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Perspectives in Psychiatric Care
ISSN 0031-5990
Biological Perspectives
Huntington’s Disease* Peter C. Kowalski, MD, David C. Belcher, DO, Norman L. Keltner, EdD, CRNP, and Jonathan S. Dowben, MD Peter C. Kowalski, MD, is Psychiatrist, Private Practice, Fort Worth, Texas, USA; David C. Belcher, DO, is Psychiatrist, Department of Psychiatry, United States Air Force, San Antonio, Texas, USA; Norman L. Keltner, EdD, CRNP, is Professor (retired), School of Nursing, University of Alabama at Birmingham, Birmingham, Alabama, USA; and Jonathan S. Dowben, MD, is Psychiatrist, Pediatric and Behavioral Health Service, Brooke Army Medical Center, San Antonio, Texas, USA. Author contact: [email protected], with a copy to the Editor: [email protected] doi: 10.1111/ppc.12121
Huntington’s disease, or HD, is a progressive inherited neurodegenerative disorder which causes disturbances in movement; specifically, choreiform or involuntary and nonrepetitive dance-like movements. It also causes a specific type of dementia and a variety of psychiatric disturbances such as depression, agitation, irritability, apathy, anxiety, delusions, and hallucinations. HD has an irreversible and fatal course and the underlying condition itself is currently untreatable. This article discusses ways to understand and treat the cognitive and psychiatric symptoms of HD. HD was first identified in 1872 by New York physician George Huntington, who studied a group of patients whose ancestors had immigrated from Suffolk, England, in 1630. These affected family members had also been followed by Huntington’s physician father and grandfather. HD currently affects approximately 30,000 people in North America, and occurs in five to eight persons per 100,000. It is less frequent in African and Asian populations, and usually presents in the third decade of life, although it may have juvenile onset. Its classic motor finding consists of writhing chorea, dysarthrias, dystonias, and rigidity. Before discussing cognitive and psychiatric symptoms, brief reviews of genetic, neuroanatomical, and physical considerations are presented. Reviews of Genetic, Neuroanatomical, and Physical Considerations Genetic Considerations HD is caused by the toxic presence of a mutant form of the protein huntingtin (Htt) which serves an important yet incompletely understood function for nerve growth and development. Everyone has the huntingtin gene on chromosome 4 and on that gene we have what is called a C-A-G
trinucleotide (i.e., three back-to-back Cytosine-AdenineGuanine nucleotides or CAGCAGCAG). This trinucleotide itself is repeated normally in all people. However, whenever the repetition of C-A-G extends too far, a neuron-killing, mutant form of huntingtin protein (mHtt) is developed. C-A-G repeats of 27 or fewer is normal while a sequence of repeats over 40 is considered abnormal and causes HD. An intermediate range from 27 to 39 repeats is found in some people, with people at the higher end of this range at risk for developing HD (Yudofsky & Hales, 2004). In the peripheral body, this abnormal protein does not kill cells, but in the brain, it does. mHtt appears to bind to a specific brain protein called HAP-1, as opposed to normal Htt binding with another protein (called HIP-1) (Yudofsky & Hales, 2004). These protein interactions appear to be what leads to nerve cell death, and this occurs most markedly in the striatum of the basal ganglia (i.e., the caudate nucleus and putamen). Huntingtin gene mutation is autosomal, meaning it is not sex linked, so a child with one affected parent has a 50% chance of inheriting HD. It is a dominant mutation, meaning that only one copy in a pair of chromosomes is sufficient to show up in the brain and cause HD (e.g., think of eye color— one brown gene [dominant] is enough to cause brown eyes but it takes two blue genes [recessive] for blue eyes). Persons with two normal copies of the huntingtin gene will not develop HD. Interestingly, a process termed “anticipation” occurs in the genetic transmission of the abnormal huntingtin gene, whereby the child of a person with HD has a greater number of C-A-G repeats than the parent did. This (i.e., a greater number of repeats) is more likely to be passed on by a father than a mother, and accounts for an earlier age of onset of HD. Neuroanatomical Considerations
*In memory of Landon W., the loving and gifted son of our friend and colleague. May Landon rest in peace. We also honor Landon’s mother, whose beautiful spirit and faithfulness to her family shine through the grim progression of this disease.
Perspectives in Psychiatric Care 51 (2015) 157–161 © 2015 Wiley Periodicals, Inc.
The brain contains certain groups of nerve cells which smoothly coordinate nervous signals from different brain levels for a variety of purposes. Muscle movement, for 157
Huntington’s Disease
example, is initiated by the motor cortex, while implementation of that action occurs via the effector neuron acting on the skeletal muscle (e.g., the hand). Intermediate nerve groups relaying those signals, located in subcortical areas deep inside and beneath the outer cortical layer, serve as relay switches for the smooth and coordinated operation of the muscular apparatus of the body. These subcortical nuclei are called the basal ganglia and consist of the caudate nucleus, the putamen, and the globus pallidus. They send signals through a brain area called the thalamus back to the cortex to reinforce the effectiveness of the cortex in movement. In return, sensory feedback transmits information about the outcome of the affected activity from the thalamus to the cortical level. In this fashion, the basal ganglia function to the cortex much like an executive assistant functions to a company’s CEO, both relaying messages to and from the top to middle level management and then throughout all portions of the organization. A company is likely to function at peak efficiency with an experienced and well-organized executive assistant in place, and is likely to function poorly when that person is sick. Similarly, if portions of the basal ganglia are affected by disease or deterioration, the whole top-down control and bottom-up feedback loop of important brain functions is seriously compromised. Physical Considerations This neuroanatomical feedback loop is called a frontalsubcortical circuit, or FSC. A forward flow of information originates in the cortex, and flows to the striatum (i.e., the caudate nucleus and putamen nuclei of the basal ganglia), meets with some additional refinement in the globus pallidus (another nuclei of the basal ganglia), and returns information via the “central warehouse” of sensory information known as the thalamus back up to the cortical level. Initially thought to function only in the process of voluntary muscle control, it has been discovered that FSCs play a central role in the regulation of affect, thought, and behavior. Degeneration of one particular basal ganglia nucleus (the medial portion of the caudate nucleus) causes excessive movements and the loss of normal inhibition of muscular control. This results in chorea, dysarthria (loss of muscle group coordination in the mouth), dystonia (loss of muscle group coordination in other areas), bradykinesia, rigidity, myoclonus, tics, and tremor. But the destruction of the caudate nucleus disrupts the principal emotional (via the orbital FSC) and memory functions (through the dorsolateral FSC) that route through this subcortical area. Cognitive and Psychiatric Symptoms Cognitive Symptoms In other types of dementias, damage occurs to actual cortical structures such as loss of hippocampus and entorhinal cortex 158
in Alzheimer’s dementia (AD), or frontal or temporal lobe atrophy in frontotemporal dementia. In HD, the central executive portion (see Table 1) of working memory (the limited capacity to hold about seven items for only very short periods) presents as impairment in episodic memory (information that is stored in longer periods with temporal and spatial context). Unlike patients with AD (see Table 2), who are unable to retrieve information from episodic memory even with recognition cues, patients with HD perform well when recognition demands are minimized, and they are able to retain information over a nearly normal period. They have little difficulty retrieving memory across the course of their lives. But because of difficulty in initiating retrieval, in a free recall task, they display trouble producing episodic memories (Campbell & Tisher, 2014). Inherent in HD is a loss of cognitive speed, and an impaired ability to organize information, shown as a decline in attention/concentration and mental flexibility. Deficits in the ability to synthesize information in order to produce alternative solutions for problems, visuospatial functioning, and planning are also present (Campbell & Tisher, 2014). An affected person’s ability to initiate behavior is diminished. Family members will complain that an HD patient “won’t do anything.” Once started on a task, however, they will follow through. Perseveration is common, as persons will become fixated on thoughts or behaviors to the detriment of other activities. Impulsivity can become a major problem, encompassing behaviors such as stealing, gambling, inappropriate sexual activities, and irritability. Temper outbursts are an outcome of loss of impulse control, confusion, and feeling overwhelmed. HD patients are challenged by the inability to perform everyday routines, losing abilities imperceptibly over time. Outbursts can become violent, and the patient may quickly forget about the incident while leaving family members upset and shaken. Unlike AD, where the implicit memory or the ability to repeat well-practiced behavioral routines is preserved, patients with HD lose implicit memory. Activities like riding a bike, playing an instrument, and driving a car progressively deteriorate, and eventually the ability to chew and swallow without choking is lost. Perception is impaired in several ways. HD patients lose the ability to recognize emotions on the face. They can remember and identify emotions, but their lack of recognition can lead to difficulties in social relationships. Their perception of time is altered, particularly the correlation of one’s internal clock with objective time. Persons who may have been punctual become late. Spatial and smell perceptions weaken. A person with HD often loses a sense that something is wrong with him, which is not necessarily psychological denial. This “organic denial,” or anosognosia, is not a willful rejection of facts, but is an outcome of disruption in frontal-subcortical circuitry. Perspectives in Psychiatric Care 51 (2015) 157–161 © 2015 Wiley Periodicals, Inc.
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Table 1. Memory Systems and Corresponding Brain Regions Memory is not a homogenous single entity in one brain area. The “Central Executive System” in prefrontal cortex coordinates information from various memory subsystems (see below). Working memory It can hold about seven items for 20–30 s. It resides in prefrontal cortex and consists of: Phonological loop—holds speech-based information (e.g., a phone number you have just heard) Visuospatial scratchpad—holds visuospatial information (e.g., looking at a street map for directions) Declarative memory Also known as explicit memory, recall is based on explicit retrieval of information. It consists of: Episodic memory—memories that are linked by co-occurrence or context; the recording and conscious recollection of personal experiences (words, faces, scenes, stories, events) are stored in separate cortical association areas. They are combined by medial temporal lobe structures including hippocampus and entorhinal cortex for whole memory retrieval, like an air traffic controller connects a specific jet to a specific runway. Storage is based on spatial or temporal context. Remembering what you had for breakfast this morning is facilitated by associations of other cues experienced at that time (e.g., the smell of fresh eggs cooking, the noises of fussy kids or a cranky spouse). The strength of retrieval diminishes from minutes to years. Semantic memory—memories that cannot be fixed as having been acquired at a specific time or location. An example would be knowing the person and year America was discovered. You would not remember where or when you first learned it; its context has been lost, but the knowledge remains. It is knowledge that is not dependent on contextual cues for retrieval. It is located in the temporoparietal association cortices. Nondeclarative memory Also known as implicit memory, memory tasks are not mediated by conscious processes, but demonstrated by performance behaviors. This is where skills and habits are stored. It is “knowing how,” rather than “knowing that.” There are several types, but the most important is: Procedural memory—retrieval of motor behaviors or sequences of tasks that have been performed (e.g., riding a bicycle). No specific brain location has been identified, but it appears to be mediated by several reciprocal parallel circuits that project from cortex to basal ganglia. The Central Executive System An integration of memory systems, sensory and perceptual structures, and effector (“that which makes things happen,” e.g., skeletal movement, visceral responses) systems. It monitors the environment, identifies relevant stimuli, devises plans of action to engage the environment, implements the plan, monitors it on the basis of an anticipated result, modifies it as needed to achieve the intended outcome, and remembers the experience. (Heindel & Salloway, 1999)
Psychiatric Symptoms Table 2. Difference Between Alzheimer’s Disease and Huntington’s Disease Alzheimer’s disease • • • • • • •
Damage to cortical areas, specifically medial temporal lobes True episodic memory impairment Patients cannot acquire new information No improvement with recognition format Patient recalls only the most recent information in free recall Rapid forgetting of information over time Actual loss of semantic memory from degeneration of cortical association areas • Procedural memory remains intact Huntington’s disease • Damage to subcortical areas: caudate nucleus (primary) and putamen • Medial temporal lobes are left intact • Degeneration of basal ganglia causes subsequent frontal-subcortical dysfunction with impairment to the central executive system component of working memory • Apparent episodic memory impairment (i.e., free recall is tested) • Good episodic memory when retrieval demands are minimized and recognition is assisted • Normal semantic memory—cortical association areas remain intact • Procedural memory is impaired due to damage to basal ganglia which causes frontal-subcortical dysfunction
Perspectives in Psychiatric Care 51 (2015) 157–161 © 2015 Wiley Periodicals, Inc.
The comorbid mental illness prevalence rate ranges from 33% to 69% in patients with HD, with the lifetime prevalence of depression in persons with HD estimated to be around 40% (Van Duijn, Kingma, & van der Mast, 2007). This, while among the most under-recognized and under-treated aspects of HD, is one of the most disabling features despite being the most treatable. It appears to be a direct neurological consequence of the brain condition, rather than a psychological reaction to this serious illness. Diagnosis is based on the same criteria for nonorganic major depressive disorder (MDD; see DSM 5), and as with MDD, other secondary causes of depression, such as hypothyroidism, stroke, head injury, and medications/abused substances, should be considered (Johnson & Paulsen, 2014). Suicidality, while high in this population (see Table 3) because of depression and impulsivity, is a natural consequence of the disease state, and is preventable. It is by no means a “rational” decision to end a life of prolonged suffering, assuming such a decision could be defended as rational. Mania, although less common than depression in HD patients, can emerge but diagnostic caution is advised due to the inherent irritability and impulsivity of the disease. Sustained and nontransient mood lability, as well as vegetative 159
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Table 3. Suicide and Huntington’s Disease — HD is uncommon, but be ready to identify its signs and symptoms, especially suicidality, because of its high prevalence in this group. Suicide rates in persons with Huntington’s disease increase up to 12-fold to that of the general population (Paulsen & Ferneyhough, 2005). — There are two critical periods during HD progression when patients are most at risk of suicide, the first at the time of diagnosis and the other when one begins to lose functional independence from neurological dysfunction (Paulsen & Ferneyhough, 2005). — Routinely screen these patients for depression and its severity. Initiate treatment and communicate with other specialty providers. — Most depression questionnaires include somatic complaint items that are commonly associated in depressed individuals without comorbid neurocognitive illness such HD. Questionnaires such as the Beck’s Depression Inventory can be confusing because patients with HD will have somatic complaints that are not directly associated with depression (Rickards et al., 2011). For example, asking a patient about weight loss, changes in sleep, and memory problems may inaccurately over-portray depression as a primary condition at the risk of under-recognizing the somatic manifestations of HD. — One particular study discovered that the best approach to adequately screen for depression in patients with HD is to include questions that relate to loss of interest, feeling of guilt, and suicidality (Rickards et al., 2011).
changes, such as sleep, energy, and appetite, will help distinguish between bipolarity and HD (Johnson & Paulsen, 2014). The full manifestations of obsessive–compulsive disorder are rare in HD patients, but persons often become preoccupied with ideas or behaviors. For those patients who experience delusions and hallucinations, intoxicants and metabolic assessment must be considered in a differential diagnostic assessment. If other causes of psychosis have been ruled out, antipsychotics may be used to suppress psychotic symptoms and chorea (Nance, Paulsen, Rosenblatt, & Wheelock, 2011). Case Report A 34-year-old male patient with HD, referred by a movement disorder neurological specialist, presented with suicidal thoughts, anger, irritability, disrupted sleep patterns, forgetfulness, impulsivity which involved stealing money from family members, and gambling away the $4,000 which he had stolen. He displayed general inactivity and social isolation, and had experienced a gradual loss of autonomy and selfdirection in his functioning. He had witnessed his father’s recent demise from HD, was angry at his own condition, and scared about his eventual deterioration. He had alienated the family member from whom he had stolen the money, and felt this relationship was broken permanently. He had speech impairment, decreased concentration, trouble maintaining grip, balance and coordination difficulties, and chorea. He had previously taken one antidepressant prescribed by a neurologist, but had never consulted any mental health personnel, and was reluctant to join an HD support group. A neuropsychologist identified severe deficits in processing speed, sustained attention, resistance to distraction, visual attention, as well as mild deficits in cognitive flexibility and abstract reasoning, verbal and visual memory, expressive language abilities, olfactory discrimination, motor strength, and speed in motor programming and inhibition. A severe depressed mood with suicidal ideation and anxiety were noted during the testing. 160
Before testing positive for HD, the patient had graduated with a degree in chemical engineering and had experienced a successful career in the public sector in administration and in dealing with the public. His career faltered after the development of slurred speech and the onset of organizational problems. After a period of reckless gambling, he moved back to live with his mother. He became more withdrawn and irritable over the subsequent years. A brain MRI revealed subcortical degeneration. He did not undergo symptomatic treatment for movement problems initially, later taking tetrabenazine on a trial basis, which seemed to help his choreiform movements, gait, and behavioral regulation. He had no premorbid psychiatric history. His mother was especially concerned about his inability to express emotions. Mental status examination showed him to be alert and cooperative, with a wide-eyed and smiling, yet blank facial expression. Choreiform movement and a writhing dance-like and jerky gait and extremity movements were apparent. He was fully oriented, and his speech was slurred and mumbling. Signs of affect were limited to tightening of facial muscles when emotionally charged topics were broached. He was open about his suicidal thoughts, but tended to speak more readily about his angry feelings than his depression. He denied ever acting upon his suicidal ideation and had no previous suicide attempts or past or present plans to hurt himself. In general, he had poor awareness of his internal emotional status. He struggled with word finding, elaboration, and reflection over his decline from his previously high level of functioning. He performed better with “cues’” and with “either-or” types of questions than with open-ended questioning. His immediate memory,when assisted with cues,was intact,as was his semantic memory.He had difficulty with processing speed and attention. No psychotic symptoms were evident. His diagnoses were dementia secondary to HD, mood disorder secondary to HD with depressive features, and a family member relational problem, as well as the underlying primary condition of HD. Perspectives in Psychiatric Care 51 (2015) 157–161 © 2015 Wiley Periodicals, Inc.
Huntington’s Disease
Medication management and supportive psychotherapy were recommended, and he met in bimonthly follow-up sessions. He was prescribed paroxetine, initially at 20 mg/day, and dosing was increased over subsequent visits because of incomplete responsiveness at lower doses. Later, olanzapine at 2.5 mg nightly was added to address sleep and anxiety difficulties, and then increased to 5 mg per night. His mood and irritability improved and participation in HD support groups and end-of-life planning was encouraged, but he was reluctant to undertake these efforts at the time of this report. References Campbell, J. J. III., & Tisher, A. (2014). Clinical assessment of dysexecutive syndromes. Psychiatric Times, 31, 34–38. Heindel, W. C., & Salloway, S. (1999). Memory systems in the human brain. Psychiatric Times, 16(6), 19–21. Johnson, A. C., & Paulsen, J. S. (2014). Understanding behavior in Huntington’s disease: A guide for professionals. New York: Huntington’s Disease Society of America.
Perspectives in Psychiatric Care 51 (2015) 157–161 © 2015 Wiley Periodicals, Inc.
Nance, M., Paulsen, J. S., Rosenblatt, A., & Wheelock, V. (2011). A physician’s guide to the management of Huntington’s disease (3rd ed.). New York: Huntington’s Disease Society of America. Paulsen, J., Ferneyhough, H., Nehl, C., Stierman, L., & The Huntington Study Group. (2005). Critical periods of suicide risk in Huntington’s disease. American Journal of Psychiatry, 162(4), 725–731. doi:10.1176/appi.ajp.162.4.725 Rickards, H., De Souza, J., Crooks, J., van Walsem, M. R., van Duijn, E., Landwehmeyer, B., & European Huntington’s Disease Network. (2011). Discriminant analysis of Beck depression inventory and Hamilton rating scale for depression in Huntington’s disease. Journal of Neuropsychiatry and Clinical Neurosciences, 23(4), 399–402. doi:10.1176/appi.neuropsych.23.4.399 Van Duijn, E., Kingma, E. M., & van der Mast, R. C. (2007). Psychopathology in verified Huntington’s disease gene carriers. Journal of Neuropsychiatry and Clinical Neurosciences, 19(4), 441–448. doi:10.1176/appi.neuropsych.19.4.441 Yudofsky, S. C., & Hales, R. E. (Eds.). (2004). Essentials of neuropsychiatry and clinical neurosciences (pp. 201–209). Arlington, VA: American Psychiatric Publishing.
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Perspectives in Psychiatric Care
ISSN 0031-5990
Biological Perspectives
Huntington’s Disease* Peter C. Kowalski, MD, David C. Belcher, DO, Norman L. Keltner, EdD, CRNP, and Jonathan S. Dowben, MD Peter C. Kowalski, MD, is Psychiatrist, Private Practice, Fort Worth, Texas, USA; David C. Belcher, DO, is Psychiatrist, Department of Psychiatry, United States Air Force, San Antonio, Texas, USA; Norman L. Keltner, EdD, CRNP, is Professor (retired), School of Nursing, University of Alabama at Birmingham, Birmingham, Alabama, USA; and Jonathan S. Dowben, MD, is Psychiatrist, Pediatric and Behavioral Health Service, Brooke Army Medical Center, San Antonio, Texas, USA. Author contact: [email protected], with a copy to the Editor: [email protected] doi: 10.1111/ppc.12121
Huntington’s disease, or HD, is a progressive inherited neurodegenerative disorder which causes disturbances in movement; specifically, choreiform or involuntary and nonrepetitive dance-like movements. It also causes a specific type of dementia and a variety of psychiatric disturbances such as depression, agitation, irritability, apathy, anxiety, delusions, and hallucinations. HD has an irreversible and fatal course and the underlying condition itself is currently untreatable. This article discusses ways to understand and treat the cognitive and psychiatric symptoms of HD. HD was first identified in 1872 by New York physician George Huntington, who studied a group of patients whose ancestors had immigrated from Suffolk, England, in 1630. These affected family members had also been followed by Huntington’s physician father and grandfather. HD currently affects approximately 30,000 people in North America, and occurs in five to eight persons per 100,000. It is less frequent in African and Asian populations, and usually presents in the third decade of life, although it may have juvenile onset. Its classic motor finding consists of writhing chorea, dysarthrias, dystonias, and rigidity. Before discussing cognitive and psychiatric symptoms, brief reviews of genetic, neuroanatomical, and physical considerations are presented. Reviews of Genetic, Neuroanatomical, and Physical Considerations Genetic Considerations HD is caused by the toxic presence of a mutant form of the protein huntingtin (Htt) which serves an important yet incompletely understood function for nerve growth and development. Everyone has the huntingtin gene on chromosome 4 and on that gene we have what is called a C-A-G
trinucleotide (i.e., three back-to-back Cytosine-AdenineGuanine nucleotides or CAGCAGCAG). This trinucleotide itself is repeated normally in all people. However, whenever the repetition of C-A-G extends too far, a neuron-killing, mutant form of huntingtin protein (mHtt) is developed. C-A-G repeats of 27 or fewer is normal while a sequence of repeats over 40 is considered abnormal and causes HD. An intermediate range from 27 to 39 repeats is found in some people, with people at the higher end of this range at risk for developing HD (Yudofsky & Hales, 2004). In the peripheral body, this abnormal protein does not kill cells, but in the brain, it does. mHtt appears to bind to a specific brain protein called HAP-1, as opposed to normal Htt binding with another protein (called HIP-1) (Yudofsky & Hales, 2004). These protein interactions appear to be what leads to nerve cell death, and this occurs most markedly in the striatum of the basal ganglia (i.e., the caudate nucleus and putamen). Huntingtin gene mutation is autosomal, meaning it is not sex linked, so a child with one affected parent has a 50% chance of inheriting HD. It is a dominant mutation, meaning that only one copy in a pair of chromosomes is sufficient to show up in the brain and cause HD (e.g., think of eye color— one brown gene [dominant] is enough to cause brown eyes but it takes two blue genes [recessive] for blue eyes). Persons with two normal copies of the huntingtin gene will not develop HD. Interestingly, a process termed “anticipation” occurs in the genetic transmission of the abnormal huntingtin gene, whereby the child of a person with HD has a greater number of C-A-G repeats than the parent did. This (i.e., a greater number of repeats) is more likely to be passed on by a father than a mother, and accounts for an earlier age of onset of HD. Neuroanatomical Considerations
*In memory of Landon W., the loving and gifted son of our friend and colleague. May Landon rest in peace. We also honor Landon’s mother, whose beautiful spirit and faithfulness to her family shine through the grim progression of this disease.
Perspectives in Psychiatric Care 51 (2015) 157–161 © 2015 Wiley Periodicals, Inc.
The brain contains certain groups of nerve cells which smoothly coordinate nervous signals from different brain levels for a variety of purposes. Muscle movement, for 157
Huntington’s Disease
example, is initiated by the motor cortex, while implementation of that action occurs via the effector neuron acting on the skeletal muscle (e.g., the hand). Intermediate nerve groups relaying those signals, located in subcortical areas deep inside and beneath the outer cortical layer, serve as relay switches for the smooth and coordinated operation of the muscular apparatus of the body. These subcortical nuclei are called the basal ganglia and consist of the caudate nucleus, the putamen, and the globus pallidus. They send signals through a brain area called the thalamus back to the cortex to reinforce the effectiveness of the cortex in movement. In return, sensory feedback transmits information about the outcome of the affected activity from the thalamus to the cortical level. In this fashion, the basal ganglia function to the cortex much like an executive assistant functions to a company’s CEO, both relaying messages to and from the top to middle level management and then throughout all portions of the organization. A company is likely to function at peak efficiency with an experienced and well-organized executive assistant in place, and is likely to function poorly when that person is sick. Similarly, if portions of the basal ganglia are affected by disease or deterioration, the whole top-down control and bottom-up feedback loop of important brain functions is seriously compromised. Physical Considerations This neuroanatomical feedback loop is called a frontalsubcortical circuit, or FSC. A forward flow of information originates in the cortex, and flows to the striatum (i.e., the caudate nucleus and putamen nuclei of the basal ganglia), meets with some additional refinement in the globus pallidus (another nuclei of the basal ganglia), and returns information via the “central warehouse” of sensory information known as the thalamus back up to the cortical level. Initially thought to function only in the process of voluntary muscle control, it has been discovered that FSCs play a central role in the regulation of affect, thought, and behavior. Degeneration of one particular basal ganglia nucleus (the medial portion of the caudate nucleus) causes excessive movements and the loss of normal inhibition of muscular control. This results in chorea, dysarthria (loss of muscle group coordination in the mouth), dystonia (loss of muscle group coordination in other areas), bradykinesia, rigidity, myoclonus, tics, and tremor. But the destruction of the caudate nucleus disrupts the principal emotional (via the orbital FSC) and memory functions (through the dorsolateral FSC) that route through this subcortical area. Cognitive and Psychiatric Symptoms Cognitive Symptoms In other types of dementias, damage occurs to actual cortical structures such as loss of hippocampus and entorhinal cortex 158
in Alzheimer’s dementia (AD), or frontal or temporal lobe atrophy in frontotemporal dementia. In HD, the central executive portion (see Table 1) of working memory (the limited capacity to hold about seven items for only very short periods) presents as impairment in episodic memory (information that is stored in longer periods with temporal and spatial context). Unlike patients with AD (see Table 2), who are unable to retrieve information from episodic memory even with recognition cues, patients with HD perform well when recognition demands are minimized, and they are able to retain information over a nearly normal period. They have little difficulty retrieving memory across the course of their lives. But because of difficulty in initiating retrieval, in a free recall task, they display trouble producing episodic memories (Campbell & Tisher, 2014). Inherent in HD is a loss of cognitive speed, and an impaired ability to organize information, shown as a decline in attention/concentration and mental flexibility. Deficits in the ability to synthesize information in order to produce alternative solutions for problems, visuospatial functioning, and planning are also present (Campbell & Tisher, 2014). An affected person’s ability to initiate behavior is diminished. Family members will complain that an HD patient “won’t do anything.” Once started on a task, however, they will follow through. Perseveration is common, as persons will become fixated on thoughts or behaviors to the detriment of other activities. Impulsivity can become a major problem, encompassing behaviors such as stealing, gambling, inappropriate sexual activities, and irritability. Temper outbursts are an outcome of loss of impulse control, confusion, and feeling overwhelmed. HD patients are challenged by the inability to perform everyday routines, losing abilities imperceptibly over time. Outbursts can become violent, and the patient may quickly forget about the incident while leaving family members upset and shaken. Unlike AD, where the implicit memory or the ability to repeat well-practiced behavioral routines is preserved, patients with HD lose implicit memory. Activities like riding a bike, playing an instrument, and driving a car progressively deteriorate, and eventually the ability to chew and swallow without choking is lost. Perception is impaired in several ways. HD patients lose the ability to recognize emotions on the face. They can remember and identify emotions, but their lack of recognition can lead to difficulties in social relationships. Their perception of time is altered, particularly the correlation of one’s internal clock with objective time. Persons who may have been punctual become late. Spatial and smell perceptions weaken. A person with HD often loses a sense that something is wrong with him, which is not necessarily psychological denial. This “organic denial,” or anosognosia, is not a willful rejection of facts, but is an outcome of disruption in frontal-subcortical circuitry. Perspectives in Psychiatric Care 51 (2015) 157–161 © 2015 Wiley Periodicals, Inc.
Huntington’s Disease
Table 1. Memory Systems and Corresponding Brain Regions Memory is not a homogenous single entity in one brain area. The “Central Executive System” in prefrontal cortex coordinates information from various memory subsystems (see below). Working memory It can hold about seven items for 20–30 s. It resides in prefrontal cortex and consists of: Phonological loop—holds speech-based information (e.g., a phone number you have just heard) Visuospatial scratchpad—holds visuospatial information (e.g., looking at a street map for directions) Declarative memory Also known as explicit memory, recall is based on explicit retrieval of information. It consists of: Episodic memory—memories that are linked by co-occurrence or context; the recording and conscious recollection of personal experiences (words, faces, scenes, stories, events) are stored in separate cortical association areas. They are combined by medial temporal lobe structures including hippocampus and entorhinal cortex for whole memory retrieval, like an air traffic controller connects a specific jet to a specific runway. Storage is based on spatial or temporal context. Remembering what you had for breakfast this morning is facilitated by associations of other cues experienced at that time (e.g., the smell of fresh eggs cooking, the noises of fussy kids or a cranky spouse). The strength of retrieval diminishes from minutes to years. Semantic memory—memories that cannot be fixed as having been acquired at a specific time or location. An example would be knowing the person and year America was discovered. You would not remember where or when you first learned it; its context has been lost, but the knowledge remains. It is knowledge that is not dependent on contextual cues for retrieval. It is located in the temporoparietal association cortices. Nondeclarative memory Also known as implicit memory, memory tasks are not mediated by conscious processes, but demonstrated by performance behaviors. This is where skills and habits are stored. It is “knowing how,” rather than “knowing that.” There are several types, but the most important is: Procedural memory—retrieval of motor behaviors or sequences of tasks that have been performed (e.g., riding a bicycle). No specific brain location has been identified, but it appears to be mediated by several reciprocal parallel circuits that project from cortex to basal ganglia. The Central Executive System An integration of memory systems, sensory and perceptual structures, and effector (“that which makes things happen,” e.g., skeletal movement, visceral responses) systems. It monitors the environment, identifies relevant stimuli, devises plans of action to engage the environment, implements the plan, monitors it on the basis of an anticipated result, modifies it as needed to achieve the intended outcome, and remembers the experience. (Heindel & Salloway, 1999)
Psychiatric Symptoms Table 2. Difference Between Alzheimer’s Disease and Huntington’s Disease Alzheimer’s disease • • • • • • •
Damage to cortical areas, specifically medial temporal lobes True episodic memory impairment Patients cannot acquire new information No improvement with recognition format Patient recalls only the most recent information in free recall Rapid forgetting of information over time Actual loss of semantic memory from degeneration of cortical association areas • Procedural memory remains intact Huntington’s disease • Damage to subcortical areas: caudate nucleus (primary) and putamen • Medial temporal lobes are left intact • Degeneration of basal ganglia causes subsequent frontal-subcortical dysfunction with impairment to the central executive system component of working memory • Apparent episodic memory impairment (i.e., free recall is tested) • Good episodic memory when retrieval demands are minimized and recognition is assisted • Normal semantic memory—cortical association areas remain intact • Procedural memory is impaired due to damage to basal ganglia which causes frontal-subcortical dysfunction
Perspectives in Psychiatric Care 51 (2015) 157–161 © 2015 Wiley Periodicals, Inc.
The comorbid mental illness prevalence rate ranges from 33% to 69% in patients with HD, with the lifetime prevalence of depression in persons with HD estimated to be around 40% (Van Duijn, Kingma, & van der Mast, 2007). This, while among the most under-recognized and under-treated aspects of HD, is one of the most disabling features despite being the most treatable. It appears to be a direct neurological consequence of the brain condition, rather than a psychological reaction to this serious illness. Diagnosis is based on the same criteria for nonorganic major depressive disorder (MDD; see DSM 5), and as with MDD, other secondary causes of depression, such as hypothyroidism, stroke, head injury, and medications/abused substances, should be considered (Johnson & Paulsen, 2014). Suicidality, while high in this population (see Table 3) because of depression and impulsivity, is a natural consequence of the disease state, and is preventable. It is by no means a “rational” decision to end a life of prolonged suffering, assuming such a decision could be defended as rational. Mania, although less common than depression in HD patients, can emerge but diagnostic caution is advised due to the inherent irritability and impulsivity of the disease. Sustained and nontransient mood lability, as well as vegetative 159
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Table 3. Suicide and Huntington’s Disease — HD is uncommon, but be ready to identify its signs and symptoms, especially suicidality, because of its high prevalence in this group. Suicide rates in persons with Huntington’s disease increase up to 12-fold to that of the general population (Paulsen & Ferneyhough, 2005). — There are two critical periods during HD progression when patients are most at risk of suicide, the first at the time of diagnosis and the other when one begins to lose functional independence from neurological dysfunction (Paulsen & Ferneyhough, 2005). — Routinely screen these patients for depression and its severity. Initiate treatment and communicate with other specialty providers. — Most depression questionnaires include somatic complaint items that are commonly associated in depressed individuals without comorbid neurocognitive illness such HD. Questionnaires such as the Beck’s Depression Inventory can be confusing because patients with HD will have somatic complaints that are not directly associated with depression (Rickards et al., 2011). For example, asking a patient about weight loss, changes in sleep, and memory problems may inaccurately over-portray depression as a primary condition at the risk of under-recognizing the somatic manifestations of HD. — One particular study discovered that the best approach to adequately screen for depression in patients with HD is to include questions that relate to loss of interest, feeling of guilt, and suicidality (Rickards et al., 2011).
changes, such as sleep, energy, and appetite, will help distinguish between bipolarity and HD (Johnson & Paulsen, 2014). The full manifestations of obsessive–compulsive disorder are rare in HD patients, but persons often become preoccupied with ideas or behaviors. For those patients who experience delusions and hallucinations, intoxicants and metabolic assessment must be considered in a differential diagnostic assessment. If other causes of psychosis have been ruled out, antipsychotics may be used to suppress psychotic symptoms and chorea (Nance, Paulsen, Rosenblatt, & Wheelock, 2011). Case Report A 34-year-old male patient with HD, referred by a movement disorder neurological specialist, presented with suicidal thoughts, anger, irritability, disrupted sleep patterns, forgetfulness, impulsivity which involved stealing money from family members, and gambling away the $4,000 which he had stolen. He displayed general inactivity and social isolation, and had experienced a gradual loss of autonomy and selfdirection in his functioning. He had witnessed his father’s recent demise from HD, was angry at his own condition, and scared about his eventual deterioration. He had alienated the family member from whom he had stolen the money, and felt this relationship was broken permanently. He had speech impairment, decreased concentration, trouble maintaining grip, balance and coordination difficulties, and chorea. He had previously taken one antidepressant prescribed by a neurologist, but had never consulted any mental health personnel, and was reluctant to join an HD support group. A neuropsychologist identified severe deficits in processing speed, sustained attention, resistance to distraction, visual attention, as well as mild deficits in cognitive flexibility and abstract reasoning, verbal and visual memory, expressive language abilities, olfactory discrimination, motor strength, and speed in motor programming and inhibition. A severe depressed mood with suicidal ideation and anxiety were noted during the testing. 160
Before testing positive for HD, the patient had graduated with a degree in chemical engineering and had experienced a successful career in the public sector in administration and in dealing with the public. His career faltered after the development of slurred speech and the onset of organizational problems. After a period of reckless gambling, he moved back to live with his mother. He became more withdrawn and irritable over the subsequent years. A brain MRI revealed subcortical degeneration. He did not undergo symptomatic treatment for movement problems initially, later taking tetrabenazine on a trial basis, which seemed to help his choreiform movements, gait, and behavioral regulation. He had no premorbid psychiatric history. His mother was especially concerned about his inability to express emotions. Mental status examination showed him to be alert and cooperative, with a wide-eyed and smiling, yet blank facial expression. Choreiform movement and a writhing dance-like and jerky gait and extremity movements were apparent. He was fully oriented, and his speech was slurred and mumbling. Signs of affect were limited to tightening of facial muscles when emotionally charged topics were broached. He was open about his suicidal thoughts, but tended to speak more readily about his angry feelings than his depression. He denied ever acting upon his suicidal ideation and had no previous suicide attempts or past or present plans to hurt himself. In general, he had poor awareness of his internal emotional status. He struggled with word finding, elaboration, and reflection over his decline from his previously high level of functioning. He performed better with “cues’” and with “either-or” types of questions than with open-ended questioning. His immediate memory,when assisted with cues,was intact,as was his semantic memory.He had difficulty with processing speed and attention. No psychotic symptoms were evident. His diagnoses were dementia secondary to HD, mood disorder secondary to HD with depressive features, and a family member relational problem, as well as the underlying primary condition of HD. Perspectives in Psychiatric Care 51 (2015) 157–161 © 2015 Wiley Periodicals, Inc.
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Medication management and supportive psychotherapy were recommended, and he met in bimonthly follow-up sessions. He was prescribed paroxetine, initially at 20 mg/day, and dosing was increased over subsequent visits because of incomplete responsiveness at lower doses. Later, olanzapine at 2.5 mg nightly was added to address sleep and anxiety difficulties, and then increased to 5 mg per night. His mood and irritability improved and participation in HD support groups and end-of-life planning was encouraged, but he was reluctant to undertake these efforts at the time of this report. References Campbell, J. J. III., & Tisher, A. (2014). Clinical assessment of dysexecutive syndromes. Psychiatric Times, 31, 34–38. Heindel, W. C., & Salloway, S. (1999). Memory systems in the human brain. Psychiatric Times, 16(6), 19–21. Johnson, A. C., & Paulsen, J. S. (2014). Understanding behavior in Huntington’s disease: A guide for professionals. New York: Huntington’s Disease Society of America.
Perspectives in Psychiatric Care 51 (2015) 157–161 © 2015 Wiley Periodicals, Inc.
Nance, M., Paulsen, J. S., Rosenblatt, A., & Wheelock, V. (2011). A physician’s guide to the management of Huntington’s disease (3rd ed.). New York: Huntington’s Disease Society of America. Paulsen, J., Ferneyhough, H., Nehl, C., Stierman, L., & The Huntington Study Group. (2005). Critical periods of suicide risk in Huntington’s disease. American Journal of Psychiatry, 162(4), 725–731. doi:10.1176/appi.ajp.162.4.725 Rickards, H., De Souza, J., Crooks, J., van Walsem, M. R., van Duijn, E., Landwehmeyer, B., & European Huntington’s Disease Network. (2011). Discriminant analysis of Beck depression inventory and Hamilton rating scale for depression in Huntington’s disease. Journal of Neuropsychiatry and Clinical Neurosciences, 23(4), 399–402. doi:10.1176/appi.neuropsych.23.4.399 Van Duijn, E., Kingma, E. M., & van der Mast, R. C. (2007). Psychopathology in verified Huntington’s disease gene carriers. Journal of Neuropsychiatry and Clinical Neurosciences, 19(4), 441–448. doi:10.1176/appi.neuropsych.19.4.441 Yudofsky, S. C., & Hales, R. E. (Eds.). (2004). Essentials of neuropsychiatry and clinical neurosciences (pp. 201–209). Arlington, VA: American Psychiatric Publishing.
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