REM BEHAVIOR DISORDER
REM Sleep Behavior Disorder and Narcoleptic Features in Anti–Ma2-associated
Encephalitis
Yaroslau Compta, MD1; Alex Iranzo, MD1; Joan Santamaría, MD1; Roser Casamitjana, PhD2; Francesc Graus, MD1
Neurology Service, 2Biochemistry Service, Hospital Clínic and Institut D’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
1
A 69-year-old man with anti-Ma2 paraneoplastic encephalitis presented
with subacute onset of severe hypersomnia, memory loss, parkinsonism,
and gaze palsy. A brain magnetic resonance imaging study showed bilateral damage in the dorsolateral midbrain, amygdala, and paramedian
thalami. Videopolysomnography disclosed rapid eye movement (REM)
sleep behavior disorder, and a Multiple Sleep Latency Test showed a
mean sleep latency of 7 minutes and 4 sleep-onset REM periods. The
level of hypocretin-1 in the cerebrospinal fluid was low (49 pg/mL). This
observation illustrates that REM sleep behavior disorder and narcolep-
tic features are 2 REM-sleep abnormalities that (1) may share the same
autoimmune-mediated origin affecting the brainstem, limbic, and diencephalic structures and (2) may occur in the setting of the paraneoplastic
anti–Ma2-associated encephalitis.
Keywords: REM sleep behavior disorder, narcolepsy, hypocretin-1, anti–
Ma2-associated encephalitis
Citation: Compta Y; Iranzo A; Santamaría J et al. REM Sleep Behavior
Disorder and Narcoleptic Features in Anti–Ma2-associated Encephalitis.
SLEEP 2007;30(6):767-769.
multiple irresistible nap episodes. The patient did not experience
cataplexy, sleep paralysis, hallucinations, hyperthermia, or weight
gain. Past medical history was unremarkable except for cigarette
smoking and arterial hypertension. On admission, neurologic
examination revealed somnolence, amnesia for recent events,
disorientation to time and place, difficulty in opening the eyes,
supranuclear vertical gaze palsy, rigidity, bradykinesia, short-step
gait, and hypophonia. A brain magnetic resonance imaging study
revealed T2-weighted and FLAIR hyperintense lesions involving
the dorsolateral midbrain and both hippocampus and amygdala
(Figure 1-A). Nocturnal polysomnography with synchronized
audiovisual recording showed fragmented and reduced sleep
with a sleep efficiency of 48% and absence of sleep spindles. No
apneic events or periodic limb movements were recorded. RBD
was detected, since REM sleep was characterized by (1) sustained
elevation of submental electromyographic tone and (2) increased
phasic activity in the submental and 4 limb muscles associated with
frequent irregular kicking and prominent truncal and limb jerking
(Figure 1-B).6 A 5-nap Multiple Sleep Latency Test performed
on the following day showed a mean sleep latency of 7 minutes
and the presence of 4 sleep-onset REM periods with associated
increased tonic and phasic submental electromyographic activity.
HLA typing was negative for the DQB1*0602 and DRB1*15
antigens. Analysis of the cerebrospinal fluid revealed a decreased
hypocretin-1 level of 49 pg/mL (normal, > 200 pg/mL). Anti–
Ma2-associated antibodies were identified in the cerebrospinal
fluid and serum. No other onconeuronal antibodies were detected.
Hence, the diagnosis of anti–Ma2-associated encephalitis was
made.
Search for an underlying cancer was negative. Serum levels
of tumor markers were normal. Routine laboratory blood tests
(including a sodium level of 141 mEq/L), testicular ultrasound,
chest radiograph, and computed tomography of the chest and
abdomen were normal. A whole-body fluorodeoxyglucose
positron emission tomography scan showed 2 small areas of
hypermetabolism in the rectum and prostate. However, repeated
computed tomography of the abdomen, colonoscopy, and the
serum prostate-specific antigen level were normal.
Despite 3 monthly courses of intravenously administered
immunoglobulin (0.4 g/Kg-1/day-1 for 5 days) and
methylprednisolone (1 g/day for 3 days), the patient’s status
ANTI–MA2-ASSOCIATED ENCEPHALITIS IS AN AUTOIMMUNE PARANEOPLASTIC DISORDER USUALLY ASSOCIATED WITH TESTICULAR CANCER. PATIENTS PRESENT
with symptoms of brainstem, limbic, and hypothalamic impairment, such as eye movement abnormalities, memory loss, and
endocrine dysfunction.1 In addition, some patients may develop
narcoleptic features such as hypersomnia and cataplexy due to
hypocretin-1 deficiency, indicating the occurrence of a rapid eye
movement (REM) sleep dysregulation of hypothalamic origin.1-5
REM sleep behavior disorder (RBD) is a REM-sleep parasomnia
characterized by increased muscle activity associated with vigorous dream-enacting behaviors during REM sleep which is caused
by brainstem and limbic system impairment.6,7 Abnormalities of
REM-sleep control such as REM-sleep intrusion into wakefulness
and persistence of muscle tone during REM sleep have not been
well characterized or described in subjects with anti–Ma2-associated encephalitis. Herein, we report a patient with anti–Ma2associated encephalitis who developed both RBD and clinical,
electrophysiologic, and biologic narcoleptic features. This case illustrates that RBD and narcolepsy are 2 REM-sleep disturbances
that may share a common autoimmune-mediated origin associated with brainstem, limbic system, and hypothalamic damage.
CASE REPORT
A 69-year-old man with no previous sleep complaints was
admitted with a 3-month history of progressive severe hypersomnia,
memory loss, short episodes of sensation of fear, apathy,
diplopia, and unsteady gait with frequent falls. Hypersomnia was
characterized by a continuous daytime tendency to fall asleep with
Disclosure Statement
This was not an industry supported study. Drs. Compta, Iranzo, Santamaría,
Casamitjana, and Graus have indicated no financial conflicts of interest.
Submitted for publication December 2006
Accepted for publication March 2007
Address correspondence to: Alex Iranzo, Neurology Service, Hospital Clinic
de Barcelona, C/ Villarroel 170, Barcelona 08036, Spain; Fax: 3493 227
5783; E-mail: [email protected]
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RBD and Narcolepsy in Anti-Ma2 Encephalitis—Compta et al
LOC-A1
ROC-A2
C3–A2
C4–A1
1 sec
O1–A2
O2–A1
Chin
LBic
RBic
LAT
RAT
Nasal
1 sec
Thor
EKG
B
A
Figure 1—Axial FLAIR brain magnetic resonance imaging study (MRI) shows bilateral hyperintensities in the amygdala (white arrows) and
dorsolateral midbrain (grey arrow) (A), and polysomnography demonstrates characteristic features of rapid eye movement (REM) sleep behavior
disorder (sustained tonic electromyogram (EMG) activity in the chin and excessive phasic EMG activity in the lower limbs channels during REM
sleep) (B).
LOC refers to left electrooculogram; ROC, right electrooculogram; A1, left ear; A2, right ear; C3, left central electroencephalogram (EEG); C4,
right central
EEG; O1, left occipital
EEG;brain
O2, rightmagnetic
occipital EEG;
Chin, chin surface
EMG; Lstudy
Bic, left biceps
surface
EMG;bilateral
R Bic, right biceps
Figure—Axial
FLAIR
resonance
imaging
(MRI)
shows
surface EMG; LAT, left anterior tibilais surface EMG; RAT, right anterior tibilais surface EMG; Nasal, nasal airflow; Thor, thoracic breathing effort; EKG, electrocardiogram.
hyperintensities in the amygdala (white arrows) and dorsolateral midbrain (grey arrow) (A),
and gliosis. Neurologic symptoms usually precede detection of
worsened. A follow-up brain magnetic resonance imaging study
a testicular germ-cell or non-small cell lung cancer, but, in some
showed additional bilateral paramedian thalamus hyperintensity
and
polysomnography
demonstrates
characteristic
of rapid
eyeis ever
movement
(REM)presubjects,features
no underlying
neoplasm
identified. Clinical
on T2-weighted and FLAIR sequences. The family refused any
further treatment. The patient’s neurologic state deteriorated
sentation depends on the area of the brain that is affected.1 In
progressively,
he died indisorder
a nursing home
12 monthstonic
after the
our patient, vertical
gaze palsy
and atypical
sleep and
behavior
(sustained
electromyogram
(EMG)
activity
in theparkinsonism
chin and were
onset of the neurologic symptoms. Permission for autopsy was
attributable to midbrain pathology, whereas short memory loss,
not granted.
episodes of fear, and personality changes were probably mediated
by limbic-system
We speculate
excessive phasic EMG activity in the lower limbs
channelsinvolvement.
during REM
sleep) that,
(B).in our patient,
DISCUSSION
RBD and the narcoleptic features were also secondary to brain
damage linked to the inflammatory process.
LOC
to left electrooculogram;
electrooculogram;
A1, leftbyear;
right atoTo the
best ofrefers
our knowledge,
this is the first documentedROC,
case right
RBD
is a parasomnia characterized
lackA2,
of muscle
of anti-Ma2 encephalitis associated with both secondary RBD
nia during REM sleep. RBD frequently occurs in the setting of
6
and narcolepsy.
This
observation
indicates
that
abnormal
manineurodegenerative
diseases.
ItEEG;
also hasO1,
been left
described
as being
ear;
C3,
left
central
electroencephalogram
(EEG);
C4,
right
central
occipital
festations of REM sleep, such as REM sleep without atonia and
associated with autoimmune disorders, such as potassium-chanREM sleep intrusion into wakefulness, may share a common aunel antibody-associated limbic encephalitis.7 RBD has not been
8
toimmune-mediated
should beEEG;
noted that
idiopathic
reportedEMG;
in subjects
with autoimmune
disorders,
EEG; O2,origin.
right Itoccipital
Chin,
chin surface
L Bic,
left bicepsparaneoplastic
surface EMG;
narcolepsy is a condition thought to be mediated by autoimmune
such as anti–Ma2-associated encephalitis. The pathophysiology
mechanisms; where clinical symptoms suggestive of RBD occur
of RBD lies in a dysfunction of the brainstem structures that regu9
Bic,
right
biceps
surface
EMG;
LAT, are
left anterior
tibilais
surface
EMG;
RAT,nucleus)
right and their
in up toR36%
of the
patients.
RBD
and idiopathic
narcolepsy
late REM-sleep
muscle
tone (e.g.,
subcoeruleus
2 disorders characterized by obscure sleep-wake boundaries. In
anatomic connections, including those with the amygdala.6 BilatRBD, components of 1 state (sustained muscle contraction chareral lesions of the dorsolateral mesopontine tegmentum of laboraanterior tibilais surface EMG; Nasal, nasal airflow;
Thor, thoracic breathing effort; EKG,
acteristic of wake) appear in another state (REM sleep), leading
tory animals produce REM sleep without atonia.6 Alternatively,
to dream-enacting behaviors. In narcolepsy, components of REM
RBD may occur in disorders associated with direct damage of the
sleep (muscle
atonia and vivid dreams) intrude into wakefulness,
limbic system and no apparent primary brainstem impairment.7 It
electrocardiogram.
manifesting as episodes of cataplexy, sleep paralysis, and hypnahas been speculated that limbic-system dysfunction contributes
gogic hallucinations.10
to the development of the characteristic frightening dreams and
Anti–Ma2-associated encephalitis is a paraneoplastic condition
the violent nature of the sleep behaviors displayed by patients
characterized by upper brainstem, limbic system, and hypothawith RBD.7 In our case, the presence of RBD was likely due to
lamic impairment. The encephalitis process reflects an abnormal
primary impairment of the REM sleep-related structures within
autoimmune-mediated response against the Ma2 protein, which
the dorsolateral midbrain tegmentum and amygdala.
is expressed in all neurons of human brain, particularly in the
Idiopathic narcolepsy is characterized by selective loss of
brainstem, hippocampus, amygdala, and diencephalic structures,
hypocretin-producing neurons in the posterior hypothalamus.
including the hypothalamus and thalamus. In these areas, patholHypocretin is a neuropeptide of hypothalamic origin that proogy studies demonstrate inflammatory infiltrates, neuronal loss,
motes wakefulness and inhibits REM sleep. Thus, impairment of
SLEEP, Vol. 30, No. 6, 2007
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RBD and Narcolepsy in Anti-Ma2 Encephalitis—Compta et al
the hypocretin system results in inappropriate intrusion of REM
sleep, leading to episodes of sleepiness and cataplexy. In idiopathic narcolepsy, an autoimmune basis is suspected because of the
strong association between narcolepsy and the HLA DQB1*0602
allele. Secondary narcolepsy occurs in focal lesions in the hypothalamus resulting in decreased hypocretin production. Hypersomnia has been noted to occur in up to 32% of the subjects with
anti–Ma2-associated encephalitis,1 but cataplexy has been reported in fewer than 3%.1-5 Low or undetectable hypocretin-1 levels in
the cerebrospinal fluid have been reported in 6 patients with anti–
Ma2-associated encephalitis and hypersomnia in whom cataplexy
was not documented.1,2,4,5 Sleep studies have been performed in
only 1 subject with anti–Ma2-associated encephalitis plus hypersomnia, showing, as in our case, reduced sleep efficiency on
nocturnal polysomnography and decreased mean sleep latency
and sleep-onset REM periods on the Multiple Sleep Latency Test.
That patient had cataplexy but the hypocretin-1 level in the cerebrospinal fluid was not measured.3 In our patient, anti–Ma2-associated encephalitis was associated with hypersomnia, sleep-onset
REM periods on the Multiple Sleep Latency Test, and a low concentration of hypocretin-1 in the cerebrospinal fluid. Thus, it can
be speculated that these narcoleptic features were likely caused
by the abnormal autoimmune response directed against the hypothalamic hypocretin-synthesizing neurons. The finding that our
patient was HLA DQB1*0602 negative suggests that this particular HLA allele was not required for some narcoleptic features to
develop in anti–Ma2-associated encephalitis.
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