system B7 Neuromusculoskeletal and movement functions b 730-749 Muscle functions b 750-789 Movement functions S1 Structures of the nervous system S7 Structures related to movement | Cognitive-perceptual: Memory Executive functions Spatial abilities Neuromuscular: Chorea Dystonia Strength Flexibility |
| Functional Abilities | |
|---|---|
| Activities and participation | |
| D1 Learning and applying knowledge D2 General tasks and demands D3 Communication D4 Mobility d 410-429 Changing and maintaining body position d 460-469 Walking and moving D5 Self care D6 Domestic life D7 Interpersonal interactions D8/9 Major life areas and community life For each functional activity, therapists should evaluate and document the level of assistance or caregiver burden needed to complete the task, and also determine the patient’s skill level (e.g. time to complete task, consistency of task performance, etc). This section can include any of the following skills, as appropriate: self-care and home management including activities of daily living (bed mobility, dressing, self care, toileting, bathing, eating, cooking, preparing meals and instrumental activities of daily living) Listing of specific skills assessed (e.g. ambulation, sitting ability, standing ability, sit to stand, wheelchair skills, stair climbing, feeding, bed mobility). Therapists should evaluate and document the functional performance of skills that are pertinent to the person with HD’s independence. | Speech Feeding, drinking (swallowing, sucking) Bathing, toileting, dressing Household chores Cooking, cleaning Walking (distance, speed, shoes) |
| Environmental Factors | |
|---|---|
| E1 Products and technology e 120 assistive products E3 Support and relationships E4 Attitudes E5 Services and systems For each functional activity, therapists should evaluate and document the level of assistance or caregiver burden needed to complete the task, and also determine the patient’s skill level (e.g. time to complete task, consistency of task performance, etc.). This section can include any of the following skills, as appropriate: Assistive and adaptive devices Environmental, home and work (job/school) barriers | Equipment: Assistive devices, feeding drinking, dressing equipment Wheelchair, brace, walker |
Specific coding for the domains are shown.
The subjective assessment allows the physiotherapist to evaluate the patient’s presenting problem(s), in the contextof their past medical history and how this may affect their ability to live independently and within society. This also provides the opportunity to build a therapeutic, collaborative relationship, and facilitate realistic goal setting. It must be noted that the patient’s caregiver(s) should be involved, particularly if the patient has difficulties communicating as a result of cognitive or physical impairment. The objective assessment should include assessment of neuromuscular, musculoskeletal (posture, range of motion, pain and muscle strength), cardio-respiratory and cardio-vascular impairments. An overview of the HD specific considerations for the physiotherapy assessment is shown in Table 7.3. These are useful to aid clinical reasoning and goal setting but are not necessarily outcomes that are sensitive to change over time. There are numerous outcome measures that have potential utility in the assessment of efficacy of physiotherapy interventions for people with HD. Measurement tools that have been used in previous HD-related studies are presented in Table 7.4 and are classified according to the WHO ICF. The Berg Balance Scale, Timed Up and Go Test and the Functional Reach Test have all been found to be valid and responsive clinical measures in HD and are considered useful to detect those at risk of falls (Busse et al., 2009; Grimbergen et al., 2008; Rao et al., 2009).
Table 7.3 Specific assessment points for consideration in Huntington’s disease
| Subjective Assessment |
|---|
| Patient information and demographics Current condition: concerns that led the patient to seek services of physiotherapist; current and prior therapeutic interventions; current stage of Huntington’s disease (HD) and age of onset Past medical history: prior hospitalizations, surgeries and pre-existing medical and other health-related conditions; family history Medications: list any medications taken for HD symptoms as well as for other medical conditions Home environment, i.e. living environment and community characteristics; family and living situation; family and caregiver resources; assistive devices and equipment Employment/work, i.e. current work situation and requirements Health status, i.e. prior functional status in self care and home management, including activities of daily living (ADLs) and instrumental activities of daily living (IADLs). Community, leisure and social activity participation General health perception/quality of life Physical function (e.g. mobility, sleep patterns, restricted bed days) Psychological function (e.g. memory, reasoning ability, depression, anxiety) Behavioural health risks (e.g. smoking, drug abuse) Level of physical fitness |
| Objective Assessment | Specific Assessment Points |
|---|---|
| Posture: Head/neck/trunk, upper extremities and lower extremities | Standing and sitting |
| Respiratory function: Lung function tests may highlight obstructive or restrictive disorders of the respiratory system. Measurement of vital capacity in supine and upright positions can identify weakness of the diaphragm (American Thoracic Society, 2002). Forced expiratory Volume in 1 second (FEV1), Forced Vital Capacity (FVC), FEV1/FVC ratio, Peak Expiratory Flow Rate (PEFR) should also be considered using standardized spirometry techniques (Miller et al., 2005). | Ausculatation Breathing patterns Cough Exercise tolerance |
| Skin integrity | Decubiti, abrasions, open wounds |
| Pain | Location, type, pain scale rating |
| Sensation | Location, type |
| Reflexes | Clonus Babinski |
| Range of motion: Head/neck/trunk, upper extremities and lower extremities | Active and passive movements |
| Movement patterns: Chorea, dystonia, bradykinesia, tremor and rigidity | Consider all affected body segments |
| Mobility: Gait assessment | Base of support Tonal changes Deviations |
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