ABSTRACT
Deep brain stimulation (DBS) is effective for Parkinson's disease (PD), dystonia, and essential tremor (ET). While motor benefits are well documented, cognitive and psychiatric side effects from the subthalamic nucleus (STN) and globus pallidus interna (GPi) DBS for PD are increasingly recognized. Underlying disease, medications, microlesions, and post-surgical stimulation likely all contribute to non-motor symptoms (NMS).
Subject(s)
Cognitive Dysfunction/etiology , Deep Brain Stimulation/adverse effects , Globus Pallidus , Mental Disorders/etiology , Parkinson Disease/therapy , Subthalamic Nucleus , Cognitive Dysfunction/therapy , Humans , Parkinson Disease/complicationsSubject(s)
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics , Parkinson Disease/genetics , Suicide, Completed/statistics & numerical data , Adolescent , Adult , Child of Impaired Parents/statistics & numerical data , Female , Humans , Male , Middle Aged , Mutation , Parents , Parkinson Disease/psychology , Risk Factors , Siblings , Young AdultABSTRACT
The phenotype of Parkinson's disease (PD) in patients with and without leucine-rich repeat kinase 2 (LRRK2) G2019S mutations reportedly is similar; however, large, uniformly evaluated series are lacking. The objective of this study was to characterize the clinical phenotype of Ashkenazi Jewish (AJ) PD carriers of the LRRK2 G2019S mutation. We studied 553 AJ PD patients, including 65 patients who were previously reported, from three sites (two in New York and one in Tel-Aviv). Glucocerebrosidase (GBA) mutation carriers were excluded. Evaluations included the Montreal Cognitive Assessment (MoCA), the Unified Parkinson's Disease Rating Scale (UPDRS), the Geriatric Depression Scale (GDS) and the Non-Motor Symptoms (NMS) questionnaire. Regression models were constructed to test the association between clinical and demographic features and LRRK2 status (outcome) in 488 newly recruited participants. LRRK2 G2019S carriers (n = 97) and non-carriers (n = 391) were similar in age and age at onset of PD. Carriers had longer disease duration (8.6 years vs. 6.1 years; P < 0.001), were more likely to be women (51.5% vs. 37.9%; P = 0.015), and more often reported first symptoms in the lower extremities (40.0% vs. 19.2%; P < 0.001). In logistic models that were adjusted for age, disease duration, sex, education, and site, carriers were more likely to have lower extremity onset (P < 0.001), postural instability and gait difficulty (PIGD) (P = 0.043), and a persistent levodopa response for >5 years (P = 0.042). Performance on the UPDRS, MoCA, GDS, and NMS did not differ by mutation status. PD in AJ LRRK2 G2019S mutation carriers is similar to idiopathic PD but is characterized by more frequent lower extremity involvement at onset and PIGD without the associated cognitive impairment.
Subject(s)
Glycine/genetics , Mutation/genetics , Parkinson Disease/genetics , Protein Serine-Threonine Kinases/genetics , Serine/genetics , Aged , Female , Genotype , Humans , Jews/genetics , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Male , Middle Aged , Parkinson Disease/ethnology , Phenotype , Regression Analysis , Severity of Illness Index , Surveys and QuestionnairesABSTRACT
The behavioral and cognitive features of the leucine-rich repeat kinase G2019S mutation in Parkinson's disease in the Ashkenazi Jewish population are not well described; therefore, we sought to more systematically characterize these features using a semistructured psychiatric interview and neuropsychological testing. Twenty-one Ashkenazi Jewish patients having the leucine-rich repeat kinase G2019S mutation were compared with age- and sex-matched Ashkenazi Jewish patients with Parkinson's disease without mutations. Although overall rates of affective disorders were not greater in mutation carriers, the carriers exhibited a 6-fold increased risk of premorbid affective disorders (odds ratio, 6.0; P = .10), as determined by the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders-IV. Of interest, we identified 2 leucine-rich repeat kinase carriers with bipolar disorder; no mutation-negative subjects had this diagnosis. Performance on the Hopkins Verbal Learning Test-Revised, Judgment of Line Orientation, and Frontal Assessment Battery was consistent with previous reports and did not differ between groups. Study findings suggest a possible association between premorbid mood disorders and leucine-rich repeat kinase Parkinson's disease, warranting further evaluation.
Subject(s)
Cognition Disorders/etiology , Genetic Predisposition to Disease/genetics , Glycine/genetics , Mood Disorders/etiology , Parkinson Disease/complications , Parkinson Disease/genetics , Protein Serine-Threonine Kinases/genetics , Serine/genetics , Aged , Aged, 80 and over , Cognition Disorders/genetics , Female , Humans , Jews/genetics , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Male , Middle Aged , Mood Disorders/genetics , Neuropsychological Tests , Psychiatric Status Rating ScalesABSTRACT
Guidelines in the Huntington disease genetic counseling community have set a standard for the process of at-risk counseling, recommending the involvement of a multidisciplinary team, which includes a psychiatrist or psychologist. Though most studies have been largely reassuring regarding the psychologic consequences of predictive testing, there are individuals presenting to testing who really want something else other than the test results, who are being pressured by others to obtain results, or who remain deeply ambivalent about testing. Particularly concerning are those testing candidates who are highly anxious or depressed at the time of presentation. Balancing the ethical principles of autonomy with beneficence and nonmaleficence requires careful exploration of the motivations behind testing to ensure that all are fully informed of alternatives, and opportunities for further support are offered when needed. This chapter illustrates 13 areas of focus and inquiry in the psychiatric interview and gives some case examples to illustrate an approach to the psychiatric assessment and counseling of highly anxious individuals seeking genetic testing.
Subject(s)
Genetic Counseling/psychology , Genetic Testing , Huntington Disease/genetics , Huntington Disease/psychology , Physician's Role , Psychiatry , HumansABSTRACT
BACKGROUND: Suicidal ideation (SI) and attempts are increased in Huntington's disease (HD), making risk factor assessment a priority. OBJECTIVE: To determine whether, hopelessness, irritability, aggression, anxiety, CAG expansion status, depression, and motor signs/symptoms were associated with Suicidal Ideation (SI) in those at risk for HD. METHODS: Behavioral and neurological data were collected from subjects in an observational study. Subject characteristics were calculated by CAG status and SI. Logistic regression models were adjusted for demographics. Separate logistic regressions were used to compare SI and non-SI subjects. A combined logistic regression model, including 4 pre-specified predictors, (hopelessness, irritability, aggression, anxiety) was used to assess the relationship of SI to these predictors. RESULTS: 801 subjects were assessed, 40 were classified as having SI, 6.3% of CAG mutation expansion carriers had SI, compared with 4.3% of non- CAG mutation expansion carriers (pâ=â0.2275). SI subjects had significantly increased depression (pâ<â0.0001), hopelessness (pâ<â0.0001), irritability (pâ<â0.0001), aggression (pâ=â0.0089), and anxiety (pâ<â0.0001), and an elevated motor score (pâ=â0.0098). Impulsivity, assessed in a subgroup of subjects, was also associated with SI (pâ=â0.0267). Hopelessness and anxiety remained significant in combined model (pâ<â0.001; pâ<â0.0198, respectively) even when motor score was included. CONCLUSIONS: Behavioral symptoms were significantly higher in those reporting SI. Hopelessness and anxiety showed a particularly strong association with SI. Risk identification could assist in assessment of suicidality in this group.
Subject(s)
Genetic Predisposition to Disease/psychology , Huntington Disease/genetics , Huntington Disease/psychology , Suicidal Ideation , Adult , Cohort Studies , Female , Humans , Logistic Models , Male , Middle Aged , Psychiatric Status Rating Scales , Risk Factors , Self ReportABSTRACT
Throughout the course of PD, opportunities abound for psychosocial interventions that can improve a patient's quality of life. The psychosocial challenges accompanying PD vary by stage of illness, though some challenges persist throughout the course of illness. As illustrated in the tables in this chapter, many of these interventions involve empathic listening and inquiry, education, challenging distorted or overly helpless thoughts and self-conceptions, and facilitating social contact and functioning. Others directly address the needs of caregivers who are confronted with the devastating effects of PD on their loved ones. Although many of the recommendations in this chapter are nonspecific and intuitive, their potential effect should not be underestimated. Although we have been unable to address all of the psychosocial issues confronted by patients facing PD, we hope that this chapter serves as a useful guide for providers looking for additional opportunities for psychosocial interventions designed to increase patient quality of life. These interventions can be delegated to other members of the team, and the assistance of psychiatrists or social workers may be warranted, but PD clinicians themselves can have the most dramatic effect on their patients because of their allocated authority and their salutary alliance with the patient.
Subject(s)
Models, Psychological , Parkinson Disease/physiopathology , Parkinson Disease/psychology , Quality of Life , Activities of Daily Living/psychology , Chronic Disease , Humans , Parkinson Disease/diagnosis , Parkinson Disease/therapy , PsychotherapyABSTRACT
Impulse control disorders (ICDs) are nonmotor complications of dopaminergic medications characterized by problems in behavioral self-control. Common management involves discontinuing or lowering dopaminergic medication, often producing motor worsening. We performed a retrospective chart review of Parkinson's disease (PD) patients treated with clozapine for ICDs. Four patients treated with clozapine for ICD were identified. Three patients were men. All 4 took dopaminergic medications at the time that ICDs developed; all received dopamine agonist therapy. ICDs included compulsive shopping, binge drinking, and hypersexuality. All 4 patients had complete resolution of symptoms while taking clozapine (12.5-37.5 mg). Two patients discontinued clozapine because of side effects. Larger studies are needed to further evaluate clozapine's role in treating PD patients with ICD.
ABSTRACT
Depression causes significant morbidity and mortality, and this also occurs in Huntington Disease (HD), an inherited neurodegenerative illness with motor, cognitive, and psychiatric symptoms. The presentation of depression in this population remains poorly understood, particularly in the prodromal period before development of significant motor symptoms. In this study, we assessed depressive symptoms in a sample of 803 individuals with the HD mutation in the prodromal stage and 223 mutation-negative participants at the time of entry in the Neurobiological Predictors of HD (PREDICT-HD) study. Clinical and biological HD variables potentially related to severity of depression were analyzed. A factor analysis was conducted to characterize the symptom domains of depression in a subset (n=168) with clinically significant depressive symptoms. Depressive symptoms were found to be more prevalent in HD mutation carriers but did not increase with proximity to HD diagnosis and were not associated with length of the HD mutation. Increased depressive symptoms were significantly associated with female gender, self-report of past history of depression, and a slight decrease in functioning, but not with time since genetic testing. The factor analysis identified symptom domains similar to prior studies in other populations. These results show that individuals with the HD mutation are at increased risk to develop depressive symptoms at any time during the HD prodrome. The clinical presentation appears to be similar to other populations. Severity and progression are not related to the HD mutation.
Subject(s)
Depression/diagnosis , Depression/etiology , Huntington Disease/complications , Huntington Disease/psychology , Prodromal Symptoms , Adult , Analysis of Variance , Female , Genetic Testing , Humans , Huntingtin Protein , Huntington Disease/genetics , Male , Middle Aged , Nerve Tissue Proteins/genetics , Psychiatric Status Rating Scales , Suicide/psychology , Trinucleotide Repeat Expansion/geneticsABSTRACT
It is generally believed that treatments are available to manage obsessive-compulsive behaviors (OCB's) in Huntington's disease (HD). However, lack of an evidence base prevents guideline development. The research literature fails to address the indications for behavioral interventions, drug selection, drug dosing, management of inadequate response to a single drug, and preferred drugs when additional behavioral symptoms comorbid to OCBs are present. In an effort to inform clinical decision-making, we surveyed an international group of experts to address these points. Survey results showed that experts utilized behavioral therapy only for patients with mild cognitive impairment. There was expert agreement that a selective serotonin reuptake inhibitor (SSRI) was the first choice drug, although clomipramine (CMI) was cited as a monotherapy choice by the smaller number of experts familiar with its use. Perceived efficacy for control of OCBs was similar for both SSRIs and CMI. Though less favored choices overall, antipsychotics (APDs) and antiepileptic mood stabilizers (AEDs) were most often used as augmentation strategies. In addition to survey results, this report reviews available studies, and lastly presents an algorithm for the treatment of OCBs in HD based on practice-based preferences obtained from this survey.
ABSTRACT
It is generally believed that treatments are available to manage irritability in Huntington's disease (HD). However, lack of an evidence base prevents the establishment of treatment guidelines for this symptom. The research literature fails to address behavioral intervention strategies, drug selection, drug dosing, management of inadequate response to a single drug, or preferred drugs when additional behavioral symptoms comorbid to irritability are present. In an effort to inform clinical decision-making we surveyed an international group of experts to address these points. The experts consistently endorsed an antipsychotic drug (APD) as first choice for treatment of urgent and aggressive irritability behaviors. However, there was variation in practice patterns for treating less severe symptoms. Serotonin reuptake inhibitors (SSRIs) were first choice drug treatments by most respondents across all geographic regions. However, APDs were also endorsed as first choice for mild or moderate irritability, more frequently in Europe than in North America and Australia. Antiepileptic mood stabilizers (AEDs) were used by fewer respondents as first choice drug. Perceived efficacy for control of mild or moderate irritability was judged somewhat higher for APDs than SSRIs or AEDs. Benzodiazepines were not used as monotherapy, but frequently as an adjunctive drug in the setting of comorbid anxiety. Though many cited lack of experience with mirtazapine, others familiar with its use in HD chose it as an alternative monotherapy, or as adjunctive therapy if insomnia was a comorbid factor. This report presents survey results, reviews available irritability studies, and lastly proposes an algorithm for the treatment of irritability in HD derived from expert preferences obtained through this survey.
ABSTRACT
The Functional Rating Scale Taskforce for pre-Huntington Disease (FuRST-pHD) is a multinational, multidisciplinary initiative with the goal of developing a data-driven, comprehensive, psychometrically sound, rating scale for assessing symptoms and functional ability in prodromal and early Huntington disease (HD) gene expansion carriers. The process involves input from numerous sources to identify relevant symptom domains, including HD individuals, caregivers, and experts from a variety of fields, as well as knowledge gained from the analysis of data from ongoing large-scale studies in HD using existing clinical scales. This is an iterative process in which an ongoing series of field tests in prodromal (prHD) and early HD individuals provides the team with data on which to make decisions regarding which questions should undergo further development or testing and which should be excluded. We report here the development and assessment of the first iteration of interview questions aimed to assess Depression, Anxiety and Apathy in prHD and early HD individuals.
ABSTRACT
The Functional Rating Scale Taskforce for pre-Huntington Disease (FuRST-pHD) is a multinational, multidisciplinary initiative with the goal of developing a data-driven, comprehensive, psychometrically sound, rating scale for assessing symptoms and functional ability in prodromal and early Huntington disease (HD) gene expansion carriers. The process involves input from numerous sources to identify relevant symptom domains, including HD individuals, caregivers, and experts from a variety of fields, as well as knowledge gained from the analysis of data from ongoing large-scale studies in HD using existing clinical scales. This is an iterative process in which an ongoing series of field tests in prodromal (prHD) and early HD individuals provides the team with data on which to make decisions regarding which questions should undergo further development or testing and which should be excluded. We report here the development and assessment of the first iteration of interview questions aimed to assess "Anger and Irritability" and "Obsessions and Compulsions" in prHD individuals.