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.

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.

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.

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), Parkinson's disease with or without mild cognitive impairment or dementia (n=32), multiple system atrophy (MSA) (n=19), Alzheimer's 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.

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.

Rem sleep without atonia--from cats to humans.

Basic science research observations often lead to unexpected surprises. It is likely that in 1965 when Dr. Michel Jouvet placed bilateral peri-locus coeruleus lesions in cats and observed REM sleep without atonia (RWA) and "oneiric" behavior that could only be explained by "acting out dreams" (or "dreaming out acts"), he recognized that it was an important observation, but had little inkling of its true significance. Nor could he even imagine that it would lead to such greater understanding of wake/sleep phenomena in humans. Likely also, the first observation of REM sleep behavior disorder (RBD) in humans was felt to be interesting and novel - again with no true appreciation of what this seemingly simple observation would lead to important clinical relationships with numerous neurodegenerative disorders. The identification of RBD in humans also buttressed the concept of state dissociation, which has served to explain many previously unexplainable human behavioral phenomena.

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 alpha-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.

Evolving concepts of human state dissociation.

The concept of state dissociation in humans was made possible only by applying information obtained from basic science animal research studies to the human condition--without which these often dramatic, and treatable conditions would have remained in the mystical, supra-natural, or psychiatric arenas, without appropriate or effective treatment options. Sleep or wakefulness occurring asynchronously in bits and pieces of the brain is a most useful concept. From our standpoint, the basic science work in the function and mechanism of sleep is pertinent, not only adding to our knowledge in these important areas for the sake of knowledge, but also in providing clinicians with important information that is of immense clinical importance. The payoff of such research has been great, and demands that it should be ongoing. The field of sleep research and sleep medicine is in a unique position to foster close interactions between basic scientists and clinicians, the result being basic science answers to clinical questions, and unanswered clinical questions guiding the direction of and reinforcing the basic science research. The clinical conditions discussed above underscore the value of close cooperation among those working at all levels: molecular, cellular, multi-cellular, and clinical. Continued study of state dissociation by both basic scientists and clinicians will undoubtedly identify and explain even more of these fascinating conditions, with important therapeutic implications. The reciprocal benefits of close collaboration between basic scientists and clinicians will continue to be realized.

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.

Diagnosis and management of parasomnias.

Parasomnias are unpleasant or undesirable behavioral or experiential phenomena that occur predominately or exclusively during sleep. These phenomena were initially thought to represent a unitary event, often attributed to psychiatric disease. Recent clinical and polygraphic analysis has revealed that they are, in fact, the result of a large number of very different conditions, most of which are diagnosable and treatable. In fact, most are not the manifestation of psychiatric disorders, and they are far more prevalent than previously suspected. Although there are many parasomnias (1,2), from a practical standpoint only the few that comprise the overwhelming majority will be discussed in this review. These include disorders of arousal, rapid-eye-movement sleep behavior disorder, nocturnal seizures, and restless legs syndrome. Most parasomnias are readily diagnosable and, more importantly, are treatable.

Parasomnias. Managing bizarre sleep-related behavior disorders.

Sleep can be a troubling experience for persons plagued by nocturnal disorders known as parasomnias. While they are "asleep," such persons may be walking, screaming in terror, rearranging furniture, eating odd food concoctions, or wielding weapons. Or they may be unable to fall asleep because of the unpleasant sensations of restless legs syndrome. Although these disorders are indeed bizarre, effective treatments are available. In this article, Drs Schenck and Mahowald discuss the evaluation and treatment of parasomnias and provide illustrative patient vignettes from their extensive experience at a sleep disorders center.

Medical-legal aspects of sleep medicine.

Sleepiness and sleep disorders are increasingly raising interesting and important medical-legal issues in three areas: violent or injurious behavior arising from the sleep period, accidents or errors in judgment caused by sleepiness behind the wheel or in the workplace, and disability determinations caused by sleepiness-induced work impairment. Sleep-related violence may be caused by many conditions, most of which are diagnosable and treatable. Legal issues raised by these behaviors are usually enigmatic. The nature of such behaviors may be extremely complex, and documenting that a given violent act was caused by such a behavior, after the fact, may be difficult. Guidelines for the medical-legal evaluation of such behaviors have been developed and are evolving. Culpability determination in sleepiness-related industrial or motor vehicle accidents is in the developmental stage, and varies by jurisdiction. Disability determination for workplace sleepiness caused by sleep disorders is in its infancy, and poses a challenge, given the erroneous but pervasive societal attitude that sleepiness is a manifestation of laziness, depression, sloth, work-avoidance behavior, or a defect of character.

Analysis of polysomnographic events surrounding 252 slow-wave sleep arousals in thirty-eight adults with injurious sleepwalking and sleep terrors.

A systematic study of electrophysiologic events [eight-channel EEG, electrocardiogram, electromyogram (EMGs)] surrounding 252 arousals from slow-wave sleep (SWS) in adults with sleepwalking (SW) and sleep terrors (ST) is reported. Hospital-based, overnight polysomnographic monitoring was conducted in 38 adults presenting to a sleep disorders center with injurious SW, ST (21 males, 17 females; mean age 29 years, range 17-69 years). Before nonbehavioral or behavioral arousals from SWS, neither EEG "delta wave buildup," nor heart rate (HR) acceleration, nor tonic/phasic EMG activation was identified. The postarousal EEG demonstrated three patterns: (a) diffuse, rhythmic, delta activity with a typical frequency of 2.2 Hz, a typical amplitude of 85 microV, and a typical duration of 20 s; (b) diffuse delta and theta activity intermixed with alpha and beta activity; and (c) prominent alpha and beta activity. Multichannel, high-voltage, delta activity was observed in <2% of all prearousal periods. HR acceleration emerged abruptly with SWS arousals, with significant changes in mean pre- versus postarousal HR (p < .001). Macrostructural sleep parameters ("sleep architecture") were intact. Therefore, our findings in adults with SW, ST strongly support the classification of SW/ST as disorders of (abrupt) arousal.

An analysis of a recent criminal trial involving sexual misconduct with a child, alcohol abuse and a successful sleepwalking defence: arguments supporting two proposed new forensic categories.

The final judgment from a recent criminal trial in the British Columbia (Canada) Supreme Court is summarized and discussed. The trial involved sexual misconduct with a child, excessive alcohol use, and a successful 'sleepwalking (SW) defence' (non-insane automatism). Our comments on this trial provide an opportunity to present our arguments buttressing two newly proposed forensic categories: (i) parasomnia with continuing danger as a non-insane automatism, which originally was proposed for cases involving recurrent, sleep-related violence, but which can also be applied to SW cases involving sleep-related sexual misconduct and alcohol abuse (and other high-risk self-abusive behaviours); (ii) (intermittent) state-dependent continuing danger, an intermediate category within the 'continuing danger' concept, with the core feature being that a person acquitted of a criminal charge on the basis of the 'SW defence' (or some other parasomnia defence), in which the SW episode was provoked by a high-risk behaviour (e.g. alcohol intoxication) should bear full legal culpability for any future episode that was provoked by a recurrence of the high-risk behaviour--provided that the individual had wilfully engaged in that behaviour.

Parasomnias including the restless legs syndrome.

The three states of mammalian being, W, REM sleep, and NREM sleep, are not mutually exclusive, and may occur simultaneously, oscillate rapidly, or appear in dissociated or incomplete form to produce primary sleep parasomnias. In addition, dysfunctions of a wide variety of organ systems may take adwide variety of organ systems may take advantage of the sleeping state to declare themselves, resulting in secondary sleep parasomnias. Contrary to popular opinion, the majority of the often bizarre and frightening experiences are not the manifestation of underlying psychological or psychiatric conditions. There is an interesting interaction between sleep-disordered breathing and parasominas. Formal study in an experienced sleep disorders center will usually reveal a diagnosable and treatable condition that explains the spells. Continued study of unusual sleep-related events undoubtedly will reveal more fascinating conditions, expanding our knowledge of sleep physiology, and strengthening the bonds between clinicians and basic-science sleep researchers.

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.