Biomarkers of neurodegeneration in isolated and antidepressant-related rapid eye movement sleep behavior disorder.

BACKGROUND AND PURPOSE: This study compared the features of isolated rapid eye movement (REM) sleep behavior disorder (iRBD) and antidepressant-related REM sleep behaviour disorder (RBD) with the aim of highlighting markers that might distinguish the two entities. METHODS: The observational cohort study included RBD patients with and without antidepressant use (antiD+ and antiD- patients, respectively), without cognitive impairment and parkinsonism. Clinical features of RBD, subtle motor and non-motor symptoms of parkinsonism, sleep architecture, REM atonia index, dopamine transporter-single photon emission computed tomography (DAT-SPECT) and skin biopsies for the intraneuronal alpha-synuclein (α-syn), were evaluated in the baseline work-up. RESULTS: Thirty-nine patients, 10 antiD+ and 29 antiD-, were included. AntiD+ patients (more frequently female) reported more psychiatric symptoms, less violent dream enactment, and less frequent hyposmia. Dermal α-syn was detected in 93.1% of antiD- versus 30% of antiD+ patients (p = 0.00024). No differences appeared in other motor and non-motor symptoms, Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III score, DAT-SPECT, or polysomnographic features. CONCLUSIONS: Patients with antidepressant-related RBD have clinical and neuropathological features suggesting a lower risk of evolution than those with iRBD.

[Sleep disorders in patients with a neurocognitive disorder]. / Les troubles du sommeil chez les patients atteints d'un trouble neurocognitif.

INTRODUCTION: Sleep disorders are prevalent in patients with a neurocognitive disorder, and diagnosis and treatment in these patients remain challenging in clinical practice. METHODS: This narrative review offers a systematic approach to diagnose and treat sleep disorders in neurocognitive disorders. RESULTS: Alzheimer's disease is often associated with circadian rhythm disorders, chronic insomnia, and sleep apnea-hypopnea syndrome. Alpha-synucleinopathies (e.g., Parkinson's disease and Lewy body dementia) are often associated with a rapid eye movement sleep behavior disorder, restless legs syndrome, chronic insomnia, and sleep apnea-hypopnea syndrome. A focused history allows to diagnose most sleep disorders. Clinicians should ensure to gather the following information in all patients with a neurocognitive disorder: (1) the presence of difficulties falling asleep or staying asleep, (2) the impact of sleep disturbances on daily functioning (fatigue, sleepiness and other daytime consequences), and (3) abnormal movements in sleep. Sleep diaries and questionnaires can assist clinicians in screening for specific sleep disorders. Polysomnography is recommended if a rapid eye movement sleep behavior disorder or a sleep apnea-hypopnea syndrome are suspected. Sleep complaints should prompt clinicians to ensure that comorbidities interfering with sleep are properly managed. The main treatment for moderate to severe obstructive sleep apnea-hypopnea syndrome remains continuous positive airway pressure, as its efficacy has been demonstrated in patients with neurocognitive disorders. Medications should also be reviewed, and time of administration should be optimized (diuretics and stimulating medications in the morning, sedating medications in the evening). Importantly, cholinesterase inhibitors (especially donepezil) may trigger insomnia. Switching to morning dosing or to an alternative drug may help. Cognitive-behavioral therapy for insomnia is indicated to treat chronic insomnia in neurocognitive disorders. False beliefs regarding sleep should be addressed with the patient and their caregiver. The sleep environment should be optimized (decrease light exposure at night, minimize noise, avoid taking vital signs, etc.). Sleep restriction can be considered as patients with a neurocognitive disorder often spend too much time in bed. The need for naps should be assessed case by case as naps may contribute to insomnia in some patients but allow others to complete their diurnal activities. Trazodone (50mg) may also be used under certain circumstances in chronic insomnia. Recent evidence does not support a role for exogenous melatonin in patients with a neucognitive disorder and insomnia. Patients in long-term care facilities are often deprived of an adequate diurnal exposure to light. Increasing daytime exposure to light may improve sleep and mood. Patients with circadian rhythm disorders can also benefit from light therapy (morning bright light therapy in case of phase delay and evening bright light therapy in case of phase advance). Rapid eye movement sleep behavior disorder can lead to violent behaviors, and the sleeping environment should be secured (e.g., mattress on the floor, remove surrounding objects). Medication exacerbating this disorder should be stopped if possible. High dose melatonin (6 to 18mg) or low dose clonazepam (0.125-0.25mg) at bedtime may be used to reduce symptoms. Melatonin is preferred in first-line as it is generally well tolerated with few side effects. Patients with restless legs syndrome should be investigated for iron deficiency. Medication decreasing dopaminergic activity should be reduced or stopped if possible. Behavioral strategies such as exercise and leg massages may be beneficial. Low-dose dopamine agonists (such as pramipexole 0.125mg two hours before bedtime) can be used to treat the condition, but a prolonged treatment may paradoxically worsen the symptoms. Alpha-2-delta calcium channel ligands can also be used while monitoring for the risk of falls. CONCLUSION: Multiple and sustained nonpharmacological approaches are recommended for the treatment of sleep disturbances in patients with neurocognitive disorder. Pharmacological indications remain limited, and further randomized clinical trials integrating a multimodal approach are warranted to evaluate the treatment of sleep disorders in specific neurocognitive disorders.

Treatment of isolated REM sleep behavior disorder using melatonin as a chronobiotic.

Melatonin is recommended as a first-line treatment in isolated REM sleep behavior disorder (iRBD), although no large patient group has been reported. To assess effects, time course and confounding factors in the treatment of patients with iRBD using melatonin, 209 consecutive patients were included in this single-center, observational cohort study. A total of 171 patients had taken melatonin according to our chronobiotic protocol (2 mg, ≥6 months, always-at-the-same-clock time, 10-11pm, corrected for chronotype), 13 had applied melatonin for about 1-3 months, and 25 underwent mixed treatments. In total, 1529 clinical evaluations were performed, including Clinical Global Impression (CGI) and a newly developed RBD symptom severity scale (Ikelos-RS), analyzed using linear mixed models. Validation of Ikelos-RS showed excellent inter-rater reliability (ρ = 0.9, P < .001), test-retest reliability (ρ = 0.9, P < .001) and convergent validity (ρ = 0.9, P < .001). With melatonin, RBD symptom severity gradually improved over the first 4 weeks of treatment (Ikelos-RS: 6.1 vs. 2.5; CGI Severity: 5.7 vs. 3.2) and remained stably improved (mean follow-up 4.2 ± 3.1years; range: 0.6-21.7years). Initial response was slowed to up to 3 months with melatonin-suppressing (betablockers) or REM sleep spoiling co-medication (antidepressants) and failed with inadequately timed melatonin intake. When melatonin was discontinued after 6 months, symptoms remained stably improved (mean follow-up after discontinuation of 4.9 ± 2.5years; range: 0.6-9.2). When administered only 1-3 months, RBD symptoms gradually returned. Without any melatonin, RBD symptoms persisted and did not wear off over time. Clock-timed, low-dose, long-term melatonin treatment in patients with iRBD appears to be associated with the improvement of symptoms. The outlasting improvement over years questions a pure symptomatic effect. Clock-time dependency challenges existing prescription guidelines for melatonin.

Movement disorders induced by psychiatric drugs that do not block dopamine receptors.

Most movement disorders in psychiatric patients are induced by neuroleptic antipsychotic medications, all of which are dopamine D2 receptor blocking drugs. These include: acute onset disorders: dystonic reactions, akathisia and the neuroleptic malignant syndrome (NMS); non-acute onset parkinsonism; and the tardive syndromes. However, many other medications, when used at recommended doses, also induce movement disorders, with tremor being the most common. With the exception of serotonin syndrome, they are rarely as severe or disabling as the neuroleptic extrapyramidal syndromes may be. The serotonin reuptake inhibiting (SSRI) drugs are associated with the serotonin syndrome, a life-threatening disorder, but may also cause tremor and akathisia. While SSRI's have been thought to occasionally cause a tardive dyskinesia-like syndrome, this almost never occurs without prior or concurrent neuroleptic exposure as well. There also are few reliable data to support an association between antidepressants and parkinsonism. Valproic acid has been shown to cause parkinsonism, and lithium may as well, in addition to both having the well-known side effect of tremors. Myoclonus and asterixis are usually induced by toxic levels of medications but may appear with therapeutic levels, particularly with anticonvulsant mood stabilizers, and clozapine. Ataxia rarely occurs with non-toxic levels of drug, particularly anticonvulsants, benzodiazepines and lithium.

Duloxetine-induced rapid eye movement sleep behavior disorder: a case report.

BACKGROUND: Tricyclic antidepressants and selective serotonin reuptake inhibitors have been reported to induce the symptoms of rapid eye movement (REM) sleep behavior disorder (RBD) or to exacerbate REM sleep without atonia. With this case report, we found an association between typical RBD and duloxetine, a serotonin-noradrenaline reuptake inhibitor. CASE PRESENTATION: We present a case of a 62-year-old woman who experienced enactment behaviors with violent dreams that were associated with increased tonic or phasic chin electromyography activity during REM sleep after treated with duloxetine. RBD symptoms were gradually reduced and completely ceased after discontinuation of duloxetine for 37 days. CONCLUSION: The current case appears to be the first observation of duloxetine-induced RBD. We describe features of RBD induced by duloxetine that are similar and different from that induced by tricyclic antidepressants and selective serotonin reuptake inhibitors.

The Prevalence and Characteristics of REM Sleep without Atonia (RSWA) in Patients Taking Antidepressants.

STUDY OBJECTIVES: The association of REM sleep without atonia (RSWA) as well as REM sleep behavior disorder (RBD) with the intake of selective serotonin reuptake inhibitors (SSRI) and selective norepinephrine reuptake inhibitors (SNRI) is well established. Our study objective was to determine the prevalence of RSWA and RBD among a group of sleep center patients taking SSRI and SNRI. METHODS: A retrospective chart review was done at our tertiary sleep center, and 10,746 consecutive records from October 1, 2007, through October 31, 2013, were searched for SSRI and SNRI names using the Sleep Cataloguer Software. RESULTS: The search resulted in 1,444 records, which were then reviewed for keywords of RSWA and RBD. The AASM scoring criteria were used to determine RSWA. Reports of 41 patients with known narcolepsy or α-synucleinopathies were excluded. The remaining records were mined for age, sex, presence of obstructive sleep apnea (OSA), type of antidepressant (SSRI or SNRI), and diagnosis for which antidepressant was prescribed. We used logistic regression analysis to adjust for age, OSA, and sex. Of the 1,444 participants on antidepressants, 176 (12.2%) had RSWA (all confirmed by the investigators) compared to 226 of the entire sleep lab population of 10,746 (2.1%), risk ratio (95% CI) 9.978 (8.149, 12.22). Seven of the 176 patients on antidepressants had RBD (0.48%) compared to 108 of 10,746 (1%), p = 0.005. CONCLUSIONS: SSRI and SNRI are associated with a higher prevalence of RSWA but not of RBD. This is independent of medication type.

Antidepressants substantially affect basic REM sleep characteristics in narcolepsy-cataplexy patients.

OBJECTIVES: Antidepressants substantially affect REM sleep characteristics and trigger manifestations of REM sleep behavior disorder (RBD) in the general, non-narcoleptic, population. Antidepressants are also frequently administrated in an attempt to suppress cataplexy. We investigated the role of antidepressants in the development of RBD in narcolepsy with cataplexy (NC) patients. PATIENTS/METHODS: Seventy-five patients diagnosed with NC were assessed by a structured interview (focused on RBD manifestations and the use of antidepressants) and night video-polysomnography followed by the multiple sleep latency test. RESULTS: Of all 75 NC patients (36 male, 39 female; mean age 46.1±18.5 years), 34 cases had a history of antidepressant use (45.3%; 18 male, 16 female). In this antidepressant-positive group, 13 patients suffered from RBD (38.2%). Among antidepressant-naïve patients, only 5 subjects (12.2%) were diagnosed with RBD. Polysomnographic data showed significantly increased REM latency (p<0.01) and reduced percentage of REM sleep (p<0.01) in the antidepressant-positive group, as well as more periodic limb movements during sleep (p=0.01). CONCLUSIONS: NC patients with a history of antidepressant use showed a three-fold higher occurrence of RBD in comparison to antidepressant-naïve patients.

Conductas anormales durante el sueño y uso de zolpidem / Abnormal behaviour during sleep and the use of zolpidem

El zolpidem es un medicamento ampliamente distribuido, comercializado y prescrito como tratamiento para el insomnio de conciliación. En el presente trabajo se describen episodios de actos complejos realizados durante el periodo de sueño, de los cuales el sujeto no tiene recuerdo alguno. Estos se asociaron al uso de zolpidem durante una semana, lapso en el que tales actos resultaron evidentes para el paciente. La creciente angustia ante la posibilidad de realizar actos sin tener conciencia de ello generó gran preocupación al paciente. Este fue el motivo de consulta, especialmente al notar que dichos episodios solo ocurrieron con posterioridad al uso por vía oral de 10 mg de zolpidem (AU)

Zolpidem is a drug widely distributed, marketed, and prescribed as treatment of sleep-onset insomnia. In the present study, a description is presented of episodes of complex acts performed while asleep sleep, of which the subject had no memory. These were associated with the use of zolpidem for one week. The increasing anxiety about the possibility of performing actions without being conscious has generated serious concern by the patient, especially when it is observed that such episodes occurred after oral use of only10 mg of zolpidem (AU)

Antidepressants Increase REM Sleep Muscle Tone in Patients with and without REM Sleep Behavior Disorder.

STUDY OBJECTIVES: REM sleep behavior disorder (RBD) is associated with antidepressant treatment, especially in younger patients; but quantitative REM sleep without atonia (RSWA) analyses of psychiatric RBD patients remain limited. We analyzed RSWA in adults receiving antidepressants, with and without RBD. DESIGN: We comparatively analyzed visual, manual, and automated RSWA between RBD and control groups. RSWA metrics were compared between groups, and regression was used to explore associations with clinical variables. SETTING: Tertiary-care sleep center. PARTICIPANTS: Participants included traditional RBD without antidepressant treatment (n = 30, 15 Parkinson disease [PD-RBD] and 15 idiopathic); psychiatric RBD receiving antidepressants (n = 30); and adults without RBD, including antidepressant-treated psychiatric (n = 30), untreated psychiatric (n = 15), and OSA (n = 60) controls. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: RSWA was highest in traditional and psychiatric RBD, intermediate in treated psychiatric controls, and lowest in untreated psychiatric and OSA controls (P < 0.01). RSWA distribution and type also differed between antidepressant-treated patients having higher values in anterior tibialis, and PD-RBD with higher submentalis and tonic RSWA. Psychiatric RBD had significantly younger age at onset than traditional RBD patients (P < 0.01). CONCLUSIONS: Antidepressant treatment was associated with elevated REM sleep without atonia (RSWA) even without REM sleep behavior disorder (RBD), suggesting that antidepressants, not depression, promote RSWA. Differences in RSWA distribution and type were also seen, with higher anterior tibialis RSWA in antidepressant-treated patients and higher tonic RSWA in Parkinson disease-RBD patients, which could aid distinction between RBD subtypes. These findings suggest that antidepressants may mediate different RSWA mechanisms or, alternatively, that RSWA type and distribution evolve during progressive neurodegeneration. Further prospective RSWA analyses are necessary to clarify the relationships between antidepressant treatment, psychiatric disease, and RBD.

Neurobehavioral, neurologic, and neuroimaging characteristics of fetal alcohol spectrum disorders.

Alcohol consumption during pregnancy can have deleterious consequences for the fetus, including changes in central nervous system development leading to permanent neurologic alterations and cognitive and behavioral deficits. Individuals affected by prenatal alcohol exposure, including those with and without fetal alcohol syndrome, are identified under the umbrella of fetal alcohol spectrum disorders (FASD). While studies of humans and animal models confirm that even low to moderate levels of exposure can have detrimental effects, critical doses of such exposure have yet to be specified and the most clinically significant and consistent consequences occur following heavy exposure. These consequences are pervasive, devastating, and can result in long-term dysfunction. This chapter summarizes the neurobehavioral, neurologic, and neuroimaging characteristics of FASD, focusing primarily on clinical research of individuals with histories of heavy prenatal alcohol exposure, although studies of lower levels of exposure, particularly prospective, longitudinal studies, will be discussed where relevant.

Antidepressants and REM sleep behavior disorder: isolated side effect or neurodegenerative signal?

OBJECTIVES: Antidepressants, among the most commonly prescribed medications, trigger symptoms of REM sleep behavior disorder (RBD) in up to 6% of users. Idiopathic RBD is a very strong prodromal marker of Parkinson disease and other synuclein-mediated neurodegenerative syndromes. It is therefore critically important to understand whether antidepressant-associated RBD is an independent pharmacologic syndrome or a sign of possible prodromal neurodegeneration. DESIGN: Prospective cohort study. SETTING: Tertiary sleep disorders center. PARTICIPANTS: 100 patients with idiopathic RBD, all with diagnosis confirmed on polysomnography, stratified to baseline antidepressant use, with 45 matched controls. MEASUREMENTS/RESULTS: Of 100 patients, 27 were taking antidepressants. Compared to matched controls, RBD patients taking antidepressants demonstrated significant abnormalities of 12/14 neurodegenerative markers tested, including olfaction (P = 0.007), color vision (P = 0.004), Unified Parkinson Disease Rating Scale II and III (P < 0.001 and 0.007), timed up-and-go (P = 0.003), alternate tap test (P = 0.002), Purdue Pegboard (P = 0.007), systolic blood pressure drop (P = 0.029), erectile dysfunction (P = 0.002), constipation (P = 0.003), depression indices (P < 0.001), and prevalence of mild cognitive impairment (13% vs. 60%, P < 0.001). All these abnormalities were indistinguishable in severity from RBD patients not taking antidepressants. However, on prospective follow-up, RBD patients taking antidepressants had a lower risk of developing neurodegenerative disease than those without antidepressant use (5-year risk = 22% vs. 59%, RR = 0.22, 95%CI = 0.06, 0.74). CONCLUSIONS: Although patients with antidepressant-associated RBD have a lower risk of neurodegeneration than patients with "purely-idiopathic" RBD, markers of prodromal neurodegeneration are still clearly present. Development of RBD with antidepressants can be an early signal of an underlying neurodegenerative disease.

Age, drugs, or disease: what alters the macrostructure of sleep in Parkinson's disease?

OBJECTIVE: To describe the alterations in the macrostructure of sleep in a large cohort of sleep-disturbed patients with Parkinson's disease (PD) and investigate influencing factors. METHODS: A cohort of sleep-disturbed but otherwise unselected PD patients (n=351) was investigated with video-supported polysomnography. We analyzed the influence of age, disease duration, disease severity, and dopaminergic medication on subjective sleep perception, sleep efficiency, the amount of slow wave sleep, awakenings, periodic leg movements in sleep (PLMS), and REM sleep behavior disorder (RBD). RESULTS: Sleep efficiency and slow wave sleep decreased with age (p=0.003 and p=0.041, respectively). The number of awakenings and the frequency of RBD increased with age (p=0.028 and p=0.006, respectively). Higher Hoehn & Yahr stages were associated with more PLMS (p=0.017). A higher daily dose of levodopa corresponded to more RBD (p<0.001). Neither disease duration nor levodopa dosage had any influence on sleep efficiency, slow wave sleep, awakenings, or PLMS. Dopamine agonists increased awakenings (p<0.001) and lowered PLMS (p<0.001). Subjective sleep perception was not influenced by any of the factors analyzed. The only path model that could be replicated identified disease severity and dopamine agonists as interdependent factors influencing awakenings and PLMS. CONCLUSION: Age leads to less sleep and a higher risk for RBD, and disease severity increases motor phenomena such as PLMS; dopamine agonists reduce PLMS but increase awakenings. No single factor analyzed influenced subjective sleep perception in this cohort of sleep disturbed PD patients.

Donepezil-induced sleep spindle in a patient with dementia with Lewy bodies: a case report.

Here, we report a case of rapid eye movement sleep behavioural disorder in an elderly patient with dementia with Lewy bodies. Pretreatment polysomnography revealed atonia during rapid eye movement sleep, absence of sleep spindles and loss of slow-wave sleep. Administration of donepezil, an acetylcholinesterase inhibitor, markedly improved delusional symptoms and cognitive function. Pretreatment polysomnography performed after donepezil administration revealed a considerable number of sleep spindles. The effects of cholinergic modulation induced by donepezil seemed to cause remarkable improvement in mental status, incorporating associated with sleep spindles generated by the thalamocortical circuit involved in this patient.

Secondary ''incidental'' REM sleep behavior disorder: do we ever think of it?

Most secondary forms of REM sleep behavior disorder are associated with neurodegenerative diseases belonging to the α-synucleinopathies or with narcolepsy. However, RBD may also occur in subacute- or acute-onset conditions involving the central nervous system, irrespective of subjects' age and sex, and with or without relapse at follow-up. These conditions include structural brain lesions (vascular, demyelinating, tumoral, iatrogenic, etc.), CNS diseases (encephalitis, Guillain-Barré syndrome, etc.), forms induced by drug consumption or alcohol withdrawal, and possibly post-traumatic stress disorder. This review focuses on these forms of RBD, which are referred to as 'acute' as they occur as incidental phenomena within the context of other subacute- or acute-onset disorders. In these cases, RBD does not appear as a 'classical' clinical feature of the underlying condition, but rather as an intercurrent, somewhat unexpected phenomenon that deserves consideration in routine clinical practice, in order to avoid misdiagnoses and mistreatments.