Carlos H. Schenck

Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behavior 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 Parkinsons disease) at a mean interval of 3.7 plus minus 1.4 (SD) years after the diagnosis of RBD, and at a mean interval of 12.7 plus minus 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 Parkinsons disease (n equals 11) and the current idiopathic RBD group (n equals 16) were indistinguishable, with two exceptions: the RBD-Parkinsons 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 Parkinsons disease in a substantial subgroup of older male RBD patients. However, a number of presumed Parkinsons disease patients may eventually be diagnosed with multiple system atrophy (straitonigral 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-Parkinsons disease, based on experimental and theoretical considerations rather than on autopsy data. NEUROLOGY 1996;46: 388-393

Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism

Objective: To determine if synucleinopathy pathology is related to REM sleep behavior disorder (RBD) plus dementia or parkinsonism. Methods: The clinical and neuropathologic findings were analyzed on all autopsied cases evaluated at Mayo Clinic Rochester from January 1990 to April 2002 who were diagnosed with RBD and a neurodegenerative disorder. Ubiquitin and/or α-synuclein immunocytochemistry was used in all cases. The clinical and neuropathologic diagnoses were based on published criteria. Results: Fifteen cases were identified (14 men). All had clear histories of dream enactment behavior, and 10 had RBD confirmed by polysomnography. RBD preceded dementia or parkinsonism in 10 (66.7%) patients by a median of 10 (range 2 to 29) years. The clinical diagnoses included dementia with Lewy bodies (DLB) (n = 6); multiple-system atrophy (MSA) (n = 2); combined DLB, AD, and vascular dementia (n = 1); dementia (n = 1); dementia with parkinsonism (n = 1); PD (n = 1); PD with dementia (n = 1); dementia/parkinsonism/motor neuron disease (n = 1); and AD/Binswanger’s disease (n = 1). The neuropathologic diagnoses were Lewy body disease (LBD) in 12 (neocortical in 11 and limbic in 1) and MSA in 3. Three also had argyrophilic grain pathology. In the LBD cases, concomitant AD pathology was present in six (one also with Binswanger’s pathology, and one also with multiple subcortical infarcts). Conclusion: In the setting of degenerative dementia or parkinsonism, RBD often reflects an underlying synucleinopathy.

REM sleep behaviour disorder: an update on a series of 96 patients and a review of the world literature

SUMMARY  REM sleep behaviour disorder (RBD) is an injurious clinical disorder of attempted dream‐enactment (‘oneirism’) in humans which has a corresponding experimental animal model involving dorsolateral pontine tegmental lesions in cats. To date, our sleep disorders centre has collected data on 96 chronic RBD cases which can be compared with pooled data on 70 chronic RBD cases from other centres contained in 26 reports published in the world literature since 1985, when our initial cases were first reported. The data from our centre and from other centres demonstrate a male predominance in RBD (87.5% vs 63.5%); indicate a similar mean age of RBD onset (52.4 y vs 55.9y); contain substantial numbers of diverse central nervous system disorders causally associated with RBD (47.9%vs 60.0%); and identify clonazepam treatment as being very effective in controlling both the (violent) dream and sleep behavioural disturbances of RBD. Our centres data additionally reveal an 80% prevalence of elevated stage 3/4 (slow‐wave) sleep% for age in RBD, and reveal a frequent presence of periodic and aperiodic limb movements during NREM sleep. Thus, RBD in humans is a complex syndrome in which there is generalized REM and NREM sleep motor dyscontrol, as was originally observed in the animal RBD model by Jouvet and Delorme in 1965.

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.

Insights from studying human sleep disorders

Problems with sleep are one of the commonest reasons for seeking medical attention. Knowledge gained from basic research into sleep in animals has led to marked advances in the understanding of human sleep, with important diagnostic and therapeutic implications. At the same time, research guided by human sleep disorders is leading to important basic sleep concepts. For example, sleep may not be a global, but rather a local, brain phenomenon. Furthermore, contrary to common assumptions, wakefulness, rapid eye movement (REM) and non-REM sleep are not mutually exclusive states. This striking realization explains a fascinating range of clinical phenomena.

Proposed Diagnostic Criteria for Night Eating Syndrome

OBJECTIVE To propose criteria for diagnosis of the night eating syndrome (NES). METHOD An international research meeting was held in April 2008, and consensus criteria for NES diagnosis were determined. RESULTS The core criterion is an abnormally increased food intake in the evening and nighttime, manifested by (1) consumption of at least 25% of intake after the evening meal, and/or (2) nocturnal awakenings with ingestions at least twice per week. Awareness of the eating episodes is required, as is distress or impairment in functioning. Three of five modifiers must also be endorsed. These criteria must be met for a minimum duration of 3 months. DISCUSSION These criteria help standardize the definition of NES. Additional aspects of the nosology of NES yet to be fully elaborated include its relationship to other eating and sleep disorders. Assessment and analytic tools are needed to assess these new criteria more accurately.

Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder.

OBJECTIVE To determine the pathologic substrates in patients with rapid eye movement (REM) sleep behavior disorder (RBD) with or without a coexisting neurologic disorder. METHODS The clinical and neuropathologic findings were analyzed on all autopsied cases from one of the collaborating sites in North America and Europe, were evaluated from January 1990 to March 2012, and were diagnosed with polysomnogram (PSG)-proven or probable RBD with or without a coexisting neurologic disorder. The clinical and neuropathologic diagnoses were based on published criteria. RESULTS 172 cases were identified, of whom 143 (83%) were men. The mean±SD age of onset in years for the core features were as follows - RBD, 62±14 (range, 20-93), cognitive impairment (n=147); 69±10 (range, 22-90), parkinsonism (n=151); 68±9 (range, 20-92), and autonomic dysfunction (n=42); 62±12 (range, 23-81). Death age was 75±9 years (range, 24-96). Eighty-two (48%) had RBD confirmed by PSG, 64 (37%) had a classic history of recurrent dream enactment behavior, and 26 (15%) screened positive for RBD by questionnaire. RBD preceded the onset of cognitive impairment, parkinsonism, or autonomic dysfunction in 87 (51%) patients by 10±12 (range, 1-61) years. The primary clinical diagnoses among those with a coexisting neurologic disorder were dementia with Lewy bodies (n=97), Parkinsons disease with or without mild cognitive impairment or dementia (n=32), multiple system atrophy (MSA) (n=19), Alzheimers disease (AD)(n=9) and other various disorders including secondary narcolepsy (n=2) and neurodegeneration with brain iron accumulation-type 1 (NBAI-1) (n=1). The neuropathologic diagnoses were Lewy body disease (LBD)(n=77, including 1 case with a duplication in the gene encoding α-synuclein), combined LBD and AD (n=59), MSA (n=19), AD (n=6), progressive supranulear palsy (PSP) (n=2), other mixed neurodegenerative pathologies (n=6), NBIA-1/LBD/tauopathy (n=1), and hypothalamic structural lesions (n=2). Among the neurodegenerative disorders associated with RBD (n=170), 160 (94%) were synucleinopathies. The RBD-synucleinopathy association was particularly high when RBD preceded the onset of other neurodegenerative syndrome features. CONCLUSIONS In this large series of PSG-confirmed and probable RBD cases that underwent autopsy, the strong association of RBD with the synucleinopathies was further substantiated and a wider spectrum of disorders which can underlie RBD now are more apparent.

A Controlled Trial of Intravenous Immunoglobulin G in Chronic Fatigue Syndrome

PURPOSE Currently, there is no established therapy for chronic fatigue syndrome (CFS), a recently defined illness that has been associated with a variety of immunologic abnormalities. Based on the hypothesis that a chronic viral infection or an immunoregulatory defect is involved in the pathogenesis of CFS, the therapeutic benefit of intravenous immunoglobulin G (IV IgG) was evaluated in a group of patients with CFS. Additionally, serum immunoglobulin concentrations and peripheral blood lymphocyte subset numbers were measured at the outset of the study, and the effect of IV IgG therapy on IgG subclass levels was determined. PATIENTS AND METHODS Thirty patients with CFS were enrolled in a double-blind, placebo-controlled trial of IV IgG. The treatment regimen consisted of IV IgG (1 g/kg) or intravenous placebo (1% albumin solution) administered every 30 days for 6 months. Participants completed a self-assessment form prior to each of the six treatments, which was used to measure severity of symptoms, functional status, and health perceptions. Patients were also asked to report adverse experiences defined as worsening of symptoms occurring within 48 hours of each treatment. RESULTS Twenty-eight patients completed the trial. At baseline, all 28 patients complained of moderate to severe fatigue, and measures of social functioning and health perceptions showed marked impairment. Low levels of IgG1 were found in 12 (42.9%), and 18 (64.3%) had low levels of IgG3. At the end of the study, no significant therapeutic benefit could be detected in terms of symptom amelioration or improvement in functional status, despite restoration of IgG1 levels to a normal range. Major adverse experiences were observed in 20% of both the IV IgG and placebo groups. CONCLUSION The results of this study indicate that IV IgG is unlikely to be of clinical benefit in CFS. In addition to the ongoing need for placebo-controlled trials of candidate therapies for CFS, an expanded research effort is needed to define the etiology and pathogenesis of this disorder.

Rapid eye movement sleep behavior disorder: Devising controlled active treatment studies for symptomatic and neuroprotective therapy-a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group

OBJECTIVES We aimed to provide a consensus statement by the International Rapid Eye Movement Sleep Behavior Disorder Study Group (IRBD-SG) on devising controlled active treatment studies in rapid eye movement sleep behavior disorder (RBD) and devising studies of neuroprotection against Parkinson disease (PD) and related neurodegeneration in RBD. METHODS The consensus statement was generated during the fourth IRBD-SG symposium in Marburg, Germany in 2011. The IRBD-SG identified essential methodologic components for a randomized trial in RBD, including potential screening and diagnostic criteria, inclusion and exclusion criteria, primary and secondary outcomes for symptomatic therapy trials (particularly for melatonin and clonazepam), and potential primary and secondary outcomes for eventual trials with disease-modifying and neuroprotective agents. The latter trials are considered urgent, given the high conversion rate from idiopathic RBD (iRBD) to Parkinsonian disorders (i.e., PD, dementia with Lewy bodies [DLB], multiple system atrophy [MSA]). RESULTS Six inclusion criteria were identified for symptomatic therapy and neuroprotective trials: (1) diagnosis of RBD needs to satisfy the International Classification of Sleep Disorders, second edition, (ICSD-2) criteria; (2) minimum frequency of RBD episodes should preferably be ⩾2 times weekly to allow for assessment of change; (3) if the PD-RBD target population is included, it should be in the early stages of PD defined as Hoehn and Yahr stages 1-3 in Off (untreated); (4) iRBD patients with soft neurologic dysfunction and with operational criteria established by the consensus of study investigators; (5) patients with mild cognitive impairment (MCI); and (6) optimally treated comorbid OSA. Twenty-four exclusion criteria were identified. The primary outcome measure for RBD treatment trials was determined to be the Clinical Global Impression (CGI) efficacy index, consisting of a four-point scale with a four-point side-effect scale. Assessment of video-polysomnographic (vPSG) changes holds promise but is costly and needs further elaboration. Secondary outcome measures include sleep diaries; sleepiness scales; PD sleep scale 2 (PDSS-2); serial motor examinations; cognitive indices; mood and anxiety indices; assessment of frequency of falls, gait impairment, and apathy; fatigue severity scale; and actigraphy and customized bed alarm systems. Consensus also was established for evaluating the clinical and vPSG aspects of RBD. End points for neuroprotective trials in RBD, taking lessons from research in PD, should be focused on the ultimate goal of determining the performance of disease-modifying agents. To date no compound with convincing evidence of disease-modifying or neuroprotective efficacy has been identified in PD. Nevertheless, iRBD patients are considered ideal candidates for neuroprotective studies. CONCLUSIONS The IRBD-SG provides an important platform for developing multinational collaborative studies on RBD such as on environmental risk factors for iRBD, as recently reported in a peer-reviewed journal article, and on controlled active treatment studies for symptomatic and neuroprotective therapy that emerged during the 2011 consensus conference in Marburg, Germany, as described in our report.

A review of nighttime eating disorders

Nighttime eating is categorized as either night eating syndrome (NES) or sleep-related eating disorder (SRED). These conditions represent an interruption in the overnight fast that characterizes human sleep. A critical review of the literature on NES and SRED will suggest that they are situated at opposite poles of a disordered eating spectrum. NES could be considered an abnormality in the circadian rhythm of meal timing with a normal circadian timing of sleep onset. Conversely, the feeding behavior in SRED is characterized by recurrent episodes of eating after an arousal from nighttime sleep with or without amnesia. Both conditions are often relentless and chronic. Multiple definitions of night eating have limited our ability to determine the exact prevalence of NES. Studies have suggested that central nervous system (CNS) serotonin modulation may lead to an effective treatment of NES. SRED is frequently associated with other sleep disorders, in particular parasomnias. Early studies have shown that the anti-seizure medication topiramate may be an effective treatment for SRED.