Modafinil for the treatment of excessive daytime sleepiness in Parkinson's disease: a case report

We report a 59 year old woman with levodopa responsive Parkinson's disease who developed excessive daytime sleepiness [Epworth Sleepiness Scale (ESS) score of 13]. Treatment with Modafinil 400 mg daily within two weeks produced a subjective improvement in her daytime sleepiness (ESS score after treatment is 8) with no significant change in her PD motor symptomotology.     

Sleep, excessive daytime sleepiness and fatigue in Parkinson's disease

Summary The objective of this questionnaire-based survey was to evaluate the prevalence and causes of sleep disturbances in 90 nondepressive patients with Parkinson's disease (PD) and 71 age-matched healthy subjects. We also assessed the prevalence and characteristics of excessive daytime sleepiness (both groups) and excessive fatigue (PD patients).A high prevalence of sleep disturbances in PD patients was found; this is to a large extent probably the result of aging. As compared with controls, patients had a more severely disturbed sleep maintenance because of nycturia, pain, stiffness, and problems with turning in bed. The prevalence of excessive dreaming is similar in both groups, but altered dream experiences almost exclusively occurred in PD.Patients rated themselves more often to be morning-types than controls. This finding may account for the reported adaptation effects in experimental settings and the reduced REM latency in PD patients.The prevalence of daytime sleepiness was similar in both groups. Excessive daytime sleepiness showed a clear diurnal pattern with a peak in the early afternoon. As for excessive fatigue, the majority of the patients did not report a preferential time for this symptom. Our findings further argue against an association of fatigue with any circadian factor, and instead suggest a relationship with the motor deficits of PD.     

Differences and similarities in the neuropsychological profile of dementia with Lewy bodies and Alzheimer's disease in the early stage

Excessive daytime sleepiness has been widely accepted as a common problem not only in Parkinson's disease (PD) but also in other related disorders. Lowered excretion of orexin A (hypocretin 1) into the cerebrospinal fluid (CSF) is known to play a pathological role in narcolepsy and secondary hypersomnia due to hypothalamic dysfunction. Although the levels of CSF orexin in PD have been previously examined, the results have been controversial, and no systematic investigation of CSF orexin excretion has been conducted on PD related disorders. In this study, orexin was measured in CSF collected by lumbar puncture in 62 patients with PD, 13 patients with dementia with Lewy bodies (DLB), 16 patients with progressive supranuclear palsy (PSP), and 7 patients with corticobasal degeneration (CBD). Levels of CSF orexin (mean ± SD pg/ml) were 302 ± 38 in PD, 297 ± 48 in DLB, 258 ± 37 in PSP, 246 ± 90 in CBD. The occurrence of low orexin levels (≤110pg/ml) was rare in both PD and DLB, and orexin levels were significantly lower in the PSP and CBD groups compared to PD (PSP: p < 0.001, CBD: p < 0.05). Orexin levels were inversely correlated with duration of morbidity in PSP but not in the other conditions studied. These findings suggest that loss of orexin neurons or impaired orexin neurotransmission might exist as a part of the neurodegeneration associated with advanced PSP with long duration of morbidity.     

Subjectively reported sleep quality and excessive daytime somnolence in Parkinson's disease with and without dementia, dementia with Lewy bodies and Alzheimer's disease

OBJECTIVE: We compared subjective sleep quality and excessive daytime somnolence (EDS) in controls, Parkinson's disease with (PDD) and without dementia (PD), dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). We investigated whether sleep dysfunction and EDS associate with motor phenotype in PD, PDD and DLB. METHOD: Assessments included the Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI). RESULTS: EDS was more frequent in PD, DLB and PDD patients than in AD. PDD, PD and DLB patients also had worse sleep quality when compared with AD and controls. Baseline postural instability-gait difficulty (PIGD) motor phenotype in PDD was associated with a higher ESS score and frequency of EDS, but this association was lost at two years. PSQI scores did not differ between PIGD dominant and non-dominant PD, PDD and DLB patients. CONCLUSION: EDS and poor sleep quality are greater in PD, PDD and DLB, compared with AD. The dissociation of EDS and motor phenotype suggests their pathophysiology is anatomically and/or temporally distinct.     

Course and risk factors for excessive daytime sleepiness in Parkinson's disease

IntroductionExcessive daytime sleepiness (EDS) is a common feature of Parkinson's disease (PD) that contributes to the disease burden and increases risk of harm. The aim of this study was to examine persistency, cross-sectional and longitudinal associations, and risk factors for EDS in patients with PD.MethodsAnalyses were performed on data from the SCOPA–PROPARK cohort, a 5-year hospital-based longitudinal cohort of over 400 PD patients who were examined annually. Cross-sectional analyses were conducted to evaluate differences between patients with and without EDS at baseline, while linear mixed models using data of all patients were used to identify factors associated with longitudinal changes in SCOPA-SLEEP-Daytime Sleepiness (SCOPA-SLEEP-DS) scores. A survival analysis was done using data of patients without EDS at baseline to identify risk factors for future EDS.ResultsEDS proved a non-persistent symptom, although persistency and the proportion of patients with EDS increased with longer follow-up. At baseline 43% of patients had EDS, while 46% of patients without EDS at baseline developed this symptom during follow-up. Male gender, poorer nighttime sleep, cognitive and autonomic dysfunction, hallucinations, less severe dyskinesias, dose of dopamine agonists and use of antihypertensives were associated with higher EDS scores over time, while use of benzodiazepines was associated with lower scores. Baseline SCOPA-SLEEP-DS score and PIGD phenotype were risk factors for future EDS.ConclusionWith longer disease duration a large proportion of patients develop EDS. Some risk factors are modifiable and patients should be monitored to improve quality of life and reduce risk of harm.     

The rostral mesencephalon in Parkinson's disease and Alzheimer's disease

Summary The rostal mesencephalon at the level of the posterior commissure was studied by light microscopy in two patients with idiopathic Parkinson's disease, one patient with Alzheimer's disease, and one patient with senile dementia of Alzheimer's type. In the Parkinsonian cases, the rostral part of the nucleus of Edinger Westphal disclosed Lewy bodies in 3% of the neurons, neurofibrillary degeneration in 2% of the neurons, and a 54% neuronal loss. In Alzheimer's disease, 2% of Edinger Westphal neurons contained neurofibrillary degeneration, whereas in senile dementia of Alzheimer's type only rare neurofibrillary degeneration was evident in this nucleus. Neuronal loss was not apparent in the nucleus of Edinger Westphal in either of the Alzheimer's cases. The pathologic changes observed in this presumably cholinergic nucleus resemble in some respects changes reported in the cholinergic centers of the basal forebrain in these diseases.In addition, the central gray matter and pretectal region in Parkinson's disease contained a patchy increase in astroglia, some with scant reactive cell bodies; however, Lewy bodies were limited to that part of the central gray matter corresponding to the nucleus of Darkschewitsch. A few neurofibrillary tangles were present in the nucleus of Darkschewitsch in both diseases.     

A study of excessive daytime sleepiness and its clinical significance in three groups of Parkinson's disease patients taking pramipexole, cabergoline and levodopa mono and combination therapy

Summary. Objective. To determine if therapy with an ergot and a non-ergot dopamine agonist and levodopa confers an increased risk of excessive daytime sleepiness and secondary "sleep attacks" in Parkinson's disease (PD). Methods. Comparative study of three clinical groups taking, pramipexole (Group 1, n = 19, 8 monotherapy), cabergoline (Group 2, n = 22, 10 monotherapy), and levodopa monotherapy (Group 3, n = 14). Clinical and demographic characteristics, occurrence of "sleep attacks", and assessment of daytime sleepiness [using the Epworth Sleepiness Scale (ESS)], recorded. Results. No patients reported "sleep attacks". Mean ESS scores: Group 1 (pramipexole) 8.0 ± 4.5 (range 0–16), Group 2 (cabergoline) 8.1 ± 3.9 (range 0–19), Group 3 (levodopa), 8.1 ± 5.5 (range 1–18). There was no significant difference between groups (p = 0.897). Scores of ≥16 indicating excessive daytime sleepiness (EDS) were evenly distributed throughout treatment groups, particularly in older patients with more advanced disease. Conclusions. Received March 31, 2000; accepted August 3, 2000     

Sleep disorders in Parkinson's disease: The contribution of the MPTP non-human primate model

To replicate the sleep–wake disorders of Parkinson's disease (PD) and to understand the temporal relationship between these sleep disturbances and the occurrence of parkinsonism, we performed long-term continuous electroencephalographic monitoring of vigilance states in unrestrained rhesus monkeys using an implanted miniaturized telemetry device and tested the effect of MPTP intoxication on their sleep–wake organization. MPTP injection yielded a dramatic disruption of sleep–wake architecture with reduced sleep efficacy that persisted years after MPTP administration. Primary deregulation of REM sleep and increased daytime sleepiness occurring before the emergence of motor symptoms were a striking feature of the MPTP effect. This was concomitant with a breakdown of dopaminergic homeostasis, as evidenced by decreased dopamine turnover measured after a single MPTP injection. In the long term, partial re-emergence of REM sleep paralleled the partial adaptation to parkinsonism, the latter being known to result from compensatory mechanisms within the dopaminergic system. Altogether, these findings highlight the suitability of the MPTP model of PD as a tool to model the sleep/wake disturbances of the human disease. Ultimately, this may help in deciphering the specific role of dopamine depletion in the occurrence of these disorders.     

脑梗死患者血清褪黑素节律改变与卒中后日间过度倦睡

目的动态观察脑梗死患者急性期血清褪黑素(melatonin,MT)的节律变化,及其与卒中后睡眠障碍的关系。方法放免法测定20例卒中患者发病后2d内、第7天、第14天的0200、0800时血清MT的浓度;18例对照组采用同样的方法测定其血清MT浓度。结果对照组、卒中组(2d内、7、14d)夜间MT浓度分别为86.14±24.94,54.08±33.33,61.93±28.44,65.81±32.15pg/L,卒中组明显低于对照组,梗死第7天后夜间MT浓度较发病1～2d显著增高;卒中组日间MT浓度与对照组之间差异无统计学意义;20例患者中3例出现日间过度倦睡,与无倦睡组相比,其夜间MT浓度更低。结论卒中患者仍有夜高昼低的MT分泌节律,但其夜间MT浓度显著下降,伴有日间过度倦睡者下降更显著。     

Sleep alterations in an environmental neurotoxin-induced model of parkinsonism

Parkinson's disease (PD) is classically defined as a motor disorder resulting from decreased dopamine production in the basal ganglia circuit. In an attempt to better diagnose and treat PD before the onset of severe motor dysfunction, recent attention has focused on the early, non-motor symptoms, which include but are not limited to sleep disorders such as excessive daytime sleepiness (EDS) and REM behavioral disorder (RBD). However, few animal models have been able to replicate both the motor and non-motor symptoms of PD. Here, we present a progressive rat model of parkinsonism that displays disturbances in sleep/wake patterns. Epidemiological studies elucidated a link between the Guamanian variant of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) and the consumption of flour made from the washed seeds of the plant Cycas micronesica (cycad). Our study examined the effects of prolonged cycad consumption on sleep/wake activity in male, Sprague-Dawley rats. Cycad-fed rats exhibited an increase in length and/or number of bouts of rapid eye movement (REM) sleep and Non-REM (NREM) sleep at the expense of wakefulness during the active period when compared to control rats. This hypersomnolent behavior suggests an inability to maintain arousal. In addition, cycad-fed rats had significantly fewer orexin cells in the hypothalamus. Our results reveal a novel rodent model of parkinsonism that includes an EDS-like syndrome that may be associated with a dysregulation of orexin neurons. Further characterization of this early, non-motor symptom, may provide potential therapeutic interventions in the treatment of PD.     

Excessive daytime sleepiness and its pattern among Indian college students

The objective of this study was to determine the prevalence and pattern of excessive daytime sleepiness (EDTS) in Indian college students. This was a cross-sectional study that was conducted among 1215 undergraduate students, using the Epworth Sleepiness Scale (ESS) and a sociodemographic survey. A high proportion (45%) of EDTS was observed, and the problem was significantly greater in participants from professional courses. A probability of association of EDTS with coffee/tea consumption, alcohol consumption and smoking was also observed in the study.     

Increased dopaminergic function in the thalamus is associated with excessive daytime sleepiness

Objectives/BackgroundExcessive daytime sleepiness (EDS) is a common disorder, which can manifest in isolation or in combination with other neurological or psychiatric disorders. We know relatively little about the mechanisms underlying the development of EDS and the clinical management of patients with EDS remains an unmet need. In this study, we hypothesised that thalamic dopaminergic function would be altered in subjects with EDS and we sought to investigate this by assessing [¹²³I]FP-CIT Single Photon Emission Computed Tomography (SPECT) data, which is a molecular imaging marker of dopamine transporter (DAT).Patients/MethodsWe performed a case–control study using people registered as healthy subjects in the Parkinson's Progression Markers Initiative database. We assessed and compared semi-quantified [¹²³I]FP-CIT-SPECT in two groups of 21 healthy subjects with and without EDS, who were matched for age, gender, years of education and Rapid eyemovement (REM) sleep behaviour disorder (RBD) Questionnaire scores.ResultsOur findings show increased thalamic DAT binding in people with EDS compared to matched healthy subjects without EDS. Higher thalamic DAT binding also correlated with worse EDS scores.ConclusionOur findings provide evidence that increased dopaminergic function in the thalamus may mediate excessive daytime sleepiness in humans.     

Excessive daytime sleepiness in Parkinson's disease: A systematic review and meta-analysis

ObjectiveTo provide a robust estimate of the prevalence of excessive daytime sleepiness (EDS) and its clinical correlates in patients with Parkinson's disease (PD).MethodWe searched the PubMed and Embase databases for studies investigating the prevalence and clinical correlates of EDS from inception to March 01, 2020. Quality assessment was performed using the Newcastle-Ottawa quality assessment scale. Random-effects models were set to pool the risk estimates. Sensitivity analyses were performed to evaluate the stability of the outcomes.ResultsAfter screening 1367 titles and abstracts, 59 studies involving 12,439 participants were included in the systematic review and meta-analysis. The pooled prevalence of EDS in PD was 35.1%, which was higher in South America, North America, Europe, and Australia than that in Asia. Compared to patients without EDS, patients with EDS had higher effect size on disease duration (0.76 years; 95% CI: 0.16–1.37, I² = 68.8%), Hoehn and Yahr (HY) stage (0.23 grade; 95% CI: 0.11–0.34, I² = 69.1%), Unified PD Rating Scale (UPDRS)-III (3.02 points; 95% CI: 1.53–4.51, I²: 61.2%), levodopa equivalent daily dose (LEDD) (141.46 mg; 95% CI: 64.17–218.77, I² = 86.1%), depression symptoms (Hedges’ g = 0.35; 95% CI: 0.15–0.55, I² = 72.0%) and male sex (OR = 1.50; 95% CI: 1.30–1.72, I² = 0).ConclusionOur results showed that approximately one-third of patients with PD had EDS, which may be associated with the severity of the disease, depression, and male sex, or a combination of neurodegeneration and medication.     

Dissociations among daytime sleepiness,nighttime sleep,and cognitive status in Parkinson's disease

BackgroundDaytime and nighttime sleep disturbances and cognitive impairment occur frequently in Parkinson's disease (PD), but little is known about the interdependence of these non-motor complications. Thus, we examined the relationships among excessive daytime sleepiness, nighttime sleep quality and cognitive impairment in PD, including severity and specific cognitive deficits.MethodsNinety-three PD patients underwent clinical and neuropsychological evaluations including the Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI). Patients were classified as having normal cognition (PD-NC), mild cognitive impairment (PD-MCI), or dementia (PDD) using recently proposed Movement Disorder Society PD-MCI and PDD criteria. Relationships between the sleep and cognitive measures and PD cognitive groups were examined.ResultsThe PD cohort included PD-NC (n = 28), PD-MCI (n = 40), and PDD (n = 25) patients. ESS scores, as a measure of daytime sleepiness, were significantly worse (p = 0.005) in cognitively impaired PD patients, particularly PDD patients. ESS scores correlated significantly with Mini-Mental State Examination scores and also with cognitive domain scores for attention/working memory, executive function, memory, and visuospatial function. In contrast, PSQI scores, as a measure of nighttime sleep quality, neither differed among cognitive groups nor correlated with any cognitive measures.ConclusionsDaytime sleepiness in PD, but not nighttime sleep problems, is associated with cognitive impairment in PD, especially in the setting of dementia, and attention/working memory, executive function, memory, and visuospatial deficits. The presence of nighttime sleep problems is pervasive across the PD cognitive spectrum, from normal cognition to dementia, and is not independently associated with cognitive impairment or deficits in cognitive domains.     

Prevalence of sleep apnea and daytime sleepiness in professional truck drivers

IntroductionThe prevalence of obstructive sleep apnea (OSA) among professional truck drivers has varied from 28 to 78% in previous studies. In this study we wanted to estimate the prevalence of OSA and OSA with both subjectively measured sleepiness and objectively measured ability to stay awake (ie obstructive sleep apnea syndrome, OSAS) among professional truck drivers in Finland.Subjects and methodsAltogether 2066 professional truck drivers received a structured questionnaire. 175 drivers had a clinical examination and sleep laboratory studies, which included respiratory polygraphy (RP) and maintenance of wakefulness test (MWT). Three groups were formed: 75 subjects with suspected sleep apnea, 75 healthy controls and a random sample of 25 subjects.Results1095 drivers answered the questionnaire. RP was performed on 172 drivers and 167 drivers participated in MWT. The mean age was 40.7 years and the mean BMI was 27.7 kgm⁻². The prevalence of sleep apnea in professional truck drivers using various criteria were: AHI ≥5: 40.1%, AHI≥ 15: 16.2% and, AHI≥ 30: 7.2%. The prevalence depended on clinical history. Prevalence of AHI≥5 varied between 20 and 56.9% and prevalence of AHI≥15 was 4.3–25%. Altogether 4.8% of subjects with AHI ≥15 had abnormally short sleep latency in MWT (<19.4 min).ConclusionsModerate sleep apnea is common among professional truck drivers but significant inability to stay awake, defined as MWT <19.4 min, is found in about one of twenty professional drivers.     

Brain iron and ferritin in Parkinson's and Alzheimer's diseases

Summary Semiquantitative histological evaluation of brain iron and ferritin in Parkinson's (PD) and Alzheimer's disease (DAT) have been performed in paraffin sections of brain regions which included frontal cortex, hippocampus, basal ganglia and brain stem. The results indicate a significant selective increase of Fe³⁺ and ferritin in substantia nigra zona compacta but not in zona reticulata of Parkinsonian brains, confirming the biochemical estimation of iron. No such changes were observed in the same regions of DAT brains. The increase of iron is evident in astrocytes, macrophages, reactive microglia and non-pigmented neurons, and in damaged areas devoid of pigmented neurons. In substantia nigra of PD and PD/DAT, strong ferritin reactivity was also associated with proliferated microglia. A faint iron staining was seen occasionally in peripheral halo of Lewy bodies. By contrast, in DAT and PD/DAT, strong ferritin immunoreactivity was observed in and around senile plaques and neurofibrillary tangles. The interrelationship between selective increase of iron and ferritin in PD requires further investigation, because both changes could participate in the induction of oxidative stress and neuronal dath, due to their ability to promote formation of oxygen radicals.Ferritin antisera were kindly provided by Dr. J. G. Joshi, Department of Biochemistry, University of Tennessee, Knoxville, TN, U.S.A.     

Association of daytime sleepiness with nigrostriatal dopaminergic degeneration in early Parkinson's disease

Abstract Introduction Many patients with Parkinson's disease (PD) report daytime sleepiness. Its etiology, however, is still not fully understood. The aim of this study was to examine if the amount of nigrostriatal dopaminergic degeneration is associated with subjective daytime sleepiness in patients with PD. Patients and methods We investigated 21 patients with PD clinically and by means of [¹²³I] FP-CIT-SPECT (DaTSCAN^R). Each patient filled in the Epworth sleepiness scale (ESS), the Parkinson's Disease Sleep Scale (PDSS), and the self-rating depression scale according to Zung (SDS) to assess sleepiness, sleep quality, and depressive symptoms. Results The mean specific dopamine transporter binding in the 21 PD patients (60.8 ± 10.4 years, nine females, median Hoehn and Yahr stage 2.0) was decreased. Nine patients were in Hoehn and Yahr stage 1 (58.7 ± 6.6 years, four females; ESS score 7.4 ± 4.5; PDSS score 105.1 ± 30.9), the other 12 patients were in Hoehn and Yahr stage 2 (62.4 ± 12.6 years, five females; ESS score 6.7 ± 4.7, PDSS score 97.1 ± 25.6). Age, gender, ESS, and PDSS scores were not significantly different in both groups. However, ESS scores showed an inverse correlation with mean DAT binding in the striatum (r = -0.627, p = 0.03), the caudate nucleus (r = -0.708, p = 0.01), and the putamen (r = -0.599, p = 0.04) in patients with Hoehn and Yahr stage 2. There was no correlation of the ESS score with age, disease duration, UPDRS motor score, PDSS score, or depression score. Conclusion Subjective daytime sleepiness seems to be associated with dopaminergic nigrostriatal degeneration in early PD.     

帕金森病与阿尔茨海默病

普遍认为帕金森病和阿尔茨海默病是两个独立的、有着显著判别的疾病。但是,相当数量为证据表明,二者具有相互重叠的临床和神经病理特征、相似的病因和病变发生机制。因此,现在有人认为这两种疾病的部分病例可能是同一种神经元退行性变疾病的不同表现形式。本文拟对此作一介绍。     

Comparing MSLT and ESS in the measurement of excessive daytime sleepiness in obstructive sleep apnoea syndrome

OBJECTIVE: The objective of this study is to compare the use of Multiple Sleep Latency Test (MSLT) and Epworth Sleepiness Scale (ESS) in measuring excessive daytime sleepiness (EDS) in patients with different severity of obstructive sleep apnoea syndrome (OSAS). METHOD: Two hundred ninety-six consecutive OSAS patients, with their EDS measured by a Chinese version of ESS and a five-nap MSLT, and their severity of OSAS (determined by respiratory disturbance index) by a nocturnal polysomnogram, were classified into mild (RDI 5-15/h, n=59), moderate (RDI 15-30/h, n=71) and severe (RDI >30/h, n=166) groups, respectively. Their ESS, MSLT and other sleep parameters were compared. RESULTS: The severe group had significantly shorter mean sleep latency (MSL=6.26+/-4.90 min) than the moderate (8.26+/-4.57 min) and mild groups had (8.07+/-4.37 min). There was no significant difference in their ESS scores. CONCLUSION: MSLT is better than ESS in the measurement of EDS in relation to the severity of OSAS in clinical patients.