Recognition and diagnosis of sleep disorders in Parkinson’s disease

Sleep disturbances are among the most frequent and incapacitating non-motor symptoms of Parkinson’s disease (PD), and are increasingly recognized as an important determinant of impaired quality of life. Here we review several recent developments regarding the recognition and diagnosis of sleep disorders in PD. In addition, we provide a practical and easily applicable approach to the diagnostic process as a basis for tailored therapeutic interventions. This includes a stepwise scheme that guides the clinical interview and subsequent ancillary investigations. In this scheme, the various possible sleep disorders are arranged not in order of prevalence, but in a ‘differential diagnostic’ order. We also provide recommendations for the use of sleep registrations such as polysomnography. Furthermore, we point out when a sleep specialist could be consulted to provide additional diagnostic and therapeutic input. This structured approach facilitates early detection of sleep disturbances in PD, so treatment can be initiated promptly.     

Bladder and bowel dysfunction in Parkinson’s disease

Summary. Bladder dysfunction (urinary urgency/frequency) and bowel dysfunction (constipation) are common non-motor disorders in Parkinson’s disease (PD). In contrast to motor disorder, the pelvic autonomic dysfunction is often non-responsive to levodopa treatment. Brain pathology mostly accounts for the bladder dysfunction (appearance of overactivity) via altered dopamine-basal ganglia circuit, which normally suppresses the micturition reflex. In contrast, peripheral enteric pathology mostly accounts for the bowel dysfunction (slow transit and decreased phasic contraction) via altered dopamine-enteric nervous system circuit, which normally promotes the peristaltic reflex. In addition, weak strain and paradoxical anal contraction might be the results of brain pathology. Pathophysiology of the pelvic organ dysfunction in PD differs from that in multiple system atrophy; therefore it might aid the differential diagnosis. Drugs to treat bladder dysfunction in PD include anticholinergic agents. Drugs to treat bowel dysfunction in PD include dietary fibers, peripheral dopaminergic antagonists, and selective serotonergic agonists. These treatments might be beneficial not only in maximizing patients’ quality of life, but also in promoting intestinal absorption of levodopa and avoiding gastrointestinal emergency. Correspondence: Ryuji Sakakibara, Sakura Medical Center, Neurology Division, Department of Internal Medicine, Toho University, 564-1 Shimoshizu, Sakura 285-8741, Japan     

Cognitive dysfunction and dementia in Parkinson’s disease

Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder mainly characterized by degeneration of dopaminergic neurons in the substantia nigra and the ventral tegmental area, in combination with a varying loss of central noradrenergic (locus coeruleus), cholinergic (nucleus basalis of Meynert) and serotonergic (dorsal raphe nuclei) integrity, leading to a multitude of motor and non-motor behavioral disturbances. Apart from the clinical motor hallmarks, in the early stages of disease, subtle cognitive dysfunction might be seen comprising mainly executive dysfunction, with secondary visuospatial and mnemonic disturbances. In about 20-40% of patients, these problems may eventually proceed to dementia, which constitutes an important risk factor for caregiver distress, decreased quality of life and nursing home placement. Dementia in PD is typically characterized by a progressive dysexecutive syndrome with attentional deficits and fluctuating cognition, often accompanied by psychotic symptoms. It is thought to be the result of a combination of both subcortical and cortical changes. PD-related dopaminergic deficiency in the nucleus caudatus and mesocortical areas (due to degeneration of projections from the substantia nigra and ventral tegmental area) and cholinergic deficiency in the cortex (due to degeneration of ascending projections from the nucleus basalis of Meynert), combined with additional Alzheimer-pathology and cortical Lewy bodies, may greatly contribute to dementia.Current treatment of dementia in PD is based on compensation of the profound cholinergic deficiency. Recent studies with the cholinesterase inhibitors galantamine, donepezil and rivastigmine show promising results in improving cognition and ameliorating psychotic symptoms, which must further be confirmed in randomized controlled trials.     

Gastrointestinal dysfunction in Parkinson’s disease

Journal of Neurology - Gastrointestinal (GI) dysfunction is prevalent in Parkinson’s disease (PD). Symptoms are evident throughout the disease course, affect the length of the GI tract and...     

Health-Related Quality of Life and sleep disorders in Parkinson’s disease

Abstract. Parkinsons disease (PD) is a chronic, progressive, disabling movement disorder with a clear impact on Health- Related Quality of Life (HRQoL). We investigated the correlations between HRQoL and sleep disorders measured with the Parkinsons disease Sleep Scale (PDSS) and the motor and non-motor aspects of the disease. A correlation was found between HRQoL and the scores from PDSS, motor and depression scales. We conclude that more attention should be paid to the non-motor aspects of PD to attempt to improve HRQoL.     

Olfactory dysfunction and cardiovascular dysautonomia in Parkinson’s disease

Several studies have reported that olfactory dysfunction is an early neuropathological manifestation of Parkinson’s disease (PD). Reduced cardiac meta-iodobenzylguanidine (¹²³I-MIBG) uptake may be one of the earliest signs of PD. We studied the relation of olfactory dysfunction to cardiovascular dysautonomia in patients with PD. The study group comprised 66 patients with PD (70.5 years) and 26 controls (70.3 years) for olfactory assessment, 21 controls (72.1 years) for cardiac ¹²³I-MIBG scintigraphy and heart rate variability (HRV), assessed using the coefficient of variation for RR intervals (HRV), and 23 controls (69.2 years) for orthostatic blood pressure response. Olfactory function was assessed by the odor stick identification test Japan (OSIT-J), and cardiovascular autonomic function was evaluated by ¹²³I-MIBG scintigraphy of the heart, the fall in orthostatic blood pressure, and HRV. Patients with PD had a significantly lower OSIT-J score than did the controls (4.1 ± 3.0 vs. 9.9 ± 1.7, p = 0.001). The OSIT-J score was unrelated to variables other than gender, including age, disease duration, motor score on the unified Parkinson’s disease rating scale, score on the mini-mental state examination, motor phenotype, visual hallucinations, and dopaminergic medication on multiple regression and logistic regression analyses. The OSIT-J score was related to the heart/mediastinum ratio of cardiac ¹²³I-MIBG uptake, the fall in orthostatic blood pressure, and HRV, after adjustment for other clinical variables. Olfactory dysfunction in PD was, thus, significantly related to both cardiac sympathetic and parasympathetic dysfunction, as well as vascular sympathetic dysfunction. As non-motor symptoms of PD, olfactory dysfunction and autonomic network failure appear to be closely related in PD.     

Olfactory dysfunction and parasympathetic dysautonomia in Parkinson’s disease

Objective

Olfactory impairment occurs early in Parkinson’s disease (PD), as may dysautonomia. We investigated the relationship between olfaction and dysautonomia as well as other non-motor manifestations of PD.

Methods

Olfaction [University of Pennsylvania Smell Identification Test (UPSIT)], autonomic function in the pupillary (constriction and redilation velocity) and cardiac systems (resting low- and high-frequency heart rate variability (LF and HF HRV), positional changes in systolic blood pressure), neuropsychiatric function [Mini-mental Status Exam (MMSE)], Hamilton Depression Scale, activities of daily living [(ADLs), Schwab and England ADLs scale], quality of life [Short Form-36 health survey, PD Questionnaire 39 (PDQ-39)], and other non-motor symptoms [Non-motor Symptoms Scale (NMSS)] were simultaneously assessed in 33 participants (15 PD, 18 controls). Group comparisons, Spearman’s coefficients and non-parametric rank-based regression were employed to characterize relationships between olfaction and non-motor features.

Results

Smell scores were lower in the PD group and correlated positively with pupil constriction velocity and HF HRV. Smell scores were correlated negatively with PDQ-39 and gastrointestinal items of the NMSS and positively with MMSE and Schwab and England ADLs. These correlated measures were not significant terms in regression models of smell scores in which age and PD diagnosis were significant and accounted for over half of the variability (R-squared 0.52–0.58).

Interpretation

This study suggests olfactory involvement occurs with parasympathetic dysautonomia in the pupillary and cardiovascular systems, involving both age-related and PD-related processes. Other non-motor features are concurrently involved, supporting the notion that aging and PD have widespread effects involving discrete portions of the autonomic and olfactory systems.     

Perceived and performance-based executive dysfunction in Parkinson’s disease

Executive dysfunction is common in early stage Parkinson’s disease (PD). We evaluated the relationship between self- and informant-report measurement of real-world executive functions as well as performance-based neuropsychological measures in mildly cognitively impaired individuals with PD and healthy controls. The PD group reported more difficulty with initiation of complex tasks compared to caregiver ratings, and processing speed was a strong predictor of self-reported executive dysfunction for the PD group, followed by depression. Processing speed and semantic verbal fluency predicted informant-reported executive dysfunction in PD. These findings highlight the contribution of speeded processing for performance of everyday executive tasks in PD.     

Determinants of autonomic dysfunction in idiopathic Parkinson’s disease

OBJECTIVES: To determine demographic or disease-related factors that may influence the severity of autonomic dysfunction in idiopathic Parkinson's disease (IPD). METHODS: 532 patients with IPD aged between 55 and 75 years were included. Severity of autonomic dysfunction was assessed using a 9-item autonomic dysfunction score (ADS). In addition, several demographic factors (e. g. age, gender, comorbidities) and disease- related (e. g. motor stage, disease duration, antiparkinsonian therapy) factors were recorded. A group of 67 age-matched healthy volunteers served as a control group. Demographic and clinical data of this cross-sectional survey were analyzed by a logistic stepwise regression model to determine independent predictors of autonomic dysfunction. RESULTS: IPD patients showed significantly higher ADS values than controls, even in the youngest age groups and in mild disease stages. Hoehn & Yahr (H&Y) stage, disease duration, age at onset and various therapy combinations all showed significant correlations with ADS. However, stepwise logistic regression revealed that age (OR 10.71; CI 7.17-16.0) and arterial hypertension (OR 3.05; CI 1.66-5.58) were the only independent risk factors associated with autonomic dysfunction. Linear regression indicated that ADS increases with age in controls as well as in patients, but with a significantly steeper slope in the latter. CONCLUSIONS: Autonomic dysfunction as an inherent feature of IPD is present already in early disease stages. According to a logistic regression model, the severity of autonomic dysfunction in IPD is primarily related to demographic but not to disease-related factors. This and the differences in predictors for motor versus autonomic decline may indicate at least partly independent neurodegenerative processes.     

Automatic processing dysfunction in Parkinson’s disease

Abstract

Simultaneous measures of Event Related Potentials (ERP) and electrodermal activity (EDA) allow the delineation of ERPs that did, and did not evoke an electrodermal ‘Orienting Reflex– (OR). The OR is an automatic reflex invoked by novel or significant stimuli. Our group have developed a model to quantify electrodermal OR activity acquired in conventional late component ERP paradigms with short interstimulus intervals. Target late component (N100, P200, N200, P300) ERPs (acquired in an auditory oddball paradigm) and EDA was examined in 15 Parkinson’s disease (PD) subjects and 50 normal controls. Singletrial target ERPs were averaged according to whether or not they elicited an electrodermal OR. Compared with controlsl the PO group showed significantly decreased N100 and N200 amplitudes in the OR related ERPs (‘orienting ERPs’). These preliminary findings suggest that conventional late component ERPs can be delineated according to whether or not they evoked an OR. The ‘orienting ERPs’ in PO showed more significant disturbances compared with controlsl than ERPs that did not evoke an OR. [Neural Res 1997; 19: 609-612]     

Zonisamide in Parkinson’s disease: a current update

Neurological Sciences - Parkinson’s disease (PD) is a progressive neurodegenerative disease due to the depletion of the neurotransmitter dopamine in basal ganglia. There is a scarcity of...     

Dysfunctional sleep beliefs in Parkinson’s disease: Relationships with subjective and objective sleep

Disturbed sleep is common in Parkinson’s disease and has a detrimental impact on functioning and quality of life. While the progression of the disease contributes to the aetiology of sleep problems in Parkinson’s disease, it is unknown whether an individual’s beliefs and attitudes about sleep play a role. In this study we sought to investigate whether dysfunctional beliefs and attitudes about sleep could be related to subjective and objective measures of sleep disturbance in Parkinson’s disease. Ninety-three patients with Parkinson’s disease completed the Dysfunctional Beliefs and Attitudes about Sleep 16 item questionnaire, which comprises four domains: Expectations, Worry/Helplessness, Consequences and Medication. Patients also completed the Pittsburgh Sleep Quality Index questionnaire and Beck Depression Inventory-II. Patients wore actigraphy watches and completed sleep diaries for 2 consecutive weeks, recording measures of sleep disturbance including Sleep Onset and Offset, Wake After Sleep Onset, Sleep Efficiency, and Wake Bouts per hour. Greater dysfunctional beliefs and attitudes in the domains of Worry/Helplessness and Medication were associated with lower perceived sleep quality and greater depressive symptoms. However, no relationships were found between dysfunctional beliefs and attitudes about sleep and any objective actigraphic measure of sleep disturbance. These findings suggest that beliefs and attitudes about sleep in Parkinson’s disease are associated with mood disturbance, rather than objective measures of sleep. Thus it is possible that interventions targeting mood may lead to more accurate perceptions of sleep and improved quality of life in Parkinson’s disease patients.     

Significance of the parkin gene and protein in understanding Parkinson’s disease

Mutations in the parkin gene cause autosomal recessive inherited juvenile parkinsonism (ARJP) and account for the majority of cases of inherited Parkinson’s disease (PD) of young onset (<45 years of age). Patients with parkin mutations commonly have atypical clinical features such as dystonia at onset, hyper-reflexia, diurnal fluctuations, and sleep benefit; however, parkin mutation patients with both typical PD symptoms and older age of onset have been identified. Parkin is a ubiquitin protein ligase (E3), a component in the pathway that attaches ubiquitin to specific proteins, designating them for degradation by the proteasome. Several substrates for parkin have been identified (CDCrel-1, o-glycosylated α-synuclein, parkin associated endothelin-like cell receptor, and synphilin). The role of these substrates in the pathogenesis of ARJP is under active study. Most patients with parkin mutations lack Lewy bodies, suggesting that functional parkin is involved in the formation of these highly ubiquitinated inclusions. Furthermore, the recognition that parkin mutations can lead to a disorder clinically similar to sporadic PD, but presumably lacking Lewy bodies, calls into question the necessity of Lewy bodies for the diagnosis of PD and nigral cell death. Studies of parkin are increasing the focus on the role of the ubiquitin-proteasome system in the pathogenesis of both familial and sporadic PD.     

Cognitive and behavioral dysfunction in Parkinson’s disease: neurochemical and clinicopathological contributions

The cognitive and behavioral sequelae (i.e., nonmotor profile) of Parkinson's disease (PD), with executive dysfunction and depression being most prominent, have typically been overshadowed due to an emphasis on motor symptomatology. The apparent categorization of PD as a disorder isolated to the dopaminergic system may be a generalization of the disease pathology. Dopamine therapy, used for the treatment of motor symptoms, has not consistently been shown to resolve nonmotor impairments. Research evidence indicates that nondopaminergic neurotransmitter systems (i.e., serotonergic, noradrenergic, & cholinergic) are disrupted in PD and may contribute to cognitive and behavioral dysfunction. Furthermore, Lewy bodies within cortical and subcortical structures can add to the nonmotor profile in PD. Pharmacological interventions for the treatment of cognitive and behavioral impairments associated with PD are few, especially for nondemented patients. The current review of the literature highlights evidence that associates nonmotor dysfunctions with neurochemical and clinicopathological correlates of PD.     

Excessive daytime sleepiness and unintended sleep in Parkinson’s disease

Patients with Parkinson's disease and parkinsonian syndromes (eg, dementia with Lewy body disease, multisystem atrophy, and Shy-Drager syndrome) suffer from daytime sleepiness. This sleepiness is common and very real, often approaching levels observed in the prototypical disorder of sudden-onset sleep, namely narcolepsy/cataplexy. Physicians need to be vigilant in assessing parkinsonian patients for sleepiness because treatment can dramatically enhance quality of life and prevent the significant morbidity and mortality that attends daytime sleepiness. Male patients with advanced disease, cognitive impairment, drug-induced psychosis, and orthostatic hypotension are most at risk for developing pathologic sleepiness. Because primary sleep disorders can coexist with parkinsonism (eg, sleep apnea, insufficient or interrupted sleep), these potential causes should be carefully assessed with polysomnography and treated appropriately. Dopaminomimetics exacerbate sleepiness in a small subset of patients in a dose-dependent fashion. Nonetheless, the primary pathologies involved in parkinsonism appear to be the greatest contributors to daytime sleepiness. Sleepiness in parkinsonism, especially a narcolepsy-like phenotype, may necessitate treatment with wake-promoting agents such as bupropion, modafinil, or traditional psychostimulants.     

Update on the clinical application of deep brain stimulation in sleep dysfunction of Parkinson’s disease

Sleep dysfunctions, including rapid eye movement sleep behavior disorder, sleep fragmentation, excessive daytime sleepiness and various other dysfunctions, can seriously affect quality of life in patients with Parkinson’s disease (PD). Emerging evidence suggests that deep brain stimulation (DBS) exerts a substantial effect when used to treat sleep dysfunctions, which are common nonmotor symptoms experienced by patients with PD. However, far less is known about the specific mechanisms underlying the effects of DBS on sleep processes and the factors that potentially influence these effects. These issues therefore need to be further clarified. Intriguingly, a number of recent studies have evaluated the effects of applying DBS to various brain targets on sleep in patients with PD. Deeper research into the efficacy of applying DBS to each brain target may help determine which region should be targeted during surgery in PD patients. Furthermore, compared with pharmacological therapy, DBS had more beneficial effects on sleep symptoms, and appropriate management involving the joint application of dopamine replacement therapy and DBS might accelerate the effects of treatment. Here, we review the potential roles DBS may play and provide clinical guidance for the use of DBS in treating sleep dysfunctions in PD patients.     

Parkinson’s disease: The treatment of drug-induced hallucinations and psychosis

Drug-induced psychosis is one of the most disabling complications of advancing Parkinson’s disease. It has also been one of the most difficult to treat. Clozapine was the first medication shown to be safe and effective in this setting, and it remains the standard by which newer atypical antipsychotics are measured. However, due to the small but significant risk of agranulocytosis and the need for frequent blood testing, alternatives have been sought. Risperidone, olanzapine, and quetiapine are new atypical antipsychotics that have each been proposed as an alternative to clozapine, but the literature concerning their use in Parkinson’s disease is conflicted and confusing. Although quetiapine appears to be the best current choice, none of these medications have equaled clozapine’s ability to safely treat drug-induced psychosis without the risk of worsening parkinsonism.     

When Parkinson’s disease patients go to sleep: specific sleep disturbances related to Parkinson’s disease

Journal of Neurology -