European guideline for the diagnosis and treatment of insomnia

This European guideline for the diagnosis and treatment of insomnia was developed by a task force of the European Sleep Research Society, with the aim of providing clinical recommendations for the management of adult patients with insomnia. The guideline is based on a systematic review of relevant meta-analyses published till June 2016. The target audience for this guideline includes all clinicians involved in the management of insomnia, and the target patient population includes adults with chronic insomnia disorder. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) system was used to grade the evidence and guide recommendations. The diagnostic procedure for insomnia, and its co-morbidities, should include a clinical interview consisting of a sleep history (sleep habits, sleep environment, work schedules, circadian factors), the use of sleep questionnaires and sleep diaries, questions about somatic and mental health, a physical examination and additional measures if indicated (i.e. blood tests, electrocardiogram, electroencephalogram; strong recommendation, moderate- to high-quality evidence). Polysomnography can be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders), in treatment-resistant insomnia, for professional at-risk populations and when substantial sleep state misperception is suspected (strong recommendation, high-quality evidence). Cognitive behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (strong recommendation, high-quality evidence). A pharmacological intervention can be offered if cognitive behavioural therapy for insomnia is not sufficiently effective or not available. Benzodiazepines, benzodiazepine receptor agonists and some antidepressants are effective in the short-term treatment of insomnia (≤4 weeks; weak recommendation, moderate-quality evidence). Antihistamines, antipsychotics, melatonin and phytotherapeutics are not recommended for insomnia treatment (strong to weak recommendations, low- to very-low-quality evidence). Light therapy and exercise need to be further evaluated to judge their usefulness in the treatment of insomnia (weak recommendation, low-quality evidence). Complementary and alternative treatments (e.g. homeopathy, acupuncture) are not recommended for insomnia treatment (weak recommendation, very-low-quality evidence).

The long-term development of non-motor problems after STN-DBS.

OBJECTIVES: Stimulation of the subthalamic nucleus (STN-DBS) is an established treatment with long-term beneficial effects on motor symptoms in patients with Parkinson's disease (PD). The long-term development of non-motor problems after STN-DBS is not fully understood. In this study, we have studied how non-motor problems develop in patients with and without STN-DBS. MATERIALS AND METHODS: We collected data from a prospectively followed cohort of patients that had been operated with STN-DBS 6-9 years before final examination and compared our findings to the longitudinal development of non-motor problems in a non-operated, comparable reference population. RESULTS: In general, the non-motor problems of advanced PD seem to develop independently of treatment with STN-DBS. We found that depressions do not worsen after STN-DBS, and the Montgomery and Aasberg Depression Rating Scale score in operated patients was substantially reduced from pre-operatively to post-operatively. Further, fatigue may represent an important unrecognized side effect of long-term stimulation, as fatigue was found to increase rapidly in operated patients already a year after surgery and continued to increase trough the 6- to 9-year follow-up. CONCLUSIONS: The non-motor problems of advanced PD seem to develop independently of treatment with STN-DBS. This may influence the strategy for choice of when to perform this therapy for eligible patients.

Motor symptoms after deep brain stimulation of the subthalamic nucleus.

OBJECTIVES: Stimulation of the subthalamic nucleus (STN-DBS) is an established treatment with long-term beneficial effects on motor symptoms in patients with Parkinson's disease (PD). The efficacy of STN-DBS on non-dopaminergic motor symptoms remains less elucidated. In this study, we have examined short- and long-term impacts of STN-DBS on the development of the postural instability and gait difficulties (PIGD) phenotype, freezing of gait (FOG), and falls. MATERIALS AND METHODS: We collected data from a prospectively followed cohort of patients that had been operated with STN-DBS 6-9 years before final examination and compared our findings to the longitudinal development of the same symptoms in a non-operated, historical reference population. RESULTS: During short-term follow-up after surgery, we observed a marked improvement in mean UPDRS-motor score from 27 to 18. We also found clear improvements in tremor, bradykinesia, rigidity, and PIGD scores. However, 6-9 years after surgery, all patients had a dominating PIGD pattern of parkinsonism and 50% of the patients had developed FOG and/or had become recurrent fallers. The disease development in a group of patients with PD from the presurgery period had a similar trajectory as among the operated patients. In addition, mean annual change of both bradykinesia and PIGD scores was nearly identical in both study groups while tremor and rigidity had a significant better development in the operated patients. CONCLUSIONS: We found that STN-DBS induces an acute improvement of PIGD symptoms. The following long-term development was however characterized by a marked progression of non-dopaminergic symptoms.

Subjective sleep problems in patients with early Parkinson's disease.

BACKGROUND AND OBJECTIVE: Sleep problems are common in Parkinson's disease (PD) and increasingly so with disease progression. The frequency of these problems and the influence of dopaminergic treatment on sleep in early stages of PD remain unclear. We have therefore in this study examined the subjective experience of sleep problems in drug-naïve patients with early PD and how these problems developed after 1 year on dopaminergic treatment using the Parkinson's Disease Sleep Scale (PDSS). METHODS: In all, 138 drug-naïve patients with early PD derived from a population-based incident cohort and 138 age- and gender-matched control subjects were thoroughly assessed for Parkinsonism, cognition, depressive symptoms and sleep by structured interviews and clinical examination at the time of diagnosis and 1 year later on medication. Sleep problems were assessed using the PDSS. RESULTS: The total PDSS score for patients with PD was lower compared with controls, 119 vs. 127 (P < 0.05) at baseline and 121 vs. 128 (P < 0.005) after 1 year on drugs. Analyses of PDSS subdomains showed more nocturnal motor off symptoms both at baseline and after 1 year (P < 0.005) and increased daytime somnolence in patients compared with control subjects (P < 0.005 at baseline and P < 0.05 after 1 year). Only minor changes in sleep scores were seen after the introduction of dopaminergic treatment. CONCLUSION: Patients with early PD report only modestly increased subjective sleep problems at the time of diagnosis compared with control subjects and dopaminergic treatment during the first year in general only slightly changed the experienced sleep problems.

Increased risk of leg motor restlessness but not RLS in early Parkinson disease.

OBJECTIVE: This study explores the risk and correlates of leg restlessness in drug-naive patients with Parkinson disease (PD) as compared to control subjects matched for age and gender. METHODS: A total of 200 drug-naive patients with early, unmedicated PD derived from a population-based incident cohort and 173 age- and gender-matched control subjects were assessed for leg restlessness by structured interviews, clinical examination, and blood samples. All subjects were Caucasian. Restless legs syndrome (RLS) was diagnosed according to the essential diagnostic criteria. RESULTS: More patients (81 of 200, 40.5%) than controls (31 of 173, 17.9%) reported leg restlessness (p < 0.001). Thirty-one (15.5%) of these patients with PD and 16 (9.2%) control subjects met RLS criteria (p = 0.07). A total of 21 (12.5%) patients and 12 (6.9%) controls with RLS remained after the exclusion of potential RLS mimics and 26 patients vs 10 control subjects with leg motor restlessness (LMR), leading to a relative risk for RLS of 1.76 (95% confidence interval [CI] 0.90-3.43, p = 0.089) and 2.84 for LMR (95% CI 1.43-5.61, p = 0.001) in PD. Except for increased sleep disturbances in patients with RLS and increased Montgomery and Åsberg Depression Rating Scale scores for patients with RLS or LMR there were no other major differences in relevant blood tests, motor or cognitive function between PD with and without RLS or LMR. CONCLUSION: LMR and not RLS occurs with a near 3-fold higher risk as compared to controls in early PD. The findings underline a need for more accurate assessments of RLS in PD and support the notion that RLS and PD are different entities.

Occurrence and clinical correlates of REM sleep behaviour disorder in patients with Parkinson's disease over time.

OBJECTIVE: To examine the occurrence and clinical and demographic correlates of REM sleep behaviour disorder (RBD) in patients with Parkinson's disease (PD) in a community-based cohort over 8 years. METHODS: 231 patients with PD were included in a population-based prevalence study in 1993. Patients were then followed prospectively and reexamined after 4 and 8 years. Semi-structured interviews for information on clinical and demographic data were applied at all study visits. Standardised rating scales of parkinsonism, depression and cognitive impairment were used. The diagnosis of probable RBD (pRBD) was based on a sleep questionnaire. Proportional-odds ordinal logistic regression models for clustered data were used to study the relationship between pRBD and various demographic and clinical variables. RESULTS: 231 patients were evaluated for RBD in 1993 and, after 4 and 8 years, 142 and 89 patients, respectively, were available for re-evaluation. The frequency of pRBD varied from 14.6% to 27% during the study period. Probable RBD was related to male gender, higher dopaminergic treatment and less severe parkinsonism. CONCLUSION: We found that the frequency of pRBD varied over time and that it is associated with male gender, less parkinsonism and higher levodopa equivalent dose. Our findings indicate that dopaminergic therapy may contribute to the expression of RBD and that RBD is symptomatic in earlier stages of PD.

Insomnia in Parkinson's disease: frequency and progression over time.

OBJECTIVES: To examine the development of nocturnal sleeping problems in patients with Parkinson's disease (PD) over an 8-year period and to study the clinical and demographic correlates of insomnia. METHODS: 231 patients were included in a population-based prevalence study in 1993, and re-examined in 1997 and 2001. At all study visits, we applied semi-structured interviews to obtain information on clinical and demographic data, as well as on nocturnal sleeping problems. Standardised rating scales of parkinsonism, depression and cognitive impairment were used. The relationship between insomnia and demographic and clinical variables was analysed using population-averaged logistic regression models for correlated data. 231 patients were included at baseline, 142 were available for re-evaluation in 1997 and 89 patients in 2001. RESULTS: Most nocturnal sleeping problems varied little in prevalence over time, whereas problems related to turning in bed and vivid dreaming or nightmares increased. Insomnia was present in 54-60% of the patients at each of the three study visits and varied considerably in individual patients over time. The presence of insomnia was closely related to disease duration, higher Montgomery-Asberg Depression Rating Scale scores and female sex. CONCLUSION: Insomnia is a highly frequent complaint in patients with PD. It fluctuates over time in individual patients, and its origin seems to be multifactorial. Physicians should be aware of the high prevalence of insomnia in patients with PD and should examine their patients for a possible coexisting depression.

Excessive daytime sleepiness in Parkinson disease: is it the drugs or the disease?

OBJECTIVE: To examine associated demographic and clinical correlates and the development of excessive daytime sleepiness (EDS) over 8 years in a community-based cohort of patients with Parkinson disease (PD). METHODS: A total of 232 patients with PD were included in a population-based prevalence study in 1993. Patients were followed prospectively and reexamined after 4 and 8 years. At all study visits, the authors administered semistructured interviews to obtain information on clinical and demographic variables. Standardized rating scales of parkinsonism, depression, and cognitive impairment were used. The diagnosis of EDS was based on a sleep questionnaire and in 2001 also on the Epworth Sleepiness Scale. Population-averaged logistic regression models for correlated data were performed to study the relationship between EDS and various demographic and clinical variables. RESULTS: Of the 232 patients included at baseline, 138 were available for re-evaluation after 4 years and 89 patients after 8 years. Frequency rates of EDS increased from 5.6% in 1993 to 22.5% in 1997 and 40.8% in 2001, with an 8-year prevalence of 54.2%. In the majority of patients, EDS was a persistent feature. In the logistic regression model, EDS was related to age, gender, and use of dopamine agonists. In those never having used dopamine agonists, hypersomnia was associated with the Hoehn and Yahr stage only. CONCLUSION: Excessive daytime sleepiness is a frequent and highly persistent feature in Parkinson disease, with multifactorial underlying pathophysiology. The authors' findings indicate that both age and disease related disturbances of the sleep-wake regulation contribute to hypersomnia in PD. Treatment with dopamine agonists also contributed to excessive daytime sleepiness in our patients.

Drug costs for patients with Parkinson's disease in two different European countries.

OBJECTIVE: To examine factors that influence drug costs in patients with Parkinson's disease (PD) and to compare the costs in two different countries. METHODS: We examined drug costs among 438 patients with PD (286 from Germany and 152 from Norway) and collected information on the patients' age, medication, disease duration, and Hoehn & Yahr stage. RESULTS: Drug expenses rose with increasing severity and duration of the disease. This increase differed somewhat between the two countries. Mean drug costs per day and patient in the German group was Euro 5.78 while it was Euro 3.92 in the Norwegian group. A higher proportion of the German patients were treated with two or more drugs, and the switch from mono- to multi-drug therapy was done earlier in the course of the disease. Dopamine agonists caused 44% of total drug costs in both countries. CONCLUSION: Different management strategies of PD have a great impact on drug costs. Surveillance of prescription habits and careful cost/benefit analyses are therefore important.

Development of daytime somnolence over time in Parkinson's disease.

The authors examined the development over time of excessive daytime sleepiness (EDS) in patients with PD by evaluating EDS among 142 patients in 1993 and 4 years later. Eleven patients were diagnosed with EDS in 1993. In all of these patients, EDS persisted 4 years later. During follow-up, 30 new patients had EDS (6% new patients per year). In 1997, 29% of the patients with PD had EDS. The development of EDS correlated with more advanced disease and dementia.

Predominant neuronal B-cell loss in L5 DRG of p75 receptor-deficient mice.

The significance of the p75 low-affinity neurotrophin receptor, for the maintenance and survival of DRG cells, was studied in p75-deficient mice. Perikarya of the L5 DRG of 12-week-old p75 receptor-deficient mice and healthy Balb C mice were compared using stereological techniques. Following systematic sampling, the optical fractionator and the planar vertical rotator were used to estimate the number and mean volume of the cell bodies of the two neuronal subpopulations. The loss of B-cells was 57% (P < 0.00001), numbers being 7300 (CV = 0.12) in controls and 3100 in p75 receptor-deficient mice (CV = 0.18). Also, A-cells showed a significant loss of 39% (P < 0.0001), numbers being 2600 (CV = 0.12) in control mice and 1500 (CV = 0.16) in p75 receptor-deficient mice. The volume of A-cells was reduced by 30% (P<0.01), from 24.700 microm3 (CV=0.17) perikarya in p75 knock-out mice to 15.100 microm3 (CV=0.17) in controls. B-cell volume did not change significantly. It is concluded that the p75 receptor plays a major role in the survival of DRG cells. The predominant loss of small B-cells indicates that the effect of neurotrophins is dependent upon the presence of the p75 low-affinity receptor.

Association of muscle strength and electrophysiological measures of reinnervation in diabetic neuropathy.

Motor function was assessed in 34 non-insulin-dependent and 19 insulin-dependent diabetic patients with macroelectromyography and isokinetic dynamometry. Fiber density (FD) and the amplitude of the macro motor unit potential (macro MUP) of the anterior tibial and lateral vastus muscles were obtained and maximal isokinetic strength of the ankle and knee extensors were determined. All patients underwent standardized clinical examination including a neurological disability score (NDS), quantitative sensory examination, and conventional motor nerve conduction studies. The amplitude of the macro MUP and FD of the anterior tibial muscle were increased in neuropathic patients without weakness (P < 0.05) and further increased in neuropathic patients with weakness (P < 0.05). The NDS was related to the FD and the amplitude of the macro MUP for the anterior tibial and lateral vastus muscle [r=0.55-0.75 (P < 0.005)]. Muscle strength of ankle and knee extensors correlated with the FD [r=-0.69 (P < 0.0001) and r=-0.58 (P< 0.001), respectively] and with the amplitude of the macro MUP of the two muscles [r=-0.63 (P < 0.0001) and r=-0.37 (P < 0.05), respectively]. Our findings support the hypothesis that loss of muscle strength in diabetic patients is due to incomplete reinnervation following axonal loss.