Download Ictal SPECT in patients with rapid eye movement

doi:10.1093/brain/awv042
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Ictal SPECT in patients with rapid eye
movement sleep behaviour disorder
Geert Mayer,1,2 Marion Bitterlich,1 Torsten Kuwert,3 Philipp Ritt3 and Hermann Stefan4
See Mahowald and Schenck for a scientific commentary on this article (doi:10.1093/brain/awv058).
Rapid eye movement sleep behaviour disorder is a rapid eye movement parasomnia clinically characterized by acting out dreams
due to disinhibition of muscle tone in rapid eye movement sleep. Up to 80–90% of the patients with rapid eye movement sleep
behaviour disorder develop neurodegenerative disorders within 10–15 years after symptom onset. The disorder is reported in 45–
60% of all narcoleptic patients. Whether rapid eye movement sleep behaviour disorder is also a predictor for neurodegeneration in
narcolepsy is not known. Although the pathophysiology causing the disinhibition of muscle tone in rapid eye movement sleep
behaviour disorder has been studied extensively in animals, little is known about the mechanisms in humans. Most of the human
data are from imaging or post-mortem studies. Recent studies show altered functional connectivity between substantia nigra and
striatum in patients with rapid eye movement sleep behaviour disorder. We were interested to study which regions are activated in
rapid eye movement sleep behaviour disorder during actual episodes by performing ictal single photon emission tomography. We
studied one patient with idiopathic rapid eye movement sleep behaviour disorder, one with Parkinson’s disease and rapid eye
movement sleep behaviour disorder, and two patients with narcolepsy and rapid eye movement sleep behaviour disorder. All
patients underwent extended video polysomnography. The tracer was injected after at least 10 s of consecutive rapid eye movement
sleep and 10 s of disinhibited muscle tone accompanied by movements registered by an experienced sleep technician. Ictal single
photon emission tomography displayed the same activation in the bilateral premotor areas, the interhemispheric cleft, the periaqueductal area, the dorsal and ventral pons and the anterior lobe of the cerebellum in all patients. Our study shows that in patients
with Parkinson’s disease and rapid eye movement sleep behaviour disorder—in contrast to wakefulness—the neural activity
generating movement during episodes of rapid eye movement sleep behaviour disorder bypasses the basal ganglia, a mechanism
that is shared by patients with idiopathic rapid eye movement sleep behaviour disorder and narcolepsy patients with rapid eye
movement sleep behaviour disorder.
1
2
3
4
Hephata Klinik, Department of Neurology, Schimmelpfengstr.6, 34613 Schwalmstadt-Treysa, Germany
Philipps University Marburg, Department of Neurology, Baldingerstrasse, 35043 Marburg, Germany
University of Erlangen, Department of Nuclear Medicine, Ulmenweg 18, 91054 Erlangen, Germany
University of Erlangen, Department of Neurology, Schwabachanlage 6, 91054 Erlangen, Germany
Correspondence to: Geert Mayer,
Hephata Klinik, Schimmelpfengstr. 6,
34613 Schwalmstadt-Treysa,
Germany
E-mail: [email protected]
Keywords: REM sleep behaviour disorder; ictal SPECT; basal ganglia; muscle atonia; sublaterodorsal nucleus
Abbreviations: DTI = diffusion tensor imaging; HLA = human leukocyte antigen; REM = rapid eye movement; SPECT = single
photon emission tomography
Received September 8, 2014. Revised December 21, 2014. Accepted December 22, 2014. Advance Access publication March 2, 2015
ß The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For Permissions, please email: [email protected]
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Introduction
Rapid eye movement (REM) sleep behaviour disorder is a
parasomnia characterized by acting out dreams with
screaming, hitting, thrashing and frequent self-injury.
It has gained major attention because 81% of the patients
with the idiopathic REM sleep behaviour disorder form
convert within 10–15 years after onset to neurodegenerative disease such as Parkinson’s disease, multisystem atrophy, or dementia of the Lewy bodies (Schenck et al., 2013).
Patients with idiopathic REM sleep behaviour disorder frequently show signs and symptoms associated with an
increased risk of developing -synucleinopathy, e.g. hyposmia, depression, constipation, and hyperechogenicity of the
substantia nigra (Stiasny-Kolster et al., 2005; Postuma
et al., 2010, 2011). To date the best biomarker of REM
sleep behaviour disorder is the amount of loss of muscle
tone inhibition during REM sleep (REM sleep without
atonia). Among the symptomatic REM sleep behaviour disorder forms, narcolepsy has a high association with REM
sleep behaviour disorder. This form is less violent than
idiopathic REM sleep behaviour disorder although in
videometric evaluation, movements are not different compared to patients with idiopathic REM sleep behaviour disorder and Parkinson’s disease plus REM sleep behaviour
disorder (Oudiette et al., 2012). Recently the European
Narcolepsy Network studied 1099 HLA DQB1*0602 positive patients with clear-cut narcolepsy cataplexy retrospectively (Luca et al., 2013). In a subgroup of 295 patients who
underwent polysomnography, 43% of the males and 54%
of the females had REM sleep behaviour disorder, which is
a much higher amount of affected females than in idiopathic REM sleep behaviour disorder. Little is known
whether idiopathic and symptomatic REM sleep behaviour
disorder share the same pathophysiology (Unger et al.,
2010). Neuropathological studies of patients with idiopathic REM sleep behaviour disorder reveal the presence
of Lewy bodies, a pathological accumulation of -synuclein
in the brainstem (Iranzo et al., 2013). Narcolepsy patients
with RBD show symptoms like hyposmia (Stiasny-Kolster
et al., 2007), depression, constipation and hyperechogenicity of substantia nigra (Unger et al., 2009); however, the
underlying pathology is the loss of hypocretinergic neurons.
These neurons in the dorsolateral hypothalamus are vulnerable to damage by genetic, autoimmune, inflammatory or
traumatic factors. In recent animal studies the sublaterodorsal nucleus (Lu et al., 2006; Clement et al., 2011) was
identified as the nucleus being responsible for motor disinhibition in REM sleep. Reciprocal GABAergic connections
between the sublaterodorsal (Lu et al., 2006) and the
ventrolateral periaqueductal grey create a ‘flip-flop’ model
for the switches between non-REM and REM sleep. The
ventrolateral periaqueductal grey and surrounding areas are
a REM-off region with inhibitory GABAergic efferents to
the sublaterodorsal nucleus (Boissard et al., 2002, 2003;
Pollock et al., 2003), whereas GABAergic REM-on nuclei
G. Mayer et al.
in the dorsal paragigantocellular reticular nucleus and the
ventrolateral periaqueductal grey inhibit the REM-off
regions (Rampon et al., 1999; Gervasoni et al., 2000;
Verret et al., 2006).The sublaterodorsal nucleus has glutamatergic efferents (Krenzer et al., 2011) and receives glutamatergic input from the lateral periaqueductal grey and
ventrolateral periaqueductal grey (Beitz, 1990), the primary
motor area of the frontal cortex, the bed nucleus of the
stria terminalis and the central nucleus of the amygdala
(Boissard et al., 2003).
Muscle atonia during REM can be explained by direct
glutamatergic projection from the sublaterodorsal to the
ventral horn, activating glycinergic and/or GABAergic
spinal interneurons in lamina VIII of the ventral spinal
horn (Krenzer et al., 2011) or by sublaterodorsal projections to the ventromedial medulla (Vetrivelan et al., 2009).
A large population of REM-on GABAergic neurons in the
gigantocellular nucleus and raphe magnus nucleus indicate
that this medullary area, which has projections to the spinal
cord, is responsible for motor inhibition during REM sleep
(Sapin et al., 2009). Sublaterodorsal nucleus lesions can
reduce excitation of the medullary magnocellular reticular
formation resulting in a reduced inhibition of spinal motor
neurons.
Several imaging studies have been performed in patients
with idiopathic REM sleep behaviour disorder in the recent
years. MRI diffusion tensor imaging (DTI) alterations in
the pons, the right substantia nigra, the olfactory region,
the thalamic radiation in the anterior limb of the capsule,
the left temporal lobe, the right occipital lobe and the
fornix have been reported (Unger et al., 2010; Scherfler
et al., 2012). Garcia-Lorenzo et al. (2013) found structural
changes in the coeruleus/subcoeruleus complex correlating
with abolished muscle atonia during REM sleep. A recent
study found altered functional connectivity between the
substantia nigra and the putamen that was more impaired
in patients with Parkinson’s disease than in patients
with REM sleep behaviour disorder (Holtbernd et al.,
2014). In patients with narcolepsy/cataplexy, DTI
showed microstructural changes in the hypothalamus, mesencephalon, pons and medulla oblongata (Menzler et al.,
2012).
Within recent years, a few case reports on neurodegeneration in narcolepsy patients have been published
(Economou et al., 2012; Scammell et al., 2012). Scammell
et al. (2012) found evidence of Alzheimer’s disease in the
brains of 12 deceased narcoleptic patients. Christine et al.
(2012) found three narcoleptic patients in a cohort of 1152
patients with Parkinson’s disease, a number that is five
times greater than expected.
Within the past 15 years we have followed-up patients
with idiopathic REM sleep behaviour disorder, narcolepsy
with and without REM sleep behaviour disorder. Whereas
many of the patients with idiopathic REM sleep behaviour
disorder showed clinical signs of neurodegeneration, only 3
of 12 narcolepsy patients with REM sleep behaviour disorder that we followed from 2003 to 2013 (Mayer et al.,
Ictal SPECT in REM sleep behaviour disorder
2013) developed mild signs of Parkinson’s disease.
To study the pathways of REM sleep behaviour disorder
in vivo we performed ‘ictal’ single photon emission tomography (SPECT) immediately at the onset of REM sleep
behaviour disorder in four patients.
Materials and methods
Recording was performed in the hospital as video-EEG longterm polysomnography (PSG) using an IT-Med System l. The
following parameters were used for documentation: 22 channel EEG (including C3-mastoid and C4 to mastoid); EOG
(four channels), respiration (nasal and oral thermistor, thoracal
and abdominal effort), bilateral EMGs of musculus mentalis,
musculus extensor digitorum brevis, musculus flexor digitorum
brevis, musculus tibialis anterior and musculus gastrocnemius.
A one-channel ECG was recorded. The polysomnography was
performed under continuous observation by experienced medical staff.
Ictal and interictal subtraction SPECT was performed after
using a semi-automatic SPECT injection device permitting immediate intravenous application of the radioligand ECD (ethyl
cysteinate dimer) with a latency 510 s between onset of clinical event and injection. SPECT scanning was carried out after
the injection. For the SPECT acquisitions, the patients were
injected with on average 898 (741–1210) MBq Tc-99m ECD
(NEUROLITEÕ , Bristol-Myers Squibb). The time of injection
for the ictal examinations was determined by EEG: REM sleep
had to last for a minimum of 10 epochs, and complex behaviour in REM sleep had to be manifest for at least 10 epochs
(Fig. 1). The interictal injection was started after at least
15 min resting conditions. The acquisitions began 30 min
after the injection and were carried out on a MultiSpect 3
(Siemens Molecular Imaging) with low-energy high-resolution
collimation. Counts were collected in an energy window of
140 keV, 10% over 120 views (40 per detector, every 3 )
with 25 s per view, a matrix size of 128 128 and a zoom
of 1.23. The views were reconstructed into 3D data sets using
filtered back projection with a Butterworth filter of fifth order
and cut-off frequency of 0.6 Nyquist. Further corrections for
scattered radiation were not applied. The photon attenuation
was corrected using Chang’s algorithm, assuming a homogenously attenuating medium. In a post-processing step, the ictal
and interictal reconstructed data sets were subtracted pixelwise from each other for every patient, after spatial co-registration and intensity normalization. Negative values were discarded, so that we obtained difference images that represented
ictal hyperperfusion. Additionally, the difference images were
coregistered to MRI images, for better anatomical assignment
of the hyperperfusion. The method has been published previously; more details can be found in Hahn et al. (2009).
The study was approved by the ethical committee of the
Chamber of Physicians Hessen. All patients gave signed informed consent.
Demographics
We studied one patient with idiopathic REM sleep behaviour
disorder, one patient with Parkinson’s disease and REM sleep
behaviour disorder and two patients with long-standing
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narcolepsy/cataplexy and REM sleep behaviour disorder. All
patients met the diagnostic criteria for REM sleep behaviour
disorder and narcolepsy according to International
Classification of Sleep Disorders, 2 (American Academy of
Sleep Medicine, 2005). The female patient with idiopathic
REM sleep behaviour disorder was diagnosed 20 years ago
and had subsequently developed signs of full-blown
Parkinson’s disease (Hoehn and Yahr stage 4) at the time of
investigation. The patient demographic data are shown in
Table 1. The movements during REM sleep prior to injection
of the tracer are shown in Table 2.
Results
All patients, independent of their REM sleep behaviour disorder type, displayed a similar pattern of activation in the
ictal SPECT. The activation included the bilateral premotor
areas, the interhemispheric cleft, the periaqueductal area,
the dorsal and ventral pons and the anterior lobe of the
cerebellum (Figs 2–5). The thalamus was activated in the
female narcolepsy patient with REM sleep behaviour disorder (Fig. 5).
Because of the ‘smearing’ principle of the filtered back
projection reconstruction, some small amounts of residual
activity can be projected outside of a patient’s skull, which
is an artefact of the method.
Discussion
To our knowledge this is the first study to report results of
ictal SPECT in patients with idiopathic REM sleep behaviour disorder, Parkinson’s disease (preceded by REM sleep
behaviour disorder) and patients with narcolepsy and REM
sleep behaviour disorder. Interestingly, the different forms
use the same pathways and activate the same cortical and
brainstem areas sparing the basal ganglia. This finding is
surprising as the basal ganglia are involved in the neural
loops of motor activity. The activated cortical, brainstem
and cerebellar areas represent a network of structures responsible for motor activity, REM sleep, muscle tone
during sleep and coordination. The involved structures
have been described in animal studies (Krenzer et al.,
2011; Luppi et al., 2011), post-mortem studies (Boeve
et al., 2007; Dugger et al., 2012) and imaging studies
(Unger et al., 2010) in humans. However, most of the
studies on neural connectivity of movements in healthy subjects have been performed during the wake state, which
makes comparison to movements in REM sleep difficult,
if not impossible.
In healthy subjects, voluntary leg movements during
wake, as measured by blood oxygen level-dependent functional MRI, result in activations in the primary sensorimotor cortex, the supplementary motor area, cingulate
motor area, the anterior cerebellar vermis, both cerebellar
hemispheres, thalamus, and right putamen (Jaeger et al.,
2014). Functional MRI studies using a finger tapping
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Table 1 Demographic and test data
Patient Age Sex Diagnosis Co-morbid
years
of RBD
diseases
CR
64
F
Clinical
PSG
RD
65
M
MH
63
F
CF
41
F
Clinical
PSG
Clinical
PSG
Clinical
PSG
RBD
Duration Cataplexy MSLT: Number TDI Olfactory
Any UPDRS Hyperech MMSE
duration narcolepsy
SL min SOREM
dysfunction EMG III
SN
years
years
PD, sleep
24
apnoea,
hypertension
Sleep
10
apnoea
Narcolepsy
14
Narcolepsy
30
NA
NA
NA
NA
NA
NA
NA
NA
29
1
5.5
3
30
1
1.1
3
13
Severe
58.8
21
Y
29
Severe
17
0
Y
30
26.5 Mild
67.1
6
Y
28
27
67.2
0
Y
28
Mild
Any EMG = 30 s epochs containing phasic and/or tonic muscle activity in REM; Hyperch SN = hyperechogeneity of substantia nigra; MMSE = Mini-Mental State Examination; MSLT =
multiple sleep latency test (five tests); PD = Parkinson’s disease; PSG = polysomnography; SOREM = sleep onset REM; UPDRS III = Unified Parkinson’s Disease Rating Scale: motor
score; RBD = REM sleep behaviour disorder; SL = sleep latency; TDI = threshold-discrimination-identification.
Table 2 Behaviour of patients before and after tracer injection
Patient
Behaviour prior to tracer injection
Behaviour after tracer injection
CR
RD
MH
CF
Kicking with legs, shouting
Twitching of both arms, spreading arms (right 4 left arm)
Talking, twitching of arms and legs, grimacing
Talking, kicking first left then right foot
Kicking, punching, rocking movements
Grasps for bedded grid, shaking it strongly, fumbling of hands
Kicking of legs, movements of pelvis, grasping
Shouting, kicking with feet, punching movements of arms
paradigm showed hypo-activation in the bilateral putamen,
right supplementary motor area and hyperactivation in the
right premotor cortex in patients with Parkinson’s disease,
which was considered to be a disruption of the corticostriatal processing (Taniwaki et al., 2013). In our patients
the bilateral activation of the premotor (supplementary
motor) areas shows the cortical activation of disinhibited
motor activity in REM sleep. Whether this is due to activation by GABAergic or glutamatergic inputs from the
‘dysfunctional’ sublaterodorsal nucleus or primarily from
the cortex needs to be answered by other methods than
ictal SPECT. The activation of the interhemispheric motor
cortex is in-line with the video polysomnographies prior to
injection of the radioligand, which show movements in
REM sleep in the lower limbs of three patients. The areas
of the dorsal medulla may represent the region of the periaqueductal grey and the sublaterodorsal that are involved
in the ‘REM-on’ mechanism. The activation of the anterior
pontine region could represent the downstream inhibition
of muscle tone during REM sleep by glycinergic mechanisms. The activation of the cerebellum is more difficult to
attribute to the known pathophysiology of REM sleep behaviour disorder, because the literature is scarce. A recent
study showed reduced grey matter volume of the anterior
lobes of both cerebellar hemispheres and the tegmental portion of the pons in patients with REM sleep behaviour
disorder compared to healthy controls (Hanyu et al.,
2012). This loss of grey matter is also found in synucleinopathies. Patients with dementia of the Lewy body type
showed specific atrophy in the midbrain, pons and
cerebellum in comparison to patients with Alzheimer’s disease (Nakatsuka et al., 2013). The anterior cerebellum is
responsible for the fine motor regulation and the timing of
movements. Based on these findings, we hypothesize that
the cerebellar activation that we found in our study affects
an atrophic cerebellum and results in an impaired coordination in REM sleep behaviour disorder patients with short,
jerky and non-fluent movements. This movement pattern
does not differ between REM sleep behaviour disorder
patients with Parkinson’s disease, idiopathic REM sleep behaviour disorder, and REM sleep behaviour disorder in
primary narcolepsy (Oudiette et al., 2012), suggesting a
common motor pathway. Despite being non-fluent and
jerky the movements of Parkinson’s disease patients with
REM sleep behaviour disorder during REM sleep contrast
with the typical hypokinetic parkinsonian movements
during wakefulness (De Cock et al., 2007). This contrast
has triggered the hypothesis that movements in REM sleep
behaviour disorder are generated by the motor cortex bypassing the extrapyramidal tract. Our study seems to confirm this hypothesis in patients with Parkinson’s disease
and REM sleep behaviour disorder and idiopathic REM
sleep behaviour disorder. This hypothesis is of further interest as REM sleep is accompanied by typical EEG changes
that are caused by cortical activation, and which are
mediated by glutamatergic projections from REM-on
regions in the brainstem (Luppi et al., 2012). If the degenerative changes in the brainstem can explain an activation
of the motor cortex, this needs to be clarified by future
studies. The REM sleep behaviour disorder movement
Ictal SPECT in REM sleep behaviour disorder
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Figure 1 Polysomnography before, at and after tracer injection. Muscle activity of musculus mentalis started 12 epochs prior to
injection of ECD tracer (blue line) and was accompanied by intermittent muscle activity of musculus mentalis (450%/epoch) and kicking
movements of the left, followed by the right leg. F8–P3 = scalp electrodes for EEG recordings; VER1/2 = vertical eye movements; HOR1/2 =
horizontal eye movements; NASAL = nasal flow; THORAKAL = thoracal excursion; ABDOMINA = abdominal excursion; EMG and EMG3 =
mentalis muscle; EXT1/2 = musculus extensor digitorum brevis; FLEX1/2 = musculus flexor digitorum brevis; TA1/2 = musculus tibialis anterior;
GAST1/2 = musculus gastrocnemius.
pattern has never been explained sufficiently by animal or
human studies. It can be hypothesized that it could be
caused by instability of the activation of the sublaterodorsal
nucleus, possibly depending on a certain threshold of afferent inputs. Recently two cell groups were identified during
pharmacologically-induced REM sleep-like episodes in rodents (Stettner et al., 2013): the adrenergic cells of the C1
group and the cells of the lateral reticular nucleus. C1 cells
are activated during REM sleep whereas lateral reticular
nucleus cells are silent. Lateral reticular nucleus neurons
belong to the spinoreticulo-cerebellar pathway in which
the intended and actual movements are compared to
allow corrections to enable swift movements. An impaired
spinoreticular pathway and the reduction of the grey matter
of the anterior lobe of the cerebellum may be the cause of
the absence of smooth movements and walking during
REM sleep without atonia. Activation of the thalamus
was found in one narcolepsy patient. This finding differs
from SPECT studies in normal REM sleep of narcolepsy
patients, which is characterized by decreased blood flow in
the thalamus (Asenbaum et al., 1995).
In humans, a recent study of the brains of three patients
with REM sleep behaviour disorder that had developed
Parkinson’s disease and dementia of the Lewy body type
(Iranzo et al., 2013) showed moderate to severe neuronal
loss, gliosis, Lewy bodies, and Lewy neurites in the brainstem (especially in the coeruleus/subcoeruleus, pons, dorsal
nucleus of the vagal nerve) and limbic system, and to a
lesser extent in cortical areas. This finding is in-line with
the results of imaging studies. Neurodegeneration is also
present in patients with narcolepsy, as could be shown by
DTI (Menzler et al., 2012). A longitudinal study in patients
with narcolepsy without cataplexy, with intermediate hypocretin-1 in the CSF, has shown that many develop cataplexy up to 26 years after the onset of excessive daytime
sleepiness, meaning that a critical threshold of age-
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Figure 2 Ictal SPECT of Patient CR, female with
Parkinson’s disease with REM sleep behaviour disorder.
Difference images of cerebral perfusion, measured by Tc-99m ECD
SPECT (in colour), overlaid on T1-MRI (greyscale). The colour of
the SPECT indicates the degree of ictal hyperperfusion, ranging from
weak (blue and green) to strong (orange and red). The arrows indicate hyperperfusion in brain regions. Median, precentral activation
(premotor area), activation of left brainstem and right anterior
cerebellum. A =anterior; H =head; P =posterior; F =foot; R=right;
L =left.
Figure 3 Ictal SPECT of Patient RD, male with idiopathic
REM sleep behaviour disorder. Difference images of cerebral
perfusion, measured by Tc-99m ECD SPECT (in colour), overlaid on
T1-MRI (greyscale). The colour of the SPECT indicates the degree of
ictal hyperperfusion, ranging from weak (blue and green) to strong
(orange and red). The arrows indicate hyperperfusion in brain regions. Bifrontal activation in premotor area, pons and anterior
cerebellum. A =anterior; H =head; P =posterior; F =foot;
R =right; L=left.
Figure 4 Ictal SPECT Patient MH, female with narcolepsy
with REM sleep behaviour disorder. Difference images of
cerebral perfusion, measured by Tc-99m ECD SPECT (in colour),
overlaid on T1-MRI (greyscale). The colour of the SPECT indicates
the degree of ictal hyperperfusion, ranging from weak (blue and
green) to strong (orange and red). The arrows indicate hyperperfusion in brain regions. Activation of median interhemispheric cleft,
bilateral activation of brainstem and left vermis. A =anterior;
H =head; P =posterior; F =foot; R =right; L=left.
dependent degeneration of hypocretinergic cells may have
occurred (Andlauer et al., 2012). DTI in narcoleptic
patients has found microstructural changes of the hypothalamus, mesencephalon, pons and medulla oblongata.
Our findings do not show involvement of the substantia
nigra, as in awake patients with idiopathic REM sleep behaviour disorder (Unger et al., 2009; Scherfler et al., 2012).
In contrast to all the neural networks of REM sleep behaviour disorder found during wakefulness (Holtbernd et al.,
2014), our findings show no involvement of the basal ganglia. The activation of this different connectivity could be
one explanation for a more fluent behaviour of patients
with Parkinson’s disease and REM sleep behaviour disorder during REM sleep. SPECT is only one among
many methods to display activation of brain areas in
actual states. It does not show the process causing activation and localization is not very precise. Therefore investigations identifying neurotransmitters involved in the
activation of this neural network must be carried out. In
contrast to idiopathic REM sleep behaviour disorder, and
Parkinson’s disease and REM sleep behaviour disorder,
which are considered to be -synucleinopathies in narcolepsy with REM sleep behaviour disorder, hypocretins are
involved in the pathology as confirmed in animal and
human studies (Knudsen et al., 2010). The activation of
the thalamus in one patient is the opposite of the
Ictal SPECT in REM sleep behaviour disorder
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comments. We express our gratitude to PD Dr. Matthias
Dütsch for technical assistance during SPECT application.
Funding
No funding was received for this work.
References
Figure 5 Ictal SPECT Patient CF, female with narcolepsy
with REM sleep behaviour disorder. Difference images of
cerebral perfusion, measured by Tc-99m ECD SPECT (in colour),
overlaid on T1-MRI (greyscale). The colour of the SPECT indicates
the degree of ictal hyperperfusion, ranging from weak (blue and
green) to strong (orange and red). The arrows indicate hyperperfusion in brain regions. Activation of median interhemispheric cleft,
asymmetric activation of brainstem, activation of thalamus.
A =anterior; H =head; P =posterior; F =foot; R =right; L=left.
deactivation that has been described in older literature
(Asenbaum et al., 1995).
There are some limitations of this study: the number of
patients is small, and they have different forms of REM
sleep behaviour disorder. There is no control group, as
ictal SPECT in patients without REM sleep behaviour disorder is not possible. SPECT does not show anatomic regions very precisely. Despite the small and heterogeneous
cohort of patients the results are robust, but should be
confirmed by further studies.
In conclusion, ictal SPECT during REM sleep has shown
that a network of cortical, cerebellar and brainstem areas—
responsible for initiating, controlling and timing motor activity—are activated in the process of REM sleep behaviour
disorder of different origin. The activated areas are in-line
with those found by different imaging techniques in
humans and in REM sleep behaviour disorder animal
models, but they spare the basal ganglia.
Acknowledgements
We thank Wolfgang Oertel from the Department of
Neurology/Philipps University Marburg for his valuable
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