Sleep-wake disturbances in Parkinson's disease: current evidence regarding diagnostic and therapeutic decisions

Sleep disorders have been frequently reported in patients with Parkinson's disease (PD). However, there is insufficient evidence to guide precise recommendations on some diagnostic and treatment strategies. Here, we review clinical studies dealing with sleep abnormalities in PD and present clinical recommendations. Previous studies describing insomnia, excessive daytime sleepiness, narcolepsy-like episodes, circadian changes, sleep-disordered breathing, rapid eye movement sleep behavior disorder, vivid dreams and restless legs syndrome are evaluated. Longitudinal studies associating sleep disorders with PD onset or clinical deterioration are rare: only one longitudinal study associated daytime sleepiness with PD onset. Evidence suggests that clinical investigations must include direct questioning about depressive symptoms, nocturnal cramps, pain, nocturia and nighttime off periods. A patient interview must be conducted regarding sleep symptoms, including nightmares, abnormal behavior during sleep, snoring, restless legs syndrome and daytime sleepiness. Initial evidence indicates that light therapy improves motor function and depression. Advice on sleep hygiene, the treatment of concomitant depression and the careful use of dopaminergic drugs and hypnosedative agents should be considered. To date, very few controlled studies are available to make a recommendation for the management of sleep-wake disturbances in PD.     

Periodic limb movements and other movement disorders in sleep: neuropsychiatric dimensions

Movement disorders such as Parkinson's disease and Tourette's syndrome, primarily manifest during wakefulness, intrude into sleep. There are some disorders, however, such as periodic limb movements in sleep, restless legs syndrome, paroxysmal nocturnal dystonia, bruxism, and somnambulism, which occur primarily during sleep. The diagnosis and management of these disorders pose a challenge to neuropsychiatric practice, not only because they may be difficult to distinguish from other neuropsychiatric disorders, but also because psychiatric disorders are often co-morbid with them. Study of these disorders is necessary for an understanding of the interaction of sleep and movement, and how disturbance in one may affect the other.     

Ropinirole in the treatment of restless legs syndrome

Ropinirole is an original nonergoline dopamine agonist indicated for the treatment of Parkinson's disease. However, recent developments in the study of restless legs syndrome have demonstrated another role for this drug. The symptoms of restless legs syndrome are responsive to dopaminergic agents such as ropinirole. The dosage of ropinirole needed to treat the symptoms of restless legs syndrome appears to be much smaller than what is necessary for Parkinson's disease therapy. The liver is primarily responsible for the metabolism of ropinirole, which has an elimination half-life of approximately 6 h. Ropinirole is generally well tolerated, with no serious adverse effects. Clinical studies have indicated that ropinirole can effectively reduce the motor symptoms of restless legs syndrome and improve overall sleep quality.     

Sublingual administration of apomorphine in the treatment of motor fluctuations in Parkinson disease]

Apomorphine, a mixed dopaminergic agonist was given sublingually to 12 patients with Parkinson's disease disabled by severe on-off fluctuations. The patient's mean age was 57 years and the duration of Parkinson's disease was 12 years. All patients were also given domperidone (60 mg/day). Apomorphine was administered as soon as the off periods appeared. On periods were observed in 11 patients, with a mean apomorphine dose of 40 mg for each administration (extremes values: 20-60 mg). One patient had no motor benefit after an apomorphine dose of 120 mg. The mean duration of daily off periods was reduced by 64 per cent in 11 patients, for a mean duration of 8 months (extremes values: 2-12 months). Four patients developed stomatitis or gingival edema and stopped treatment. This pilot study shows that sublingual apomorphine, during a mean period of 8 months, significantly decreases off periods in parkinsonian patients. Others studies are necessary to confirm these results.     

Improvement of sleep quality in patients with advanced Parkinson's disease treated with deep brain stimulation of the subthalamic nucleus.

Most Parkinson's patients complain about sleep problems. The subjective effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) on nocturnal disabilities and sleep quality was elucidated by the recently established Parkinson's disease sleep scale (PDSS). The DBS-treated group obtained significant improvement of motor function assessed by the Unified Parkinson's Disease Rating Scale. The mean total PDSS improved significantly after surgery whereas no change was found for the control group. Significant improvements of individual questions were obtained for overall sleep quality and motor symptoms whereas nocturia and daytime sleepiness did not change despite significant reduction of parkinsonian medication.     

Sleep dysfunction in Parkinson's disease

The frequency of sleep complaints in patients with Parkinson's disease (PD) is estimated to be between 60-90% and a variety of either disease-related or secondary mechanisms and the dopaminergic treatment itself contributes to the development of different sleep disturbances. These comprise slight, fragmented sleep with increased number of arousals and awakenings, and PD-specific motor phenomena such as nocturnal immobility, rest tremor, eye-blinking, dyskinesias, and other phenomena such as periodic and nonperiodic limb movements in sleep, restless legs syndrome, fragmentary myoclonus, and respiratory dysfunction in sleep. Depression and hallucinations/psychosis further complicate the picture. The incidence of REM sleep behavior disorder (RBD) with nightmares and violent behavior is increased in PD and may occur as a preclinical disease-related symptom. A careful sleep history of patients and their partners, polysomnograms when necessary, motor and psychiatric assessments should precede individual treatment strategies, which include adjusting dopaminergic daytime treatment, benzodiazepines for RBD, reduction of anticholinergic drugs, and, if necessary, clozapine for nocturnal psychosis.     

Association of restless legs syndrome,pain, and mood disorders in parkinson's disease

Purpose/Aims: The objectives of the study were to analyze the association between Parkinson's disease and restless legs syndrome, and to explore the relationship between mood disorder comorbidity (anxiety and depression), pain, and restless legs syndrome. Methods: This study included 123 Parkinson's disease patients and 123 non-Parkinson's disease patients matched for age and gender, and evaluated for anxiety severity, depression severity, pain severity, pain interference, pain disability, and restless legs syndrome prevalence. This was performed using semi-structured interviews and a neurological examination through the restless legs syndrome diagnostic criteria and the following inventories; Hospital Anxiety and Depression Scale, Brief Pain Inventory, and Pain Disability Index. Results: Parkinson's disease patients had significantly greater anxiety severity, depression severity, pain severity, pain interference, pain disability, and restless legs syndrome prevalence in comparison to controls. In addition, Parkinson's disease patients’ comorbid for anxiety and depression had significantly greater pain severity, pain interference, and pain disability, but not RLS prevalence, in comparison to Parkinson's disease only, Parkinson's disease anxiety, and Parkinson's disease depression patients. Conclusions: Pain interference, pain severity, and pain disability is greater among Parkinson's disease patients with anxiety and depression, in comparison to Parkinson's disease patients without anxiety and depression. On the contrary, the prevalence of restless legs syndrome was not found to be relevant.     

Variable expressivity in familial restless legs syndrome

A 62-year-old man with a 20-year history of excessive daytime somnolence and kicking during sleep was an obligate carrier of the restless legs syndrome gene because his paternal grandfather, father, and all three of his children had symptoms of restless legs syndrome. The patient himself, however, denied motor restlessness after a careful and exhaustive medical history and he was originally believed to have periodic movements in sleep without restless legs. Close clinical observation did reveal nighttime motor restlessness, although the patient continued to deny its importance. Polysomnography showed frequent periodic movements in sleep. We conclude that there can be variable expressivity of the clinical features in familial restless legs syndrome and that there are probably some relatively nonrestless patients with prominent periodic movements in sleep who are carriers of the restless legs syndrome gene. Some sleep-disordered patients who are believed to have only periodic movements in sleep may have a forme fruste of autosomal dominant restless legs syndrome. If one does not examine these patients carefully at night and take an adequate family history, one may miss the diagnosis of restless legs syndrome.     

Deep brain stimulation of the subthalamic nucleus: effectiveness in advanced Parkinson's disease patients previously reliant on apomorphine

OBJECTIVES: To assess the efficacy of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with advanced Parkinson's disease previously reliant on apomorphine as their main antiparkinsonian medication. METHODS: Seven patients with motor fluctuations despite optimal medical treatment given as predominantly apomorphine infusion (n=6), or intermittent apomorphine injections (n=1) underwent bilateral STN DBS using frameless stereotactic surgery. Standard assessments of parkinsonism and motor fluctuations, using Unified Parkinson's Disease Rating Scale (UPDRS) were performed before and six months after surgery. Assessments were performed both on and off medication, and postoperative with the stimulators switched on and off. RESULTS: Bilateral STN DBS improved motor scores (UPDRS III) by 61% when off medication (p<0.05). Clinical fluctuations (UPDRS IV items 36-39) were reduced by 46.2% (p<0.05). Total daily apomorphine dose was reduced by 68.9% (p<0.05) and apomorphine infusion via a pump was no longer required in four patients. There were no operative complications. Two patients required treatment for hallucinations postoperatively but there was no significant change in mini-mental state examination. CONCLUSIONS: In patients with advanced Parkinson's disease, previously reliant on apomorphine, bilateral STN DBS is an effective treatment to reduce motor fluctuations and enable a reduction in apomorphine use.     

Subcutaneous apomorphine in the treatment of Parkinson''s disease.

Apomorphine a dopamine receptor agonist was given subcutaneously to 57 levodopa treated parkinsonian patients with refractory off-period disabilities for a median period of 16 months. In 30 given intermittent suprathreshold injections the mean number of hours spent in a disabling off state fell from 6.9 to 2.9. Similar benefit was observed in 21 patients receiving continuous infusions with additional boluses on demand by mini-pump (mean reduction of hours off from 9.9 to 4.5). Twelve patients have been treated for over two years without tachyphylaxis or loss of response. The incidence of neuropsychiatric side-effects has been low (7%). Six patients failed to show a sustained worthwhile response; severe disabilities during "on" periods being the major problem. Subcutaneous apomorphine is proposed as an effective treatment for patients with incapacitating "off" period disabilities refractory to oral medication and should be considered before experimental implantation procedures.     

Acute low single dose of apomorphine reduces periodic limb movements but has no significant effect on sleep arousals: a preliminary report.

STUDY OBJECTIVES: To investigate the effects of apomorphine on the frequency of periodic limb movements during sleep (PLMS) and on sleep architecture. DESIGN: Nine patients presenting PLMS (including eight patients with restless legs syndrome) underwent three consecutive night sleep recordings. They received a single dose of 0.5 mg subcutaneous apomorphine at bedtime the third night. RESULTS: When computing PLMS during four 2-h periods of sleep, a significant period by apomorphine-effect was demonstrated, with a marked reduction of PLMS during the first 4 h post-injection (P < 0.01). No significant differences were found in sleep macroarchitecture between the three recorded nights, excepted a slight reduction in sleep latency during the third night (P < 0.05). Despite the decreased number of PLMS after apomorphine injection, there were significant changes neither in the total number of arousals nor in the index of arousals per hour of sleep. CONCLUSION: Our results add further support to the dopaminergic hypothesis in the generation of PLMS. The persistence of arousals suggests that they are not simply the consequence of PLMS but a primary phenomenon, not related with the dopaminergic system.     

Sleep disturbances in Parkinson's disease

Parkinson's disease is a progressive disorder of the central nervous system. Degeneration of the dopaminergic neurons is the main cause of the disease. The basic symptoms of Parkinson's disease are bradykinesia, rigidity and resting tremor. Disturbances of the autonomous nervous system, depression, dementia and sleep disorders are common, too. People with Parkinson's disease suffer from insomnia, excessive daytime sleepiness, "sleep attacks", nightmares, REM sleep behaviour disorder, periodic limb movement in sleep, restless legs syndrome and sleep apnea syndrome. The main cause of sleep disorders in Parkinson's disease are age-connected changes in sleep architecture, disturbances of neurotransmission, movement disturbances in sleep, medications and concomitant diseases. The authors present the current state of knowledge on sleep disorders in Parkinson's disease, especially, the role of dopaminergic therapy, methods of diagnostics and treatment as well as the influence of sleep disturbances on patient's quality of life.     

The effect of nocturnal physiological sleep on various movement disorders

Thirty-one subjects affected by different movement disorders underwent polygraphic and videotape monitoring during nocturnal sleep, to assess movement patterns during the night. It was possible to distinguish two categories of disorders according to their pattern of movements. In the largest group (Meige's syndrome, blepharospasm, amyotrophic choreoacanthocytosis, Tourette syndrome, tonic foot, hemiballism) abnormal movements were still present during sleep, but decreased in frequency and amplitude in all stages. The second group presented three syndromes (nocturnal paroxysmal dystonia, nocturnal myoclonus, restless legs syndrome), in which light non-rapid-eye-movement sleep induced a strong activation of abnormal movements, whereas rapid-eye-movement sleep suppressed them.     

Restless legs syndrome and nocturnal myoclonus: initial clinical manifestation of familial amyloid polyneuropathy.

Restless legs syndrome was the first isolated clinical manifestation in four siblings of a family with familial amyloid polyneuropathy. Clinical and electrophysiological evidence of peripheral neuropathy appeared after a variable time interval. Polysomnography showed abnormal sleep patterns and nocturnal myoclonus in all patients. The restless legs syndrome responded favourably to clonazepam.     

Assessment of sleepiness and unintended sleep in Parkinson's disease patients taking dopamine agonists

OBJECTIVE: We sought to determine if patients with Parkinson's disease (PD), taking dopamine agonists (DAs) and reporting unintended sleep episodes (SEs), exhibit physiologically defined daytime sleepiness and can thus be differentiated from those taking DAs but not reporting SEs. METHODS: Twenty-four patients with abnormal Epworth Sleepiness Scale scores of >10 who were taking DAs were enrolled into one of two groups: those with SEs (SE+, n=16) and those without (SE-, n=8). Three consecutive days of testing included two nights of polysomnography followed by the Multiple Sleep Latency Test (MSLT). RESULTS: Overall frequency of pathological sleepiness (MSLT <5 min) was 42% (10/24). Mean levels of sleepiness, frequencies of pathological sleepiness, and naps with stage 2 or REM-sleep were similar between SE+ and SE- groups. Sleep tendency was similar in patients prescribed pergolide, ropinirole, and pramipexole combined with levodopa. Polysomnography testing revealed no significant differences between the groups in total sleep time, sleep efficiency, sleep architecture, or presence of restless legs syndrome or periodic leg movements. There was no relation between degree of nocturnal sleep disturbance and level of daytime sleepiness. CONCLUSIONS: The results of this study suggest SEs in PD patients occur upon a background of excessive daytime sleepiness and are unrelated to nocturnal sleep or use of a specific DA.     

Subcutaneous apomorphine in late stage Parkinson's disease: a long term follow up

OBJECTIVES—Despite the recent introduction of newperoral drugs as well as neurosurgical methods for Parkinson'sdisease, treatment of late stage parkinsonian patients remainsdifficult and many patients become severely handicapped because offluctuations in their motor status. Injections and infusions ofapomorphine has been suggested as an alternative in the treatment ofthese patients, but the number of studies describing the effects ofsuch a treatment over longer time periods is still limited. Theobjective was to investigate the therapeutic response and range of sideeffects during long term treatment with apomorphine in advancedParkinson's disease.
METHODS—Forty nine patients (30 men, 19 women; agerange 42-80 years) with Parkinson's disease were treated for 3 to 66 months with intermittent subcutaneous injections or continuousinfusions of apomorphine.
RESULTS—Most of the patients experienced a longterm symptomatic improvement. The time spent in "off" wassignificantly reduced from 50 to 29.5% with injections and from 50 to25% with infusions of apomorphine. The quality of the remaining"off" periods was improved with infusion treatment, but wasrelatively unaffected by apomorphine injections. The overall frequencyand intensity of dyskinesias did not change. The therapeutic effects ofapomorphine were stable over time. The most common side effect waslocal inflammation at the subcutaneous infusion site,whereas the most severe were psychiatric side effects occurring in 44%of the infusion and 12% of the injection treated patients.
CONCLUSION—Subcutaneous apomorphine is a highlyeffective treatment which can substantially improve the symptomatologyin patients with advanced stage Parkinson's disease over a prolongedperiod of time.

     

Restless legs with antiepileptic drug therapy

The restless legs syndrome is generally benign but is occasionally associated with anemia, metabolic disorder, or polyneuropathy. Leg restlessness with disruptive nocturnal myoclonus has been described as a sleep disorder. We report two patients with complex partial and secondarily generalized seizures, who developed restless legs while taking methsuximide and phenytoin. They had no evidence of metabolic disturbance or neuromuscular disease, although one patient had fragmented sleep and disruptive myoclonus on polysomnography, and leg restlessness subsided with change of antiepileptic drugs. These symptoms could reflect transient alteration in peripheral nerve function not evident by examination or electrophysiologic studies, sleep disturbance by antiepileptic drugs or the effects of temporal lobe seizure foci on perception of the physiologic state of nerves and muscles.     

Continuous subcutaneous infusion of apomorphine for the treatment of Parkinson's disease

Apomorphine administered by subcutaneous infusion has been used efficiently in parkinsonian patients to treat severe motor fluctuations and levodopa-induced dyskinesias. Despite increasing evidence of its efficacy and its relative safety, apomorphine infusion therapy is still underused. This article reviews pharmacokinetic properties, efficacy, tolerability and indications of apomorphine infusion in Parkinson's disease.