Website Edition: August/September 2010

The Neuropsychiatry of Chorea

By Mark Walterfang, MD
Neuropsychiatry Unit
Royal Melbourne Hospital
Melbourne Australia
Special to The Movement Disorder Society

Note: The following article is based on an original work by Mark Walterfang, Andrew Evans and Dennis Velakoulis

Introduction

The neurodegenerative choreas invariably involve pathological changes in the basal ganglia. The resulting cognitive and psychiatric impairments, which are often presenting symptoms prior to the onset of motor disturbance, may be more disabling than the motor manifestations of the disease for patients, relatives and carers1. Our understanding of the functions of the corticosubcortical circuits of the brain which are affected - and the motor, cognitive, and emotional functions they subserve-has evolved significantly in recent years.

Cortical association areas are linked by multiple loops that run through the basal ganglia and thalamus and then return to the cortex. Each of the five main loops or circuits (motor, oculomotor, cognitive, associative, and limbic) receives multiple cortical inputs, which are integrated and project to a restricted thalamic region and then to a single cortical region2. A significant proportion of these project to the prefrontal cortex (PFC), including motor, associative, and limbic cortical regions. These loops are not anatomically separate; and as a result, cognitive, motor, and emotional loops can interact in the striatum to modulate each other's output to the cortex3. For this reason, disorders that affect the basal ganglia generally do not discriminate between these circuits and tend to present with comorbid cognitive, motor, and emotional disturbances, as in McHugh's model of basal ganglia disorders as "triadic" and presenting with the "3 Ds": dyskinesia, dementia, and depression1, 4.

Huntington Disease

Huntington disease (HD) very frequently presents with psychiatric illness comorbid with, or preceding, the neurological features of the disorder. Loss of neurons in particular brain regions, especially the caudate and putamen contributes, to the characteristic behavioural, cognitive, and motor disturbances of the disease. Not only does HD present with significantly elevated rates of major psychiatric illness, but its autosomal dominant pattern of inheritance-and the resulting 50% likelihood of siblings and offspring of a proband being affected by an untreatable degenerative disorder-results in a devastating psychosocial burden on HD patient and family.

The Psychiatric Sequelae of Predictive Testing

The development of international guidelines for the genetic testing process in HD has contributed to the development of high-quality programs for those at risk and their families5 and has been important in minimizing adverse psychiatric morbidity. A 1999 study identified that 44 of 4,527 (0.97%) people who participated in predictive HD testing had either completed suicide (n = 5) or attempted suicide (n = 21) or had a psychiatric hospitalization (n = 18) following an HD predictive test result6. The risk was greatest in those with a positive test result, symptoms at the time of diagnosis, or preexisting psychiatric illness. Follow-up studies of predictive testing outcomes have identified higher rates of depression in asymptomatic carriers followed up for periods of up to 5 years7-9, although it is challenging to separate the effects of the testing result from the effects of illness progression over time.

Psychopathology in Presymptomatic Gene Carriers

Several studies have compared gene carriers to at-risk non-carriers for psychiatric symptoms, to identify whether such symptoms increase the closer the gene carrier is to onset of neurological symptoms. Gene carriers exhibit more symptoms than gene-negative subjects in depression and anxiety, and gene-positive subjects with more neurological symptoms exhibit more psychiatric symptoms10. Furthermore, as carriers approach the onset of neurological symptoms, they exhibit more depressive symptoms over time11. The early onset of psychiatric symptoms, predating neurological or cognitive symptoms, may result from early subcortical pathology with involvement of nonmotor circuitry. For gene carriers, reliable prevalence estimates are problematic, but it has been suggested that 35%-95% of HD patients will have a major psychiatric disorder (affective disorders, schizophrenia-like disorder, OCD, personality disorders) or psychiatric symptoms (e.g., apathy, irritability, aggression, lability)12-14.

Depression and Anxiety

Earliest studies suggested that 41% of HD patients were diagnosed with a major affective disorder (32% major depression, 9% bipolar disorder), which had preceded the development of chorea in two-thirds of patients15. A review of six high-quality studies identified a prevalence of depressed mood of 33%-69%16. As illness progresses, rates may actually decrease as cognitive deficits advance and insight reduces17. There appears to be little relationship between CAG repeat length and the probability of developing a psychiatric disorder, or with the severity of the disorder. The high prevalence of depression in HD may thus be due to neurobiological vulnerability factors in gene carriers, interacting with psychological and psychosocial factors. This may be the result of a disrupted limbic circuit in HD, which connects the amygdala and anterior cingulate with the ventral striatum and the medial and ventral lateral PFC, and the cognitive circuit, which connects the caudate head with the lateral PFC18. Disrupted connections between the PFC and ventral striatum may be core to the functional impairments in major depression19, 20, and disruption to these loops in HD may produce the vulnerable substrate that interacts with psychosocial stressors to result in depressive illness. In six studies which have reported anxiety symptoms in HD gene carriers, the prevalence ranged 28%-61%13, 14, 17, 21-23. It is unclear, however, whether these high prevalence rates relate to psychological and psychosocial consequences of the illness or to an underlying neurobiological vulnerability to anxiety states.

Obsessive-Compulsive Disorder/Symptoms

A quarter or more of HD patients may have obsessional or compulsive symptoms at presentation to a specialist clinic24, and these symptoms are increased in asymptomatic HD gene carriers compared to at-risk non-gene carriers25. The prevalence of obsessive-compulsive symptoms increases up to threefold by the later stages of illness compared to the prevalence in asymptomatic subjects26. That these patients have greater executive dysfunction on neuropsychological assessment than patients without these symptoms, suggesting this is a marker for patients with more severe cognitive impairment27.

Psychosis

The rates of psychosis in HD samples has been described as ranging from 9%-17%28-30; acknowledging the variability in the methods for ascertainment of psychosis, the prevalence of psychosis in patients with HD (approximately 10%) is far greater than that within the general population (about 1%). Psychosis is known to cluster in some HD pedigrees31,32, suggesting that that modifying genes may interact with the Huntingtin gene to predispose to the development of psychosis or that the HD gene acts to lower the threshold for the emergence of schizophrenia in individuals already carrying vulnerability factors31.

Huntington Disease-Like Disorders

The Huntington disease-like (HDL) disorders 1-4 present as phenocopies of HD and should be considered in patients who present with the clinical picture of HD but do not exhibit the HD mutation. HDL4 has been molecularly identified as spinocerebellar ataxia17.

HDL1

HDL1, an autosomal dominant disorder associated with a 192-nucleotide repeat expansion in the prion protein (PRP) gene33, 34, has been associated with depression, aggression, and personality change as precursors to rigidity, chorea, dysarthria, and basal ganglia atrophy, which eventually progressed to dementia34, 35. Chorea has been associated with PRP repeat expansions in other pedigrees36, 37.

HDL2

HDL2 is an autosomal dominant, neurodegenerative condition due to a CTG expansion in the junctophilin-3 gene (JPH3)38, 39 and is estimated to account for up to 15% of patients with an HDL condition who do not carry the HD mutation40. The pedigree described by Margolis and colleagues had depression, anxiety, and psychosis, in addition to more dysexecutive behaviors including apathy, perseveration, irritability, and eventually dementia39. Similar symptoms have been found in other cohorts41-43.

HDL3

HDL3 has been described in an Arabian family as an autosomal recessive disorder associated with an abnormality on chromosome 4p15.3; as it presents in childhood, a psychiatric presentation is unlikely44.

Benign Hereditary Chorea

Benign hereditary chorea is an autosomal dominant disorder with typical onset before the age of 5 but extending into adolescence, associated with a mutation in the TITF-1 gene on chromosome 1445. Psychiatric symptoms are not prominent46-49, although anxiety and depression50 and psychosis51 have been described.

Chorea-acanthocytosis

Significant psychopathology is common in chorea-acanthocytosis (ChAc; see accompanying article by Rodrigues Riccioppo),52-54 occurring in up to 60% of patients54-56. Frank psychiatric illness may precede the onset of neurological disturbance in some cases by up to a decade. The most prominent feature is behavioural change and executive impairment56,57. OCD symptoms may occur in 25% of patients, including recurrent intrusive thoughts (obsessions) and compulsions regarding checking, cleanliness, symmetry, and hoarding56,58-64. The characteristic mutilation of the lips and tongue has also been conceptualized along the OCD spectrum as a pure motor compulsion65. Serotonergic medication can be effective in the treatment of OCD in ChAc patients56,60. Schizophrenia-like psychosis presents less commonly than OCD-type illness in ChAc61,63,64,66-68, but may predate the onset of neurological symptoms by months or years, and presents with auditory hallucinations and bizarre and/or persecutory delusions. Ultimately, executive impairment leads to a typical frontosubcortical dementia54,69.

The high rate of OCD in ChAc56 suggests that disruption of key frontal-subcortical loops plays a significant role in its genesis. The head of the caudate, particularly affected in ChAc70, plays a key role in the lateral orbitofrontal loop (LOFL), where it serves to integrate information from the anterior cingulate, orbitofrontal, and dorsolateral PFC to determine the behavioural and motor programs that occur to resolve conflict or facilitate decision making71,72. Disruptions to this loop appear to relate to the symptoms in OCD patients, with impaired decision making due to alterations to LOFL transmission being at the core of this deficit in OCD patients73,74.

McLeod Syndrome

More than 80% of patients with McLeod syndrome (MLS; see accompanying article by Rodrigues Riccioppo)52,54,75-78 present with neuropsychiatric illness at some stage during their illness course76, most commonly with schizophrenia-like psychosis and OCD. Neuropsychiatric presentations often predate chorea and other neurological manifestations76,79. OCD-like syndromes have commonly reported80-83, although psychotic disorders - characterised by thought disorder, persecutory delusions, and auditory hallucinations - may be more common76,82,84. Schizophrenia-like psychosis in MLS has been reported to respond to both typical and atypical antipsychotics82,84. In common with other frontostriatal disorders such as ChAc and HD, executive dysfunction is common in MLS and often presents as behavioural disturbance75,76. The prevalence of significant dysexecutive syndromes in MLS patients, combined with neuroimaging evidence85, reinforces the crucial role of frontostriatal circuits in modulating behavior and the impact on this circuitry if one crucial node in the network is disrupted.

Dentatorubropallidoluysian Atrophy

Dentatorubropallidoluysian atrophy (DRPLA) is a choreiform disorder caused by triplet repeat expansion of the atrophin gene on chromosome 12p13.3186. The clinical features of this rare disorder are largely restricted to small case series and case reports, the majority from the Japanese literature. The most common psychiatric presentation appears to be that of psychosis86,87, characterised by auditory hallucinations and persecutory delusions, and which responds to neuroleptic medication. Ultimately, dementia supervenes.

Wilson Disease

Wilson disease (WD) is an autosomal recessive disorder caused by a mutation in the ATP7B gene, coding a copper transport protein, with resultant copper accumulation in the liver, kidney, skeletal system, putamen and globus pallidus88. Symptoms usually appear between the ages of 6 and 20 years, but may present much later. Between 35-65% of WD patients report psychiatric symptoms at the time of initial presentation89-91 and at any one time, up to one-half of patients have current psychiatric symptoms92 and a quarter have a definable axis I illness93. Four symptom clusters have been identified in WD; mood and affective change, behavior and personality change, psychosis, and cognitive impairment94. Personality changes, particularly irritability and aggression, are very common90,95. Mood disturbance, including both depression and mania, appears to be the most common neuropsychiatric illness96,97. Depressive symptoms in WD appear to correlate with regional serotonin transporter availability in the basal ganglia98,99. Psychotic presentations with prominent delusions have been reported100-103, although OCD has only been reported once in WD104. Neurologically symptomatic patients display a range of cognitive difficulties, including impairments of frontal-executive ability, aspects of memory, and visuospatial processing92,105,106. After initiating treatment with chelation therapy, the disease often stabilizes or improves; but disease progression under treatment is more likely for neuropsychiatric than for hepatic symptoms107. Resolution of neuropsychiatric illness with chelation has been reported97,102,108,109. Depression has been reported to respond to both tricyclic antidepressants and selective serotonin reuptake inhibitors110-112, and psychosis to atypical medications such as olanzapine, risperidone, quetiapine, and clozapine, which have a low propensity to cause movement disorders101,113-115. These agents should be used with caution because of the increased risk of agranulocytosis in the presence of hypersplenism or penicillamine treatment.

Pantothenate Kinase-associated Neurodegeneration

Patients with pantothenate kinase-associated neurodegeneration (PKAN; see accompanying article by Kruer and Hayflick)116-118 frequently develop cognitive decline119-122, although this may be quite variable, with earlier-onset patients being more severely affected123. The pattern of cognitive impairment often implicates executive function and attention124, and impairment may predate motor signs125. Psychiatric signs, such as behavioural disturbances118, OCD126,127, tic disorders128, psychosis129, and depression130, are common, occurring in up to half of patients120.

Aceruloplasminemia

Cognitive impairment is the presenting feature in up to one-half of patients with aceruloplasminemia136 (see accompanying article by Kruer and Hayflick)131-135. This is characterized by executive dysfunction137-139 and cognitive slowing138. Typical schizophrenia-like psychosis has been reported in AC, with decline in self-care, persecutory delusions, and auditory hallucinations138.

Neuroferritinopathy

The majority of patients with neuroferritinopathy (NF; see accompanying article by Kruer and Hayflick)140-141 develop cognitive impairment, which typically follows a frontostriatal pattern. Disinhibition and emotional lability often present in early stages, with other executive impairments such as reduced verbal fluency developing over decades, ultimately resulting in a subcortical dementia141,142, which may progress to akinetic mutism143. The psychiatric illnesses that have been associated with NF have been neuroleptic-resistant psychotic disorders144,145.

Treatment of Psychiatric Disturbance in Neurodegenerative Chorea

Treatment of psychiatric disturbance in the neurodegenerative choreas is relatively uncomplicated in that the treatments that are used for psychosis, mood disorders, OCD, and other illnesses are those used in primary psychiatric illness, with a few caveats1. The clinician dealing with choreiform disorders needs to be vigilant for the presence of psychiatric illness as untreated major mental disorders can add considerably to functional impairment of the patient and carer burden. While it occurs less commonly than psychosis or mania, depression is commonly underdiagnosed, particularly if the patient has difficulty in communicating or if the debilitating neurological symptoms result in clinicians and carers labeling a depressive illness as "understandable." Additionally, differentiation of depressive illness from apathy and social withdrawal can often be difficult; evaluation of accompanying symptoms that may be indicative of neurovegetative disturbance, such as changes in appetite, sleep or agitation, may be helpful.

Depressive illnesses generally respond well to antidepressant treatment, particularly with the more recent classes of antidepressants. These have increasing specificity for enhancing serotonergic transmission but less of the anticholinergic and antihistaminic effects of older antidepressants (which may worsen cognitive impairment), as well as a very wide therapeutic index. As in patients with a major depressive illness in the absence of a neurological condition, full remission is sometimes only effected with the addition of antipsychotic medication. ECT can be a very effective treatment for otherwise treatment-resistant illness in patients with choreiform disorders146,147. For patients with secondary mania, the use of sodium valproate or carbamazepine is preferred1.

The treatment of psychosis can be more problematic in choreiform disorders as these predominantly dopamine-blocking agents do not readily discriminate between motor and nonmotor aspects of the striatum. Small-dose, high-potency neuroleptics (usually those with a high dopamine D2 receptor affinity such as haloperidol and risperidone) are useful in suppressing chorea and may also be effective antipsychotics; however, when dosages need escalation to control psychotic symptoms, worsening parkinsonism may cause significant motor problems, particularly in gait and mobility, increasing the risk of falls. Use of newer agents with less D2 receptor blockade, in addition to 5-hydroxytryptamine 2 (5-HT2) receptor blockade, may be preferable148. Medications such as olanzapine and quetiapine (alone or occasionally in combination) can often be used to provide adequate treatment of psychosis without significant worsening of motor symptoms.

Limited evidence exists on the treatment of compulsive disorders, but the authors (in addition to scattered reports in the literature) have found that serotonergic medications are helpful in reducing compulsive behaviours and movements in some patients. There is an increased risk of worsening chorea and parkinsonism in patients with vulnerable basal ganglia circuitry149, but this usually responds to careful dose titration. For irritability, agitation, and stereotyped behaviours, the use of antidepressants, antipsychotics, and mood stabilizers can be helpful. Treatment of apathy is much more problematic as stimulant medication often worsens motor symptoms in these disorders.

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Mark WalterfangAbout Dr. Mark Walterfang, MD

Dr Mark Walterfang is a consultant psychiatrist and neuropsychiatrist from the Neuropsychiatry Unit, Royal Melbourne Hospital, Melbourne, Australia. He has interests in the neuropsychiatry and neuroimaging of degenerative disorders, including chorea-acanthocytosis, Niemann-Pick type C, and frontotemporal dementia, and undertook his PhD work in the neuroimaging of connectivity in schizophrenia. He may be reached by e-mail at mark.walterfang@mh.org.au