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Tesis doctoral
“Caracterización clínica, polisomnográfica y evolutiva del
trastorno de conducta de sueño REM idiopático”
Doctorando: Ana Fernández Arcos
Filiación:
Unidad de Trastornos del Sueño, Servicio de Neurología, Hospital
Clínic-IDIBAPS.
Director de tesis: Dr. Alejandro Iranzo de Riquer
Línea de investigación: Neurociencias Clínicas y Experimentales
AGRADECIMIENTOS
Esta tesis ha sido posible gracias al apoyo de muchas personas
que me han acompañado en el camino hasta llegar aquí.
Al Dr. Joan Santamaria, quien me contagió de la pasión por el
sueño. Ha sido un honor ser alumna suya y su forma de trabajar
siempre será un referente para mí.
Gracias al Dr. Álex Iranzo, por darme la oportunidad de trabajar
en este proyecto, dirigirlo y supervisarlo.
Al Dream Team: a Mònica Serradell, por ser tan buena compañera y
ser el pilar que sustenta estos trabajos. A Carles Gaig por estar
siempre dispuesto a ayudar. A Ana Tercero por todo el apoyo. A
Marc Guaita por su guía.
Al equipo PPMI: Al Dr. Eduard Tolosa por aceptarme en su equipo,
ha sido un privilegio poder trabajar con usted. Gracias a Lola
Vilas por estar siempre a mi lado (a mi derecha frente al altar o
comiendo fresas en la Quinta Avenida), a Laura Maragall por todos
esos ratitos que nos hacían los días difíciles más llevaderos. A
Alicia Garrido, Meritxell Santos y Donina Obiang, porque fue un
placer trabajar con vosotras.
Gracias a los pacientes por su amabilidad, por su altruismo y
solidaridad. A los participantes del proyecto PPMI por enseñarme
tanto.
A mi madre y mi hermana por su apoyo incondicional. A Aída por
ser la mejor amiga que se puede tener. Gracias a los Sánchez por
aceptarme en la familia, en especial a Arantxa que siempre se
alegró de mis logros.
A Dani por todos los años nuevos de este mundo y a Marina por
ponerlo todo en órbita.
ÍNDICE
PRESENTACIÓN ……………………………………………………………………………………………………………… 1
ABREVIACIONES …………………………………………………………………………………………………………… 3
1. INTRODUCCIÓN ……………………………………………………………………………………………………… 4 1.1. Aspectos generales sobre el sueño ……………………………………… 4
1.2. Fisiología del sueño REM ……………………………………………………………… 5
1.3. Definición del TCSR …………………………………………………………………………… 7
1.4. Fisiopatología del TCSR ………………………………………………………………… 7
1.5. TCSR idiopático vs. secundario ………………………………………………… 8
1.5.1. Enfermedades neurológicas …………………………………………… 9
1.5.2. TCSR secundario a una lesión estructural …… 11
1.5.3. TCSR secundario al uso de medicamentos ………… 11
1.6. Epidemiología TCSR ……………………………………………………………………………… 12
1.7. Características clínicas ……………………………………………………………… 12
1.8. Diagnóstico ………………………………………………………………………………………………… 13
1.8.1. Cuestionarios …………………………………………………………………………… 14
1.8.2. Video-Polisomnograma ………………………………………………………… 14
1.8.3. Criterios diagnósticos …………………………………………………… 19
1.8.4. Diagnóstico diferencial ………………………………………………… 21
1.9. Importancia del TCSR idiopático …………………………………………… 27
1.9.1 Riesgo de lesiones …………………………………………………………………………… 27 1.9.2 Implicaciones pronósticas ………………………………………………………… 24
2. HIPÓTESIS ……………………………………………………………………………………………………………… 30 3. OBJETIVOS ……………………………………………………………………………………………………………… 31 4. RESULTADOS …………………………………………………………………………………………………………… 32
4.1. Trabajo 1. The clinical phenotype of idiopathic
rapid eye movement sleep behavior disorder at presentation:
A study in 203 consecutive patients …………………………………………………… 33
4.2. Trabajo 2. Diagnostic value of isolated mentalis
vs. mentalis plus upper limb electromyography in idiopathic
REM sleep behavior disorder patients eventually developing
a neurodegenerative syndrome ……………………………………………………………………… 48
4.3. Trabajo 3. Neurodegenerative disorder risk in idiopathic REM sleep behavior disorder: study in 174 patients ……………………………………………………………………………………………………………… 59
5. DISCUSIÓN CONJUNTA DE RESULTADOS………………………………………………… 68 6. CONCLUSIONES …………………………………………………………………………………………………… 72 7. REFERENCIAS BIBLIOGRÁFICAS………………………………………………………………… 73
1
PRESENTACIÓN
Esta tesis doctoral se estructura según las directrices
de la normativa para la presentación de tesis doctorales
como compendio de publicaciones aprobada por la Comisión de
Doctorado del Consejo de Gobierno en fecha 24 de Julio de
2008 y modificada el 28 de abril de 2010, al amparo del
régimen previsto en el RD 99/2011 del 28 de enero.
La presente memoria se basa en tres trabajos que
pertenecen a una misma línea de trabajo: el estudio del
trastorno de conducta de sueño REM idiopático (TCSRI). El
primer trabajo (The clinical phenotype of idiopathic rapid
eye movement sleep behavior disorder at presentation: A study
in 203 consecutive patients) fue publicado en 2016 en la
revista indexada SLEEP con un factor de impacto de 5,135. Es
un estudio descriptivo detallado sobre una cohorte grande de
pacientes diagnosticados en un único centro de referencia en
patología del sueño. Además de realizar una caracterización
del cuadro clínico del TCSRI, se destacan aspectos menos
conocidos de esta entidad. El interés de sus resultados
radica en incrementar el conocimiento del trastorno.
El segundo trabajo (Diagnostic value of isolated
mentalis vs. mentalis plus upper limb electromyography in
idiopathic REM sleep behavior disorder patients eventually
developing a neurodegenerative syndrome) fue publicado en
2017, también en la revista SLEEP. Compara la sensibilidad
diagnóstica de dos métodos de cuantificación de la actividad
electromiográfica durante el sueño REM en el TCSRI. Este
estudio pone a prueba ambos métodos, con los puntos de corte
propuestos en otras publicaciones, en el estudio basal de
pacientes con TCSRI que posteriormente desarrollaron el
cuadro clínico completo de una enfermedad neurodegenerativa.
2
El tercer y último estudio (Neurodegenerative Disorder
Risk in Idiopathic REM Sleep Behavior Disorder: Study in 174
Patients) fue publicado en 2014 la revista PLOS One, con un
factor de impacto de 2,766. Este trabajo evalúa el riesgo
del desarrollo de una enfermedad neurodegenerativa en
pacientes con TCSRI, en una cohorte grande y un seguimiento
más prolongado que en las observaciones publicadas
previamente.
3
ABREVIACIONES
AASM: American Academy of Sleep Medicine
AMS: atrofia multisistémica
CPAP: continuous positive airway pressure, presión positiva continua en la vía aérea
DCL: deterioro cognitivo leve
DCLw: demencia con cuerpos de Lewy
EA: enfermedad de Alzheimer
EEG: electroencefalograma
EMG: electromiograma
EP: enfermedad de Parkinson
EOG: electrooculograma
GABA: ácido gamma-butírico
ICSD: International Classification of Sleep Disorders
NREM: no REM
REM: rapid eye movement en inglés, movimientos oculares
rápidos
SPECT: tomografía de emisión por fotón único
TCSR: Trastorno de conducta del sueño REM
TCSRI: Trastorno de conducta del sueño REM idiopático
V-PSG: Video-polisomnograma
4
1. INTRODUCCIÓN
1.1. Aspectos generales sobre el sueño El sueño es un estado fisiológico activo, reversible y
recurrente en el que disminuye el nivel de consciencia, es
decir, se reduce la capacidad de percepción y de respuesta
a estímulos ambientales. Es proceso dinámico, constituido
por varias fases orquestadas por el sistema nervioso central.
La alteración de los mecanismos implicados puede traducirse
en problemas del sueño que además de tener graves
implicaciones sobre la calidad de vida de la persona pueden
reflejar el estado de su cerebro.
El sueño puede diferenciarse en sueño REM (de rapid eye
movement en inglés o movimientos oculares rápidos) y el sueño
no REM (NREM). El sueño NREM, a su vez, se subdivide en tres
fases de sueño de acuerdo con las reglas de estadificación
de la American Academy of Sleep Medicine (AASM).1 La
estadificación o codificación del sueño se basa en el
electroencefalograma (EEG), el electrooculograma (EOG) y la
electromiografía (EMG) de superficie sobre el músculo
mentalis en el mentón.2 Las diferentes fases de sueño se
suceden en ciclos de unos 90 minutos de duración que se
repiten a lo largo de la noche, con predominio de sueño NREM
en la primera parte de la noche y una mayor proporción de
sueño REM de madrugada.
El patrón principal del sueño NREM muestra una actividad
EEG síncrona con ondas características denominadas husos de
sueño, complejos K y ondas delta.1 El sueño REM fue descrito
por primera vez por Aserinsky y Kleitman en 1953 y se
caracteriza por una actividad electroencefalográfica rápida
y desincronizada.3 Durante el sueño REM fisiológico se
produce una atonía muscular debido a paralización de la
mayoría de los músculos esqueléticos exceptuando la
musculatura respiratoria, el oído interno y la musculatura
5
ocular extrínseca. Esta parálisis transitoria evita que se
produzcan movimientos en un periodo en el que se sueña con
frecuencia.
Los estados de vigilia, sueño NREM y sueño REM
transcurren mediante mecanismos localizados en diferentes
estructuras cerebrales.4 La vigilia se produce por la
actividad del sistema reticular ascendente y la activación
del núcleo dorsal del rafe (neuronas serotoninérgicas),
locus coeruleus (neuronas noradrenérgicas), protuberancia
(neuronas colinérgicas), prosencéfalo (neuronas
colinérgicas), núcleo tuberomamilar (neuronas
histaminérgicas) y el hipotálamo (neuronas
hipocretinérgicas). Todos estos núcleos controlan la vigilia
y el despertar a través de proyecciones talámicas y
corticales. Las neuronas responsables del inicio y
mantenimiento del sueño se encuentran en el área preóptica,
en el núcleo medial y ventrolateral del hipotálamo. Producen
una inhibición de los sistemas de vigilia mediante los
neurotransmisores galanina y acido gamma-aminobutírico
(GABA). El sueño NREM se mantiene principalmente por la
inhibición de las neuronas gabaérgicas del núcleo reticular
del tálamo sobre la corteza cerebral.
1.2. Fisiología del sueño REM
El circuito implicado en la génesis del sueño REM se
encuentra en el tronco encefálico, prosencéfalo basal y el
hipotálamo.5,6 Se considera que la transición entre sueño
NREM y REM se debe a un mecanismo que actúa como interruptor
o “flip-flop” que alterna la actividad neuronal REM-ON y
REM-OFF para facilitar o interrumpir el sueño REM. La
principal estructura responsable del inicio del sueño REM es
el núcleo subceruleus, compuesto por neuronas
6
glutamatérgicas y gabaérgicas.5 Se encuentra en la unión
mesencéfalo-protuberancial, medial al núcleo motor del
nervio trigémino y ventral al locus ceruleus. Otras
estructuras promotoras del sueño REM son los núcleos
tegmentales laterodorsal y pedunculopontino compuestos por
neuronas colinérgicas. El núcleo magnocelularis, localizado
ventromedial en el bulbo raquídeo, compuesto por neuronas
gabaérgicas y glicinérgicas facilita el sueño REM mediante
la inhibición de áreas promotoras de la vigilia como el locus
ceruleus, el rafe dorsal y la región ventrolateral de la
sustancia gris periacueductal. Ésta última posee una función
dual: por un lado, activa el sueño REM a través de la
inhibición el locus coeruleus y el rafe dorsal y por otro
puede inhibirlo a través del locus subceruleus.
Otras estructuras como el prosencéfalo basal, con
proyecciones al locus subceruleus influyen sobre el sueño
REM. A nivel hipotalámico, las neuronas productoras de
hormona concentrada de melanina están activas durante el
sueño REM y en el área preóptica ventrolateral se envían
proyecciones gabaérgicas a las neuronas inhibidoras del
sueño REM en la región ventrolateral de la sustancia gris
periacueductal. Finalmente, en el sistema límbico se activan
durante el sueño REM neuronas glutamatérgicas de la amígdala
que estimulan el núcleo subceruleus.
La atonía muscular fisiológica durante el sueño REM se
produce por un mecanismo inhibitorio sobre las motoneuronas
de la medula espinal.7 Las estructuras principales de este
mecanismo son el núcleo subceruleus y el núcleo
magnocelularis.8 Las neuronas glutamatérgicas del núcleo
subceruleus activan el núcleo magnocelularis y también
actúan de manera directa sobre las interneuronas espinales
con actividad inhibitoria.
Las funciones del sueño REM aún no han sido definidas.
El sueño REM se ha asociado característicamente a soñar,
7
aunque también se sueña durante el sueño NREM.9 Se considera
que el sueño REM está implicado en el neurodesarrollo y el
aprendizaje motor y que los pequeños movimientos que se
producen durante esta fase de sueño contribuyen al desarrollo
del sistema sensitivo-motor. A su vez, contribuye a la
formación y consolidación de determinados tipos de memoria
y a la plasticidad cortical.10
1.3. Definición del trastorno de conducta de sueño REM
Las parasomnias son conductas anormales durante el
sueño. El TCSR es una parasomnia del sueño REM que aparece
en la edad adulta, caracterizado por movimientos y/o
conductas durante el sueño REM representando el contenido de
los sueños. Fue descrito como entidad nosológica en 1986 por
el psiquiatra Carlos Schenck y el neurólogo Mark Mahowald a
partir de cinco casos diagnosticados en la Universidad de
Minnesota.11 Los movimientos suelen ser bruscos y en
ocasiones vigorosos como sobresaltos, puñetazos o patadas.
Pueden ser simples o más elaborados con conductas
finalísticas y pueden contener algún elemento de
vocalización como gemidos, gritos o lloros.12 Los sueños
acostumbran a ser pesadillas de contenido violento en las
que el paciente o sus allegados sufren una agresión y la
persona toma partido o responde defendiéndose.13,14
1.4. Fisiopatología del TCSR
El conocimiento de los circuitos responsables del sueño
REM y la patogénesis del TCSR se basa en estudios de modelos
animales. El primer modelo de TCSR fue descrito a finales de
los años 50 por el neurocientífico Michel Jouvet en Lyon.
Demostró que lesiones en la protuberancia en gatos causaban
comportamientos similares en el sueño REM a los que más tarde
se describieron en pacientes con TCSR.15 Estudios posteriores
demostraron que al lesionar específicamente núcleos de la
8
protuberancia o el bulbo raquídeo se produce un sueño REM
sin atonía muscular análogo al TCSR de los humanos, donde el
animal (gatos, ratas) presenta conductas anómalas mientras
duerme, como si estuviera representando un sueño.7 El equipo
liderado por Pierre Luppi en Lyon ha creado un nuevo modelo
de TCSR en ratas para estudiar los mecanismos neuroanatómicos
y fisiopatológicos de la enfermedad. Son estudios de
manipulación genética centrados en los núcleos
sublaterodorsal (SLD) y ventromedial reticular, análogos al
núcleo subceruleus y magnocelularis en humanos,
respectivamente. Han demostrado el papel específico de las
neuronas glutamatérgicas del núcleo SLD y de las neuronas
inhibitorias que contienen GABA y glicina en el núcleo
ventromedial reticular en la atonía muscular durante el sueño
REM.8,16
La pérdida de atonía característica del TCSR durante el
sueño REM podría producirse por lesiones de pequeño tamaño
en el núcleo subceruleus. Lesiones con una mayor afectación
de este núcleo podrían producir una alteración en la cantidad
y duración de los periodos de sueño REM, aunque esto no
acostumbra a producirse en el TCSR.17
1.5. TCSR idiopático vs. secundario Se considera el trastorno idiopático (TCSRI) o primario
cuando aquellas personas que lo padecen no tienen ninguna
enfermedad neurológica y se descarta la relación temporal
del trastorno con el inicio o interrupción de la toma de
algún medicamento.
Es secundario cuando forma parte de la sintomatología
de una enfermedad (por ejemplo, en la enfermedad de Parkinson
(EP) o la narcolepsia), se produce a consecuencia de una
lesión estructural o se relaciona con el inicio o la
interrupción de algún tratamiento.
9
1.5.1. Enfermedades neurológicas
El TCSR puede ser parte de las manifestaciones clínicas
de enfermedades neurodegenerativas, fundamentalmente en
aquellas en las que se produce el depósito de alfa-sinucleína
(sinucleinopatías) como en la EP, la demencia por cuerpos de
Lewy (DCLw) o la atrofia multisistémica (AMS).18,19 En estas
enfermedades el TCSR puede preceder o aparecer
concomitantemente a la sintomatología cardinal
(parkinsonismo, demencia). Todas ellas tienen en común la
afectación de estructuras del tronco encefálico en las
primeras etapas de la enfermedad.20,21 La prevalencia del TCSR
en la EP es aproximadamente del 30-50%,22,23 en la DCLw varía
según estudios entre el 35-80%24,25 y en la AMS es del 88-
100%.26,27
La Tabla 1 muestra la frecuencia de TCSR diagnosticado
en diferentes enfermedades neurodegenerativas. En la
enfermedad de Alzheimer (EA), la enfermedad
neurodegenerativa más frecuente y primera causa de demencia,
el TCSR es excepcional. Esta enfermedad tiene un perfil
anatomopatológico diferente a las sinucleinopatías, con el
depósito cerebral de proteína amiloide y tau en regiones que
no regulan el sueño REM. Los casos descritos de TCSR y
diagnóstico de EA en los que se había realizado un estudio
postmortem se hallaron evidencias de patología típica de EA
junto con presencia de cuerpos de Lewy típicos de la
enfermedad con cuerpos de Lewy.28
10
Tabla 1. Prevalencia del TCSR secundario a enfermedades
neurodegenerativas.
Atrofia multisistémica26,27 88-100%
Parkinsonismo atípico de la isla de
Guadalupe29
78%
Enfermedad de Parkinson idiopática22,23 30-50%
Demencia con cuerpos de Lewy24,25 34-83%
Parálisis supranuclear progresiva30,31 13-30%
EP asociada a la mutación LRRK232 15%
Esclerosis lateral amiotrófica33 5%
EP asociada a la mutación parkin 234 Pocos casos descritos
Ataxia espinocerebelosa tipo 235
Pocos casos descritos
Ataxia espinocerebelosa tipo 336 Pocos casos descritos
Degeneración corticobasal37 Casos anecdóticos
Demencia frontotemporal38 Casos anecdóticos
Enfermedad de ALzheimer28 Casos anecdóticos
LRRK2: Gen Leucine-rich repeat kinase 2
El TCSR puede estar presente en enfermedades de origen
autoinmune. La mayoría de los pacientes con la enfermedad
anti-IgLON5, presentan una combinación de parasomnia NREM y
REM con apneas obstructivas y estridor.39 En la narcolepsia
tipo 1, una enfermedad que cursa con somnolencia diurna, se
produce una alteración de la regulación en el sueño REM que
se manifiesta con episodios de cataplejía, parálisis del
sueño, alucinaciones hipnagógicas e inicios de sueño en fase
REM.40 El 45-61% de los pacientes con narcolepsia tienen
clínica sugestiva de TCSR y en el 36-43% se detecta mediante
video-polisomnograma (V-PSG).41 En la Tabla 2 se enumeran las
enfermedades autoinmunes que pueden cursar con TCSR.
11
Tabla 2. Prevalencia del TCSR secundario a enfermedades
autoinmunes.
Enfermedad anti-IgLON539 90%
Narcolepsia41 36-43%
Esclerosis múltiple42 1.4%
Encefalitis LGI1*43 Pocos casos descritos
Encefalitis límbica asociada a
anticuerpos anti-Ma244
Algún caso descrito
Síndrome de Guillain-Barré45 Algún caso descrito
LGI1: Anti-leucine-rich glioma inactivated protein 1
*encefalitis previamente denominada “por anticuerpos anticanales de potasio”
1.5.2. TCSR secundario a una lesión estructural
El TCSR puede aparecer de manera aguda o subaguda, en
relación temporal con otros síntomas, al producirse una
lesión estructural localizada en el tronco encefálico o en
el sistema límbico.46 Ha sido descrito en el contexto de
lesiones vasculares,47 en relación con tumores y en lesiones
de origen inflamatorio. La clínica de TCSR puede aparecer a
consecuencia de lesiones desmielinizantes en la esclerosis
múltiple y ha sido descrita de manera puntual como la
manifestación inicial de la enfermedad.48 El tratamiento de
la enfermedad que ocasiona la lesión puede en algunos casos
mejorar o incluso resolver el cuadro de TCSR.49
1.5.3. TCSR secundario al uso de medicamentos
Algunos fármacos pueden estar implicados en la
presencia del TCSR. Los antidepresivos tricíclicos, los
inhibidores de la recaptación de serotonina o los inhibidores
de la recaptación de serotonina y noradrenalina pueden
interferir en la inhibición gabaérgica sobre las
12
motoneuronas espinales durante el sueño REM. A consecuencia
de ello puede producirse una ausencia de atonía durante el
sueño REM de manera aislada.50 En algunos casos puede
aparecer el cuadro completo de TCSR, aunque es discutible si
este trastorno es un efecto secundario del fármaco o éste es
un desencadenante de un TCSR latente.51
Un efecto similar se da en algunos pacientes que
recibían tratamiento con betabloqueantes liposolubles, a
pesar de que el mecanismo es menos conocido.52 Se han descrito
casos aislados de TCSR en pacientes con EP tratados con
selegilina53 y en pacientes con EA con rivastigmina.54
1.6. Epidemiología TCSR
La prevalencia de TCSR “probable”, detectado mediante
cuestionarios, en mayores de 60 años es del 5.5-8.8%.55,56 Los
estudios realizados con confirmación V-PSG muestran una
prevalencia de TCSR (tanto idiopático como secundario) entre
el 1-2%57,58 y de TCSRI de 0.7%.59 En un estudio de un único
centro se determinó que de los pacientes que consultan por
trastornos del sueño, el 4.8% se diagnostican de TCSR, siendo
idiopáticos el 1.6%.60 Es posible que el trastorno esté aún
infradiagnosticado.
1.7. Características clínicas Los pacientes con TCSR suelen tardar varios años en
consultar a su médico por las conductas durante el sueño,
debido a que consideran que los síntomas no son patológicos,
son poco frecuentes, no creen que tengan tratamiento o creen
que mejorarán con el tiempo.61
La mayoría de los pacientes que consultan y se
diagnostican con V-PSG son hombres en la séptima década de
la vida.12,62 Las conductas representando los sueños son con
mayor frecuencia violentas, aunque también se pueden
13
representar actitudes agradables.13 Aparecen en los momentos
en que fisiológicamente aparece el sueño REM, cuando la
persona lleva unas dos horas dormido y de madrugada, dado
que es entonces cuando se produce una mayor proporción de
sueño REM. Los pacientes permanecen con los ojos cerrados y
no suelen abandonar la cama, si se les despierta están
perfectamente orientados y en ocasiones pueden relatar el
contenido de sus sueños, que puede relacionarse con aquellas
conductas objetivadas por su pareja de cama. Las conductas
y el contenido de los sueños pueden ser o no recordados por
el propio paciente. Cuando no lo son es necesario un testigo
de su sueño para ser explicadas. En algunos casos se les da
una mayor importancia a las conductas cuando a consecuencia
de ellas se ha producido una lesión al propio paciente o a
su pareja tras una caída de la cama o un golpe.63
Estudios epidemiológicos han relacionado el tabaquismo
(al contrario que en la EP), el antecedente de lesiones
craneales y un menor tiempo de estudios con un mayor riesgo
de TCSR.64-66 A nivel ambiental se ha encontrado una asociación
con la exposición a pesticidas y la agricultura,64 la
exposición a disolventes químicos65 y el trabajo en minas de
carbón.66
1.8. Diagnóstico
El diagnóstico del TCSR requiere en primer lugar que el
paciente considere el problema lo suficientemente importante
para consultar por ello y que el profesional sanitario que
le atienda reconozca el cuadro y lo oriente correctamente.
Es necesario que tanto la población general como los
profesionales conozcan la entidad clínica y existan unidades
de sueño que puedan hacer un diagnóstico de certeza con una
anamnesis completa y un V-PSG.
14
1.8.1. Cuestionarios
Los cuestionarios pueden evaluar la presencia de TCSR
en la población general y en grupos de pacientes con
enfermedades neurológicas.67-71 La mayoría de ellos fueron
diseñados para ser autoadministrados.67-69 Tienen
limitaciones importantes debido a que los pacientes deben
ser conscientes de sus movimientos durante el sueño y
recordar al menos en parte el contenido de sus sueños. En
caso contrario es determinante la presencia de un compañero
de cama o un testigo de los episodios para poder detectar el
trastorno. Con el objetivo de evaluar a pacientes que no son
conscientes del trastorno y también a aquellos que sufren
deterioro cognitivo se han diseñado cuestionarios dirigidos
tanto al propio paciente como a su compañero de cama70 o
únicamente al compañero de cama.71 Si el paciente no es
consciente, no tiene compañero de cama o éste no se da cuenta
de las conductas pueden producirse falsos negativos en los
cuestionarios de cribaje. Por otra parte, pueden producirse
falsos positivos en sujetos con la misma clínica que
pacientes con TCSR pero con un REM normal.
1.8.2. Video-polisomnograma
La prueba de elección para el diagnóstico del TCSR es
el V-PSG. En los pacientes con TCSR, durante la fase sueño
REM, se objetivan movimientos oculares rápidos en el EOG y
una actividad EEG desincronizada y de bajo voltaje que
acostumbran a ser normales.1 Sin embargo, en lugar de atonía
muscular y una ausencia de movimientos, el EMG de superficie
muestra actividad muscular (Figuras 1-3) y en el registro
audiovisual aparecen movimientos o conductas anormales.11,12
15
Figura 1. Época de sueño REM normal de 30 segundos con atonía fisiológica en el canal de EMG de superficie en el músculo mentalis
(flecha).
EOG: electrooculograma; EEG: electroencefalograma; EMG: electromiograma; FDS:
flexor superficial de los dedos en los antebrazos
Figura 2. Época de sueño REM de 30 segundos en paciente con TCSR. Los canales de EMG muestran actividad fásica excesiva en músculos
mentalis (flechas azules) y FSD (flexor superficial de los dedos
en los antebrazos (flecha verde)).
EOG: electrooculograma; EEG: electroencefalograma; EMG: electromiograma; FDS:
flexor superficial de los dedos en los antebrazos
16
Figura 3. Época de sueño REM de 30 segundos de duración en paciente con TCSR. El canal EMG de músculo mentalis muestra actividad
tónica sostenida (flecha roja) y actividad fásica excesiva
(flechas azules) y en el canal EMG del músculo FSD (flexor
superficial de los dedos, en los antebrazos) se observa actividad
fásica excesiva (flechas verdes).
EOG: electrooculograma; EEG: electroencefalograma; EMG: electromiograma; FDS:
flexor superficial de los dedos en los antebrazos
La actividad EMG en el sueño REM de los pacientes con
TCSR se denomina “incremento de actividad” o “actividad
excesiva”.11 Consta de dos tipos: actividad sostenida o
tónica y actividad intermitente o en brotes, denominada
fásica (Figuras 2 y 3). La actividad muscular puede
cuantificarse en función de la proporción de tiempo en que
se produce la actividad EMG en relación con el tiempo total
de sueño REM.72 Se han propuesto diversos métodos para la
evaluación de la actividad muscular. Éstos pueden ser
visuales, con el inconveniente de que requieren una formación
muy específica y tiempo para evaluarlo; o automatizados,
cuya limitación principal es la capacidad de seleccionar
correctamente el sueño REM y descartar la presencia de
artefactos.
Los métodos propuestos hasta la fecha y recomendados
por los criterios diagnósticos actuales de la AASM son tres
(Tabla 3).73-76 Los métodos visuales se diferencian en los
17
músculos evaluados, la delimitación de tiempo y los puntos
de corte a partir de los cuales se considera que la actividad
es excesiva o anormal. El músculo mentalis es el más empleado
debido a que forma parte de los criterios para la
codificación de las diferentes fases de sueño,1 a pesar de
que es un músculo muy susceptible a artefactos respiratorios
(ronquidos o apneas). Para mejorar la sensibilidad del
diagnóstico PSG se han estudiado otros músculos y se ha
determinado que evaluar la actividad muscular en las
extremidades superiores puede incrementarla.77,78 El grupo
SINBAR (Sleep Innsbruck Barcelona) concluyó en un estudio
que la combinación de la actividad muscular en extremidades
superiores junto con el músculo mentalis logra una óptima
sensibilidad y especificidad para distinguir pacientes con
TCSRI de controles sanos.75
18
Tabla 3. Métodos de cuantificación recomendados por la International Classification of Sleep
disorders.73
S: sensibilidad; E: especificidad; TCSRI: trastorno de conducta de sueño REM idiopático; TCSR: trastorno de conducta de sueño REM; AMS: atrofia
multisistémica; SAS: síndrome de apneas durante el sueño; EP: enfermedad de Parkinson; FSD: flexor superficial de los dedos en los antebrazos
Autor, año Método Pacientes
estudiados (n)
Delimitación
sueño REM
(segundos)
Músculo
estudiado Actividad y puntos de corte S (%) E (%)
Montplaisir
et al., 201070
Visual Clínica compatible
con TCSRI (80) y
controles sanos
(80)
Miniépocas
(2)
Épocas (30)
Mentalis Tónica ≥30% 73.8 90.0
Fásica ≥15% 80.0 87.5
Tónica y/o fásica 88.9 82.5
Ferri et al., 201171
Automa-
tizado
TCSRI sin
tratamiento (31),
TCSRI con
tratamiento (8),
TCSR secundario a
AMS (10), SAS (5),
controles sanos
jóvenes (25) y
mayores (10)
Miniépocas
(1 y 2)
Épocas (30)
Mentalis Índice de atonía
durante el sueño REM
<0.9 74.3 91.4
<0.8
38.5 100
Frauscher
et al., 201272
Visual
TCSRI (15), TCSR
secundario a EP
(15) y controles
sanos (30)
Miniépocas
(3)
Épocas (30)
Mentalis “combinación de tónica y fásica”
≥18.2% 100
Combinación
mentalis y
FSD
“combinación de
tónica y fásica” en
mentalis y actividad
fásica en FSD
≥31.9%
100
19
En los pacientes con TCSR puede hallarse en el registro
audiovisual la presencia de movimientos simples, bruscos
como mioclonias en extremidades o sobresaltos generalizados
hasta conductas finalísticas (por ejemplo: saludar,
gesticular o dar una patada como chutando un balón); todo
ello sincronizado con el PSG que avala que el paciente se
encuentra en la fase REM del sueño.12 Es frecuente la
presencia de vocalizaciones, que en ocasiones pueden ser
breves o ininteligibles y en otras pueden ser más elaboradas
como discursos o incluso canciones.
1.8.3 . Criterios diagnósticos
El diagnóstico del TCSRI requiere un estudio V-PSG para
detectar la ausencia de atonía muscular durante el sueño REM
asociada a la presencia de movimientos anormales. Los
criterios diagnósticos actuales,73 establecidos por la
International Classification of Sleep Disorders (ICSD-3) son
los siguientes: 1) episodios repetidos de vocalizaciones y/o
conductas vigorosas durante el sueño; 2) que los episodios
ocurran durante el sueño REM, registrado por V-PSG o se
presuma que es así por historia clínica; 3) demostración en
el V-PSG de sueño REM sin atonía y, 4) que el trastorno no
pueda ser explicado por otra alteración del sueño, enfermedad
psiquiátrica, un fármaco o el abuso de sustancias.
Los criterios de la ICSD han variado en las diferentes
ediciones con el paso de los años (Tabla 4),73,79,80
principalmente restando importancia a la clínica del
paciente a costa de incrementar el valor de los hallazgos
objetivos del V-PSG. Además, se acepta que el TCSR pueda
estar asociado a una enfermedad neurológica.
20
Tabla 4. Criterios diagnósticos del TCSRI en las diferentes ediciones de la International Classification of Sleep
Disorders
ICDS: International Classification of Sleep Disorders; PSG: Polisomnograma
ICDS-175 ICDS-276 ICDS-369
Anamnesis
Queja del paciente por una conducta violenta o lesiva durante el sueño
Conductas lesivas, potencialmente lesivas o molestas relacionadas con el sueño
Episodios repetidos de
vocalizaciones y/o conductas complejas relacionadas con el sueño.
Tipo de
conductas o
movimientos
Movimiento de una extremidad o del cuerpo
asociado al contenido del sueño
Al menos uno de los siguientes:
1.Comportamientos lesivos durante el sueño 2.Los sueños parecen representados
3.Las conductas durante el sueño alteran la
continuidad del sueño
PSG
Al menos uno de los siguientes:
1. Aumento excesivo del tono EMG del mentón
2. Actividad excesiva fásica intermitente en
el EMG del mentón y uno o más de los
siguientes:
a.sacudidas excesivas en extremidades o en
el cuerpo b.conductas complejas, vigorosas
o complejas
Presencia de sueño REM sin atonía
Conductas anormales durante el sueño REM documentadas durante la
monitorización con PSG
Exclusión y
otros
Ausencia de actividad epiléptica asociada Ausencia de actividad
epileptiforme en el EEG durante el
sueño REM a menos que el TCSR
pueda ser distinguido claramente
de cualquier crisis epiléptica
asociada al sueño REM concurrente
Puede estar relacionada con trastornos
neurológicos
No puede ser atribuida a una
enfermedad neurológica
Otros trastornos del sueño pueden estar
presentes, pero no son la causa de la
conducta.
No puede ser atribuida a otro trastorno del sueño
No relacionada con trastornos mentales
La alteración del sueño no puede ser atribuida a enfermedad
mental, tratamiento médico o abuso de sustancias
21
1.8.4 . Diagnóstico diferencial
El TCSR debe diferenciarse de otros trastornos del sueño
que cursan con movimientos o conductas anormales durante el
sueño y en ocasiones pesadillas (Tabla 5). El estudio V-PSG
es imprescindible para el diagnóstico diferencial del TCSR.
Tabla 5. Trastornos que pueden imitar clínicamente el TCSR.
Trastornos del despertar
Síndrome de apneas durante el sueño
Crisis epilépticas nocturnas
Movimientos periódicos de las piernas
Trastorno del sueño asociado a un trauma
Estados disociativos
Simulación
Los trastornos del despertar o parasomnias NREM
incluyen los despertares confusos, el sonambulismo y los
terrores nocturnos.81 Son trastornos típicos de la edad
pediátrica, aunque el sonambulismo y los terrores nocturnos
pueden persistir en la edad adulta en aproximadamente un 2%
y los despertares confusos en un 6% de la población. Los
despertares confusos en el adulto suelen ocurrir en relación
con la polifarmacia. Consisten en despertares abruptos en
los que el paciente se encuentra desorientado varios minutos.
El sonambulismo cursa con un despertar incompleto,
alteración de la consciencia y deambulación, algo
infrecuente en el TCSR. Los terrores nocturnos son episodios
de despertar con miedo intenso y activación del sistema
22
simpático con midriasis, taquicardia, taquipnea y
diaforesis.
En algunos casos de síndrome de apneas durante el sueño
los despertares al final de las apneas desde sueño NREM y
REM pueden ir acompañados de vocalizaciones y conductas
similares al TCSR. Al tratar las apneas con dispositivos de
presión continua de aire (CPAP) estas conductas
desaparecen.82
La epilepsia asociada con el sueño cursa con crisis
focales desencadenadas durante el sueño NREM. Ocurren
principalmente al principio de la noche y tienen una duración
corta. Se manifiestan como movimientos estereotipados y
tienen un inicio y final bruscos.83
El trastorno por movimientos periódicos de las piernas
puede imitar la sintomatología del TCSR. Las personas que lo
sufren pueden tener pesadillas y movimientos periódicos muy
prominentes que se extiendan a la cabeza, brazos o tronco.
También pueden aparecer conductas o vocalizaciones en los
despertares después de un movimiento. En una serie de
pacientes hubo mejoría de la clínica al tratarlos con
agonistas dopaminérgicos.84
Las personas con un trastorno del sueño asociado a un
trauma presentan pesadillas y conductas anormales durante el
sueño.85 El desencadenante es una experiencia traumática y
se ha descrito principalmente en supervivientes de zonas de
conflicto y en militares. Con frecuencia se acompaña del
trastorno por estrés postraumático. Hay pocos estudios con
registros V-PSG que hayan documentado la presencia de
conductas representando los sueños. Se registra sueño REM
sin atonía sin llegar a alcanzar los niveles de actividad
muscular de los pacientes con TCSR. A diferencia del TCSR,
las pesadillas suceden tanto durante el sueño REM como en el
sueño NREM y existe activación simpática.
23
Finalmente, en algunos casos hay que descartar un
trastorno disociativo durante el sueño o incluso que el
paciente pueda simular la clínica para justificar un
determinado comportamiento.86
1.9 Importancia del TCSR idiopático
1.9.1. Riesgo de lesiones
Es importante diagnosticar el TCSR ya que durante las
conductas hay riesgo de lesiones a los propios pacientes o
a sus parejas de cama. Se producen con una frecuencia del
33-69% según estudios.87-89 Las lesiones son de gravedad
variable, hasta el punto de tener consecuencias legales.90,91
El TCSR es uno de los diagnósticos a tener en cuenta cuando
los pacientes presentan lesiones mientras duermen.92 Según un
estudio, los pacientes con TCSRI tienen mayor riesgo de
hacerse daño que los que tienen un TCSR secundario así como
aquellos que recuerdan más el contenido de los sueños y los
que mueven las extremidades en las conductas durante el sueño
REM.93
Algunos pacientes colocan parapetos a modo de
protección en el dormitorio para evitar hacerse daño durante
alguno de los episodios.11 El tratamiento sintomático del
TCSR está indicado para reducir las pesadillas y el riesgo
de lesiones.94 El único tratamiento efectivo es el clonazepam
y la melatonina, a pesar de que no se han realizado estudios
aleatorizados que lo demuestren científicamente. El
clonazepam es la única benzodiacepina que se ha demostrado
eficaz en dosis de 0.5 a 2 mg aunque se desconoce el mecanismo
de acción. La melatonina es una hormona secretada por la
glándula pineal, por lo que no es considerada un fármaco
sino un suplemento. Se emplea para tratar alteraciones del
24
ritmo circadiano y para el TCSR se administra en dosis de 3
a 12 mg.
1.9.2. Implicaciones pronósticas
Desde su primera descripción, se ha demostrado que las
personas diagnosticadas de TCSRI tienen un riesgo aumentado
de padecer enfermedades neurodegenerativas causadas por una
sinucleinopatía, como la EP, DCLw o la AMS. La evidencia se
sustenta en la presencia de síntomas y signos de estas
enfermedades en los pacientes con TCSRI (por ejemplo, pérdida
de olfato o déficit de transportador de dopamina demostrado
por tomografía de emisión por fotón único -SPECT-), la
demostración de depósitos de alfa-sinucleína en tejido
nervioso periférico (como en el colon) y el desarrollo del
síndrome neurodegenerativo después de unos años de
seguimiento a los pacientes.
Sintomatología acompañante, anormalidades a la exploración
y pruebas complementarias
Los síndromes neurodegenerativos están formados por un
abanico amplio de síntomas además de la clínica clásica que
los define. En la EP95, la DCLw96 y la AMS97 pueden aparecer
síntomas previos al parkinsonismo o la demencia, denominados
pródromos de la enfermedad. Los pacientes con TCSRI presentan
con frecuencia otros síntomas y signos dentro del espectro
prodrómico de estas enfermedades neurodegenerativas (Tabla
6).
25
Tabla 6. Hallazgos en pacientes con TCSRI
Signos leves de parkinsonismo
Hiposmia
Disautonomía
Depresión
Alteración en test neuropsicológicos
Cuando se exploran con detalle los movimientos de los
pacientes con TCSRI pueden encontrarse signos de
parkinsonismo leves o sutiles. Pueden estar presentes en el
momento del diagnóstico o aparecer a lo largo del
seguimiento.98 Los primeros signos del desarrollo de un
parkinsonismo son la hipofonía y la hipomímia seguidos de la
disminución del braceo al caminar.
La hiposmia y el estreñimiento son problemas
inespecíficos de manera aislada, aunque junto con otros
síntomas, pueden formar parte de la clínica de enfermedades
neurodegenerativas. En pacientes diagnosticados con TCSRI se
encuentran con una mayor frecuencia que en controles sanos.99
Trastornos autonómicos, como alteraciones urinarias,
disfunción eréctil o hipotensión ortostática también pueden
estar presentes.100
Los pacientes con TCSRI pueden presentar depresión, ya
ésta forma parte de las enfermedades neurodegenerativas de
manera intrínseca.101 Algunos estudios observan una mayor
frecuencia de tratamiento con antidepresivos en pacientes
con TCSRI respecto a controles.66 Tal y como se comentó en el
apartado de “TCSR secundario al uso de medicamentos” el
tratamiento con antidepresivos podría desenmascarar un TCSR
26
latente y por lo tanto podría ser que los pacientes con
depresión y TCSR fuesen diagnosticados más precozmente.51
Los pacientes con TCSRI, a pesar de no tener quejas
cognitivas, presentan algunas alteraciones en los estudios
neuropsicológicos. Diferentes series han hallado
alteraciones en funciones visuo-espaciales,102 atención,
funciones ejecutivas y memoria verbal,103 así como memoria
prospectiva.104
Además de todos estos síntomas y signos, si se realizan
pruebas complementarias pueden encontrarse los hallazgos
enumerados en la Tabla 7:
Tabla 7. Hallazgos en las pruebas complementarias realizadas
en pacientes con TCSR.
Resonancia
magnética
Alteraciones en tronco encefálico (especialmente en
regiones implicadas en el control del sueño REM y en
sustancia negra), ganglios basales (con alteración
del circuito estriado-tálamo-palidal), regiones
subcorticales y corticales.105-108
EEG Enlentecimiento en vigilia y aumento de frecuencias
delta y theta.103
Ecografía
transcraneal
Hiperecogeneicidad en la sustancia negra.109
SPECT de
transportador de
dopamina
Disminución de la captación del trazador en el
estriado.110
Gammagrafía con
MIBG
Reducción de la captación cardíaca del trazador111
PET (diferentes
trazadores)
Aumento de perfusión en protuberancia, putamen e
hipocampos, con disminución en algunas regiones
corticales.112
Activación de la microglía en la sustancia negra y
disminución de la función dopaminérgica en el
putamen.113
EEG: electroencefalograma; SPECT: tomografía de emisión por fotón único; MIBG: yodo-123-
metayodobenzilguanidina; PET: tomografía por emisión de positrones
27
Presencia de patología típica de enfermedades
neurodegenerativas en pacientes con TCSRI
Estudios postmortem de pacientes con TCSRI han
demostrado la presencia de cuerpos de Lewy y pérdida neuronal
con gliosis en estructuras del tronco encefálico como la
sustancia negra, el núcleo subceruleus y pedunculopontino en
la protuberancia y el núcleo magnocelularis en el bulbo.114,115
Los pacientes con EP presentan agregados de sinucleína
en tejido nervioso periférico. Del mismo modo, varios
estudios con pacientes diagnosticados con TCSRI, sin
presentar aún la sintomatología cardinal de la EP u otras
enfermedades neurodegenerativas, han documentado la
presencia de sinucleína en mucosa y submucosa colónica,116
glándula submandibular,117 glándula salivar menor,118 glándula
parótida119 y piel.120,121
Desarrollo de enfermedad a lo largo del seguimiento clínico
Varias series con seguimiento longitudinal de pacientes
con TCSRI han observado que con el tiempo desarrollan un
síndrome neurodegenerativo, principalmente la EP, DCLw, DCL
o AMS.
Schenck et al. fueron los primeros en describir esta
asociación al comprobar que 11 de 29 (38%) pacientes habían
desarrollado una enfermedad neurodegenerativa a los cuatro
años de seguimiento122 y que, 16 años más tarde, este
porcentaje de pacientes aumentó al 81%.123 En nuestro grupo
en Barcelona se realizó un estudio de seguimiento de 44
pacientes con TCSRI. El porcentaje de diagnóstico de un
síndrome neurodegenerativo fue del 45% tras 5 años de
seguimiento.124 Siete años después, el 82% de los pacientes
habían desarrollado enfermedad con una media de 10.5 años de
seguimiento.125 En este trabajo y en otras series se ha
28
calculado el riesgo estimado de desarrollar una enfermedad
neurodegenerativa mediante curvas de Kaplan-Meier (Tabla 8).
Tabla 8. Riesgo estimado del desarrollo de un síndrome
neurodegenerativo en series de pacientes con TCSRI.
Grupo de
investigación
Año de
publicación n
Riesgo estimado de
enfermedad
neurodegenerativa desde el
diagnóstico
Wing et al.126 2012 71
4.7% a los 3 años; 8.5% a
los 5 años; 21% a los 7 años
y 38.1% a los 9 años
Iranzo et al.125 2013 44
34.8% a los 5 años; 73.4% a
los 10 años; 92.5% a los 14
años
Postuma et al.127 2015 89 30% a los 3 años; 66% a los
7.5 años
Postuma et al.64
(multicéntrico)
2015 279
25% a los 3 años; 41% a los
5 años
Youn et al.104 2016 84 9% a los 3 años; 18% a los
5 años; 5% a los 6 años
Las diferencias entre publicaciones pueden atribuirse
en parte a que algunos grupos de investigación incluyen en
las series de TCSRI a pacientes que tienen un deterioro
cognitivo leve.64,104,127,128 Otros grupos, sin embargo,
consideran que el deterioro cognitivo leve se trata de un
estado previo a la demencia y es (como la EP, la DCLw y la
AMS) uno más de los diagnósticos que se realizan en pacientes
con TCSRI después de un tiempo de seguimiento.125,129
29
En resumen, en esta introducción se exponen aspectos
fisiopatológicos, clínicos y diagnósticos del TCSRI. Los
pacientes que sufren esta parasomnia pueden lesionarse a
consecuencia de las conductas durante el sueño y tienen un
mayor riesgo de ser diagnosticados en el futuro de una
enfermedad neurodegenerativa. Es una entidad de interés para
la investigación ya que su estudio incrementa el conocimiento
sobre aspectos fisiopatológicos del sueño REM y es un
marcador altamente específico de fases tempranas de las
enfermedades caracterizadas por el depósito de sinucleína.
30
2. HIPÓTESIS
1) En una serie larga y homogénea de pacientes consecutivos
con TCSRI, pueden describirse las características
demográficas y clínicas en su momento de presentación
en una unidad de trastornos de sueño, destacando
elementos no descritos o poco enfatizados previamente.
2) En el diagnóstico V-PSG del TCSRI, la evaluación
cuantitativa de la actividad muscular del músculo
mentalis junto con músculos de las extremidades
superiores en la fase REM es más sensible que evaluar
únicamente el músculo mentalis.
3) En una serie grande y homogénea de pacientes
consecutivos con TCSRI seguidos prospectivamente
durante años, la aparición de una enfermedad
neurodegenerativa es frecuente y similar a la descrita
previamente en nuestro mismo centro con una serie más
pequeña y con menor tiempo de seguimiento.
31
3. OBJETIVOS
1) Describir las características demográficas y clínicas
de los pacientes con TCSRI en el momento de presentación
en una unidad de sueño.
2) Evaluar si la evaluación electromiográfica conjunta del
músculo mentalis y de los músculos de las extremidades
superiores es más sensible para el diagnóstico del TCSRI
que la evaluación única del músculo mentalis.
3) Conocer la frecuencia de aparición de una enfermedad
neurodegenerativa en los pacientes con TCSRI.
32
4. RESULTADOS
33
TRABAJO NÚMERO 1.
The clinical phenotype of idiopathic rapid eye movement
sleep behavior disorder at presentation: A study in 203
consecutive patients
Fernández Arcos, A., Iranzo, A., Serradell, M., Gaig C.,
Santamaria J.
SLEEP 2016; 39: 121-132.
34
EL FENOTIPO CLÍNICO DEL TRASTORNO DE CONDUCTA DE SUEÑO REM
IDIOPÁTICO EN SU PRESENTACIÓN: UN ESTUDIO EN 203 PACIENTES
CONSECUTIVOS
Objetivo: Describir el fenotipo clínico de los pacientes
afectos del trastorno de conducta de sueño de movimientos
oculares rápidos (siglas REM en inglés) (TCSRI) en su
presentación en una unidad de trastornos de sueño.
Métodos: Revisión de la historia clínica de 203 pacientes
consecutivos con TCSRI identificados entre 1990 y 2014. El
TCSRI fue diagnosticado por historia clínica y la
demostración video-polisomnográfica de sueño REM con aumento
de actividad electromiográfica asociada a conductas
anormales.
Resultados: El 80% de los pacientes fueron hombres con una
mediana de edad de 68 años (rango, 50-85 años). Además del
cuadro clínico ya conocido del TCSRI, se evidenciaron otras
características de interés: el 44% de los pacientes
recordaban sus conductas anormales durante el sueño y el 70%
referían dormir bien. En la mayoría de estos casos los
compañeros de cama fueron fundamentales para convencer a los
pacientes para consultar. En el 11% de los pacientes el TCSRI
se sospechó a partir de un cuestionario específico cuando
consultaban por otros motivos. El 7% no recordaba tener
pesadillas. El 24% de los pacientes se levantó de la cama de
forma ocasional y con frecuencia estos sujetos desarrollaron
posteriormente una demencia con cuerpos de Lewy. Para
diagnosticar correctamente el TCSRI, el video-polisomnograma
tuvo que ser repetido en el 16% de los pacientes debido a
que el sueño REM fue insuficiente o a artefactos en el
electromiograma por apneas coexistentes. Algunos sujetos que
también tenían apneas obstructivas del sueño explicaron una
mejoría parcial de los síntomas del TCSR después del
tratamiento con una mascarilla de presión positiva continua
35
en las vías respiratorias. No haber tratado los síntomas del
TCSR con clonazepam tuvo como consecuencia un mayor riesgo
de lesiones relacionadas con el sueño. El seguimiento clínico
de los pacientes demostró la aparición de una enfermedad
neurodegenerativa, incluso en pacientes con formas leves o
presentaciones atípicas del TCSRI (p.e. pacientes que
referían dormir bien, inicio del TCSRI coincidiendo con
evento vital, deambulación nocturna) indicando que el
desarrollo de estas enfermedades es independiente de la
presentación clínica del TCSRI.
Conclusiones: Describimos la cohorte más grande hasta la
fecha (2016) de pacientes con TCSRI, diagnosticada en un
único centro. Destacamos características frecuentes que no
han sido descritas o no han sido suficientemente enfatizadas
en publicaciones anteriores. Los médicos deberían conocer
las manifestaciones del cuadro clínico completo del TCSRI,
un trastorno del sueño que representa el inicio de una
enfermedad neurodegenerativa.
SLEEP, Vol. 39, No. 1, 2016 121 Clinical Phenotype of IRBD—Fernández-Arcos et al.
NEUROLOGICAL DISORDERS
The Clinical Phenotype of Idiopathic Rapid Eye Movement Sleep Behavior Disorder at Presentation: A Study in 203 Consecutive PatientsAna Fernández-Arcos, MD; Alex Iranzo, MD; Mónica Serradell, BSc; Carles Gaig, MD; Joan Santamaria, MDNeurology Service, Multidisciplinary Sleep Disorders Unit, Hospital Clinic de Barcelona, University of Barcelona Medical School, IDIBAPS, CIBERNED, Barcelona, Spain
Objective: To describe the clinical phenotype of idiopathic rapid eye movement (REM) sleep behavior disorder (IRBD) at presentation in a sleep center.Methods: Clinical history review of 203 consecutive patients with IRBD identified between 1990 and 2014. IRBD was diagnosed by clinical history plus video-polysomnographic demonstration of REM sleep with increased electromyographic activity linked to abnormal behaviors.Results: Patients were 80% men with median age at IRBD diagnosis of 68 y (range, 50–85 y). In addition to the already known clinical picture of IRBD, other important features were apparent: 44% of the patients were not aware of their dream-enactment behaviors and 70% reported good sleep quality. In most of these cases bed partners were essential to convince patients to seek medical help. In 11% IRBD was elicited only after specific questioning when patients consulted for other reasons. Seven percent did not recall unpleasant dreams. Leaving the bed occurred occasionally in 24% of subjects in whom dementia with Lewy bodies often developed eventually. For the correct diagnosis of IRBD, video-polysomnography had to be repeated in 16% because of insufficient REM sleep or electromyographic artifacts from coexistent apneas. Some subjects with comorbid obstructive sleep apnea reported partial improvement of RBD symptoms following continuous positive airway pressure therapy. Lack of therapy with clonazepam resulted in an increased risk of sleep related injuries. Synucleinopathy was frequently diagnosed, even in patients with mild severity or uncommon IRBD presentations (e.g., patients who reported sleeping well, onset triggered by a life event, nocturnal ambulation) indicating that the development of a neurodegenerative disease is independent of the clinical presentation of IRBD.Conclusions: We report the largest IRBD cohort observed in a single center to date and highlight frequent features that were not reported or not sufficiently emphasized in previous publications. Physicians should be aware of the full clinical expression of IRBD, a sleep disturbance that represents a neurodegenerative disease.Commentary: A commentary on this article appears in this issue on page 7.Keywords: bed partner, dream-enacting behaviors, idiopathic REM sleep behavior disorder, medical consultation, nightmares, sleep qualityCitation: Fernández-Arcos A, Iranzo A, Serradell M, Gaig C, Santamaria J. The clinical phenotype of idiopathic rapid eye movement sleep behavior disorder at presentation: a study in 203 consecutive patients. SLEEP 2016;39(1):121–132.
INTRODUCTIONRapid eye movement (REM) sleep behavior disorder (RBD) is a condition characterized by nightmares and dream-enacting behaviors emerging in REM sleep.1 Patients with the idiopathic form of RBD (IRBD) have no cognitive and no motor com-plains.2–9 Population-based epidemiological data indicate that IRBD is not as rare as initially believed, mostly occurring in indi-viduals older than 60 y.10 Longitudinal studies conducted in sleep centers showed that in most patients with an initial diagnosis of IRBD the synucleinopathies dementia with Lewy bodies (DLB), Parkinson disease (PD), and multiple system atrophy (MSA) eventually developed.11–15 Thus, it is accepted that IRBD repre-sents the prodromal state of these neurodegenerative diseases.16,17
RBD occurs in 25% to 65% of patients with PD, antedating the onset of parkinsonism by several years in 20% to 30% of them.5,9,18–21 However, fewer than 1% of patients with PD com-plain about RBD symptoms to their primary care physician before receiving a diagnosis of PD.22 In individuals with IRBD, reasons for not seeking medical help include (1) belief that their dream-enacting behaviors represent a non-pathological phenom-enon which is thought to be benign, (2) perception that symp-toms are not severe or not frequent enough to consult a doctor, (3)
pii: sp-00260-15 http://dx.doi.org/10.5665/sleep.5332
SignificanceIRBD is an early manifestation of a neurodegenerative disease. This study describes the clinical findings of a large IRBD cohort that was identified over a long observational period. Using rigorous electromyographic and audiovisual criteria on polysomnography for the diagnosis of IRBD, the detailed description of 203 consecutive patients confirmed previous well-known observations and highlighted important findings that were nor recognized or not sufficiently emphasized in the medical literature. General physicians, sleep specialists and neurologists should be aware of the full profile of IRBD described in this study to improve the early detection and correct identification of this condition. This is important for patient management and counseling and will be of great interest when neuroprotective strategies become available.
belief that symptoms may resolve with time, (4) unawareness of the sleep behaviors in patients who sleep alone, and (5) embar-rassment to report them.5,6,23 However, when patients finally de-cide to seek medical consultation they may receive no support or inappropriate advice because clinicians are not yet aware of RBD or it is misdiagnosed as another disorder such as sleepwalking or epilepsy.24 Thus, IRBD is often underdiagnosed because of lack of knowledge of the disorder. Education about the existence, clinical characteristics, and importance of IRBD is crucial to im-prove its early detection. Identification of individuals with IRBD is important for patient management and counseling, and to in-clude them in future disease-modifying clinical trials.
Description of clinical manifestations of IRBD at presenta-tion is limited to a few series.2,3,25,26 The majority of these se-ries, however, combined subjects with primary (idiopathic) and secondary forms and in some studies RBD was not confirmed by polysomnography. We herein report a comprehensive and detailed characterization of a large IRBD cohort of 203 con-secutive patients in whom a diagnosis was made during a 24-y period at the presentation to a sleep center, where we have identified several aspects that were not reported or not suffi-ciently emphasized in previous series.
SLEEP, Vol. 39, No. 1, 2016 122 Clinical Phenotype of IRBD—Fernández-Arcos et al.
METHODSThe cohort comprises all the 203 consecutive individuals in whom IRBD was diagnosed at the tertiary referral sleep center of the Hospital Clínic de Barcelona, Barcelona, Spain, between August 1990 and November 2014. The Hospital Clínic de Bar-celona serves a population of about 500,000 from Barcelona city, one that is close in proximity to the hospital. The Hospital Clínic de Barcelona also admits referrals from residents living in other Barcelona neighborhoods, and other cities from Barce-lona province, Catalonia, and Spain.
In the current study, the clinical histories of these 203 pa-tients were reviewed. We first provide cross-sectional clinical and video-polysomnographic (V-PSG) data of patients at presentation, and then longitudinal data on the effect of drug therapy on RBD symptomatology and also on the development of neurodegenerative diseases with time. The study was ap-proved by the Hospital Clinic of Barcelona ethics committee and available participants gave written informed consent.
Diagnosis of IRBDAll patients received a diagnosis of IRBD according to the following criteria: (1) history of dream-enacting behaviors; (2) V-PSG showing REM sleep with increased electromyo-graphic (EMG) activity associated with abnormal behaviors; (3) absence of a neurodegenerative disease; (4) lack of motor and cognitive complaints, and (5) the clinical picture not better explained by another sleep disorder, medical disorder, medi-cation, or substance abuse.1,5,27–30 Patients with a diagnosis of mild cognitive impairment (MCI)31 at the initial visit were excluded in this series because they were considered to have already started cognitive symptoms of a neurodegenerative disease. Patients with RBD who clearly identified the introduc-tion of a medication (e.g., antidepressants, beta-blockers) with the onset of RBD symptomatology were excluded because they were considered to have secondary RBD, and not IRBD.
Clinical Assessment at the Initial VisitAt presentation, neurologists from the sleep center conducted a medical history that included demographic and clinical data, and current medications. As part of the routine clinical prac-tice of the sleep center, a comprehensive semistructured sleep interview was conducted and focused on sleep habits and complaints, estimated age of RBD onset, dream recall and its content, self-awareness and characteristics of abnormal motor and vocal behaviors during sleep, resulting injuries from vig-orous sleep behaviors, and overall subjective sleep quality. The bed partner or anyone who witnessed the patient’s sleep was encouraged to substantiate and to complete the sleep history. Excessive daytime sleepiness was evaluated with the Epworth Sleepiness Scale32 and a score greater than 10 was considered indicative of excessive daytime sleepiness. Restless legs syn-drome was diagnosed according to accepted criteria.33
V-PSG Confirmation of RBDAfter the initial visit, all patients underwent an all-night V-PSG to confirm the diagnosis of RBD. V-PSG included electroencephalogram (C3, C4, O1, and O2, referred to the contralateral ear; F3 and F4 were added in 2007), right and
left electro-oculograms, surface EMG of the mentalis, surface EMG of the right and left biceps brachii (from 1991 to 2007) or flexor digitorum superficialis (from 2008 to 2014) in the upper limbs, surface EMG of the right and left anterior tibialis in the lower limbs, electrocardiogram, nasal and oral airflow as-sessment, thoracic and abdominal movement assessment, and measurement of oxyhemoglobin saturation. Sleep stages were scored according to standard criteria with the allowance for REM sleep without atonia.30,34
For the diagnosis of RBD we did not establish a minimal amount of REM sleep time if clear dream enactment behaviors occurred during REM sleep. A repeat V-PSG was performed when the baseline study did not show clear behavioral and EMG RBD-features during the recording, no other causes of dream enactment behaviors were detected, and we were still convinced that clinical history was typical for RBD.
When patients were receiving clonazepam, melatonin, or antidepressants, the medication dose was gradually decreased and withdrawn at least 4 w before V-PSG, when possible. If patients had been using continuous positive airway pressure (CPAP) therapy for comorbid obstructive sleep apnea syn-drome, V-PSG was done with the patients using the CPAP mask at the optimal prescribed pressure.
When V-PSG detected concomitant obstructive sleep apnea, patients were offered treatment with CPAP. Those who accepted this therapy underwent a second V-PSG study where CPAP was titrated to eliminate snoring, apneic events, arousals, and oxyhemoglobin desaturations in all body posi-tions and sleep stages. We noted that in some patients with co-morbid obstructive sleep apnea the presence of EMG artifacts from apneic-related arousals did not allow to assess properly the EMG activity in REM sleep, making difficult to be sure whether the patient had RBD or not. This situation occurred in the initial V-PSG study and also persisted in some cases during the CPAP titration study. In these cases a third V-PSG study was performed with patients using their new prescribed CPAP mask in order to evaluate adequately the EMG activity in REM sleep without artifacts from respiratory events.
Treatment of RBD SymptomatologyWhen the diagnosis of IRBD was confirmed by V-PSG, pa-tients were offered medical therapy for RBD symptomatology when clinically required (e.g., potential injurious dream-en-acting behaviors, disturbing nightmares, and vigorous sleep behaviors resulting in patients or bed partners’ restless sleep). Clonazepam was chosen as the first-line therapy1,25,35 and was started at 0.25 or 0.50 mg at bedtime. The dosage was in-creased during follow-up visits in 0.25- or 0.50-mg increments, taking into account the clinical response and side effects. Pa-tients with comorbid obstructive sleep apnea were treated with clonazepam once apneas were eliminated with CPAP therapy. When clonazepam was ineffective or associated with side ef-fects, it was either switched to melatonin or melatonin was added to clonazepam.35,36 Melatonin was initially prescribed at 3 mg at bedtime and it was increased in 3-mg increments until reaching optimal clinical response. During the follow-up visits, the effect of clonazepam and melatonin was clinically assessed by both the patient and the bed partner to reduce the frequency
SLEEP, Vol. 39, No. 1, 2016 123 Clinical Phenotype of IRBD—Fernández-Arcos et al.
and intensity of the dream-enacting behaviors and nightmares. In each patient the effect of these drugs was classified as sub-stantial success, partial success, and no response.3,5
Clinical Follow-UpWhen clonazepam or melatonin was first prescribed, patients were followed at 1- to 3-mo intervals to evaluate the efficacy and potential side effects of these drugs. Patients were routinely followed every 3 to 12 mo at our sleep center after optimal therapy was reached.13,14 When we suspected the emergence of parkinsonism or cognitive decline during the follow-up visits, patients were formally assessed by neurologists of the Move-ment Disorders or Memory units through detailed clinical his-tory, neurological examination, and neuropsychological tests, as previously described.13,14 PD,37 DLB,38 MSA,39 and MCI31
were diagnosed according to accepted criteria.In the current study we reviewed whether in patients with
IRBD a defined neurodegenerative syndrome developed with time and its types, with special interest to assess if patients with unnoticed clinical features at presentation were also prone to manifest a neurodegenerative disease with time.
Statistical AnalysisDescriptive data are reported as median, mean, standard de-viation, number, and percentage. Duration of RBD was defined
as the interval between the estimated reported onset of RBD symptoms and the time of the last follow-up visit or death. Follow-up duration was defined as the interval from diagnosis of IRBD at our sleep center with V-PSG to the time of the last evaluation or death. The onset of a defined neurodegenera-tive syndrome (PD, DLB, MSA, and MCI) was determined as the date when the diagnosis was made. Clinical comparisons of IRBD characteristics between men and women were done using the Student t-test, Mann-Whitney U test and chi-square test, as appropriate. P values less than 0.05 were considered to be significant. All analyses were done with SPSS version 18.0 (Armonk, IBM Corp, NY, USA).
RESULTS
Demographic FindingsIRBD was diagnosed in 203 consecutive patients between 1990 and 2014 (Figure 1). During this same period of time, 53 ad-ditional patients were also referred to our sleep center because of suspected IRBD but when it was confirmed that they had RBD on V-PSG, we found that their RBD was secondary and not idiopathic. In these 53 cases we found that RBD was sec-ondary to either a previously undiagnosed neurological condi-tion (n = 19) or to the introduction of a medication (n = 34). The neurological disorders diagnosed at first assessment were PD
Figure 1—Flow chart describing patients with idiopathic and secondary REM sleep behavior disorder.
SLEEP, Vol. 39, No. 1, 2016 124 Clinical Phenotype of IRBD—Fernández-Arcos et al.
(n = 2), DLB (n = 1), MSA (n = 1),40 and MCI (n = 15). Clear temporal association between the RBD onset and the introduc-tion of a drug included two cases associated with beta-blockers (both with bisoprolol)41 and 32 with antidepressants (sertraline in eight, fluoxetine in five, venlafaxine in five, clomipramine in four, paroxetine in three, citalopram in three, escitalopram in two, duloxetine in one, and mirtazapine in one).
The 203 patients with confirmed IRBD were 162 men (79.8%) and 41 women (20.2%) with a median age at estimated IRBD onset of 63 y (range, 40 to 81 y), median age at diagnosis of IRBD of 68 y (range, 50 to 85 y), and median interval be-tween estimated IRBD onset and IRBD diagnosis of 4 y (range, 0.5 to 30 y). The median age at last visit was 74 y (range, 58 to 92 y) and the median follow-up from IRBD diagnosis to the last visit or to death was 5 y (range, 0.1 to 17 y).
Forty-eight patients, 43 men and 5 women (23.6%), were re-ferred to our sleep center between August 1990 and December 2003, and 155 (76.4%) between January 2004 and November 2014 (Figure 2). All patients lived in Catalonia. Their origin was Barcelona city in 54.2% cases, Barcelona province in 37.4%, and other locations in Catalonia in 8.4%.
Five patients (2.5%) reported having a first-degree relative with dream-enacting behaviors during adulthood. None of these five relatives sought medical attention for these behaviors and thereby none had a formal diagnosis of RBD or other cause of dream-enacting behaviors. We had access to one of these five relatives, and evaluation through clinical history and V-PSG showed that he had obstructive sleep apnea and not RBD.
Medical HistorySixty patients (29.5%) had previously received a diagnosis of depression and in 32 of them (15.7%) depression antedated
the onset of IRBD symptoms. Fifty-three of the 203 patients (26.1%) were taking antidepressants at presentation and none of them noticed a temporal relationship between the introduction of the antidepressant and the onset of RBD symptomatology.
At presentation, 25 patients (12.3%) had a previous diag-nosis of obstructive sleep apnea syndrome and 21 of these 25 were under adequate CPAP therapy.
Seven patients (3.4%) had a medical history of sleepwalking. In six, sleepwalking onset was at childhood and disappeared at adolescence. A 69-y-old man had sleepwalking that started at childhood and persisted at the time of his first visit in our sleep center. He was self-referred because at the age of 67 y he started to experience violent sleep behaviors in bed (e.g., punching, kicking) and frightening nightmares (e.g., being attacked by unfamiliar people) that he had never experienced before. In these seven subjects with medical history of sleepwalking, V-PSG in our sleep center demonstrated RBD and no episodes of nonrapid eye movement (NREM) sleep parasomnia.
Three patients (1.5%) had a diagnosis of epilepsy because of seizures during wakefulness, and all three had been taking carbamazepine for more than 10 y. None of them had expe-rienced seizures during sleep and they had been free of day-time seizures during the past 10 to 22 y. In these three patients, V-PSG in our sleep center confirmed RBD and ruled out the occurrence of epileptiform activity and seizures during both NREM sleep and REM sleep.
Reasons for ReferralOne hundred eighty patients (88.7%) consulted their doctors because of dream-enacting behaviors and then were referred to our sleep center. Nine patients asked their primary physician to be referred after they learned in the media that our group had published in the medical literature that dream-enacting behaviors may herald a neurodegenerative disease. Two IRBD subjects (1%) first reported their own RBD symptoms while at-tending a medical interview to their spouses at our sleep center where we asked their spouses about dream-enacting behaviors. These two subjects were surprised to learn that these behaviors were not normal, when they always assumed that they were not medically important.
Twenty-three patients (11.3%) were not referred because of dream-enacting behaviors but because of possible obstructive sleep apnea (n = 15) or hypersomnia (n = 8) instead. However, specific questioning during the semistructured sleep interview at their first visit unmasked a concomitant chronic history typ-ical of RBD. In these 15 patients with suspected sleep apnea, V-PSG showed RBD plus obstructive sleep apnea in nine cases, and RBD plus snoring without apneas in six. In the eight sub-jects referred because of hypersomnia V-PSG showed RBD; after clinical history and V-PSG, hypersomnia was attributed to concomitant obstructive sleep apnea in five and secondary to comorbid depression in three.
Sleep DataThirty-two patients (15.8%) slept alone and had no witness to complete the sleep history. The remaining 171 patients (84.2%) had a bed partner or a roommate who could describe the pres-ence and characteristics of their abnormal sleep behaviors. Six
Figure 2—Graph depicting temporal distribution of men and women in whom idiopathic REM sleep behavior disorder was diagnosed between August 1990 and November 2014.
20
15
10
5
0
1990
1992
1994
1996
1998
2000
2002
2004
2006
2008
2010
2012
2014
Year of Diagnosis of IRBD
Men Women
SLEEP, Vol. 39, No. 1, 2016 125 Clinical Phenotype of IRBD—Fernández-Arcos et al.
patients (3.0%) were able to determine the date of onset of RBD because they associated it with a highly stressful situa-tion (a robbery, a fraud, a cancer diagnosis) or a few days after a surgical procedure (a pacemaker implantation, and cardiac bypass surgery in two patients). Neuroimaging was unremark-able in all six subjects with IRBD onset associated with a life event. Most of the remaining patients and bed partners had difficulty stating the exact year when RBD symptoms started, the course of the symptoms, and the frequency of episodes per week or per month.
One hundred thirteen subjects (55.7%) were aware of their abnormal sleep behaviors. The remaining 90 (44.3%) had no recollection of their RBD episodes, and most of the relevant information had to be obtained from the bed partner.
One hundred forty-two patients (69.9%) reported good sleep quality and 66 of them (46.5%) were totally unaware of their abnormal sleep behaviors. The remaining 76 were aware of their abnormal sleep actions but considered them not disrup-tive enough to deserve medical consultation. The spouses of those patients who self-perceived sleeping well had to con-vince them to seek medical attention.
Eighteen patients (8.9%) had restless legs syndrome. Sixty-five patients (32.0%) complained of daytime somnolence. The mean Epworth Sleepiness Scale score was 8.3 ± 4.7 points, and 62 patients (32.5%) scored more than 10 points.
Dream-Enacting Behaviors (Tables 1 and 2)Most frequent motor behaviors were punching (87.2%) and kicking (81.8%) and most common vocalizations were talking (95.6%) and screaming (90.1%). Behaviors suggested
to bed partners an emotional component involving violence (punching in 177 cases) or fear (screaming in 183 cases), but also joy (laughing in 109 cases, singing in 31 cases), suffering (crying in 89 cases, howling in one case), annoyance (swearing in 79 cases, barking in two cases, roaring in one case), and love (kissing in three cases). Occasionally, patients also dis-played nonviolent elaborated activities such as giving a po-litical speech (three cases), teaching a lesson (one case), and purposeful-looking gestures (shuffling, picking things, and riding). Patients who experienced these nonviolent behaviors also displayed aggressive behaviors during the same or dif-ferent nights. In one patient, a behavior resembling sexual intercourse with an imaginary partner and accompanied by a disgusting comment occurred on a single night, as reported by his wife.
The majority of the behaviors were confined to the bed with the patient lying down or less frequently sitting up (35.5%). Forty-nine patients (24.1%) also left the bed; 21 (10.3%) got out of bed and awakened shortly after touching the floor with their feet, 18 (8.9%) walked round the bedroom, seven (3.4%) left the bedroom, and three (1.5%) left the house. Running was reported in two (1.0%) cases (one of them while dreaming of lions threatening him). In most of these 49 patients, however,
Table 1—Abnormal sleep behaviors.
n (%)Self-awareness of sleep behaviors 113 (55.7)Motor behaviors
Punching 177 (87.2)Kicking 166 (81.8)Falling out of bed 157 (77.3)Gesturing 148 (72.9)Knocking down the night stand 135 (66.5)Sitting up in the bed 72 (35.5)Getting out of the bed 49 (24.1)Assaulting the bed partner 44 (21.7)Biting 17 (8.4)
Measures of protection in bedroom 108 (53.2)Patients injured 119 (58.6)Bed partners injured 43 (21.1)Vocalizations
Talking 194 (95.6)Screaming 183 (90.1)Moaning 130 (64.0)Laughing 109 (53.7)Crying 89 (43.8)Swearing 79 (38.9)Singing 31 (15.3)Barking 2 (1.0)
Table 2—Unpleasant dream recall.
n (%)Unpleasant dream recall 188 (92.6)Dream content
Attacked by someone 156 (76.8)Arguing with someone 129 (63.5)Chased by someone 113 (55.7)Falling from a cliff 97 (47.8)Attacked by an animal 81 (39.9)
Dog 27 (33.3)Snake 15 (18.5)Lion 10 (12.3)Bull 9 (11.1)Horse 5 (6.2)Insect 5 (6.2)Cat 4 (4.9)Rat 4 (4.9)Tiger 3 (3.7)Pig 3 (3.7)Wolf 2 (2.5)Crocodile 2 (2.5)Cow 2 (2.5)Mole 1 (1.2)Piranha 1 (1.2)Wild boar 1 (1.2)
Action-filled sports 32 (15.8)Football (soccer) 26 (81.3)Boxing 2 (6.3)Skiing 1 (3.1)Basketball 1 (3.1)Motorcycling 1 (3.1)Cycling 1 (3.1)
Children in a life-threatening situation 26 (12.8)
SLEEP, Vol. 39, No. 1, 2016 126 Clinical Phenotype of IRBD—Fernández-Arcos et al.
leaving the bed occurred only 1 or 2 nights within a RBD his-tory of several years. None of these 49 patients who got out of bed had a history of epilepsy and only one was a sleepwalker. V-PSG of all 49 subjects demonstrated RBD and did not show epileptiform activity, seizures, or a NREM sleep parasomnia.
One hundred fifty-seven patients (77.3%) fell out of bed (in most of the cases less than five times), 44 (21.7%) assaulted their spouses (pulling off their hair or grabbing them by the neck), and 17 bed partners (8.4%) were bitten. Sleep related injuries occurred in 119 patients (58.6%) and 43 spouses (21.1%). Injuries resulted from jumping out of bed, attempting strangulation, punching or biting the bed partner, and hitting the wall or the nightstand. Injuries included ecchymoses in 70 patients, lacerations in 43, bone fractures in 11 (ribs in four cases, toes in three, collar bone in two, carpus in one, and radius plus ulnar in one), and shoulder dislocation in 1. None of the violent sleep behaviors and injuries led to forensic or medical-legal consequences.
One hundred eight patients (53.2%) took measures to protect themselves and their spouses, such as sleeping in a separate bed or bedroom (56 cases), sleeping in a larger bed (one case), making changes in their bedroom (77 cases) such as removing or protecting the nightstand or other pieces of furniture with hard surfaces and sharp corners (23 cases), installing bed rails (15 cases), placing cushions, pillows, blankets, teddy bears, or a mattress on the floor adjacent to the bed (13 cases), using pillows, wooden screens, or chair barricades to separate the patient from the spouse, the wall, or the nightstand (12 cases),
tying the hands into bed with ropes or straps (four cases), and wearing self-made padded gloves (one case).
Dream Recall (Tables 2 and 3)Fifteen patients (7.4%) did not recall unpleasant dreams. The remaining 188 patients (92.6%) reported nightmares, which were vivid, intense, and negatively toned. Most common night-mares included violence or stressful situations such as fighting (76.8%), arguing (63.5%), and being chased (55.7%) by an imag-inary aggressor, usually unfamiliar people (e.g., strangers with a blurred face) or frightening animals. Patients were always involved in the nightmare, fighting back vigorously defending themselves or protecting their loved ones from a physical at-tack or, less frequently, from a humiliation. Nightmares often contained settings and activities related to the patients’ past. Dreaming about playing sports included aggressive behaviors (e.g., kicking the opponent while playing football) or an ex-citing emotional component (e.g., “I was playing football and I scored a beautiful Chilena-goal”, “I was playing football and I desperately asked Messi -the famous Barcelona team football player- to pass me the ball”). Some patients, however, recalled enjoyable and funny dreams (e.g., “playing cards”, “friends telling jokes”) whereas the bed partner noted that the sleeper was laughing. Dreams did not include bizarre elements, situa-tions, settings, or characters, and did not express concerns or worries about the patients’ daily life, or references to friendli-ness, sexual interactions, or respiratory events (e.g., choking or drowning in the sea).
Table 3—Examples of dream content and related dream-enacting behaviors and vocalizations.
Patient (age/sex) Dream Content Related BehaviorsMale, 65 y Lions were attacking him He roared loudly and woke upMale, 62 y Unknown people were robbing him He punched, hit the wardrobe, and broke his carpusMale, 63 y Someone was chasing him and he jumped into a river to
escapeHe jumped out of the bed
Male, 70 y He ran and killed a wild boar He kickedFemale, 72 y Her grandson died She screamed and cried and woke up with tears in her eyesMale, 79 y He was fighting against an intruder He pulled his wife’s hairFemale, 62 y She was caught and fought back She bit her husbandMale, 78 y A ship left with his files and he jumped to the sea He jumped out of the bedMale, 78 y Playing football; he kicked the ball He kicked and hit the wallMale, 57 y His granddaughter was drowning in the swimming pool and
he jumped into the water to save her He jumped out of the bed
Male, 70 y A dog was chasing him He screamedMale, 64 y A train was about to run over him He jumped out of the bedFemale, 64 y Someone put a straitjacket on her She struggled to take off her pajamas while kickingMale, 63 y A dog was attacking him He said “a dog wants to eat me”Male, 73 y Four men were raping his wife and daughters He hit the nightstand Male, 71 y He was playing dominoes with his friends and shuffling the
domino pieces at the tableHe moved his hands in a shuffling motion
Male, 63 y He was catching crabs at the seaside He was moving his arms under the bed as if looking for something
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Twenty-eight subjects (13.8%) avoided watching thrillers and action films on television fearing that they may trigger nightmares that could lead to violent behaviors during their sleep. One hundred thirty subjects (69.1%), though, reported sleeping well despite recalling nightmares.
Sex Differences (Table 4)When compared to women, men displayed more frequently aggressive behaviors (e.g., punching, assaulting the bed partner) and vocalizations (e.g., swearing), recalled more violent and action-filled dreams (e.g., fights, arguments, sports) and were more likely to have a bed partner. When com-pared to men, women dreamed more commonly about children in life-threating situations and had depression more commonly. Of the 48 patients receiving a diagnosis between 1990 and 2003, only five (10.4%) were women. The proportion of women increased to 23.2% during the period 2004–2014 (Figure 2).
Polysomnographic ConfirmationAt the time of baseline V-PSG study, 22 pa-tients (10.8%) were receiving antidepressants that could not be withdrawn because of severe depression (n = 21) or severe bipolar disorder (n = 1). In these patients, as mentioned previ-ously, development of RBD symptoms was not related to the introduction of antidepressants. Four patients taking clonazepam and one taking melatonin refused to withdraw these medica-tions before baseline V-PSG. However, despite the use of clonazepam and melatonin the diag-nosis of RBD could be made in these five indi-viduals because V-PSG showed clear REM sleep with increased EMG activity associated with vigorous behaviors.
To confirm the diagnosis of IRBD a second V-PSG study had to be done in 32 (15.8%) pa-tients. In 17 of these 32 patients (six of them were taking antidepressants) REM sleep was not recorded (n = 11) or we judged that there was not sufficient REM sleep time to assess if they had RBD (n = 6). In five additional patients, de-spite a compelling clinical history of IRBD and having sufficient REM sleep time (range, 15 to 119 min), increased EMG was not seen in REM sleep and typical RBD behaviors were not cap-tured. In these five cases, a second V-PSG study confirmed the occurrence of IRBD showing excessive EMG activity linked to kicking and prominent body jerking in REM sleep. In seven additional patients we were not able to evaluate the EMG activity in REM sleep because of fre-quent EMG artifacts from apneic events. In the three remaining patients technical problems did not allow REM sleep to be evaluated properly.
Table 4—Differences between men and women with IRBD.
Men(n = 162)
Women (n = 41) P
Age at IRBD diagnosis (y), mean ± SD 68.6 ± 6.1 68.8 ± 6.7 0.825RBD duration (y), mean ± SD 10.2 ± 6.4 9.9 ± 7.2 0.138RBD follow-up duration (y), mean ± SD 5.7 ± 4.3 4.3 ± 3.1 0.096Depression 34 (21.0) 26 (63.4) < 0.001Presence of a bed partner 145 (89.5) 26 (63.4) < 0.001Self-awareness of sleep behaviors 92 (56.8) 21 (51.2) 0.521Motor behaviors
Punching 146 (90.1) 31 (75.6) 0.013Kicking 136 (84.0) 30 (73.2) 0.110Falling out of bed 123 (75.9) 34 (82.9) 0.339Gesturing 114 (72.2) 34 (82.9) 0.159Knocking down the night stand 110 (68.3) 25 (61.0) 0.372Sitting up in the bed 49 (34.5) 23 (59.0) 0.006Getting out of bed 42 (25.9) 7 (17.1) 0.237Assaulting bed partner 42 (27.3) 2 (4.9) 0.002Biting 14 (9.2) 3 (7.3) 0.712
Measures of self-protection 86 (53.1) 22 (53.7) 0.948Patients injured 93 (57.4) 26 (63.4) 0.485Bed partners injured 36 (22.2) 7 (17.1) 0.471Vocalizations
Talking 154 (95.1) 40 (94.6) 0.487Screaming 143 (88.3) 40 (97.6) 0.075Moaning 103 (66.5) 27 (65.9) 0.943Laughing 89 (55.3) 20 (48.8) 0.456Crying 68 (42.8) 21 (51.2) 0.332Swearing 71 (44.4) 8 (19.5) 0.004Singing 24 (15.2) 7 (17.1) 0.767
Dream contentUnpleasant dream recall 99 (61.1) 29 (70.1) 0.491Attacked by someone 133 (82.6) 23 (56.1) < 0.001Arguing with someone 111 (68.9) 18 (43.9) 0.003Chased by someone 87 (55.1) 26 (63.4) 0.336Falling from a cliff 71 (44.7) 26 (63.4) 0.032Attacked by an animal 66 (41.5) 15 (36.6) 0.567Action-filled sports 32 (20.4) 0 0.002Children in a life-threatening situation 13 (8.0) 13 (31.7) < 0.001Treated with clonazepam 131 (80.9) 36 (87.8) 0.299Completely successful therapy with clonazepam
77 (47.5) 15 (36.6) 0.208
RBD follow-up duration in patients in whom the condition was diagnosed after 2003 (y), mean ± SD*
4.0 ± 3.1 3.7 ± 2.6 0.871
Development of a defined neurodegenerative syndrome in patients in whom IRBD was diagnosed after 2003*
26 (21.8)PD = 5
DLB = 14MCI = 7
4 (11.1)PD = 1
DLB = 1MSA = 1MCI = 1
0.153
Values presented as n (%) unless otherwise indicated. *Of the 48 patients in whom IRBD was diagnosed between 1990 and 2003, 43 were men, and only five (10.4%) were women. Of these five women, a defined neurodegenerative syndrome developed in three after a median follow-up of 9.62 y (range, 3–10 y). In 36 of the 43 men, a defined neurodegenerative syndrome was diagnosed after a median follow-up of 5.26 y (range, 0.5–15 y) years. SD, standard deviation.
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Among these 32 subjects, a second V-PSG study confirmed IRBD in 26. The remaining six patients (3.0%) had to undergo a third V-PSG study because in the two previous studies there was not sufficient REM sleep time (n = 3, two of them were still taking antidepressants) or REM sleep was interfered by EMG artifacts from apneic events during both baseline and CPAP titration studies (n = 3). In all six patients, this third V-PSG confirmed IRBD.
At presentation, 21 patients were under CPAP therapy be-cause of a previous diagnosis of obstructive sleep apnea. During follow-up visits we prescribed CPAP to 28 additional subjects (14.9%) because baseline V-PSG showed an increased apnea-hypopnea index.
Therapy for RBD SymptomatologyBefore referral, physicians treated patients’ dream-enacting behaviors with clonazepam (n = 26), other benzodiazepines (n = 14), antiepileptic drugs (n = 4, phenobarbital, lamotrigine, carbamazepine, and oxcarbamacepine), dopaminergic agents (n = 3, levodopa/carbidopa, ropinirol, and pramipexol), zolp-idem (n = 2), melatonin (n = 1), haloperidol (n = 1), and imipra-mine (n = 1). Only patients taking clonazepam and melatonin reported a sustained therapeutic benefit with these compounds. With the exception of clonazepam and melatonin, we discon-tinued all these medications after we made the formal diag-nosis of IRBD with V-PSG.
After the diagnosis of IRBD was made, we prescribed clon-azepam to 167 patients (82.3%). The mean clonazepam effec-tive dose was 1.0 ± 0.8 mg (range, 0.25–4), and treatment was considered completely successful in 92 (55.1%), partially suc-cessful in 52 (31.1%), and unsuccessful in 4 (2.4%). We have no information concerning the effect of clonazepam in 19 patients.
In 36 patients (17.7%), we initially considered it not necessary to start treatment because patients and bed partners judged the clinical RBD severity to be mild (according to the estimated frequency and intensity of the reported dream-enacting behav-iors and recalled nightmares). Follow-up showed that lack of treatment in these 36 patients resulted in sleep related injuries in 11 patients and in 5 bed partners. During follow-up, the pro-portion of sleep related injuries was more frequent in those who did not received treatment than in those that were treated with clonazepam (36.1% versus 8.4%, P < 0.001).
Sixty-five patients (38.9%) experienced side effects related to clonazepam, including morning sedation (n = 35), dizziness (n = 9), sexual impotence (n = 7), urinary incontinence (n = 5), and others effects (e.g., fatigue, malaise, heartburn, dyspepsia, constipation). Clonazepam had to be withdrawn in 15 patients (9.0%) due to these adverse effects.
Thirty-two patients (15.7%) were treated with melatonin. Clonazepam was replaced by melatonin in eight subjects who experienced side effects. Melatonin was added to clon-azepam in 24 patients in whom clonazepam dose had to be reduced due to side effects or in whom clonazepam was not successful. Of the eight patients taking only melatonin, the median dose was 6 mg (range, 1.9–9 mg), and it was consid-ered partially successful in one patient and unsuccessful in four. In the three remaining patients we have no information regarding the effect on taking only melatonin. The only side
effect reported related to melatonin was morning sedation in one subject.
In patients with concomitant obstructive sleep apnea syn-drome, 23 of 49 subjects (46.9%) who received treatment with CPAP reported mild to moderate decrease (but not elimina-tion) of the frequency and severity of unpleasant dreams and abnormal sleep behaviors.
Phenoconversion to a Neurodegenerative DiseaseSixty-nine patients (34.0%) received a diagnosis of defined neurodegenerative syndrome after a median follow-up of 5 y. Emerging disorders were DLB (n = 32), PD (n = 22), MSA (n = 2), and MCI (n = 13). Details and risk of conversion to a defined neurodegenerative syndrome for most patients were previously described in previous other studies.13,14
Among the subjects in whom IRBD was diagnosed during the period 2004–2014, the frequency of patients receiving a di-agnosis of a defined neurodegenerative syndrome was similar between men and women (Table 4). During the period 1990–2003 there were 43 men and five women. Of these five women, PD developed in three, and one died and one was lost both with the diagnosis of IRBD at their last visit. Among the 43 men, 36 (83.7%) received a diagnosis of defined neurodegenerative syndrome (DLB in 17, PD in 13, MSA in one and MCI in five), five remained idiopathic, and one died and one was lost both with the diagnosis of IRBD at their last visit.
A substantial proportion of patients presenting with un-common IRBD features also converted to a defined neu-rodegenerative syndrome. Of the 23 subjects in whom dream-enacting behaviors were not the initial complaint at referral, nine (39.1%) had an eventual diagnosis of PD (n = 5), DLB (n = 2), MSA (n = 1), or MCI (n = 1). In two of the six patients (33.3%) who estimated the onset of RBD associated with a life event, a neurodegenerative disease developed (PD in one and DLB in one).
Of the 49 subjects who reported leaving the bed at night, 20 (40.8%) eventually received a diagnosis of defined neuro-degenerative syndrome (DLB in 14, MCI in three, and PD in three). Three of the seven who reported leaving the bedroom received a diagnosis of MCI (n = 2) and DLB (n = 1). Of the three patients who reported leaving the house, DLB developed in two and one died with the diagnosis of IRBD at his last visit. Of the 69 patients in whom a defined neurodegenerative syndrome developed, DLB or MCI were more likely to develop than PD in those who left the bed (P = 0.043).
Among the 53 patients who were taking antidepressants at presentation, 12 (22.6%) later received a diagnosis of DLB (n = 5), PD (n = 4), MCI (n = 2), and MSA (n = 1), and the remaining 41 subjects remained idiopathic. In 22 of these 53 patients, antidepressants could not be withdrawn at the mo-ment of the baseline V-PSG. Of these 22, nine (44.1%) reported that IRBD symptoms were initiated by a median of 5 y (range, 1–13 y) before the introduction of antidepressants. The other 13 patients (55.9%) reported that the start of antidepressant therapy antedated by a mean of 9 y (range, 1–37 y) the onset of IRBD. Of these 13, follow-up showed that in four patients RBD symptoms persisted when antidepressants were with-drawn after the resolution of depression (in two of these four
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subjects, a new V-PSG without taking antidepressants showed the persistence of RBD). Follow-up of the remaining nine pa-tients showed that two died with the diagnosis of IRBD at their last visit, MCI developed in one, and six remained idiopathic after a median follow-up of two y (range, 0.5 to 6 y). These six patients were three men and three women, had a median age at IRBD diagnosis of 67.5 y (range, 58–85 y), had the diagnosis of major depression (n = 5) and bipolar disorder (n = 1), and were treated with citalopram (n = 3), venlafaxine (n = 1), clomip-ramine (n = 1), and mirtazapine (n = 1).
Of the five patients who had no abnormal sleep behaviors in baseline V-PSG (but were demonstrated in a second study confirming RBD), DLB developed in one, MCI developed in one, and three remained idiopathic.
DISCUSSIONTo the best of our knowledge, this is the largest series evalu-ating the clinical features of patients with the idiopathic form of RBD. Previous publications describing the clinical charac-teristics of IRBD were either much smaller, included heteroge-neous samples of patients with IRBD combined with secondary to neurological disorders, lacked confirmation of RBD with V-PSG, or were multicenter. Other publications focused in a single aspect of IRBD (e.g., age of symptom onset, dream con-tent) and did not cover the full clinical phenotype, as we did.
The current work represents the characterization of 203 con-secutive patients who received a diagnosis over a 24-y period. In addition to the already known profile, we have noticed the following findings that were not reported or were not suffi-ciently emphasized in previous publications: (1) an important proportion of IRBD patients report good sleep quality and is unaware of their nocturnal movements and vocalizations; (2) bed partners are essential to describe the behaviors and to con-vince their spouses to seek medical consultation; (3) the occur-rence of IRBD can be elicited by specific questioning in some individuals referred for other problems; (4) leaving the bed and even walking may occur and appears to entail an increased risk for DLB; (5) some patients do not recall unpleasant dreams; (6) in some cases the correct diagnosis of IRBD cannot be made by a single V-PSG study; (7) even though the severity of IRBD symptoms may appear mild by clinical history, there is still an important risk of injuries if the parasomnia is left untreated; and (8) CPAP may improve (but not eliminate) IRBD symp-tomatology in subjects with comorbid obstructive sleep apnea.
Reasons for ReferralOnly 23.6% of the patients were referred between 1990 and 2003, when IRBD was unknown among the majority of physi-cians. We noted that during this first period, neurologists and general practitioners treated IRBD symptoms before referral with either antiepileptic drugs (because dream-enacting be-haviors were misinterpreted as being seizures) or with ben-zodiazepines (because doctors assumed that dream-enacting behaviors were simply indicative of poor sleep quality). The majority of the patients, though, presented between 2004 and 2014. This may be explained by several factors, including (1) an increased knowledge of the clinical importance of sleep dis-orders, (2) an increasing body of knowledge about IRBD and
its clinical relevance among members of the medical profes-sion, particularly neurologists and sleep specialists, (3) recog-nition by physicians from Barcelona city and province that our sleep center was capable and keen to make diagnoses, evaluate, and follow-up IRBD cases, and (4) coverage by the media of some of our publications. Overall, these factors could explain why in the period 2004–2014, referral physicians treated their patients with clonazepam (the first- line therapy for RBD) and more patients were identified. Despite these factors, underdi-agnosis persists in most of the individuals in the general popu-lation with IRBD.10
The median interval between estimated onset of IRBD symptoms and medical consultation was 4 y. A large group of patients were aware of their sleep behaviors but they con-sidered them nonpathological or not severe enough to require medical consultation. Failure to recognize IRBD manifes-tations as pathological can be attributed to mild severity of the symptoms in some patients who were not concerned by their injury potential, and the belief that their dream-enacting behaviors constitute a normal phenomenon. Many patients believed that dream-enacting behaviors were a benign phe-nomenon and decided to seek medical advice only when these behaviors became violent, resulted in injuries, lasted for sev-eral years, and did not resolve with time. In many instances, the insistence of the bed partner was crucial to convince their spouses (particularly to those patients who were completely unaware of their actions) to consult a doctor. This is important to recognize when using self-administered questionnaires for IRBD screening.
In some individuals, a history of dream-enacting behav-iors was elicited only upon specific questioning when they presented because of other symptoms. This finding was also noted in another study where only one of 11 IRBD patients was referred because of suspected parasomnia.42
It is thought that in the general population there is a group of individuals with a mild form of IRBD who are not likely to seek medical help.4 Interestingly, eight of our 23 patients in whom a RBD history was not a spontaneous complaint were some years later diagnosed with PD, DLB or MCI. This is in agreement with several studies showing that the majority of the PD patients (in whom RBD preceded parkinsonism) did not seek medical attention because of dream-enacting behav-iors prior to their diagnosis of PD.5,22,43 It appears that patients with milder forms who do not seek medical attention for IRBD are also at high risk for development of a neurodegenerative disease.
Gender DifferencesOur work confirms previous reports showing that patients in whom IRBD is diagnosed in a sleep center are predominantly men.2,3,14,15,25,26 It is unclear why men predominate in IRBD. A plausible explanation is a referral bias. In our study the clinical expression in men was more violent than in women, with men displaying more vigorous sleep behaviors and recalling more aggressive and action-filled dreams. Because sex hormones are normal in men with IRBD,44 our data are in line with the hypothesis that IRBD manifests differently in men and women, making men more prone to seek medical attention.45–47 This
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difference may have a biological basis, because males show more physical aggressiveness than females in most mammalian species.48,49
Age at OnsetThe minimum age at estimated IRBD onset was 40 y and the minimum age at diagnosis was 50 y. This is in concordance with studies showing that individuals younger than 50 y in whom RBD was diagnosed, they do not have an idiopathic condition. These subjects have secondary forms of RBD as-sociated with narcolepsy, parasomnia overlap disorder or the introduction of antidepressants.4 In people younger than 40 y, the underlying conditions of severe dream-enacting behaviors are sleepwalking, sleep terrors, frontal lobe epilepsy, dissocia-tive states, and malingering, but not idiopathic RBD.4
Dream Content and EnactmentOur data are in agreement with previous series showing that dream content ranges from frightening to funny and that dream-enacting behaviors may be nonviolent and elaborated or violent, leading to injuries and requiring measures of pro-tection.50–52 However, we noted that despite this impressive clinical picture, IRBD seems not to disrupt sleep quality be-cause an important number of patients are unaware of their actions and report good sleep quality. This might be explained by several factors including that sleep architecture is not im-portantly disrupted,30 abnormal behaviors are usually brief, and that IRBD is characterized by an important night-to-night variability where patients can spend nonviolent RBD nights.
IRBD activities were mainly confined to the bed. However, 49 patients left the bed, with some leaving the room and even the house. Although these behaviors were only displayed once or twice within several years of RBD history, our data indicate that ambulation does not exclude the occurrence of IRBD.53,54 We found that a neurodegenerative disease linked to cognitive impairment (DLB and MCI) with time was likely to develop in these patients. More common causes of nocturnal wandering were excluded in all 49 IRBD subjects. However, it is impos-sible to know if these episodes of ambulation in our IRBD sub-jects represented RBD episodes or confusional awakenings in subjects with predementia. In all our patients with comor-bidities that may mimic RBD symptoms (e.g., sleepwalking, obstructive sleep apnea, epilepsy) V-PSG demonstrated frank RBD and did not show NREM sleep parasomnia episodes, sei-zures, or epileptiform activity.51,52,54,55
In our series, none of the violent sleep behaviors and injuries led to forensic or medical-legal consequences, although this has been reported in IRBD.56
Previously Unnoticed or Not Sufficiently Emphasized Clinical FeaturesThey included onset of IRBD associated with a life-event epi-sode,4,57 perceiving good sleep quality, lack of dream recall, nocturnal ambulation, and coexistence with previous diagnosis of sleepwalking and epilepsy.58 These features complement the full characterization of the IRBD clinical phenotype. Follow-up of the patients with these features showed that PD and DLB developed in an important number of them, indicating that the
diagnosis of IRBD that we made was correct. This also sug-gests that the development of a neurodegenerative disease is independent of the clinical presentation of IRBD.
The Role of AntidepressantsMedications, especially antidepressants, are associated with RBD.59 It is still unclear if antidepressants can trigger the clinical manifestations of RBD in the setting of a latent neuro-degenerative process. When patients report a clear temporal as-sociation between the introduction of an antidepressant and the onset of RBD, the sleep disorder is considered secondary.27–29 Alternatively, when the antidepressant is not temporally as-sociated with the onset of RBD, the sleep disorder is labeled as idiopathic.27–29 However, it is possible that in some patients taking antidepressants for years a hypothetically cumulative effect of the drug might be responsible for precipitating the onset of RBD. We identified a small group of six elderly pa-tients with severe affective disorders who might belong to this category where V-PSG could not be performed without with-drawing antidepressants. These six individuals have remained idiopathic after a median follow-up of two (range 0.5 to 6) y. Longer follow-up, neuroimaging data, and postmortem neuro-pathology of these subjects are needed to elucidate this aspect.
PSG ConfirmationIn all 203 cases, V-PSG revealed REM sleep with increased EMG activity linked to abnormal behaviors. In 15.7% of the patients, baseline V-PSG was not confirmatory of RBD mainly because sufficient REM sleep was not achieved (probably due to the use of antidepressants or due to the first-night effect), and because artifacts from untreated obstructive sleep apnea did not allow evaluation of EMG activity. When we stopped the use of antidepressants and provided therapy with CPAP, the diagnosis of IRBD could be performed with a second V-PSG study. In addition, in four IRBD patients baseline V-PSG was not definitive to confirm the occurrence of IRBD because it showed lack of frank behavioral motor and vocal manifesta-tions. A second study, though, confirmed IRBD in these four cases. This suggests an important night-to-night variability in the clinical manifestations of IRBD that in some cases may require a second confirmatory study.60–62
Therapy for RBD SymptomatologyClonazepam was used in the first article formally describing human IRBD in 19861 and is currently considered the first-line therapy for this parasomnia.35,63,64 We noted that clonazepam was very effective and relatively well tolerated, and therefore we still decide to use it as a first choice even though melatonin was first reported to be effective in 1997.65
Half of our subjects with comorbid obstructive sleep apnea reported that CPAP therapy improved (but not resolved) their IRBD symptomatology before the introduction of clonazepam or melatonin. This is in agreement with the description that patients with obstructive sleep apnea may experience the same dream-enacting behaviors and disturbing dreams that those with confirmed IRBD.55 Thus, it seems that the coexistence of obstructive sleep apnea may aggravate the typical RBD symptoms of subjects with confirmed IRBD. The reported
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partial improvement with CPAP might result from a decrease in dream recall and subsequently a reduction in dream-enacting behaviors.66
Strengths and LimitationsStrengths of the current study are the large number of indi-viduals receiving a diagnosis over a long period of time and that inclusion criteria were restrictive, requiring both clinical history and V-PSG confirmation of abnormal REM sleep be-haviors linked with increased EMG activity. Some limitations should be noted. First, because the study is retrospective com-plete information was not available in some instances. Second, dream content was assessed through a semistructured inter-view and not through systematic analyses.67 Finally, most cases presenting to our sleep center may be more likely to suffer the most severe form of IRBD. Thus, some of our findings may not be generalizable to all IRBD patients in the community.
CONCLUSIONSIn summary, we have identified several aspects in IRBD that should not be missed by the general physician, neurologist, and the sleep specialist when facing a subject presenting with dream-enacting behaviors. We believe that our study helps to better characterize and recognize the full clinical spectrum of IRBD, a condition that currently is considered a specific marker of PD and DLB. Education of the general population and phy-sicians on the characteristics and importance of IRBD would improve early detection of this condition. This will be of great interest when neuroprotective strategies become available.
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44. Iranzo A, Santamaria J, Vilaseca I, Martinez de Osaba MJ. Absence of alterations in serum sex hormones levels in idiopathic REM sleep behavior disorder. Sleep 2007;30:803–6.
45. Tatman JE, Sind JM. REM behavior disorder manifests differently in women and men. Sleep Res 1996;25:380.
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47. Bjonara KA, Dietrichs E, Toft M. REM sleep behavior disorder in Parkinson’s disease-Is there a gender difference? Parkinsonism Related Disord 2013;19:120–2.
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49. Kalin NH. Primate models to understand human aggression. J Clin Psychiatry 1999;60:29–32.
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SUBMISSION & CORRESPONDENCE INFORMATIONSubmitted for publication May, 2015Submitted in final revised form August, 2015Accepted for publication August, 2015Address correspondence to: Alex Iranzo, Neurology Service, Hospital Clinic de Barcelona, C/ Villarroel 170, Barcelona 08036, Spain; Fax: 3493-227-5783; Email: [email protected]
DISCLOSURE STATEMENTThis was not an industry supported study. The authors have indicated no financial conflicts of interest. There was no off-label or investigational use.
48
TRABAJO NÚMERO 2.
Diagnostic value of isolated mentalis vs. mentalis plus
upper limb electromyography in idiopathic REM sleep
behavior disorder patients eventually developing a
neurodegenerative syndrome
Fernández Arcos, A., Iranzo, A., Serradell, M., Gaig, C.,
Guaita, M., Salamero, M., Santamaría, J.
SLEEP 2017; 40 (4).
https://doi.org/10.1093/sleep/zsx025
49
VALOR DIAGNÓSTICO DE LA ELECTROMIOGRAFÍA DE ÚNICAMENTE EL
MÚSCULO MENTALIS O VS. MÚSCULO MENTALIS COMBINADO CON
MÚSCULOS DE LAS EXTREMIDADES SUPERIORES EN PACIENTES CON EL
TRASTORNO DE CONDUCTA DE SUEÑO REM IDIOPÁTICO QUE
POSTERIORMENTE DESARROLLAN UN SÍNDROME NEURODEGENERATIVO
Objetivos del estudio: Comparar dos montajes
electromiográficos (EMG), el del músculo mentalis frente a
la combinación del mentalis junto a músculos de extremidades
superiores en el diagnóstico video-polisomnográfico (V-PSG)
de pacientes con trastorno de conducta de sueño REM
idiopático (TCSRI) que posteriormente fueron diagnosticados
de un síndrome neurodegenerativo clínicamente definido.
Métodos: Se incluyeron 49 pacientes. El diagnóstico de TCSR
se basó en la historia típica de este trastorno y el V-PSG
demostrando un sueño REM con incremento cualitativo de la
actividad EMG y/o conductas anormales detectadas en el
registro audiovisual. La cuantificación de la actividad EMG
(tónica, fásica y “la combinación de tónica y fásica”) en el
músculo mentalis y en extremidades superiores (bíceps
braquial-BB, n=36 o flexor superficial de los dedos-FSD,
n=13) se realizó manualmente y se comparó con los puntos de
corte conocidos.
Resultados: Nueve (18.4%) pacientes presentaron actividad
tanto tónica como fásica por debajo de los puntos de corte
para el montaje de únicamente el músculo mentalis y cuatro
de ellos (11.1%) tuvieron además valores por debajo del punto
de corte para el músculo mentalis combinado con el BB. Los
13 pacientes estudiados con el FSD estuvieron por encima del
punto de corte de mentalis combinado con FSD. Para el
diagnóstico del TCSRI, la sensibilidad del montaje de sólo
el músculo mentalis fue de 81.6% y para la combinación del
músculo mentalis con los músculos de extremidades superiores
fue de 91.8% (p=0.03). El análisis audiovisual mostró
50
conductas anormales durante el sueño REM en los nueve
pacientes con valores por debajo de los puntos de corte.
Conclusión: La cuantificación de la actividad EMG en
extremidades superiores combinada con el mentalis aumenta la
capacidad de diagnosticar TCSRI cuando se compara con la
medición aislada del músculo mentalis. Detectar las
conductas anormales típicas durante el sueño REM con un
análisis audiovisual es fundamental para el diagnóstico de
TCSRI en paciente con valores EMG por debajo de los puntos
de corte.
1
pii: zsx025 http://dx.doi.org/10.1093/sleep/zsx025
Diagnostic Value of Isolated Mentalis—Fernández-Arcos et al.SLEEP, Vol. 40, No. 4, 2017
ORIGINAL ARTICLE
Diagnostic Value of Isolated Mentalis Versus Mentalis Plus Upper Limb Electromyography in Idiopathic REM Sleep Behavior Disorder Patients Eventually Developing a Neurodegenerative SyndromeAna Fernández-Arcos, MD1; Alex Iranzo, MD1; Mónica Serradell, BSc1; Carles Gaig, MD1; Marc Guaita, MD1; Manel Salamero, MD2; Joan Santamaria, MD1
1Neurology Service, Multidisciplinary Sleep Disorders Unit, Hospital Clinic de Barcelona, University of Barcelona Medical School, IDIBAPS, CIBERNED, Barcelona, Spain; 2Psychiatry Service, Multidisciplinary Sleep Disorders Unit, Hospital Clinic de Barcelona, University of Barcelona Medical School, IDIBAPS, Barcelona, Spain
Study Objectives: To compare two electromyographic (EMG) montages, isolated mentalis muscle versus mentalis in combination with upper limb muscles in the baseline diagnostic video-polysomnography (V-PSG) of patients with idiopathic REM sleep behaviors disorder (IRBD) who eventually were diagnosed with a clinically defined neurodegenerative syndrome.Methods: Forty-nine patients were included. At baseline, diagnosis of RBD was based on a typical history of dream enactment behaviors plus V-PSG showing REM sleep with qualitative increased EMG activity and/or abnormal behaviors. Quantification of EMG activity (tonic, phasic and “any”) in the mentalis and upper limb muscles (biceps brachii-BB, n = 36 or flexor digitorum superficialis-FDS, n = 13) was performed manually and compared with published cut-offs.Results: Nine (18.4%) patients had either tonic or phasic EMG below the cut-offs for the isolated mentalis and four of them (11.1 %) also had values below the cut-off for the mentalis combined with BB. All 13 patients recorded with the FDS were above the mentalis combined with FDS cut-off. For the diagnosis of IRBD, sensitivity of isolated mentalis was 81.6% and of the combination of mentalis plus upper limb muscles was 91.8% (p = .03). Audiovisual analysis showed abnormal REM sleep behaviors in all nine patients with values below the cut-offs.Conclusion: Quantification of EMG activity in the upper limbs combined with the mentalis increases the ability to diagnose IRBD when compared with the isolated measurement of the mentalis. Detection of typical abnormal behaviors during REM sleep with audiovisual analysis is essential for the diagnosis of IRBD in patients with EMG values below the published cut-offs.Keywords: Idiopathic REM sleep behavior disorder, electromyographic quantification, mentalis, upper limbs, flexor digitorum superficialis, biceps brachii.
INTRODUCTIONREM sleep behavior disorder (RBD) is a parasomnia character-ized by nightmares and repeated episodes of abnormal move-ments and vocalizations during REM sleep.1–3 An accurate diagnosis of RBD is particularly important in idiopathic RBD (IRBD) because the parasomnia usually heralds a defined neu-rodegenerative syndrome such as mild cognitive impairment (MCI), dementia with Lewy bodies (DLB), Parkinson disease (PD) or more rarely multiple system atrophy (MSA).4–7
Video-polysomnography (V-PSG) showing excessive amounts of sustained (tonic) or intermittent (phasic) electromy-ographic (EMG) activity during REM sleep is required for the diagnosis of RBD.2 The definition of what constitutes “exces-sive” EMG activity and the body muscles where it should be measured have been the focus of several studies.8–11
For the diagnosis of IRBD, quantification of EMG activity exclusively in the mentalis muscle is a common practice in many sleep centers since this muscle is routinely used for sleep scoring.12 Isolated quantification of EMG activity of the mentalis has good discriminative power8–10 and cut-off levels of 30% for tonic and 15% for phasic EMG activity have been proposed for the correct identification of IRBD.9 EMG recording of the mentalis, however, is prone to include breathing and snoring artifacts and may be atonic in epochs in
which abnormal behaviors typical of RBD occur only in the limbs.10,11 Therefore, investigators have examined additional muscles for the diagnosis of IRBD.11 The anterior tibialis has low discriminative power because this muscle in healthy peo-ple often shows benign distal movements which are not specific for RBD.9,10 In contrast, EMG activity in upper limb muscles, such as the flexor digitorum superficialis (FDS) or the biceps brachii (BB), in addition to the mentalis, has a high discrimi-native power11 when using cut-off levels of 31.9% and 21.8%, respectively.10
It is currently unclear which method of quantification is pref-erable to diagnose IRBD. Ideally, the optimal system would be the one that best identifies patients with IRBD. However, since there is not an independent marker or a gold standard for diag-nosis of IRBD other than V-PSG, there is some circularity in this issue: only subjects with high amounts of EMG activity in REM sleep are diagnosed with IRBD, whereas those with lower amounts (but displaying some typical RBD manifesta-tions in REM sleep) may not be diagnosed with the condition. For instance, one study using EMG quantification9 only in the mentalis found values within normal range in 11.8% of subjects diagnosed with IRBD using clinical history. Other studies have also found some overlap in the values of EMG activity between patients and controls.10,13 These observations indicate that there
Statement of SignificanceA correct diagnosis of idiopathic REM sleep behavior disorder (IRBD) is crucial because it carries a high risk of a neurodegenerative disease. Our study compares two currently used electromyographic montages, isolated mentalis versus mentalis combined with upper limb muscles in the baseline video-polysomnogram of IRBD patients who later developed a neurodegenerative syndrome. We found that the montage of mentalis combined with upper limbs identifies best patients with IRBD. However, video-recording of abnormal behaviors in REM sleep is essential to diagnose the condition in a small subset of patients with EMG values within the normal range.
These findings are relevant to increase the diagnostic accuracy of IRBD while using video-polysomnography.
2 Diagnostic Value of Isolated Mentalis—Fernández-Arcos et al.SLEEP, Vol. 40, No. 4, 2017
are patients with a clinical picture highly suggestive of IRBD that have EMG values within the proposed normal range of EMG activity during REM sleep.
One way to overcome these difficulties is to study patients that were diagnosed initially with IRBD and eventually devel-oped a defined neurodegenerative syndrome. Since IRBD in those patients was “per se” an early manifestation of the under-lying disease, it is reasonable to assume that their clinical pic-ture corresponded to “true” IRBD, no matter the quantity of EMG activity found in the baseline V-PSG study.
The aim of this study was to compare quantitative EMG measures between the isolated mentalis and the combination of the mentalis with upper limb muscles in the baseline diag-nostic V-PSG of IRBD patients who later developed a defined neurodegenerative syndrome. This would elucidate which EMG montage in PSG is more adequate for the diagnosis of IRBD.
METHODS
Patient SelectionWe selected all patients who were diagnosed with IRBD at the Hospital Clinic de Barcelona, Barcelona, Spain, from January 2000 to June 2015. Diagnosis of IRBD in our center required: (1) clinical history of dream-enacting behaviors; (2) V-PSG showing REM sleep with qualitative increased EMG activity and/or abnormal movements/behaviors in REM sleep; and (3) and absence of a defined neurodegenerative syndrome. We did not establish a minimal amount of EMG activity in REM sleep if clear dream-enactment behaviors typical of RBD (eg, prom-inent body jerking, punching, kicking, shouting) were detected during REM sleep in the videotape analysis. When the diag-nosis of IRBD was made, patients were clinically followed-up as previously described.5 We identified 49 patients who devel-oped a clinically defined neurodegenerative syndrome disease (PD, DLB, MCI or MSA) according to current criteria.14–17 In order for the scorer of EMG activity not to be influenced by the knowledge that the patients were diagnosed with a defined neu-rodegenerative syndrome, V-PSG studies from IRBD patients with similar age and gender distribution who remained dis-ease-free after at least 5 years of follow-up (n = 36) were also quantified. All the studies were anonymized and the scorer was blind for the outcome (converted to a defined neurodegenera-tive syndrome or remained disease-free). The results of EMG quantification of the patients who remained disease-free were not used in this study.
Exclusion criteria were treatment with antidepressants, mela-tonin and benzodiazepines (including clonazepam) at the time of the baseline V-PSG, and technical artifacts preventing proper EMG quantification. We did not exclude patients that showed mild to moderate obstructive sleep apnea in V-PSG but we care-fully excluded from quantification all REM sleep epochs with respiratory-related EMG increases (regular breathing, snoring or apnea/hypopnea-induced arousals). The ethics committee of Hospital Clinic of Barcelona approved this study.
Polysomnographic VariablesAll patients underwent a full-night PSG study with synchro-nized audiovisual recording with a digital polygraph (Deltamed, software version 1998, Paris, France). V-PSG included
electroencephalogram (EEG) (C3, C4, O1, and O2, referred to the contralateral ear; F3 and F4 were added in 2007), right and left electro-oculograms, surface mentalis EMG and right and left anterior tibialis EMG. From 2000 to 2007 we recorded upper limb EMG activity from right and left BB, and in the right and left FDS from 2007 to 2015.11 V-PSG also included electrocardiogram, nasal and oral air-flow assessment, thoracic and abdominal movement assessment, body position and meas-urement of oxyhemoglobin saturation.
Sleep stages were scored according to American Academy of Sleep Medicine12 criteria with allowance to score REM sleep despite excessive EMG activity in the mentalis muscle channel. The occurrence of the first rapid eye movement was used to determine the onset of a REM sleep stage. The end of a REM sleep stage was determined when either no REMs were detected in three consecutive minutes or an awakening, K complex, or spindles were observed.12 A new REM sleep stage was consid-ered when it occurred 30 minutes after the previous episode.
Analysis of EMG ActivityIn each V-PSG study, quantification of tonic, phasic, and “any” (either tonic or phasic) EMG activity was performed manually during REM sleep. EMG activity in REM sleep was quantified using 30-second epochs and 3-second miniepochs. All move-ment artifacts and increases in EMG tone due to arousals were excluded from analysis. A trained sleep scorer (AF) who was blinded to the patient’s outcome (converted to a defined neu-rodegenerative syndrome or remained disease-free) performed the EMG quantification. In doubtful cases, the recordings were reviewed and discussed with the rest of the team until agree-ment was reached.
The EMG activity was analyzed in all channels using a sam-pling rate of 256 Hz, a low-frequency filter at 10 Hz, high-fre-quency filter at 100 Hz, and a display sensitivity of 5 μV/mm. Impedances of surface EMG electrodes had to be lower than 10 kΩ. Tonic EMG activity was scored only in the mentalis muscle channel using 30-second epochs with a display sensitiv-ity of 5 μV/mm although in case of doubt a 3 μV/mm display and/or a ruler were used to better discriminate the signal ampli-tude. The reference background EMG signal was the lowest one recorded in the same REM sleep stage analyzed, or if contin-uous EMG activity in REM sleep occurred, the one recorded in the most stable and relaxed adjacent previous NREM sleep epochs.
Each epoch was scored as “tonic” in the mentalis when the increased sustained EMG activity was present in more than 50% of the total 30-second epoch duration with an amplitude of at least twice the background EMG activity or more than 10 µV. The periods of PSG shorter than a full 30-second epoch of sleep, mainly occurring at the end of each REM sleep stage, were not included in the analysis. The rate of tonic EMG activ-ity was calculated as the number of 30-second epochs with this EMG activity divided by the whole number of 30-second epochs during REM sleep.
Phasic EMG activity of three muscles (mentalis and either right and left BB or right and left FDS) was quantified during REM sleep. Each EMG channel was displayed isolated on the computer screen and scored independently from the other mus-cles. After the scoring of a muscle was completed, the process
3 Diagnostic Value of Isolated Mentalis—Fernández-Arcos et al.SLEEP, Vol. 40, No. 4, 2017
was repeated in the remaining two muscles. Phasic EMG events were defined as any burst of EMG activity lasting 0.1–5 sec-onds with an amplitude exceeding twice the background EMG activity during REM sleep. Each 3-second miniepoch in each EMG channel was scored as “0” when phasic EMG activity was absent and “1” when phasic EMG activity was present. Three-second miniepochs were also scored as having or not having “any” EMG activity, irrespective of whether it contained tonic, phasic or a combination of both types of EMG activity in the mentalis. The rates of phasic and “any” EMG activity in the mentalis were calculated as the proportion of 3-second minie-pochs during REM sleep containing the corresponding type of muscle activity. In the upper limbs only phasic EMG activ-ity was quantified and the proportion of 3-second miniepochs during REM sleep containing this type of EMG activity was calculated.
In addition, we scored the rates of “any” EMG activity in the mentalis associated with phasic EMG activity in the right and left upper limbs. In this EMG montage a 3-second miniepoch was computed as having EMG activity when at least one of the three muscles evaluated had EMG activity (at least one score of “1”), and as not having EMG activity when none of the muscles in the combination had “any” or phasic EMG activity measure.
Classification of Patients According to Different Cut-Offs and Emerging DiseaseWe identified the number of patients with EMG activity rates below previously published cut-offs for IRBD diagnosis. For the isolated mentalis muscle we used the cut-off of ≥30% for tonic EMG activity or ≥15% for phasic EMG activity, as refer-ence, as previously published.9 For the combination of menta-lis plus upper limb muscles we used the cut-off of ≥31.9% for “any” EMG activity in the mentalis with the right and left FDS (SINBAR montage) and of ≥21.8 % for “any” mentalis with the right and left BB.10
Video AnalysisWhen EMG measurements during REM sleep did not reach the previously published proposed cut-offs, we reviewed the video tapes of the same V-PSG studies to see if they contained the typical abnormal movements, behaviors and vocalizations dis-played by patients with IRBD during REM sleep. Visual anal-ysis was performed in conjunction with the PSG recording and the excluded epochs (due to respiratory events, eg,) during the quantification were also excluded from the video analysis. The intensity of these manifestations was classified as mild, moder-ate or severe according to a system previously described in our center.18
Statistical AnalysisDescriptive demographic, clinical and PSG data are given as mean ± standard deviations, counts and frequencies. Comparison of demographic variables between the group of patients who developed a defined a neurodegenerative syn-drome and those who remained idiopathic was done with a chi square test and T-Student, as appropriated. Comparison of rates of EMG activity between the different defined neurodegenera-tive syndromes was performed with T-Student. Since sensitivity of mentalis combined with upper limb muscles should ever be
equal or greater than the mentalis alone, comparison of sensi-tivities was done with unilateral binomial tests.
SPSS 19 for Windows (SPSS, Inc., Chicago, IL) was used for all statistical analyses.
RESULTS
Demographic, Clinical, and PSG DataWe studied 49 patients (43 men) with IRBD who later were diagnosed with a clinically defined neurodegenerative syn-drome (15 PD, 19 DLB, 2 MSA and 13 MCI) at the age of 73.6 ± 5.1 (range, 60–85) years and after a mean follow-up of 4.7 ± 3.1 years. Mean age at diagnosis of IRBD was 68.6 ± 5.3 years. There were no significant differences in demo-graphic variables between patients who developed a clinically defined neurodegenerative syndrome and those who remained disease-free (Table 1).
Polysomnographic data are shown in Table 2. A mean of 89.1 ± 42.9 epochs and 964.0 ± 444.6 3-second miniepochs of REM sleep were analyzed. The mean apnea/hypoapnea index (AHI) was 14.7 ± 16.2. Twenty-eight (57.1%) patients had AHI lower than 10. Six of these 28 were previously diagnosed with obstructive sleep apnea syndrome, were effectively treated with continuous positive airway pressure and wore the mask during their diagnostic V-PSG. Sixteen patients (32.6%) had an AHI greater than 15. Five of these 16 patients had apneas and hypopneas exclusively related to the supine position but REM sleep was recorded in the lateral position not containing respiratory-related arousals. Eleven (22.4%) patients had an AHI greater than 15 with a mean AHI during REM sleep of 32.5 ± 14.7 (range, 17.8–62.7). In these 11 patients, we care-fully excluded from EMG analysis the 30-second epochs and 3-second miniepochs containing respiratory related arousals or awakenings. The excluded epochs were 37.0 ± 18.9 % of the total epochs in REM sleep leaving 82.6 ± 24.5 epochs for analysis. The number of scored 30-second epochs and 3-sec-ond miniepochs was similar in the group of 11 patients with apneic events during REM sleep and the 38 remaining patients (82.6 ± 24.5 vs. 91.0 ± 47.0, p = .576 and 910.4 ± 247.2 vs. 979.5 ± 488.7, p = .655, respectively).
Quantification of EMG Activity and Audiovisual AnalysisRates of tonic, phasic and “any” EMG activity in individual and combined muscles are shown in Table 3.
Twenty-seven (55.1%) patients did not reach the ≥30% cut-off for tonic EMG activity in the mentalis and nine of them had values below the 15% cut-off for phasic EMG activity. Therefore, nine (18.4%) patients had “normal” values of EMG activity in the mentalis (Figure 1, Table 4). Evaluation of the audiovisual recordings of these nine patients during REM sleep showed abnormal manifestations typical of RBD that were clas-sified as mild in six patients, moderate in one and severe in two (Table 4). V-PSG also excluded RBD potential mimics (eg, severe obstructive sleep apnea, prominent periodic leg move-ments in sleep, NREM sleep parasomnias, nocturnal epilepsy) in these nine individuals.
Follow-up of these nine subjects showed that two eventually developed PD, three DLB and four MCI. The mean age at diag-nostic V-PSG in this group of nine patients was 69.7 ± 4.7 years,
4 Diagnostic Value of Isolated Mentalis—Fernández-Arcos et al.SLEEP, Vol. 40, No. 4, 2017
the mean estimated RBD duration was 7.4 ± 6.9 years and the mean number of scored 3-second miniepochs was 953.1 ± 256.4. All nine individuals were men and four (44.4%) were referred to our sleep center because of other sleep complaints and not because of the dream-enacting behaviors (two because unex-plained hypersomnolence and two for suspected obstructive sleep apnea). However, in these four patients specific question-ing during the semistructured sleep interview at their first visit demonstrated a concomitant chronic history typical of RBD.
In 36 (73.5%) patients the upper limb EMG activity was eval-uated in the BB and in the remaining 13 (26.5%) in the FDS. All the 13 patients who underwent V-PSG using the EMG SINBAR montage (mentalis plus bilateral FDS) had EMG values above the cut-off for the diagnosis of IRBD (≥31.9%; Figure 2a). Four (11%) of the 36 patients who underwent baseline V-PSG using the EMG montage of the mentalis plus bilateral BB had EMG values below the cut-off for the diagnosis of IRBD (≥21.8%; Figure 2b). All four subjects did not reach either the tonic (≥30%) or the pha-sic (≥15%) cut-offs values using only the mentalis. In all of them the audiovisual recordings showed abnormal manifestation typ-ical of RBD (Table 4). Follow-up of these four subjects showed that one eventually developed PD, one DLB and two MCI.
Overall, for the diagnosis of IRBD, quantification of EMG activity in the mentalis plus upper limb muscles had a sensitiv-ity of 91.8%, whereas the sensitivity for the isolated mentalis was of 81.6% (unilateral binomial test, p = .03).
The rates of tonic EMG activity (Table 5) in the mentalis muscle in the 15 patients who developed PD were significantly higher than those of the 32 patients that developed DLB or MCI or in the 19 who developed DLB. There were no signif-icant differences in the measurement of phasic EMG activity
Table 2—Polysomnographic Variables of the 49 Patients With IRBD Who Eventually Developed a Clinically Defined Neurodegenerative Syndrome.
Time in bed, min 464.5 ± 42.8
Total sleep time, min 345.3 ± 62.9
Sleep efficiency, % 74.4 ± 12.0
Wake after sleep onset, min 95.2 ± 58.0
Sleep stage, %
N1 22.3 ± 11.4
N2 44.0 ± 9.4
N3 15.1 ± 10.1
REM 15.6 ± 7.3
Sleep-onset latency, min 21.5 ± 14.1
REM sleep latency, min 114.7 ± 80.4
REM sleep stages, n 2.8 ± 1.0
30-s epochs, n 89.1 ± 42.9
3-s miniepochs, n 964.0 ± 444.6
AHI index 14.7 ± 16.2
PLMS index 18.7 ± 25.9
AHI = apnea-hypoapnea index (number of apneas and hypoapneas per hour of sleep); IRBD = idiopathic REM sleep behavior disorder; PLMS index = periodic leg movements in sleep (number of periodic leg move-ments in sleep per hour of sleep); REM = rapid eye movement. Values are expressed as mean ± standard deviation.
Table 1—Demographic Characteristics of IRBD Patients Who Developed a Clinically Defined Neurodegenerative Syndrome and Those Who Remained Idiopathic.
Demographic variables
N Not remained idiopathic Remained idiopathic p
49 36
Sex, male (n, %) 43 (87.8%) 26 (72.2%) .070
Age at estimated IRBD onset (years) 62.1 ± 5.6 61.5 ± 8.3 .702
(range, 50–73) (range, 44–77)
Interval from estimated IRBD onset to diagnosis of IRBD by V-PSG (years) 6.5 ± 5.5 5.1 ± 4.2 .192
(range, 1–25) (range, 1–20)
Age at IRBD diagnosis (years) 68.6 ± 5.3 66.7 ± 7.4 .157
(range, 56–78) (range, 49–79)
Follow-up (years)a 4.7 ± 3.1 7.9 ± 2.12 .001
(range, 0.5–12) (range, 5–13)
IRBD = idiopathic REM sleep behavior disorder; V-PSG = video-polysomnography. Values are expressed as mean ± standard deviation and range, frequency and percentage. V-PSG: polysomnography with audiovisual recording.aInterval from diagnosis of IRBD in our sleep center to diagnosis of a clinically defined neurodegenerative syndrome or to the last visit in those subjects who remained idiopathic.
5 Diagnostic Value of Isolated Mentalis—Fernández-Arcos et al.SLEEP, Vol. 40, No. 4, 2017
in the mentalis and in the measurement of combined “any” EMG activity in the mentalis with bilateral phasic BB between patients who developed PD and those who developed DLB or MCI or in the patients who developed DLB. There were not sufficient patients on the groups of each neurodegenerative syn-drome to compare the measurement of combined “any” EMG activity in the mentalis with bilateral phasic FDS.
DISCUSSIONWe have shown in this study including patients with IRBD who later develop a clinically defined neurodegenerative syndrome that the EMG recording of the upper limbs in addition to the mentalis
muscle is important for the correct identification of IRBD. If we had only used the mentalis we would have missed 18.4% of true IRBD patients. Our results support the concept that record-ing upper limb muscles increases the ability to identify IRBD by V-PSG. This may be in part due to the fact that the mentalis do not detect epochs when the patient displays abnormal behaviors involving only the limbs and not the head, which is a common sit-uation in RBD.11 A previous study showed that isolated recording of the mentalis does not capture 35.5% of the behavioral events seen or heard on video while simultaneous recording of mentalis, right and left FDS only misses 4.6% of 3-second miniepochs con-taining motor events or vocalizations.19
Table 3—Electromyographic Activity of the 49 Patients Who Eventually Developed a Clinically Defined Neurodegenerative Syndrome.
Muscle
Tonic EMG activity in the mentalis (%) 33.8 ± 33.8 (0–95.9)
Phasic EMG activity in the mentalis (%) 29.2 ± 15.3 (8.2–74.9)
“Any” EMG activity in the mentalis (%) 49.5 ± 28.1 (8.2–93.0)
Combined “any” EMG activity in the mentalis with bilateral phasic BB (%) (n = 36) 56.2 ± 27.2 (8.9–94.7)
Combined “any” EMG activity in the mentalis with bilateral phasic FDS (%) (n = 13) 67.4 ± 20.1 (37.8–96.3)
Phasic EMG activity in the right BB (n = 36) 17.2 ± 13.3 (1.3–52.3)
Phasic EMG activity in the left BB (n = 36) 17.0 ± 15.0 (0.5–56.3)
Phasic EMG activity in right FDS (%) (n = 13) 19.6 ± 13.7 (2.4–51.7)
Phasic EMG activity in left FDS (%) (n = 13) 20.3 ± 11.3 (4.4–41.3)
BB = biceps brachii; EMG = electromyography; FDS = flexor digitorum superficialis.Values are expressed as mean ± standard deviation and range.
Figure 1—Percentages of tonic EMG activity (1a) and phasic EMG activity (1b) in the mentalis of the 49 patients who eventually devel-oped a clinically defined neurodegenerative syndrome (horizontal bar indicates the previously published proposed cut-off of 30% and 15% respectively).9
6 Diagnostic Value of Isolated Mentalis—Fernández-Arcos et al.SLEEP, Vol. 40, No. 4, 2017
The EMG quantification of combined upper limbs and menta-lis muscles, as proposed by the SINBAR group,10,11 would have missed four (8.2%) IRBD patients. These four patients would
have not been qualified as having “excessive” EMG activity dur-ing REM sleep in any of the two EMG montages. In these four cases visualization of abnormal behaviors typical of RBD with
Figure 2—(2a) Percentages of “any” EMG activity in the mentalis plus phasic EMG activity in the bilateral flexor digitorum superficialis (FDS) of the 13 patients who eventually developed a clinically defined neurodegenerative syndrome using this EMG montage (horizontal bar indi-cates the previously published proposed cut-off of 31.9%) (2b) Percentages of “any” EMG activity in the mentalis plus phasic EMG activity in the bilateral biceps brachii (BB) of the 36 patients who eventually developed a clinically defined neurodegenerative syndrome using this EMG montage (horizontal bar indicates the previously published proposed cut-off of 21.8%).10
Table 4—Electromyographic Activity Measures and Audiovisual Findings in the Nine Patients Who Had Electromyographic Activity in the Mentalis Below the Proposed Cut-Offs for the Diagnosis of RBD.
Patient Emerging condition
Tonic EMG activity in the mentalis (%)
Phasic EMG activity in the mentalis (%)
“Any” EMG activity in the mentalis plus phasic EMG activity in upper limbs (%)
Severity and types of abnormal manifestations typical of RBD detected in the audiovisual recordings during REM sleepa
1 DLB 21.6b 8.6b 48.8 (BB) Moderate (upper limbs elevation with jerks)
2 MCI 3.7b 13.6b 44.0 (FDS) Severe (lower limbs kicking)
3 PD 2.3b 12.1b 28.4 (BB) Mild (proximal four limbs jerking)
4 MCI 0b 10.6b 25.9 (BB) Mild (proximal four limbs jerking)
5 DLB 1.0b 14.4b 22.9 (BB) Mild (proximal four limbs jerking)
6 DLB 3.8b 10.9b 17.6b (BB) Mild (lower limbs jerking and repetitive hand movements)
7 MCI 1.4b 10.8b 15.0b (BB) Mild (sudden moderate trunk and four limbs jerking)
8 PD 2.8b 8.7b 13.5b (BB) Mild (proximal lower limbs jerking)
9 MCI 0b 8.2b 8.9b (BB) Severe (repetitive lower limbs kicking)
BB = biceps brachii; DLB = dementia with Lewy bodies; FDS = flexor digitorum superficialis; MCI = mild cognitive impairment; MSA = multiple system atro-phy; PD = Parkinson disease; RBD = REM sleep behavior disorder. Values are expressed as percentages.aNone of the nine patients had vocalizations during the recording.bRates below the proposed cut-offs for the diagnosis of IRBD (the proposed cut-offs for the diagnosis of IRBD are the following: ≥30% for tonic EMG activity in the mentalis, ≥15% for phasic EMG in the mentalis, ≥21.8% for “any” EMG activity in the mentalis plus bilateral biceps brachii, and ≥31.9 for “any” EMG activity in the mentalis plus bilateral flexor digitorum superficialis).
7 Diagnostic Value of Isolated Mentalis—Fernández-Arcos et al.SLEEP, Vol. 40, No. 4, 2017
synchronized audiovisual recording was determinant for making the diagnosis of IRBD. This finding indicates that identification in REM sleep of behavioral abnormalities typical of RBD by audio-visual analysis in V-PSG is essential for the diagnosis of IRBD.
Abnormally increased EMG activity in the mentalis (both pha-sic and tonic) is considered an essential requirement in the diagno-sis of RBD.2 In our study, however, there were patients who later developed a defined neurodegenerative syndrome that clearly had very low levels of mentalis EMG activity and even in five cases tonic EMG activity was absent in any of the REM epochs ana-lyzed. Several factors can account for this observation. First, we cannot exclude that the rates of muscular activity in these sub-jects could be higher if a second V-PSG night would have been recorded (intra-individual night to night variability). Second, methodological aspects in the quantification of EMG activity may also be responsible of these variabilities (eg, using two or four times the background amplitude; using 2 or 3-second miniepochs for quantifying phasic activity; using 20 vs. 30-second epochs9,10; having an absolute amplitude criteria; or differences in defining the background for the tonic activity).9–11,20,21 Finally, it is also possible that there are true IRBD patients with a different pro-files showing low amounts of EMG activity in the mentalis dur-ing REM sleep. In fact, seven of the nine patients who had EMG activity below the cut-offs for the mentalis were later diagnosed with cognitive impairment (MCI or DLB). We have found in this study that IRBD patients who developed PD had higher amounts of tonic EMG activity in the mentalis than those who developed DLB or MCI. In line with this finding, another study20 reported that IRBD patients converting to PD had higher rates of tonic EMG activity in the mentalis than patients remaining disease-free.
Strengths of our study are the inclusion of a homogeneous group of subjects with IRBD who later developed a defined neurodegenerative syndrome, the fact that the scorer was blind to the condition of the subjects, that we included a detailed anal-ysis of the audiovisual recordings, and that we excluded indi-viduals who were treated with medications capable to modify the quantity of muscular activity during REM sleep. A possible limitation of this study was the inclusion of patients with mild to moderate sleep apnea. It is unknown if an elevated index of respiratory events interferes with the analysis of EMG activ-ity after arousals and respiratory-related EMG increases in the mentalis were carefully excluded from the measurements.9,22 Although the presence of apneic events during REM sleep might decrease the number of 30-second epochs and 3-second miniepochs available for analysis, we did not find, however,
differences in the duration of the REM sleep between patients with apneic events and those without them. Also, we cannot fully exclude that the evaluation of the FDS instead of the BB could have produced higher rates of EMG activity and reduce the number of false negatives, since all 13 patients evaluated with the FDS had values above the cut-offs.
In summary, this is the first study comparing two different manual EMG methods for the diagnosis of IRBD analyzing patients who eventually developed a clinical defined neurodegen-erative syndrome. We have been able to show that measurement of EMG activity in the upper limbs combined with the mentalis when compared with the isolated measurement of the mentalis increases the ability to diagnose IRBD. In addition, we found that detection with V-PSG of abnormal motor and vocal events during REM sleep in a patient with a history of dream-enacting behav-iors is determinant to perform the diagnosis of IRBD, particularly in those few cases with low levels of EMG activity in REM sleep.
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4. Schenck CH, Boeve BF, Mahowald MW. Delayed emergence of a parkinsonian disorder or dementia in 81% of older men initially diag-nosed with idiopathic rapid eye movement sleep behavior disorder: a 16-year update on a previously reported series. Sleep Med. 2013; 14(8): 744–748.
5. Iranzo A, Molinuevo JL, Santamaría J, et al. Rapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study. Lancet Neurol. 2006; 5(7): 572–577.
6. Postuma RB, Gagnon JF, Vendette M, Fantini ML, Massicotte-Marquez J, Montplaisir J. Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder. Neurology. 2009; 72(15): 1296–1300.
7. Iranzo A, Tolosa E, Gelpi E, et al. Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behav-iour disorder: an observational cohort study. Lancet Neurol. 2013; 12(5): 443–453.
8. Consens FB, Chervin RD, Koeppe RA, et al. Validation of a polysom-nographic score for REM sleep behavior disorder. Sleep. 2005; 28(8): 993–997.
9. Montplaisir J, Gagnon JF, Fantini ML, et al. Polysomnographic diagnosis of idiopathic REM sleep behavior disorder. Mov Disord. 2010; 25(13): 2044–2051.
Table 5—EMG Activity in Each Type of Emerging Disease.
PD (n = 15) DLB (n = 19) MCI (n = 13) p (PD vs. DLB) p (PD vs. DLB + MCI)
Tonic EMG activity in mentalis (%) 48.2 ± 36.5a 24.6 ± 25.4 27.2 ± 38.1 .036 .034
Phasic EMG activity in mentalis (%) 35.4 ± 19.4 26.5 ± 10.9 26.4 ± 16.0 .103 .069
Combined “any” EMG activity in mentalis with bilateral phasic BB (%) (n = 36)a
63.8 ± 31.4 (n = 11)
54.9 ± 20.2 (n = 16)
42.3 ± 34.0 (n = 7)
.377 .238
BB = biceps brachii; PD = Parkinson disease; DLB = dementia with Lewy bodies; MCI = mild cognitive impairment; EMG = electromyography. Values are expressed as mean ± standard deviation.aTwo patients were diagnosed with multiple system atrophy and are not shown in the table.
8 Diagnostic Value of Isolated Mentalis—Fernández-Arcos et al.SLEEP, Vol. 40, No. 4, 2017
10. Frauscher B, Iranzo A, Gaig C, et al.; SINBAR (Sleep Innsbruck Barcelona) Group. Normative EMG values during REM sleep for the diagnosis of REM sleep behavior disorder. Sleep. 2012; 35(6): 835–847.
11. Frauscher B, Iranzo A, Högl B, et al.; SINBAR (Sleep Innsbruck Barcelona group). Quantification of electromyographic activity during REM sleep in multiple muscles in REM sleep behavior disorder. Sleep. 2008; 31(5): 724–731.
12. Iber C. Ancoli-Israel S, Chesson A, Quan SF. AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications. 1st ed. Westchester, IL: American Academy of Sleep Medicine; 2007.
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SUBMISSION & CORRESPONDENCE INFORMATIONSubmitted for publication November, 2016Submitted in final revised form December, 2016Accepted for publication February, 2017Address correspondence to: Joan Santamaria, Neurology Service, Hospital Clinic de Barcelona, C/ Villarroel 170, Barcelona 08036, Spain. Telephone: 3493-227-5413; Fax: 3493-227-5783; Email: [email protected]
DISCLOSURE STATEMENT
None declared.
59
TRABAJO NÚMERO 3.
Neurodegenerative disorder risk in idiopathic REM sleep
behavior disorder: study in 174 patients
Iranzo, A., Fernández-Arcos, A., Tolosa, E.,
Serradell, M., Molinuevo, JL., Valldeoriola, F.,
Gelpi, E., Vilaseca, I., Sánchez-Valle, R., Lladó, A.,
Gaig, C., Santamaria, J.
PLoS ONE 2014;9(2): e89741.
doi:10.1371/journal.pone.0089741
60
RIESGO DE ENFERMEDAD NEURODEGENERATIVA EN PACIENTES AFECTOS
DEL TRASTORNO DE CONDUCTA DE SUEÑO REM IDIOPÁTICO: ESTUDIO
EN 174 PACIENTES
Objetivo: Calcular el riesgo de ser diagnosticado de una
enfermedad neurodegenerativa en una serie grande de
pacientes con trastorno de conducta de sueño REM idiopático
(TCSRI) con un seguimiento largo.
Métodos: Con el método Kaplan-Meier, calculamos el riesgo de
la tasa de supervivencia (libre de enfermedad
neurodegenerativa) en todos los pacientes diagnosticados y
seguidos en nuestra unidad de trastornos de sueño entre
noviembre de 1991 y julio de 2013.
Resultados: La muestra incluye 174 pacientes con una mediana
de edad al diagnóstico del TCSRI de 69 años y una mediana de
seguimiento de cuatro años tras el diagnóstico. El riesgo de
de ser diagnosticado de una enfermedad neurodegenerativa
tras el diagnóstico de TCSRI fue del 33.1% a los cinco años,
75.7% a los diez años y del 90.9% a los 14 años. La mediana
de tiempo de conversión fue de 7.5 años. Los diagnósticos
que se establecieron (37.4%) fueron demencia con cuerpos de
Lewy (DCLw) en 29 pacientes, enfermedad de Parkinson (EP) en
22 pacientes, atrofia multisistémica (AMS) en dos, y
deterioro cognitivo leve (DCL) en 12. En seis casos en los
que se realizó autopsia, el estudio neuropatológico detectó
pérdida neuronal y cuerpos de Lewy.
Conclusiones: En una muestra grande de pacientes con TCSRI
y seguimiento clínico largo se observa que la mayoría de los
pacientes son diagnosticados con el tiempo de una
sinucleinopatía (EP, DCLw y con menos frecuencia AMS). El
TCSRI representa la fase prodrómica de las sinucleinopatías.
Nuestros hallazgos en TCSRI tienen implicaciones importantes
en la práctica clínica, en la investigación de los fenómenos
61
iniciales de las sinucleinopatías y en el diseño de ensayos
clínicos con medicaciones neuroprotectoras.
Neurodegenerative Disorder Risk in Idiopathic REMSleep Behavior Disorder: Study in 174 PatientsAlex Iranzo1,2*, Ana Fernandez-Arcos1, Eduard Tolosa1,2, Monica Serradell1, Jose Luis Molinuevo1,
Francesc Valldeoriola1,2, Ellen Gelpi3, Isabel Vilaseca4, Raquel Sanchez-Valle1, Albert Llado1,
Carles Gaig1,2, Joan Santamarıa1,2
1 Neurology Service, Hospital Clınic de Barcelona, IDIBAPS, Barcelona, Spain, 2 CIBERNED, Barcelona, Spain, 3 Neurological Tissue Bank, Biobanc-Hospital Clinic, IDIBAPS,
Barcelona, Spain, 4 Otorhinolaryngology Service, Hospital Clınic de Barcelona, CIBER Enfermedades Respiratorias, Bunyola, Spain
Abstract
Objective: To estimate the risk for developing a defined neurodegenerative syndrome in a large cohort of idiopathic REMsleep behavior disorder (IRBD) patients with long follow-up.
Methods: Using the Kaplan-Meier method, we estimated the disease-free survival rate from defined neurodegenerativesyndromes in all the consecutive IRBD patients diagnosed and followed-up in our tertiary referal sleep center betweenNovember 1991 and July 2013.
Results: The cohort comprises 174 patients with a median age at diagnosis of IRBD of 69 years and a median follow-up offour years. The risk of a defined neurodegenerative syndrome from the time of IRBD diagnosis was 33.1% at five years,75.7% at ten years, and 90.9% at 14 years. The median conversion time was 7.5 years. Emerging diagnoses (37.4%) weredementia with Lewy bodies (DLB) in 29 subjects, Parkinson disease (PD) in 22, multiple system atrophy (MSA) in two, andmild cognitive impairment (MCI) in 12. In six cases, in whom postmortem was performed, neuropathological examinationdisclosed neuronal loss and widespread Lewy-type pathology in the brain in each case.
Conclusions: In a large IRBD cohort diagnosed in a tertiary referal sleep center, prolonged follow-up indicated that themajority of patients are eventually diagnosed with the synucleinopathies PD, DLB and less frequently MSA. IRBDrepresented the prodromal period of these conditions. Our findings in IRBD have important implications in clinical practice,in the investigation of the early pathological events occurring in the synucleinopathies, and for the design of interventionswith potential disease-modifying agents.
Citation: Iranzo A, Fernandez-Arcos A, Tolosa E, Serradell M, Molinuevo JL, et al. (2014) Neurodegenerative Disorder Risk in Idiopathic REM Sleep BehaviorDisorder: Study in 174 Patients. PLoS ONE 9(2): e89741. doi:10.1371/journal.pone.0089741
Editor: Mathias Toft, Oslo University Hospital, Norway
Received December 30, 2013; Accepted January 22, 2014; Published February 26, 2014
Copyright: ! 2014 Iranzo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: No current funding sources for this study. Therefore, the (potential) funders had no role in study design, data collection and analysis, decision topublish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: [email protected]
Introduction
REM sleep behavior disorder (RBD) is a parasomnia charac-terized by dream-enacting behaviors associated with REM sleepwithout muscle atonia [1,2,3]. Longitudinal studies conducted insleep centers have shown that patients diagnosed with theidiopathic form of RBD (IRBD) may eventually be diagnosedwith a neurological disorder such as Parkinson disease (PD) anddementia with Lewy bodies (DLB) [4,5,6,7,8]. In a recent study weassessed the first 44 IRBD individuals diagnosed in our tertiaryreferral sleep center between 1991 and 2003 and found that after amedian follow-up of 10.5 years, 82% were diagnosed with PD,DLB and less frequently multiple system atrophy (MSA) and mildcognitive impairment (MCI). The estimated risk of definedneurodegenerative syndrome from the diagnosis of IRBD was34.8% at five years, 73.4% at ten years and 92.5% at 14 years [8].These findings, in a group of 44 individuals with long and closefollow-up, indicate that most IRBD subjects develop a synucleino-
pathy with time. Since additional IRBD patients have beendiagnosed and followed-up in our sleep center, we aimed toconfirm our initial observation in a larger cohort of subjects thatcomprises all the 174 consecutive IRBD cases diagnosed up to July2013. Confirmation of our previous findings in a much largercohort would strongly support the notion that IRBD is amanifestation of prodromal PD, DLB or MSA. This would carryimportant implications in patient management, in understandingthe pathophysiology of the various disorders associated withabnormal synuclein deposition, and could provide the opportunityto test disease-modifying strategies before the onset of motor andcognitive symptoms.
Methods
In the present study we determined the risk of development adefined neurodegenerative syndrome in all the consecutive 174
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subjects that were diagnosed with IRBD between November 1991and July 2013.
Patients’ AssessmentIn all instances the diagnosis of IRBD required history of
dream-enacting behaviors, video-polysomnography detection ofREM sleep with increased muscular activity associated withabnormal behaviors, absence of known neurodegenerative diseas-es, lack of motor and cognitive complaints, normal neurologicalexamination, and RBD not explained by a brain lesion (e.g.,stroke, demyelinating plaque, encephalitis) or by the introductionor withdrawal of any medication or substance (e.g., antidepres-sants, beta-blockers) [1,2,3].
The methods of clinical assessment at first and follow-up visitshave been described elsewhere [7,8]. In brief, patients werereferred to our sleep center where they or their bed partnersreported abnormal sleep behaviors. When the diagnosis of IRBDwas confirmed by video-polysomnography, patients underwentroutine follow-up visits every 3–12 months in our sleep centerwhere neurologists experienced in both sleep and neurodegener-ative disorders assessed sleep quality. If during follow-up visitsneurologists, patients or relatives noted the appearance ofsymptoms or signs suggestive of an emerging neurologicaldisorder, the patient was referred for detailed assessment to ourmovement disorders or memory disorders units. Neurologists fromthese units then formally assessed patients through detailed clinicalhistory, comprehensive neurological examination and neuropsy-chological tests when cognitive impairment was suspected.Diagnoses criteria applied were those accepted for PD, dementia,DLB, MSA and MCI [9,10,11,12,13]. If patients were not able orwilling to attend our clinic, they were offered to undergo homeand home-nursing visits by a neurologist (A.I) and a neuropsy-chologist (M.S) from our sleep center.
In the current study, to assess the presence and nature of adefined neurodegenerative syndrome, clinical records werereviewed, and all available patients were scheduled at our clinic(or at their homes or nursing homes) between February andAugust 2013. During these assessments, we conducted a detailedmedical history, a neurological examination and neuropsycholog-ical testing when cognitive symptoms were first reported ornoticed. The clinical outcome of the patients (those who remainedwith IRBD or those who were eventually diagnosed with a definedneurodegenerative syndrome) was determined in all cases bymeans of direct, face-to-face clinical interviews, neurologicalexaminations and neuropsychological tests. Diagnoses were notdone by telephone interviews. We also reviewed the neuropath-ological findings (according to a protocol previously described [8])of six patients from our cohort who died and donated their brainto the Neurological Tissue Bank of the Biobank-Hospital Clinic deBarcelona-IDIBAPS.
The study was approved by the Hospital Clinic of Barcelonaethics committee and all participants or, when appropriate, theirrelatives, gave written informed consent for clinical and post-mortem neuropathological evaluations.
Statistical AnalysisDescriptive data are reported as median, mean, deviation
standard, number or percentage. Duration of RBD was defined asthe interval between the reported onset of RBD symptoms(according to patients’ and bed partners’ estimation) and the timeof the last follow-up assessment or death. The date of IRBDdiagnosis was defined as the date when video-polysomnographydemonstrated REM sleep without atonia linked to abnormalbehaviors. Follow-up duration was defined as the interval from
diagnosis of IRBD to the time of the last visit or death. The onsetof a defined neurodegenerative syndrome (PD, DLB, MSA andMCI) was determined as the date when the diagnosis was madeaccording to accepted clinical criteria. Duration of any emergingdefined neurodegenerative syndrome was defined as the intervalbetween the time of its diagnosis and the time of the last follow-upassessment or death.
The risk of developing a defined neurodegenerative syndromein the 174 subjects from the cohort was estimated by means of theKaplan–Meier method.14 Disease-free survival rate was assessedfrom the date of IRBD diagnosis to the date of the diagnosis ofdefined neurodegenerative syndrome or to the last follow-up visitfor censored observations (subjects who died or were lost to follow-up).
Demographic and clinical variables were compared between thefirst 44 subjects reported previously [8] and the remaining 130with Student’s t test and x2 test, as appropriate. The risk ofdeveloping a neurodegenerative syndrome was calculated for thetwo groups, and comparisons were assessed with the log rank test.
P values less than 0.05 were considered to be significant. Allanalyses were done with SPSS version 20.0.
Results
In our sleep center, 174 individuals were diagnosed with IRBDbetween November 1991 and July 2013. With the exceptions ofthe duration of follow-up and the duration of RBD, there were nodemographic and clinical differences between the first 44 subjectswho were diagnosed between November 1991 and March 2003and the remaining 130 who were diagnosed between April 2003and July 2013 (Table 1).
Patients were 136 (78.2%) men and 38 (21.8%) women with amedian age at estimated RBD onset of 62.0 (range, 40 to 81) years,median age at diagnosis of IRBD of 69.0 (range, 50 to 85) years,and median interval between estimated RBD onset and IRBDdiagnosis of 4.0 (range, 0.5 to 30) years. The median age at lastvisit was 74.0 (range, 57 to 91) years and the median follow-upfrom IRBD diagnosis to the last visit or to death was 4.0 (range,0.1 to 15) years.
By the 2013 assessment, 65 (37.4%) patients were diagnosedwith a defined neurodegenerative syndrome, 103 (59.2%)remained disease-free, and 6 (3.4%) were lost to follow-up withthe diagnosis of IRBD at their last visit. Emerging diagnoses wereDLB in 29 subjects, PD in 22 (6 developed dementia after thediagnosis of PD), MCI in 12 and MSA in two. These two subjectswere diagnosed with MSA of the cerebellar subtype based on thepresence of cerebellar signs plus dysautonomic features (e.g.,orthostatic hypotension, urinary incontinence and erectile dys-function). Follow-up visits disclosed the development of rigid-akinetic parkinsonism unresponsive to levodopa in both, andstridor due to bilateral vocal cord paralysis in one. None of ourIRBD patients were diagnosed with pure autonomic failure. In 25of the 29 subjects who were diagnosed with DLB, a previousperiod of MCI was recognized, and the median interval betweenthe diagnosis of MCI and DLB was 2.0 (range, 1 to 7) years. Twopatients with the diagnosis of MCI developed PD after two years,and they have not developed dementia or visual hallucinationsafter 2.4 and 3.1 years of follow-up.
In the 65 subjects diagnosed with a defined neurodegenerativesyndrome, the median interval between estimated RBD onset anddiagnosis of a defined neurodegenerative syndrome was 11.0(range, 2 to 24) years, and the median interval between IRBDdiagnosis and diagnosis of a defined neurodegenerative syndromewas 4.0 (range, 0.5 to 13) years. The risk of a defined
Neurodegeneration in Idiopathic RBD
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neurodegenerative syndrome from IRBD diagnosis was 33.1% atfive years, 75.7% at ten years, and 90.9% at 14 years (Figure 1).The median conversion time in our sample was 7.560.5 years(95% CI 6.5 to 8.4). No difference in the risk of developing aneurodegenerative syndrome was found between the first 44patients and the subsequent 130 patients (p = 0.319) (Figure 2).
During the follow-up period, 32 (18.4%) subjects were deceased.Twenty-four of them were clinically diagnosed during life with adefined neurodegenerative syndrome (11 with DLB, 10 with PDand 3 with MCI), and the remaining eight had the diagnosis ofIRBD at their last follow-up visit. Six patients with theantemortem diagnoses of DLB (n = 3), PD (n = 2, one of themwith associated dementia) and MCI (n = 1) were brain donors. Intwo of them (the one with PD without dementia, and the one withMCI) the peripheral autonomic nervous system was also availablefor examination. In the brain, all six cases presented variableneuronal loss, gliosis and alpha-synuclein immunoreactive Lewypathology (Lewy bodies and Lewy neurites) in vulnerable regionssuch as the olfactory bulb, dorsal motor nucleus vagal nerve,central raphe nucleus, the nuclei that regulate REM sleep muscleatonia (gigantocellular reticular nucleus, pedunculopontine nucle-us and coeruleus/subcoeruleus complex), substantia nigra parscompacta, limbic structures (amygdala and anterior cingulatecortex), and nucleus basalis of Meynert. Lewy pathology was alsodetected in the neocortex of the three patients with theantemortem diagnoses of DLB and of the PD patient whodeveloped dementia, corresponding in all of them to Lewy bodyBraak stage 5 [15]. In the patient with the antemortem diagnosisof PD who did not develop dementia and in the patient with MCI,Lewy pathology was observed in the olfactory bulb, entirebrainstem and amygdala, preserving neocortical areas (Lewy bodyBraak stage 4) [15]. In these two patients, a-synuclein aggregateswere observed in several regions of the peripheral autonomicnervous system such as the paravertebral sympathetic chain,epicardial fat tissue ganglia and myenteric plexus. As commonly
seen in patients with Lewy body disorders [16,17], concomitantpathologies were observed and included 1) Alzheimer typepathology in two of the donors with the clinical diagnosis ofDLB, 2) small vessel disease with microvascular lesions in two DLBcases and the PD subject without dementia, and 3) argyrophilicgrain pathology in the PD patient with dementia, in one DLB caseand in the MCI case.
Discussion
This is the largest study with long term follow-up of IRBD. In acohort of 174 patients that were closely followed during a medianperiod of 4.0 years, survival curves showed that the estimated riskof a defined neurodegenerative syndrome from the time of IRBDdiagnosis was 33.1% at five years, 75.7% at ten years, and 90.9%at 14 years. Patients were clinically diagnosed with PD, DLB,MSA and MCI. In patients who underwent postmortem brainexamination, the antemortem diagnoses of PD and DLB wereconfirmed showing neuronal loss and widespread Lewy-typepathology in selective brain regions. The patient with MCI andlack of parkinsonism and dementia also had widespread Lewy typepathology. The current study confirms our first observation [8]that the majority of patients with IRBD that seek medical attentionare eventually diagnosed with a synucleinopathy. Ours is ahomogenous cohort where demographics, clinic characteristicsand survival curves are similar between the 44 subjects diagnosedbetween 1991 and March 2003 [8] and the subsequent 130subjects diagnosed between April 2003 and July 2013.
Similar results have been found by two other studies whereIRBD patients diagnosed in sleep tertiary centers were clinicallyfollowed. The nature of disorders (synucleinopathies) evolvingfrom these two cohorts is very similar to what we have found inour study. In the first study, Schenck et al. found that parkinson-ism developed in 11 of 29 (38%) IRBD subjects nearly four yearsafter the diagnosis of IRBD and almost 13 years after the onset ofRBD [4]. After 16 additional years of follow-up, 21 (72.4%) IRBD
Table 1. Comparison between the first 44 subjects who were diagnosed with IRBD between November 1991 and March 2003, andthe following 130 who were diagnosed between April 2003 and July 2013.
Patients diagnosed with IRBDbetween November 1991 andMarch 2003 (n = 44)
Patients diagnosed with IRBDbetween April 2003 andJuly 2013 (n = 130) P value
Sex (male/female) 39/5 97/33 0.052
Age at estimated RBD onset (years) 62.7567.34 (45–77) 62.3267.92 (40–81) 0.744
Age at RBD diagnosis (years) 69.0766.56 (56–85) 68.5766.32 (50–85) 0.655
RBD duration (years) 16.5065.07 (8–31) 10.1666.65 (1–34) ,0.0001
Follow-up duration after diagnosisof RBD (years)
9.6463.34 (1–15) 3.5062.72 (0.1–10) ,0.0001
Self-awareness of abnormal sleep behaviors 28(63.6%) 70(54.3%) 0.279
Unpleasant dream recall 42(95.5%) 118(90.8%) 0.323
Age at diagnosis of emerging definedneurodegenerative syndrome (years)
74.6465.60 (60–85) 74.3164.13 (64–80) 0.793
Diagnoses of emerging definedneurodegenerative syndrome (n)
PD = 16 DLB = 15 MSA = 1 MCI = 4 PD = 6 DLB = 14 MSA = 1 MCI = 8
Estimated risk of conversion after5 years of IRBD diagnosis (%)
34.8 22.6
Estimated risk of conversion after10 years of IRBD diagnosis (%)
73.4 72.2
Data are given in number, mean, standard deviation and range. RBD = REM sleep behavior disorder; PD = Parkinson disease; DLB = dementia with Lewy bodies;MSA = multiple system atrophy; MCI = mild cognitive impairment.doi:10.1371/journal.pone.0089741.t001
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patients from the original cohort where diagnosed with PD in 13cases, DLB in three, MSA in two, unspecified dementia in one,and Alzheimer’s disease with autopsy-confirmed combinedAlzheimer’s disease pathology plus Lewy pathology in two. ThreeIRBD subjects were lost during the follow-up period [5]. In thisstudy, the presence of MCI was not evaluated and the risk ofdisease was not examined using survival curves and statisticalanalysis. In a second series, Postuma et al. found that 26 of 93(28%) IRBD patients developed a neurodegenerative disorderafter a mean follow-up of five years; PD in 14, DLB in seven,dementia that met clinical criteria for Alzheimer’s disease (but alsofor possible DLB) in four, and MSA in one. Survival curvesshowed that the estimated risk of a neurodegenerative disease afterRBD diagnosis was 17.7% at five years, 40.6% at 10 years, and52.4% at 12 years [6]. When compared with our study, the lowerconversion rate and the lower estimated risk of developingneurodegenerative disease found by Postuma et al. may beexplained by methodological aspects. In the study by Postumaet al. the design was retrospective (while ours was prospective), thestatus of 15 patients was assessed through telephone interviews(while all of our patients were assessed by in-person examinationseven examining them at their homes and nursing-homes), 20(17.7%) of their initial 113 patients where lost during the follow-up
(while we lost only six 23.4%2 of 174 subjects), neuropathologicconfirmation of a disease was not provided (in our study this wasdone in six subjects), the mean age at the time of the study was 65years (while in ours it was 74 years), and MCI was not consideredas a disease outcome.
Our findings indicate that there is a strong and specificassociation of IRBD with PD and DLB, and that this parasomniacan be considered in most cases a prodromal manifestation. In PD,other clinical features known to precede the motor symptoms suchas hyposmia, constipation, depression and hypersomnia are muchless specific since only a small number of individuals with thesesymptoms are eventually diagnosed with PD [18,19]. Thispositions IRBD as an optimal target population to study theprodromal stage of the synucleinopathies and eventually to testdisease-modifying strategies in these disorders before motor andcognitive changes have developed.
The findings of our study have clinical relevance and researchimplications. The investigation of patients with IRBD offers aunique opportunity to obtain information of the aetiology,pathogenesis and progression of the prodromal stage of thesynucleinopathies. In IRBD, clinical, neuroimaging, biochemical,proteomic and genetic studies will help to better understand themechanisms of neurodegeneration and to design interventions
Figure 1. Rates of neurological-disease-free-survival according to the time of IRBD diagnosis in the 174 patients from the cohort.doi:10.1371/journal.pone.0089741.g001
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with potential disease modifying properties. To date, severalstudies have added weight to the concept that IRBD represents inmost cases an evolving synucleinopathy in its earliest phases.Several studies have found that IRBD patients display clinical (e.g.,hyposmia [20], depression [21], autonomic dysfunction [21]) andneuroimaging (e.g., decreased dopamine transporter binding inthe striatum [22], substantia nigra hypechogenicity [22], increasedmean diffusivity in the pons [23]) abnormalities which arecharacteristic features of the synucleinopathies. Overall, thesestudies suggest that at the time IRBD is diagnosed a neurodegen-erative process is already widespread in the nervous system. Ofthese abnormalities, the combination of hyposmia with colourvision impairment [20], and the combination of substantia nigrahyperechogenicity with decreased striatal dopamine transporteruptake [21] may identify those IRBD patients who are at increasedshort-term risk for being diagnosed with a synucleinopathyaccording to accepted clinical criteria. Prospective studies havefurther shown that while colour vision and olfactory dysfunction[20,24] remains stable over time, dopamine transporter imagingshows progressive decline in striatal tracer uptake [25]. Thus,dopamine transporter imaging, and not olfactory and colour visionfunctions, serve better as a marker of progression in IRBD.
The finding that IRBD patients are later frequently diagnosedwith DLB and PD with associated dementia suggests that both
disorders may represent different phenotypes from the samecondition. MCI is an intermediate stage between normal cognitivefunction and dementia where individuals have cognitive com-plaints, deficits in neuropsychological tests and their daily livingactivities are preserved [13]. In our study MCI was considered adisease outcome. This is because in the particular setting of IRBD,MCI can be considered an abnormal condition which frequentlyevolves into DLB and PD. This is based on the following data.First, MCI occurs in nearly 20% of untreated PD patients at thetime of initial diagnosis [26], and predicts conversion to dementia[27]. Of note, two our MCI patients have developed parkinsonismbut not dementia or hallucinations to date. Second, most IRBDpatients seen in sleep centers who develop MCI are eventuallydiagnosed with DLB [8]. Third, IRBD patients that develop MCIbut no dementia show markers of a synucleinopathy such asdecreased striatal dopamine transporter, hyperechogenicity of thesubstantia nigra and hyposmia [8]. Fourth, in patients with MCIwith comorbid RBD who later develop dementia, postmortemexamination shows Lewy-body pathology [28]. Finally, in apopulation-based study involving 651 individuals, RBD conferreda 2.2-fold increased risk of developing MCI over a 4-year period ofobservation [29]. The above data is supported by our currentobservation in one patient who developed MCI (and not dementiaor parkinsonism) and neuropathology demonstrated neuronal loss
Figure 2. Rates of neurological-disease-free-survival according to the time of IRBD diagnosis in the first 44 patients from the cohort(doted line) and the remaining 130 (continuous line).doi:10.1371/journal.pone.0089741.g002
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and widespread alpha-synuclein related Lewy body pathologyinvolving the peripheral nervous system, olfactory bulb, entirebrainstem (including the substantia nigra) and the limbic system.
Limitations of our study should be acknowledged. Our study didnot include a control group of healthy subjects without RBD whowere followed-up on during a similar time period. In the presentstudy, the proportion of IRBD subjects that developed aneurological condition was 37% over a median follow-up periodof 4 years. This proportion is greatly superior to the estimatedprevalence of these neurological disorders in a population ofindividuals of similar age and sex distribution [30,31,32,33]. Ourcohort comprises patients who were self-referred to a tertiary sleepcenter. It is uncertain if our observations can be generalized to theindividuals with IRBD in the general population that do not seekmedical attention. Strenghts of our study include confirmation ofRBD by polysomnography in all cases, a large number of studysubjects, and a long and close follow-up (which included home andhome-nursing visits when needed) reflected by a low number (3%)of patients who were lost. In addition, pathological confirmation
was available in six cases and clinical outcome (disease free ordiagnosed with a defined neurodegenerative syndrome) was in allcases determined by in-person assessment through clinical historyand neurological evaluation.
In summary, our study shows that a majority of IRBD patientswith prolonged follow-up are diagnosed with the synucleinopathiesPD, DLB and MSA. IRBD represents the prodromal period ofthese conditions. Our findings in IRBD have important implica-tions in clinical practice, in the investigation of the earlypathological events occurring in the synucleinopathies, and forthe design of future trials with potential disease-modifying agents.
Author Contributions
Conceived and designed the experiments: AI AFA ET MS JLM FV EG IVRSV ALL CG JS. Performed the experiments: AI AFA ET MS JLM FVEG IV RSV ALL CG JS. Analyzed the data: AI AFA ET MS JLM FV EGIV RSV ALL CG JS. Contributed reagents/materials/analysis tools: AIAFA ET MS JLM FV EG IV RSV ALL CG JS. Wrote the paper: AI AFAET MS JLM FV EG IV RSV ALL CG JS.
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5. DISCUSIÓN CONJUNTA DE LOS RESULTADOS
Los trabajos presentados como parte de la memoria de
esta tesis doctoral describen aspectos clínicos,
diagnósticos y pronósticos del TCSRI.
El primer trabajo (The clinical phenotype of idiopathic
rapid eye movement sleep behavior disorder at presentation:
A study in 203 consecutive patients) muestra la experiencia
durante 24 años en la Unidad de Sueño del Hospital Clínic de
Barcelona en pacientes diagnosticados del TCSRI. En su
momento de publicación en 2016 era la serie más grande
publicada y en ella se describen las características clínicas
principales del TCSRI. En el estudio se corroboran aspectos
demográficos ya conocidos,63 como la predominancia en
hombres, la edad al diagnóstico y el tiempo de retraso desde
el inicio de la sintomatología hasta el diagnóstico. Aunque
por la edad de los pacientes y la prevalencia de los
trastornos del sueño fuese esperable hallar un porcentaje
elevado de alteraciones concomitantes (como el insomnio y
apneas), es remarcable que en algunos casos fuesen éstos los
motivos de consulta y sólo tras la anamnesis se sospechase
por primera vez el TCSRI. Casi la mitad de los pacientes no
eran conscientes del trastorno e incluso una proporción
mayoritaria de las personas incluidas en el estudio referían
dormir bien. En esos casos la existencia de un compañero/a
fue fundamental para detectar el trastorno. Al contrario de
lo que esperábamos, algunos de los pacientes podían
determinar el día en que se iniciaron los síntomas al
relacionarlo con algún evento vital que les ocurrió (como
ser atracados o una intervención quirúrgica). Otro de los
hallazgos que no habían sido descritos anteriormente fue que
algunos de los pacientes explicaban que en alguna ocasión se
habían levantado de la cama y deambulado aparentemente
dormidos. Vimos que estos pacientes desarrollaron con mayor
69
frecuencia déficits cognitivos (DCL y DCLw). Al comparar los
pacientes por sexos, los hombres referían presentar más
conductas agresivas y sueños con más acción. Los pacientes
que no recibieron tratamiento con clonazepam se lastimaban
por la noche más que aquellos tratados, al representar sus
sueños cayéndose de la cama o golpeando a sus parejas o a
ellos mismos.
El conocimiento clínico del TCSRI es de gran importancia
para poder detectar esta parasomnia y hacer un correcto
diagnóstico. Por un lado, posibilita ayudar a los pacientes
para reducir el sufrimiento que les ocasionan las pesadillas
y el riesgo de lesiones durante el sueño. Por otro lado,
permite proporcionarles una información sobre el riesgo de
desarrollar una enfermedad neurodegenerativa. Este estudio
pretende incrementar el conocimiento clínico del TCSRI para
identificarlo y disminuir el tiempo de retraso del
diagnóstico.
El segundo trabajo (Diagnostic value of isolated
mentalis vs. mentalis plus upper limb electromyography in
idiopathic REM sleep behavior disorder patients eventually
developing a neurodegenerative syndrome) evalúa el
diagnóstico V-PSG del TCSRI. Se comparan dos métodos de
cuantificación de la actividad EMG durante el sueño REM.74,75
Ambos métodos son recomendados en los criterios diagnósticos
de la tercera edición de la International Classification of
Sleep Disorders, aunque no se conoce cuál de es mejor.73 La
muestra de pacientes incluidos en el estudio tiene mayor
relevancia al tratarse del estudio basal de aquellos
pacientes que posteriormente fueron diagnosticados de una
sinucleinopatía (EP, DCLw, AMS) y por tanto el tiempo
demostró que la clínica de TCSRI era parte de la
sintomatología inicial de estas enfermedades. Según nuestros
hallazgos, la cuantificación de la actividad EMG del músculo
70
mentalis junto a los músculos de las extremidades superiores
tiene una mayor sensibilidad diagnóstica que la
cuantificación aislada del músculo mentalis. Es relevante
conocer que, del mismo modo que en anteriores estudios,74,75
algunos de los pacientes presentaron una menor actividad EMG
de la propuesta en los puntos de corte y en estos casos el
registro audiovisual es esencial para poder realizar el
diagnóstico del TCSRI al observarse conductas anormales en
la fase REM. El análisis cuantitativo de la actividad EMG
únicamente en el músculo mentalis puede ser una fuente de
falsos negativos en el diagnóstico del TCSRI.
Este estudio inclina la balanza hacia un método concreto
de cuantificación, el de la actividad EMG del músculo
mentalis junto con músculos de las extremidades superiores,
sobre la cuantificación únicamente del músculo mentalis. Así
mismo, reafirma la necesidad de realizar un registro
audiovisual sincronizado para detectar movimientos o
conductas típicas del TCSRI. Incrementar el conocimiento
sobre los métodos diagnósticos del TCSRI es importante para
poder aumentar la sensibilidad diagnóstica en la práctica
clínica diaria y para unificar criterios en futuros proyectos
de investigación.
El tercer trabajo (Neurodegenerative Disorder Risk in
Idiopathic REM Sleep Behavior Disorder: Study in 174
Patients) evalúa el riesgo de ser diagnosticado de una
enfermedad neurodegenerativa una vez diagnosticado el TCSRI.
El riesgo estimado de los pacientes con TCSRI de desarrollar
un síndrome neurodegenerativo es elevado (un 90.9% a los 14
años desde el diagnóstico).
Este artículo, con la serie más grande de pacientes
publicados hasta la fecha de su publicación (2014), apoya
los hallazgos encontrados previamente en nuestro grupo125 y
confirma los datos obtenidos por otros autores en otros
71
países.126-127 Contribuye a incrementar el conocimiento para
la práctica clínica diaria, sustentando la necesidad de un
seguimiento del paciente y de proporcionarle información
sobre su pronóstico. Subraya además el interés que tiene el
TCSRI como un trastorno específico de la fase inicial o
prodrómica de las sinucleinopatías.
En conjunto, estos tres trabajos contribuyen a
incrementar el conocimiento global sobre el TCSRI, un
trastorno del sueño que supone una oportunidad para
comprender los mecanismos fisiopatológicos de las
sinucleinopatías en su fase más precoz y para investigar
terapias que puedan detener o frenar el curso de la
enfermedad.
72
6. CONCLUSIONES
1. El TCSRI tiene una serie de características clínicas
homogéneas en una serie grande de pacientes. Algunas
son típicas, ya conocidas, como tener pesadillas o
realizar conductas vigorosas durante el sueño. Otras no
habían sido descritas o no se habían enfatizado
suficientemente, como que la mayoría de los pacientes
explican que duermen bien, que de forma ocasional se
levantan de la cama o que puede sospecharse el TCSRI a
partir de consultar por otro trastorno de sueño.
2. En el diagnóstico del TCSRI mediante V-PSG, la
cuantificación de la actividad muscular durante el
sueño REM en el músculo mentalis junto a músculos de
las extremidades superiores tiene una mayor
sensibilidad que la evaluación única en el músculo
mentalis. El análisis audiovisual puede ser
determinante en los pocos casos en que la actividad
muscular en el sueño REM no es excesiva.
3. El riesgo estimado de los pacientes con TCSRI de ser
diagnosticados de una enfermedad neurodegenerativa es
muy elevado, un hecho que indica que este trastorno es
una manifestación inicial de estas enfermedades.
73
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