Cannabidiol can improve complex sleep-related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson's disease patients: a case series.

WHAT IS KNOWN AND OBJECTIVE: Cannabidiol (CBD) is the main non-psychotropic component of the Cannabis sativa plant. REM sleep behaviour disorder (RBD) is a parasomnia characterized by the loss of muscle atonia during REM sleep associated with nightmares and active behaviour during dreaming. We have described the effects of CBD in RBD symptoms in patients with Parkinson's disease. CASES SUMMARY: Four patients treated with CBD had prompt and substantial reduction in the frequency of RBD-related events without side effects. WHAT IS NEW AND CONCLUSION: This case series indicates that CBD is able to control the symptoms of RBD.

Risk stratification for phenoconversion in patients with isolated REM sleep behavior disorder. A follow-up study from Turkey. / Estratificación del riesgo de fenoconversión al parkinsonismo en pacientes con trastorno de conducta del sueño REM aislado. Estudio de seguimiento en un centro de Turquía.

INTRODUCTION: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is one of the strongest prodromal markers of alpha-synucleinopathies. We aimed to investigate non-invasive clinical and quantitative predictors of phenoconversion from iRBD to parkinsonism. PATIENTS AND METHODS: We prospectively followed-up a total of 45 patients (57.8% men) for eight years. Clinical assessments, Sniffin' Sticks Odor Identification Test, Farnsworth-Munsell 100 Hue Color Vision test, Beck Depression Inventory and Rome III Criteria for constipation were performed. Polysomnographic parameters, sleep spindles, electroencephalographic (EEG) spectral analysis, heart rate variability (HRV) were analyzed. RESULTS: Eight patients (17.8%) showed phenoconversion to parkinsonism after a mean duration of 3.2 ± 1 years. Odds ratio for predicting phenoconversion was highest for patients =60 years of age with anosmia and constipation -44.8 (4.5-445.7); kappa = 4.291-. Duration, frequency or density of sleep spindles failed to demonstrate significant correlations. In EEG spectral analysis, lower alpha power in occipital region during wakefulness and REM sleep was significantly correlated with phenoconversion. Slowing in EEG spectrum power, together with age =60 years, anosmia and constipation, resulted in the highest odds ratio -122.5 (9.7-1543.8); kappa = 3.051-. CONCLUSIONS: It is of great importance to have a world-wide perspective of phenoconversion rates from iRBD to overt neurodegeneration, since racial and geographical factors may play important modifying roles. Relatively younger age and shorter disease duration may also be confounding factors for lower rate in our study. Neurophysiological biomarkers seem to be important predictors of phenoconversion, though more research is needed to establish subtypes of iRBD with different probabilities of evolution to overt synucleinopathy.

TITLE: Estratificación del riesgo de fenoconversión al parkinsonismo en pacientes con trastorno de conducta del sueño REM aislado. Estudio de seguimiento en un centro de Turquía.Introducción. El trastorno aislado de la conducta del sueño con movimientos oculares rápidos (iRBD) es uno de los marcadores prodrómicos más potentes de las alfa-sinucleinopatías. Nuestro objetivo fue investigar los predictores clínicos y cuan­titativos no invasivos de la fenoconversión de iRBD a parkinsonismo. Pacientes y métodos. Se siguió prospectivamente a un total de 45 pacientes (57,8% hombres) durante ocho años del período de estudio. Se realizaron evaluaciones clínicas, la prueba de identificación de olores Sniffin' Sticks, la prueba Farnsworth-Munsell 100 Hue Color Vision, el inventario de depresión de Beck y los criterios de Roma III para el estreñimiento. Se analizaron parámetros polisomnográficos, husos del sueño, análisis espectral electroencefalográfico (EEG) y variabilidad de la frecuencia cardíaca. Resultados. Ocho pacientes (17,8%) mostraron fenoconversión a parkinsonismo después de una duración media de seguimiento de 3,2 ± 1 año. La odds ratio para predecir la fenoconversión fue más alta para los pacientes =60 años con anosmia y estreñimiento ­44,8 (4,5-445,7); kappa = 4,291­. La disminución de la potencia del espectro EEG, junto con la edad =60 años, la anosmia y el estreñimiento, dio como resultado el índice de odds más alto ­122,5 (9,7-1543,8); kappa = 3,051­. Conclusiones. Es de gran importancia tener una perspectiva mundial de las tasas de fenoconversión de iRBD a neurodegeneración manifiesta, ya que los factores raciales y geográficos pueden desempeñar importantes papeles modificadores. Los biomarcadores neurofisiológicos parecen ser predictores importantes de la fenoconversión, aunque se necesita más investigación para establecer subtipos de iRBD con diferentes probabilidades de evolución hacia una sinucleinopatía manifiesta.

Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease.

REM sleep behaviour disorder (RBD) is a parasomnia characterized by the loss of normal skeletal muscle atonia during REM sleep with prominent motor activity accompanying dreaming. The terminology relating to RBD, and mechanisms underlying REM sleep without atonia and RBD based on data in cat and rat are presented. Neuroimaging data from the few published human cases with RBD associated with structural lesions in the brainstem are presented, in which the dorsal midbrain and pons are implicated. Pharmacological manipulations which alter RBD frequency and severity are reviewed, and the data from human neuropathological studies are presented. An anatomic framework and new schema for the pathophysiology of RBD are proposed based on recent data in rat regarding the putative flip-flop switch for REM sleep control. The structure in man analogous to the subcoeruleus region in cat and sublaterodorsal nucleus in rat is proposed as the nucleus (and its associated efferent and afferent pathways) crucial to RBD pathophysiology. The association of RBD with neurological disease ('secondary RBD') is presented, with emphasis on RBD associated with neurodegenerative disease, particularly the synucleinopathies. The hypothesized pathophysiology of RBD is presented in relation to the Braak staging system for Parkinson's disease, in which the topography and temporal sequence of synuclein pathology in the brain could explain the evolution of parkinsonism and/or dementia well after the onset of RBD. These data suggest that many patients with 'idiopathic' RBD are actually exhibiting an early clinical manifestation of an evolving neurodegenerative disorder. Such patients may be appropriate for future drug therapies that affect synuclein pathophysiology, in which the development of parkinsonism and/or dementia could be delayed or prevented. We suggest that additional clinicopathological studies be performed in patients with dementia or parkinsonism, with and without RBD, as well as in patients with idiopathic RBD, to further elucidate the pathophysiology and also characterize the clinical and pathophysiological relevance of RBD in neurodegenerative disease. Furthermore, longitudinal studies in patients with idiopathic RBD are warranted to characterize the natural history of such patients and prepare for future therapeutic trials.

An assessment of cognitive function and mood in chronic fatigue syndrome.

Data were gathered regarding the associates of chronic fatigue syndrome (CFS) with: (1) speed of cognitive processing, (2) motor speed, (3) ability to sustain attention, and (4) mood. Patients were given a brief neuropsychological test battery before and after double-blind treatment with terfenadine or placebo and completed a daily mood rating scale (Positive and Negative Affect Schedule) during the study. CFS patients exhibited slower cognitive processing and motor speed and lower positive affect, as compared to data reported from previous studies of healthy subjects and other patient groups; however, CFS patients did not exhibit deficits in sustained attention in comparison to other groups. The CFS patients' ability to attend to verbal versus figural stimuli and mood ratings were different from those reported in studies of patients with depression. Because of methodological limitations, these findings are preliminary, but they encourage further assessment of cognitive dysfunction and mood in CFS.

A polysomnographic and clinical report on sleep-related injury in 100 adult patients.

In 100 consecutive adults who came to a sleep disorders center complaining of repeated nocturnal injury, polysomnographic study identified five disorders: night terrors/sleepwalking (N = 54), REM sleep behavior disorder (N = 36), dissociative disorders (N = 7), nocturnal seizures (N = 2), and sleep apnea (N = 1). Ninety-five patients sustained ecchymoses, 30 had lacerations, and nine had fractures. DSM-III axis I disorders (past or current) were found in 48.1% of the group with night terrors/sleepwalking and in 30.6% of the group with REM sleep behavior disorder; these were mainly affective disorders. In these two groups, clonazepam controlled the symptoms of 51 of the 61 patients to whom it was given.

The role of a sleep disorder center in evaluating sleep violence.

To review the state-dependent nature of violence and present a clinically useful classification of sleep violence, this article reviews our experience with sleep-related violence, establishing a differential diagnosis, methods of evaluation, and treatment options. The study occurs in a full-service clinical sleep disorders center evaluating approximately 1000 patients annually with an active participation of 16 physicians representing seven specialties. The patients were self-, physician-, or court/social service-referred for evaluation of violent or injurious behaviors associated with the sleep period. Interventions were dependent on the final diagnosis following clinical and (usually) sleep laboratory evaluation. The main outcome measures were self-reported. During routine clinical evaluations at a multidisciplinary sleep disorder center, it has become apparent that violence is often state-dependent, occurring only during the sleep period, resulting from a number of both neurologic and psychiatric conditions (including malingering and Munchausen syndrome by proxy). In such cases, careful clinical and laboratory evaluation usually results in a specific diagnosis, with effective therapeutic recommendations. Violence may be state-dependent. It is clear that violent behaviors may arise from the sleep period, often without conscious awareness on the part of the subject. This has social, forensic, and clinical implications, and may help contribute to the understanding of violence in general.

Dissociated states of wakefulness and sleep.

Both sleep clinicians and basic science researchers have been witness to a wide variety of unusual clinical and experimental phenomena that represent admixtures, incomplete declaration, or rapid oscillations of the three states of being: wakefulness, rapid eye movement (REM) sleep, and nonrapid eye movement sleep. The concept of state dissociation provides an explanation for a wide variety of bizarre clinical phenomena, including the symptoms of narcolepsy, REM sleep behavior disorder, disorders of arousal (such as sleep terrors, sleepwalking, and sleep drunkenness), automatic behavior, and some "out-of-body" experiences. The purpose of this review is to provide an overview and perspective of such conditions, encourage systematic and detailed study of these "experiments in nature," and underscore the interdependence of clinicians and researchers.

Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder.

We report longitudinal data on a group of 29 male patients 50 years of age or older who were initially diagnosed as having idiopathic REM sleep behavior disorder (RBD) after extensive polysomnographic and neurologic evaluations. Thirty-eight percent (11/29) were eventually diagnosed as having a parkinsonian disorder (presumably Parkinson's disease) at a mean interval of 3.7 +/- 1.4 (SD) years after the diagnosis of RBD+, and at a mean interval of 12.7 +/- 7.3 years after the onset of RBD. To date, only 7% (2/29) of patients have developed any other neurologic disorder. At the time of RBD diagnosis, data from the RBD group with eventual Parkinson's disease (n = 11) and the current idiopathic RBD group (n = 16) were indistinguishable, with two exceptions: the RBD-Parkinson's disease group had a significantly elevated hourly index of periodic limb movements of non-REM sleep and an elevated REM sleep percentage. RBD was fully or substantially controlled with nightly clonazepam treatment in 89% (24/27) of patients in both groups. Thus, RBD can be the heralding manifestation of Parkinson's disease in a substantial subgroup of older male RBD patients. However, a number of presumed Parkinson's disease patients may eventually be diagnosed with multiple system atrophy (striatonigral degeneration subtype). Our findings indicate the importance of serial neurologic evaluations after RBD is diagnosed and implicate the pedunculopontine nucleus as a likely site of pathology in combined RBD-Parkinson's disease, based on experimental and theoretical considerations rather than on autopsy data.

Long-term, nightly benzodiazepine treatment of injurious parasomnias and other disorders of disrupted nocturnal sleep in 170 adults.

PURPOSE: To assess the efficacy, dose stability, safety, and abuse potential of long-term, nightly benzodiazepine treatment of chronic disorders of disrupted nocturnal sleep. PATIENTS AND METHODS: During a 12-year period, one author evaluated and treated 170 adult referrals for > or = 6 months with nightly benzodiazepine therapy for longstanding, sleep-disruptive disorders: injurious sleepwalking and sleep terrors (69); rapid eye movement sleep behavior disorder (52); chronic, severe insomnia (25); and restless legs syndrome/periodic limb movement disorder (24). RESULTS: Complete/substantial control of the sleep disorders was achieved by 146 patients (86%); 8% had adverse effects requiring medication changes; 2% had relapses of alcohol or chemical abuse requiring hospitalization; another 2% at times misused their medications. A total of 136 patients received clonazepam nightly for a mean 3.5 (+/- 2.4) years, with no significant difference in inital versus final mean dose: 0.77 mg (+/- 0.46) versus 1.10 mg (+/- 0.96). Similar results were obtained with chronic alprazolam treatment and with other benzodiazepine treatments. CONCLUSION: Long-term, nightly benzodiazepine treatment of injurious parasomnias and other disorders of disrupted nocturnal sleep resulted in sustained efficacy in most cases, with low risk of dosage tolerance, adverse effects, or abuse. Data from this study on the treatment of chronic, severe insomnia (a small subset of all insomnia) are not generalizable to the typical insomnia patient.

A case-control study to assess possible triggers and cofactors in chronic fatigue syndrome.

PURPOSE: To assess possible triggers and cofactors for chronic fatigue syndrome (CFS) and to compare levels of selected cytokines between cases and an appropriately matched control group. PATIENTS AND METHODS: We conducted a case-control study of 47 cases of CFS obtained through a regional CFS research program maintained at a tertiary care medical center. One age-, gender-, and neighborhood-matched control was identified for each case through systematic community telephone sampling. Standardized questionnaires were administered to cases and controls. Sera were assayed for transforming growth factor-beta (TGF-beta), interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and antibody to Borrelia burgdorferi and Babesia microti. RESULTS: Cases were more likely to have exercised regularly before illness onset than controls (67% versus 40%; matched odds ratio (MOR) = 3.4; 95% CI = 1.2 to 11.8; P = 0.02). Female cases were more likely to be nulliparous prior to onset of CFS than controls (51% versus 31%; MOR = 8.0; 95% CI = 1.03 to 170; P = 0.05). History of other major factors, including silicone-gel breast implants (one female case and one female control), pre-morbid history of depression (15% of cases, 11% of controls) and history of allergies (66% of cases, 51% of controls) were similar for cases and controls. However, cases were more likely to have a diagnosis of depression subsequent to their diagnosis of CFS compared to a similar time frame for controls (MOR = undefined; 95% CI lower bound = 2.5; P < 0.001). Positive antibody titers to B burgdorferi (one case and one control) and B microti (zero cases and two controls) were also similar. CONCLUSIONS: Further investigation into the role of prior routine exercise as a cofactor for CFS is warranted. This study supports the concurrence of CFS and depression, although pre-morbid history of depression was similar for both groups.

A polysomnographically documented case of adult somnambulism with long-distance automobile driving and frequent nocturnal violence: parasomnia with continuing danger as a noninsane automatism?

A case of childhood-onset somnambulism is reported in which a 43-year-old man presented with repeated sleep-related injuries incurred during violent nocturnal activity, which included frenzied running, throwing punches and wielding knives. He had also driven an automobile a long distance during a presumed somnambulistic state. His wife had been repeatedly injured, and she felt that her life was threatened by his nocturnal violence 2-3 times yearly. Polysomnography (PSG) documented multiple episodes of complex and violent behaviors arising exclusively from stage 3/4 sleep, thus confirming the diagnosis of somnambulism. Other causes of sleep-related violence were excluded. The patient responded promptly to treatment with bedtime clonazepam, and benefit was maintained at 5-year follow-up. Although this strictly clinical case did not have any legal repercussions, it does carry forensic implications, particularly when placed in the context of the published medical literature on PSG-documented parasomnias (somnambulism, rapid eye movement sleep behavior disorder) containing explicit examples of recurrent violence, at times life-threatening, directed toward the bed partner and others. Thus, a new medical-legal concept is proposed, consisting of "parasomnia with continuing danger" as a noninsane automatism. Treatment guidelines, within the context of forensic medicine, are presented.

Status dissociatus--a perspective on states of being.

During the course of routine clinical study, it has become apparent that the all-or-none concept of state determination (wakefulness, nonrapid eye movement sleep, rapid eye movement sleep) does not always exist, and that ambiguous, multiple, or rapid oscillation of state-determining variables appear in a wide variety of experimental and clinical situations. Six cases of extreme state dissociation are presented, with a review of the human and animal clinical and experimental literature. This multiple component concept of state determination must be kept in mind when pharmacologic or lesion studies are employed to suppress one or another state. Such manipulation may suppress some of the commonly used markers for that state (i.e., polygraphic) without affecting other variables of that state. The existence of mixed states will be a challenge to the development of automated computerized polysomnogram scoring.

A parasomnia overlap disorder involving sleepwalking, sleep terrors, and REM sleep behavior disorder in 33 polysomnographically confirmed cases.

A series of 33 patients with combined (injurious) sleepwalking, sleep terrors, and rapid eye movement (REM) sleep behavior disorder (viz. "parasomnia overlap disorder") was gathered over an 8-year period. Patients underwent clinical and polysomnographic evaluations. Mean age was 34 +/- 14 (SD) years; mean age of parasomnia onset was 15 +/- 16 years (range 1-66); 70% (n = 23) were males. An idiopathic subgroup (n = 22) had a significantly earlier mean age of parasomnia onset (9 +/- 7 years) than a symptomatic subgroup (n = 11) (27 +/- 23 years, p = 0.002), whose parasomnia began with either of the following: neurologic disorders, n = 6 [congenital Mobius syndrome, narcolepsy, multiple sclerosis, brain tumor (and treatment), brain trauma, indeterminate disorder (exaggerated startle response/atypical cataplexy)]; nocturnal paroxysmal atrial fibrillation, n = 1; posttraumatic stress disorder/major depression, n = 1; chronic ethanol/amphetamine abuse and withdrawal, n = 1; or mixed disorders (schizophrenia, brain trauma, substance abuse), n = 2. The rate of DSM-III-R (Diagnostic and Statistical Manual, 3rd edition, revised) Axis 1 psychiatric disorders was not elevated; group scores on various psychometric tests were not elevated. Forty-five percent (n = 15) had previously received psychologic or psychiatric therapy for their parasomnia, without benefit. Treatment outcome was available for n = 20 patients; 90% (n = 18) had substantial parasomnia control with bedtime clonazepam (n = 13), alprazolam and/or carbamazepine (n = 4), or self-hypnosis (n = 1). Thus, "parasomnia overlap disorder" is a treatable condition that emerges in various clinical settings and can be understood within the context of current knowledge on parasomnias and motor control/dyscontrol during sleep.

Additional categories of sleep-related eating disorders and the current status of treatment.

Sleep-related eating disorders distinct from daytime eating disorders have recently been shown to be associated with sleepwalking (SW), periodic limb movement (PLM) disorder and triazolam abuse in a series of 19 adults. We now report eight other primary or combined etiologies identified by clinical evaluations and polysomnographic monitoring of 19 additional adults (mean age 40 years; 58% female): i) obstructive sleep apnea (OSA), with eating during apnea-induced confusional arousals (n = 3); ii) OSA-PLM disorder (n = 1); iii) familial SW and sleep-related eating (n = 2); iv) SW-PLM disorder (n = 1); v) SW-irregular sleep/wake pattern disorder (n = 1); vi) familial restless legs syndrome and sleep-related eating (n = 2); vii) anorexia nervosa with nocturnal bulimia (n = 2) and viii) amitriptyline treatment of migraines (n = 1). In our cumulative series of 38 patients (excluding six with simple obesity from daytime overeating), 44% were overweight (i.e. > 20% excess weight) from sleep-related eating. Nightly sleep-related binge eating (without hunger or purging) had occurred in 84% of patients. Onset of sleep-related eating was also closely linked with i) acute stress involving reality-based concerns about the safety of family members or about relationship problems (n = 6), ii) abstinence from alcohol and opiate/cocaine abuse (n = 2) and iii) cessation of cigarette smoking (n = 2). Current treatment data indicate a primary role of dopaminergic agents (carbidopa/L-dopa; bromocriptine), often combined with codeine and clonazepam, in controlling most cases involving SW and/or PLM disorder. Fluoxetine was effective in two of three patients. Nasal continuous positive airway pressure therapy controlled sleep-related eating in two OSA patients.

Sleep-related eating disorders: polysomnographic correlates of a heterogeneous syndrome distinct from daytime eating disorders.

Over a 5-yr period, 19 adults presented to our sleep disorders center with histories of involuntary, nocturnal, sleep-related eating that usually occurred with other problematic nocturnal behaviors. Mean age (+/- SD) at presentation was 37.4 (+/- 9.1) yr (range 18-54); 73.7% of the patients (n = 14) were female. Mean age of sleep-related eating onset was 24.7 (+/- 12.9) yr (range 5-44). Eating occurred from sleep nightly in 57.9% (n = 11) of patients. Chief complaints included excessive weight gain, concerns about choking while eating or about starting fires from cooking and sleep disruption. Extensive polysomnographic studies, clinical evaluations and treatment outcome data identified three etiologic categories for the sleep-related eating: (a) sleepwalking (SW), 84.2% (n = 16); (b) periodic movements of sleep (PMS), 10.5% (n = 2) and (c) triazolam abuse (0.75 mg hs), 5.3% (n = 1). DSM-III Axis 1 psychiatric disorders (affective, anxiety) were present in 47.4% (n = 9) of the patients, and only two patients had a daytime eating disorder (anorexia nervosa), each in remission for 3-7 yr. Nearly half of all patients fulfilled established criteria for being overweight, based on the body mass index. Onset of sleep-related eating was linked directly to the onset of SW, PMS, triazolam abuse, nicotine abstinence, chronic autoimmune hepatitis, narcolepsy, encephalitis or acute stress. In the SW group, 72.7% (8/11) of patients had nocturnal eating and other SW behavior suppressed by clonazepam (n = 7) and/or bromocriptine (n = 2) treatment. Both patients with PMS likewise responded to treatment with combinations of carbidopa/L-dopa, codeine and clonazepam. Thus, sleep-related eating disorders can generally be controlled with treatment of the underlying sleep disorder.

Chronic behavioral disorders of human REM sleep: a new category of parasomnia.

Four men, aged 67-72 years, had 4-month to 6-year histories of injuring themselves or their spouses with aggressive behaviors during sleep, often during attempted dream enactment. A 60-year-old woman had disruptive though nonviolent sleep and dream behaviors. Polysomnography did not detect seizures but did document REM sleep pathology with variable loss of chin atonia, extraordinarily increased limb-twitch activity, and increased REM ocular activity and density. A broad range of REM sleep behaviors was recorded on videotape, including stereotypical hand motions, reaching and searching gestures, punches, kicks, and verified dream movements. Stage 3-4 slow wave sleep was elevated for age in all patients. NREM sleep was devoid of harmful behaviors, although three men had periodic myoclonus. There was no associated psychiatric disorder, whereas serious neurologic disorder was closely associated in four cases: olivo-ponto-cerebellar degeneration, Guillain-Barré syndrome, subarachnoid hemorrhage, and an atypical dementia. Two patients had immediate and lasting sleep behavioral suppression induced by clonazepam, and another patient had the same response with desipramine. All instances of drug discontinuation prompted immediate relapse. In four cases there was associated dream hyperactivity, which resolved with behavioral control. These REM sleep neurobehavioral disorders constitute another category of parasomnia, replicate findings from 21 years ago in cats receiving pontine tegmental lesions, and offer additional perspectives on human behavior, neurophysiology, pharmacology, and dream phenomenology.

Prominent eye movements during NREM sleep and REM sleep behavior disorder associated with fluoxetine treatment of depression and obsessive-compulsive disorder.

The clinical polysomnographic (PSG) reports of 2,650 consecutive adults studied during 41 months were reviewed retrospectively to identify all patients treated with fluoxetine or tricyclic antidepressants. The PSG reports of four other adult groups were also reviewed: periodic limb movement (PLM) disorder (n = 28); sleep terror/sleepwalking (ST/SW) (n = 54); rapid eye movement (REM) sleep behavior disorder (RBD) (n = 70); patients with clinically unremarkable sleep during two consecutive PSG studies (n = 30). Standard PSG recording and scoring methods were employed. A total of 1.5% (n = 41) and 2.0% (n = 52) of patients were receiving fluoxetine or tricyclics (amitriptyline or nortriptyline, n = 31; imipramine or desipramine, n = 16; protriptyline or trimipramine, n = 5). A selective association between fluoxetine and extensive, prominent eye movements in nonrapid eye movement (NREM) sleep was detected, utilizing Fisher's exact one-tailed statistic (p less than 0.00001 for each comparison). The detection rates were fluoxetine, 48.8% (20/41); tricyclics, 5.8% (3/52); RBD, 4.3% (3/70); objectively normal sleepers, 3.3% (1/30); PLM, ST/SW, 0% (0/82). These groups had similar mean ages (31.5-45.4 years) and gender distributions (50.0-60.7% male), apart from RBD. The effect of fluoxetine, a potent and specific serotonin reuptake inhibitor, on NREM eye movements is postulated to derive from potentiation of serotonergic neurons that inhibit brainstem "omnipause neurons", which, in turn, inhibit saccadic eye movements, thus resulting in disinhibited release of saccades. In addition, a 31-year-old man with obsessive-compulsive disorder developed RBD soon after starting fluoxetine therapy, which persisted at PSG study 19 months after fluoxetine discontinuation.

A controlled study of serum anti-locus ceruleus antibodies in REM sleep behavior disorder.

The newly identified association of human nonnarcoleptic rapid eye movement (REM) sleep behavior disorder (RBD) with human leukocyte antigen (HLA) DQw1 class II genes raises the possibility that RBD may arise from autoimmune mechanisms. Two recent case reports involving postmortem brain stem histochemical analyses in elderly males with RBD identified severe monoaminergic cell loss in the locus ceruleus (LC). Thus, we designed a study to detect anti-LC antibodies in RBD. Ten Caucasian males (mean age, 66 years) with polygraphically confirmed RBD (n = 5, idiopathic RBD: n = 5, RBD with Parkinson's disease), but without narcolepsy, idiopathic hypersomnia, or autoimmune disease, were recruited for this study, along with 10 Caucasian male controls (mean age, 63 years) without a history of sleep disorder or autoimmune disease. In a blinded design, sera from the RBD patients and their controls were tested against human LC and other brainstem neurons. Brainstem tissue was obtained from autopsies of neurologically normal individuals. The presence of anti-LC antibodies was examined using immunohistochemistry on brainstem sections. Sections incubated with sera from normal individuals and sera from patients with paraneoplastic antineuronal antibodies (anti-Hu and anti-Ri) were used as controls. No reactivity with LC or any other brainstem area was identified with sera from either RBD patients or their controls, or from the other group of normal individuals. In contrast, sera from patients with paraneoplastic anti-Hu and anti-Ri antibodies reacted strongly with nuclei of LC and other brainstem neurons, sparing the nucleoli, and reacted to a lesser extent with the cytoplasm of these neurons. Therefore, it is unlikely that human RBD is associated with anti-LC antibodies. However, an autoimmune process in RBD has not been excluded by this study.

Injurious sleep behavior disorders (parasomnias) affecting patients on intensive care units.

There are no previous reports on parasomnias (sleep behavior disorders) affecting patients on intensive care units (ICUs). During 8 years of clinical practice, we evaluated over 200 adults with complaints of injurious, sleep-related behaviors, 20 of whom had ICU admissions while their parasomnias had been active and generally undiagnosed/untreated. Mean age during ICU confinement was 62.8 (+/- SD 13.1) years; 85.0% (17/20) were males. Patients underwent comprehensive clinical examinations along with extensive polysomnographic and audiovisual monitoring (electrooculogram, 9 channel EEG with paper speeds of 15 and 30 mm/sec, electromyogram [submental and 4 limbs], EKG, airflow). The polysomnographic studies were diagnostic for the REM sleep behavior disorder (vigorous dream-enactment during rapid eye movement [REM] sleep) in 85.0% (17/20) of patients, and for night terrors/sleepwalking in 15.0% (3/20). Three groups of parasomnia-ICU relationships were identified: i) Parasomnias originating in ICUs, stroke-induced (n = 3); ii) Admission to ICUs resulting from parasomnia-induced injuries: C2 odontoid process fracture and C3 spinous process fracture with severe concussion (n = 2); iii) Parasomnias in patients admitted to ICUs for various other medical problems (n = 15). Physicians should be thus alerted about the possibility of injurious, but usually treatable, parasomnias in ICU patients.

Severe, childhood-onset, idiopathic, life-long insomnia responding selectively to opiate therapy: case report with 19 year follow-up.

BACKGROUND: Idiopathic (primary) insomnia can be difficult to treat; only two prior cases responsive to opiate therapy have been reported. A case is now presented of severe, idiopathic, childhood-onset, familial insomnia, with increased libido, absence of psychopathology, tardive emergence of restless legs syndrome (RLS), and selective response to opiate therapy. CASE REPORT: A 39-year-old woman was referred in 1981 by her physician who had discovered 3 years earlier that propoxyphene treatment of migraines also controlled her chronic insomnia. She had experienced severe insomnia since childhood, and during early adulthood the insomnia intensified, as she would sleep 0-3 h nightly and never napped. Daily generalized motor restlessness resulted in her frequently walking around the house while feeling exhausted. The quality of her life was considerably compromised by her insomnia, motor restlessness, and by an increased libido that was present since puberty and that was only partially relieved by having sex repeatedly with her husband. RESULTS: Nightly opiate therapy for 19 years has controlled the insomnia, motor restlessness, and excessive libido without affecting her normal libido. The insomnia had not responded to treatment with >25 agents covering >10 pharmacologic categories. During her first (unmedicated) polysomnographic (PSG) study in 1981, she slept 0 min while spending 436 min in bed. In 1984, four consecutive PSG studies were conducted in a design that confirmed the efficacy of propoxyphene therapy of her insomnia. In 1990, an ambulatory PSG revealed two runs of EEG rhythmic paroxysmal activity arising from sleep and wakefulness, without clinical correlate. Neurologic history was negative for seizures, but positive for complete right carotid artery occlusion and three transient ischemic attacks. At age 55 years, typical RLS emerged that was controlled with levodopa therapy, and a concurrent relapse of insomnia was controlled with oxycodone replacing propoxyphene. CONCLUSIONS: Nightly opiate therapy of severe idiopathic (primary) insomnia can remain effective during very long-term clinical follow-up. Guidelines are provided for when to consider such an unusual treatment in other cases of severe, chronic insomnia.