Early Warnings: Neuropsychiatric Manifestations of Huntington Disease

CLINICAL

First recognized in 1872 by George Huntington, MD, Huntington disease (HD) is a neurodegenerative disorder that is characterized by progressive decline in motor functioning, cognition, and behaviors.¹ In North America, approximately 30,000 individuals have this illness, and an additional 150,000 individuals are at risk for developing it.² HD tends to occur more commonly among individuals of European descent, with a prevalence rate of 10 to 15 per 100,000. The incidence of HD is approximately 4.7 to 6.9 new cases per million per year in the Western population.³ The median age of diagnosis for HD is approximately 40 years.² It is rare for HD to be diagnosed among individuals 20 years or younger, or among individuals 65 years or older. HD affects men and women equally.

Neuropathology of HD

The neuropathological hallmark among individuals with HD is the progressive atrophy of caudate nucleus and putamen due to neuronal loss.⁴ The clinical features of HD occur due to the loss of medium-sized projection spiny neurons in the dorsal striatum, which express the dopaminergic type 1 or 2 receptors. As the illness progresses, global neuronal loss and generalized cerebral atrophy occur, and the overall brain weight can decrease by up to 40%. These medium-sized projection spiny neurons use the inhibitory transmitter γ-aminobutyric acid and either dynorphin, enkephalin, or substance P as cotransmitters. It is thought that the loss of inhibitory input from the medium-sized spiny neurons, which usually exert an inhibitory effect, is the reason for the uncontrolled movements characteristic of individuals with HD. Individuals with HD also have intranuclear inclusions and protein aggregates in the dystrophic neurons of both the striatum and cortex.⁵ Additionally, the number of cortical inclusions correlates directly with the length of the CAG repeat expansion and the age of onset of the illness. Furthermore, these intranuclear inclusions tend to appear before the loss in brain weight. The loss of brain weight precedes the loss of body weight and the onset of neurological symptoms.

Clinical Features of HD

There is significant variability in the type, timing, and progression of clinical symptoms.⁴ The clinical course can be divided into premanifest and manifest periods.⁶ The premanifest period can be further divided into presymptomatic and prodromal periods. During the presymptomatic period, which is approximately 10 to 15 years before the onset of symptoms, individuals are not clinically distinguishable from those individuals without HD. During the prodromal period, individuals present with subtle motor, cognitive, and behavioral symptoms. Once individuals enter the manifest period with prominent motor, cognitive, and behavioral symptoms, the symptoms continue to progress and worsen, and the illness is ultimately fatal. The median survival time from the onset of motor symptoms is approximately 18 years.³

The symptoms of HD can be divided into 2 broad categories: progressive motor symptoms and neuropsychiatric symptoms.² A diagnosis of HD is made only when the characteristic motor features manifest, even among individuals who are gene positive.

The motor symptoms of HD can be divided into 2 main categories: abnormal involuntary movements and impaired voluntary movements.¹ Among individuals with HD, the most common abnormal movements are characteristic of chorea, which is among the early presenting symptoms, especially among individuals with adult-onset HD. Impaired voluntary movements are more common among individuals with earlier-onset HD (younger than 21 years).⁷ They are seen among patients with adult-onset HD during the severe stages of the illness. Impaired voluntary movements include motor incoordination, bradykinesia, rigidity, dystonia, gait disturbances, and eye movement abnormalities.⁴ Dysarthria and dysphagia are seen in later stages of the illness, often leading to choking and aspiration. Table 1 describes common treatments for motor symptoms.^1,8

Manifestations

Neuropsychiatric symptoms are often present well before the motor symptoms manifest, sometimes decades prior, and include depression, irritability/aggression, executive dysfunction (eg, apathy, obsessive-compulsive behaviors), psychosis, cognitive decline, and dementia.^1,7

Individuals with the HD gene who are presymptomatic exhibit a higher prevalence of neuropsychiatric symptoms.⁴ Neuropsychiatric complaints are the presenting symptom in approximately half of individuals. Among symptomatic individuals, more than 70% have neuropsychiatric symptoms, with symptoms often waxing and waning. Neuropsychiatric symptoms are often multifactorial in origin and are considered to be the most burdensome symptoms for caregivers and family members.⁹

In a study of 1993 individuals with HD mutations from 15 European countries, 73% of the participants had some neuropsychiatric symptom within the past month.¹⁰ Moderate to severe apathy and depression were seen in 28.1% and 12.7% of the participants, respectively. Similarly, irritable and aggressive symptoms were present in 13.9% of the participants, and 13.2% of the participants showed obsessive/compulsive behaviors (OCBs). However, moderate to severe psychotic symptoms were found in only 1.2% of the participants. Apathy was more prevalent in advanced stages of the disease (11% in early stages vs 54.6% in advanced stages); it may be the only neuropsychiatric symptom that is linearly related to progressive neurodegeneration. Additionally, the presence of all neuropsychiatric symptoms during the previous month was associated with a positive psychiatric history, and a past episode of depression was particularly associated with neuropsychiatric symptoms, except for psychosis.

DEPRESSION. Depressed mood, loss of interest, guilt, and suicidality were more indicative of depression than somatic symptoms (eg, poor appetite, sleep disturbances, and psychomotor slowing).⁷ In patients with HD, depression is more common among women.¹⁰ Independent correlates of depression include a positive psychiatric history for depression, OCBs, a previous suicide attempt, and the use of benzodiazepines or antidepressants.

Suicidal ideation is also common in individuals with HD (Figure).¹¹ According to a recent review, lifetime rates of suicide attempts range from 6.4% to 16%, and the percentage of deaths from suicide range from 2.2% to 10%. The risk factors include the presence of psychiatric comorbidities, especially depression, followed by anxiety, aggression, and previous suicide attempt. Other related risk factors include irritability, apathy, OCBs, psychosis, history of suicidal ideation, alcohol abuse, and the use of antidepressants. No consistent evidence showed that the risk for suicide was associated with sex, ethnicity, having children, history of incarceration, severity of motor dysfunction, disease stage, and specific neuronal loss or pathophysiologic circuit.

Examining the neuropsychiatric symptoms in a European HD cohort (REGISTRY) study, 24.7% of individuals with HD reported mild irritability/aggression, and 13.9% reported moderate to severe irritability/aggression.¹⁰ The prevalence of moderate to severe irritability and aggression increased as disease stage progressed, from 10.4% in the milder stages to 19.6% in the later stages. Independent correlates included male sex, younger age, history of depression, psychosis, and a previous suicide attempt.

OBSESSIVE-COMPULSIVE DISORDER. One review found the prevalence of OCBs ranged from 5% to 52%, whereas perseverative behaviors (PBs) occurred in approximately 75% of the individuals.¹² Individuals with premanifest HD reported more OCBs when compared with gene-negative controls. However, individuals with manifest HD reported a higher rate of OCBs when compared with those with premanifest HD. Both OCBs and PBs are associated with duration and severity of HD, but they tend to decrease in the most advanced stage of the disease. A formal diagnosis of obsessive-compulsive disorder is also more prevalent than in the general population, and it is often classified as “obsessive-compulsive and related disorders due to another medical condition” using the DSM-5 criteria. OCBs tend to cause significant distress and impairment in functioning. PBs often occur without the individual’s full awareness or insight into their occurrence.

PSYCHOSIS. A recent study of 7966 participants with manifest HD found that 12.95% had a history of psychosis.¹³ Only 2.83% of participants with premanifest HD had a history of psychosis. The mean age of psychosis onset was 48.34 years, and these individuals had mild-to-moderate psychosis. A family history of psychosis in a first-degree relative was documented in 27.5% of participants with psychosis. Factors associated with psychosis in manifest HD included lower education level, unemployment, single marital status, depression, decreased verbal fluency score, and decreased total functional capacity. Psychosis was also associated with younger age of clinical HD diagnosis and younger age of motor symptom onset, and it was correlated with a general decrease in cognitive capacity.

ANXIETY DISORDERS. Available evidence indicates that between 13% and 71% of individuals may present with symptoms of anxiety.⁴ Anxiety can occur at any stage of the disorder, including the prodromal stage, but it does not appear to be a measure of disease progression.¹⁴ Anxiety may present as generalized anxiety, social anxiety, anticipatory anxiety, or panic, or as posttraumatic stress disorder, and it may co-occur with depression. Anxiety may occur as a result of environmental factors as well as cognitive and physical impairments. It can also be confused with akathisia, which occurs as a result of medications (eg, antipsychotics or tetrabenazine) used to treat HD symptoms.

SLEEP DISORDERS. Approximately 90% of individuals report sleep problems, including insomnia, difficulties in falling asleep, frequent nocturnal awakenings, and excessive daytime sleepiness.¹⁵ Available evidence indicates that some sleep disorders are found in the early phase of the disease, even during the illness’ premanifest stage. These disorders may be associated with comorbid psychiatric disorders, especially mood and anxiety disorders. Involuntary movements and increased motor activity may also contribute to sleep difficulties. Many drugs that are used to improve the core symptoms of HD may also contribute to sleep disturbances, including amantadine, clonazepam, diazepam, L-DOPA olanzapine, quetiapine, riluzole, sodium valproate, tetrabenazine, deutetrabenazine, and venlafaxine.

COGNITION. Due to the degenerative nature of HD, individuals develop gradually progressive cognitive decline.⁷ Individuals develop the prototypical frontal-subcortical type of dementia, with frontal-executive disturbances, attentional deficits, and reductions in processing speed.¹⁶ These symptoms are the result of striatal and thalamic degeneration as well as degeneration in the caudate nucleus and putamen. As the illness progresses, abnormalities in visuomotor integration, visual perception, mental rotation, language production, and organization occur. However, the rate of progression of cognitive decline varies significantly among individuals, suggesting that other mechanisms (including environmental and genetic variables) may contribute to the neuropathological and clinical progression of cognitive decline.

Treatment

Available evidence indicates a comprehensive and multidisciplinary approach is required. Given the complexity of the illness’ clinical presentation, it should be treated by a group of providers including physicians, nurses, occupational and speech therapists, physical therapists, and social workers.⁹ Both nonpharmacological and pharmacological management strategies have benefited individuals with HD-associated neuropsychiatric symptoms.¹⁴ The use of nonpharmacological treatment strategies often complements pharmacological treatments. A thorough multidisciplinary team assessment can assist in identifying the environmental and medical triggers and causes of neuropsychiatric symptoms, which then can be used in developing individualized treatment plans. Cognitive dysfunction can be reduced by structured daily schedules, providing cues, and having regular routines. In addition, respite care may significantly relieve caregiver burden.

There are no controlled trials for the pharmacotherapy of neuropsychiatric manifestations of HD, but evidence has been gathered from published case reports, case series, and an expert-based consensus guideline (Table 2).^8,9,14,17

Concluding Thoughts

HD is a progressive and often fatal neurodegenerative disorder that is associated with severe motor and neuropsychiatric manifestations. The neuropsychiatric manifestations of HD can occur decades before the motor symptoms of HD become apparent, and they are associated with pathological changes that occur within the striatum and cortical regions of the brain, including the frontal lobes. Only apathy appears to be linearly related to the progressive neurodegeneration associated with HD. These manifestations are associated with significant disabilities and cause distress to both the individual with HD and their caregivers.

Currently, there are no disease-modifying strategies for the treatment of individuals with HD. Available treatment strategies focus on comprehensive multidisciplinary assessments and appropriate management of symptoms. There are no controlled studies for the treatment of neuropsychiatric manifestations of HD, but available evidence indicates efficacy for both nonpharmacological and pharmacological treatment modalities. The goal of treatment is to improve the quality of life for both the individual with HD and their caregivers.

Dr Tampi is professor and chairman, Department of Psychiatry & Behavioral Sciences, Cleveland Clinic Akron General, Akron, Ohio, and is the section chief for geriatric psychiatry, Cleveland Clinic, Cleveland, Ohio. Ms Weber is the manager of Behavioral Health Social Work, Cleveland Clinic Akron General, Akron, Ohio. Dr Masterson, is an attending psychiatrist, Department of Psychiatry & Behavioral Sciences, Cleveland Clinic Akron General, Akron, Ohio.

References

1. Stahl CM, Feigin A. Medical, surgical, and genetic treatment of Huntington disease. Neurol Clin. 2020;38(2):367-378.

2. Dayalu P, Albin RL. Huntington disease: pathogenesis and treatment. Neurol Clin. 2015;33(1):101-114.

3. Bates GP, Dorsey R, Gusella JF, et al. Huntington disease. Nat Rev Dis Primers. 2015;1:15005.

4. My Goh A, Wibawa P, Loi SM, et al. Huntington’s disease: neuropsychiatric manifestations of Huntington’s disease. Australas Psychiatry. 2018;26(4):366-375.

5. Gil JM, Rego AC. Mechanisms of neurodegeneration in Huntington’s disease. Eur J Neurosci. 2008;27(11):2803-2820.

6. Ross CA, Aylward EH, Wild EJ, et al. Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat Rev Neurol. 2014;10(4):204-216.

7. Teixeira AL, de Souza LC, Rocha NP, et al. Revisiting the neuropsychiatry of Huntington’s disease. Dement Neuropsychol. 2016;10(4):261-266.

8. Videnovic A. Treatment of Huntington disease. Curr Treat Options Neurol. 2013;15(4):424-438.

9. Loi SM, Walterfang M, Velakoulis D, Looi JC. Huntington’s disease: managing neuropsychiatric symptoms in Huntington’s disease. Australas Psychiatry. 2018;26(4):376-380.

10. van Duijn E, Craufurd D, Hubers AAM, et al; European Huntington’s Disease Network Behavioural Phenotype Working Group. Neuropsychiatric symptoms in a European Huntington’s disease cohort (REGISTRY). J Neurol Neurosurg Psychiatry. 2014;85(12):1411-1418.

11. Kachian ZR, Cohen-Zimerman S, Bega D, et al. Suicidal ideation and behavior in Huntington’s disease: systematic review and recommendations. J Affect Disord. 2019;250:319-329.

12. Oosterloo M, Craufurd D, Nijsten H, van Duijn E. Obsessive-compulsive and perseverative behaviors in Huntington’s disease. J Huntingtons Dis. 2019;8(1):1-7.

13. Jaini A, Yomtoob J, Yeh C, Bega D. Understanding HD psychosis: an analysis from the ENROLL-HD database. Tremor Other Hyperkinet Mov (N Y). 2020;10:16.

14. Anderson KE, van Duijn E, Craufurd D, et al. Clinical management of neuropsychiatric symptoms of Huntington disease: expert-based consensus guidelines on agitation, anxiety, apathy, psychosis and sleep disorders. J Huntingtons Dis. 2018;7(3):355-366.

15. Herzog-Krzywoszanska R, Krzywoszanski L. Sleep disorders in Huntington’s disease. Front Psychiatry. 2019;10:221.

16. Martinez-Horta S, Sampedro F, Horta-Barba A, et al. Structural brain correlates of dementia in Huntington’s disease. Neuroimage Clin. 2020;28:102415.

17. Li Y, Hai S, Zhou Y, Rong Dong B. Cholinesterase inhibitors for rarer dementias associated with neurological conditions. Cochrane Database Syst Rev. 2015;(3):CD009444. ❒