Sundowning and circadian rhythm disorders in dementia -...

Sundowning and circadian rhythm disorders in dementia

Sleep disorders and disruptive nocturnal behaviours
are commonly reported in people with senile dementia
and present both a significant clinical problem and a
cause of increased stress for caregivers.

Neuronal degeneration of cholinergic Nucleus basalis
Meynert (NBM) neurons promote rest-activity distur-
bance and Sundowning in Alzheimer’s disease. NBM neu-
rons modulate the activity of the mainly cholinergic
suprachiasmatic nucleus (SCN) and the induction of
NONREM sleep. Sundowning might be explained as a
syndrome occurring when arousal is to be processed
while the neocortex is already turned “off” to
(NONREM) sleep. The therapeutic measures should thus
primarily be aimed at the stimulation of the circadian
system and enforcing “external Zeitgebers”. Pharmaco-
logically, application of cholinergic enhancers i.e.
cholinesterase inhibitors and melatonin supports and
should stabilize the weakened structures.

Key words : Sleep disorder ; old age ; dementia ; neu-
roleptics ; melatonin ; sundowning ; bright light
therapy ; PLMS.


Klaffke S, Staedt J. Sundowning and circadian rhythm disorders in dementia. Acta neuol belg 2006; 106:168-175.


Introduction


Sleep disorders and disruptive nocturnal behav-
iours are commonly reported in people with senile
dementia and present both a significant clinical
problem and a cause of increased stress for care-
givers. According to a large study in Germany 51%
of caregivers experience disruptions of sleep conti-
nuity, on average 2.4 per night (Grassel 2000). In
fact, many caregivers cite sleep disturbances,
including night wandering and confusion, as the
main reason for institutionalizing the elderly (Coen
et al. 1997, Pollak et al. 1990). With increasing age
qualitative as well as quantitative changes in sleep
occur, and approximately 38% of the over-65-year-
old report sleep disturbances according to epidemi-
ological studies. 36% suffer from sleep onset dis-
turbances and up to 29% suffer from disturbances
of sleep continuity (Foley 1995). Subjectively
experienced sleep disturbances correlated negatively
with cognitive performance in a 3-year follow-up
(Jelicic et al. 2002). According to the literature, 34-
43% of the patients with Alzheimer’s Disease (AD)
experience sleep disturbances (Cacabelos et al.
1996, Tractenberg et al. 2003). The extent to which
the night sleep is disturbed is said to correlate with
severity of dementia (Bliwise et al. 1995).


Sleep disturbances in elderly


There are two main types of sleep : rapid eye
movement (REM) sleep and nonrapid eye move-
ment (NONREM) sleep, which has four stages.
People normally cycle through the four stages of
NONREM sleep, usually followed by a brief inter-
val of REM sleep, four or five times every night.
Sleep progresses from stage I, during which the
sleeper can be awakened easily to stage IV, during
which the sleeper can be awakened only with diffi-
culty. In stage IV, blood pressure is at its lowest,
and heart and breathing rates are at their slowest.
During REM sleep, electrical activity in the brain is
unusually high, somewhat resembling that during
wakefulness. The eyes move rapidly, and muscles
may jerk involuntarily. The rate and depth of
breathing increase, but the muscles, except for the
diaphragm, are greatly relaxed. The first period of
REM typically lasts 10 minutes, with each recur-
ring REM stage lengthening, and the final one
lasting up to 40min (see figure 1). The stage-
respective dimensions of sleep change relatively to
age. In particular, there is a diminished consolida-
tion of NONREM sleep (see figure 2). Patients
with dementia, have lower sleep efficiency, an
increase in the length of stage I sleep, a decrease in
stage III and stage IV ; more sleep disruptions and
awakenings, episodes of nocturnal wandering and
an increase in daytime napping.

In addition other factors have to be considered
causing sleep disturbances in old age like sleep
apnea syndrome (SAS), restless leg syndrome
(RLS), or nycturia or an enuresis nocturna (Bliwise
et al. 2004).

Sleep apnea is defined as an absence of air flow
at the nose and mouth for at least 10seconds.
Obstructive apnea is defined as the absence of air
flow despite respiratory efforts. Central apnea, less
common, is characterized by absence of respirato-
ry efforts. Mixed apneas begin centrally, followed
by obstruction. People with SAS may experience
waking with gasping, confused wandering in the
night, and thrashing during sleep. Among healthy
older adults living in community settings, the
prevalence of SAS is 28% in men and 20% in
women. SAS occurs in 42% of people with demen-
tia who live in nursing homes and correlates with
cognitive function (Martin et al. 2005). One of the
main risk factors for obstructive SAS is obesity,
causing an increased size and fat content of the
pharyngeal tissues, soft palate and uvula. During
the apneas, the oxygen level in the blood falls caus-
ing many of the daytime symptoms such as exces-
sive drowsiness. In some cases pulmonary hyper-
tension may develop leading to right sided heart
failure or cor pulmonale. Obstructive SAS is also
associated with systemic hypertension, cardiac
arrhythmia, ischemic heart disease and stroke.
Therefore sleep apnea is more often associated
with multi-infarct or vascular dementia than with
Alzheimer’s dementia (Bassetti et al. 1996).
Weight management and avoiding alcohol and
sedatives (which can exacerbate SAS by further
relaxing the pharyngeal muscles) at bedtime may
relieve SAS. In some individuals continuous posi-
tive airway pressure (CPAP) may be required.
Patients which AD can also tolerate CPAP but com-
pliance in long-term use may be difficult (Ayalon et
al. 2006).

Another common cause for sleep disturbances is
restless legs syndrome (RLS) with a prevalence of
about 29% in the elderly (Obler 1991). RLS is
characterized by unpleasant limb sensations, usual-
ly described as a creeping or crawling feeling,
sometimes as a tingling, cramping, burning or just
plain pain, that are precipitated by rest and relieved
by activity. Some patients have no definite sensa-
tion, except for the need to move. In up to 50% the
arms are affected as well. There is a definite wors-
ening of the discomfort when lying down at night
or during other forms of inactivity, including just
sitting. About 80% of RLS patients also experience
Periodic Limb Movements in Sleep (PLMS).
PLMS is characterized by sudden jerking or bend-
ing of the legs during sleep ranging from small
shudders of the ankles and toes to kicking and flail-
ing of the arms and legs. The periodic jerking often
wakes the individual and significantly disturbs their
quality of sleep. PLMS can occur independently in
up 45% of elderly (Ancoli-Israel et al. 1991). RLS
is caused by a functional disturbance in the
dopaminergic system (Staedt et al. 1995). Treat-
ment of first choice consists of dopaminergic drugs
or dopamine agonists such as pergolide or
pramipexole (Montplaisir et al. 1996, Staedt et al.
1998). PLMS is greatly underdiagnosed especially
in people with dementia who are unable to describe
their symptoms. However, if a deterioration or dis-
ruption of sleep is noticed in patients taking anti-
depressants or neuroleptics, PLMS should be
considered, since antidepressants, in particular
SSRI and also neuroleptics potentially induce or
exacerbate PLMS (Horiguchi et al. 1999, Kraus et
al. 1999, Wetter et al. 2002, Yang et al. 2005).
PLMS can be easily diagnosed by actigraphy
placed on the ankle of each leg (Ancoli-Israel et al.
2003, King et al. 2005, Sforza et al. 2005).
Actigraphy is highly tolerated even in severely
demented patients and makes home recordings
more accessible, permitting the evaluation of
patients in their natural sleeping environment and
minimizing laboratory effects likely to alter the
patient’s typical sleep patterns (see figure 3).

Circadian rhythm disorders in dementia

Circadian rhythmicity, regulated by the
suprachiasmatic nucleus (SCN), is observed in
secretion of several hormones such as melatonin,
body temperature and heart rate among other phys-
iological functions. Specific ganglion cells in the
inner retinal layer project light information to the
SCN via the retinohypothalamic tract. From here,
messages are transmitted via a neural pathway to
the pineal gland which secretes melatonin – the
chemical circadian pacemaker. Melatonin secretion
is suppressed by light but increased at night during
sleep, and is a sensitive marker of light shift
changes in circadian rhythm. The SCN is also
involved in the regulation of arousal level or sleep-
wake rhythm via projections to the anterior and
posterior hypothalamus (Miller 1993). Circadian
disorders, such as sleepwake cycle disturbances,
are associated with aging, and even more pro-
nounced in dementia. Many studies have reported
disrupted melatonin production and rhythms in
aging and in AD that are taking place as early as in
the very first preclinical AD stages (neuropatholog-
ical Braak stage I-II) (Wu and Swaab 2005). Since
an Alzheimer pathology underlies approximately
70% of dementing diseases (Neuropathology
Group of the MRC CFAS 2001), the potential
impact of the neurophysiological changes of
Alzheimer’s dementia on the rest-activity regula-
tion should be discussed. Neuronal degeneration in
the Nucleus basalis Meynert (NBM) is one of the
most prominent features (McGeer et al. 1984,
Reinikainen et al. 1988). The NBM could be
defined as a cholinergic nuclear area which belongs
to the ascending reticular activation system
(ARAS) and which innervates the neocortex.
There, acetylcholine reduces the resting/voltage-
dependent potassium membrane potential and thus
increases neuronal excitability (reagibility). NBM
neurons show a bursting and a tonic firing pattern.
Whereas the latter might be associated with
NONREM sleep, faster release of acetylcholine
might underlie wakefulness (Nunez 1996). During
the wake phase cholinergic pathways also inhibit
the nuclei reticulares thalami (Steriade 2004).
During the sleep phase this inhibitory influence
disappears and the nuclei reticulares thalami induce
a GABA-modulated NONREM sleep synchroniza-
tion. Thus it is understandable that in Alzheimer’s
dementia an increasing cholinergic deficit produces
EEG frequency decelerations which complicate the
differentiation of the sleep-wake EEG with increas-
ing severity of dementia. Accordingly, an extreme-
ly low cell density in the NBM and a low activity
of the choline acetyltransferase in the cortex of
patients with the highest delta activity is found
(Riekkinen et al. 1990). The decreasing activity of
the SCN and the synthesis of melatonin that
diminishes in accordance with the progression of
the illness (as determined by the Braak stages) (Wu
et al. 2003) facilitate the disturbed rest-activity
rhythm in AD along with reduced so-called “exter-
nal zeitgebers” (physical activity, social isolation,
low light intensity in living areas). While napping
may be an expression of a disrupted sleep-night-
structure, it has been shown to induce changes in
the circadian rhythm when performed in the
evening hours (Yoon et al. 2003).

Sundowning

The synopsis of these neuropathological changes
in the SCN and the NBM makes the occurrence of
rest-activity disturbances more easily understand-
able. The most spectacular disturbance is “sun-
downing”. This term describes a delusional and
often delirious state which occurs at twilight or
during early night (Bliwise 1994). People with
dementia may become more confused, restless and
insecure, hallucinations may occur. It can be worse
after a move or change in the person’s routines.
Data on the prevalence are varying from 10 to 25%
in institutionalized patients (Evans 1987, Martin et
al. 2000) and even higher numbers in Alzheimer’s
patients living at home reaching up to 66%
(Gallagher-Thompson et al. 1992). A decrease of
the activity of the SCN, the so-called “internal zeit-
geber”, could play a major role for the occurrence
of sundowning. In favor of this assumption is the
fact that sundowning usually occurs at twilight
with reduced light intensity and the fact that rays of
light have a stimulating effect on the SCN via the
glutamatergic retinohypothalamic tract (Belenky
and Pickard 2001). The reduced lightmediated
activation of the SCN could thus negatively influ-
ence the arousal level and induce a desynchroniza-
tion of the rest-activity rhythm. In line with the lat-
ter assumption, sundowning intensity increases
with reduction and phase delay of the temperature
amplitude (Volicer et al. 2001).

To our opinion, the sundowning in AD, is patho-
physiologically based on a cortical activation
(arousal reaction) with concurrently reduced indi-
rect SCW mediated base activation which is addi-
tionally enhanced by the cholinergic deafferentia-
tion of the cortex and the reduced cholinergic
inhibition of the nuclei reticulares thalami. Putting
it more simply, sundowning is characterized by an
arousal (e.g. fear due of impaired visual orienta-
tion, vocalizations of other residents) whereas the
neocortex is “turned off”, programmed toward
NONREM sleep. Because of the cholinergic deaf-
ferentiation of the cortex the patient is then not able
to build up the attentional capacity necessary for
the processing of arousal. As a consequence, the
stimulus causing the arousal cannot be processed
and agitation persists or even augments. In this line
disruptive vocalizations of elderly demented typi-
cally occurs more often during the afternoon and
evening hours (Burgio et al. 2001).

Interestingly, patients with dementia with Lewy
bodies (DLB) are especially sensitive to anti-
cholinergic agents, indicating marked cholinergic
dysfunction.

Post-mortem studies of brain tissue from
patients with DLB revealed a severe depletion of
the NBM with 75% to 80% loss of large choliner-
gic neurons (in AD 50% to 70% loss of cholinergic
neurons) (Jellinger 2000), and a severely reduced
cholinergic activity in the reticular thalamic nucleus
associated with hallucinations and fluctuating con-
sciousness (Perry et al. 1997).

Sedative psychotropic medication applied in the
treatment of sundowning and nocturnal agitation is
to be considered problematic since benzodiazepines
or neuroleptics further weaken the already instable
sleepwake rhythms and further decrease neuronal
metabolic activity. Furthermore, the possibility that
low-dose antipsychotic treatment and treatment
with benzodiazepine is associated with increased
risk of cerebrovascular events in elderly patients
with dementia has been raised (Finkel et al. 2005).
Anyhow, others suggested that preexisting cere-
brovascular risk factors might interact with some
atypical antipsychotics increasing the risk of events
(Liperoti et al. 2005). It seems therefore plausible
that sedative psychotropic medication on the one
hand increase duration of hospitalization (Yuen et
al. 1997) and on the other hand promotes confusion,
impaired cognition and excessive sedation with
danger of falling (Ancoli-Israel and Kripke 1989,
Stoppe et al. 1999). Consequently, substances
physiologically stimulating the circadian timing
system in a specific way should be applied.
Pharmacological candidates are cholinesterase
inhibitors and melatonin.

Cholinesterase inhibitors are the therapy of
choice for the treatment of AD and have also shown
efficacy in other forms of dementia (McKeith et al.
2000, Samuel et al. 2000, Feldman et al. 2001,
Aarsland et al. 2002, Erkinjuntti et al. 2002, Black
et al. 2003, Kurz et al. 2003, Moretti et al. 2003,
Wilkinson et al. 2003, Bullock 2004, Burns et al.
2004, Malouf and Birks 2004). Metaanalysis
showed that they also influence non-cognitive
symptoms and reduce psychotic symptoms, espe-
cially in Lewy body dementia (McKeith et al. 2000,
Trinh et al. 2003). They should be applied at day-
time in demented patients, especially when distur-
bances of circadian rhythms or sundowning occur.

Melatonin is believed to predominantly inhibit
the activity of the SCN via Mel1a,b receptors (Liu et
al. 1997, Jin et al. 2003). Exogenously adminis-
tered melatonin possesses a circadian-phase-
dependent hypnotic property (Wyatt et al. 2006)
improving sleep only when endogenous melatonin
is absent. Melatonin should be given after light
therapy at 8 p.m.

Results of a functional MRI study demonstrate
that melatonin modulates brain activity in a manner
resembling actual steep although subjects are fully
awake. Furthermore, the fatigue inducing effect of
melatonin on brain activity is essentially different
from that of sleep deprivation thus revealing differ-
ences between fatigues related to the circadian
steep regulation as opposed to increased homeosta-
tic sleep need (Gorfine et al. 2006). However,
placebo-controlled studies on the application of
melatonin showed contradictory results. Asayama
et al. (2003) found a significant decrease in noctur-
nal activity, a prolongation of sleep and an
improvement of cognition after 4 weeks of admin-
istering melatonin (3 mg), whereas Serfaty et al.
(2002) did not find an amelioration of sleep after
the administering of 6 mg of melatonin over a peri-
od of 2 weeks. Singer et al. (2003) found after two
months of administration of either 2,5 mg sustained-
release melatonin, 10 mg melatonin or placebo, no
statistically significant differences in objective sleep
measures for any of these groups although non-
significant trends for increased nocturnal total
sleep time and decreased wake after sleep onset
were observed in the melatonin groups relative to
placebo. Trends for a greater percentage of subjects
having more than a 30-minute increase in nocturnal
total sleep time in the 10 mg melatonin group and
for a decline in the day-night sleep ratio in the
2.5 mg sustained-release melatonin group, com-
pared to placebo, were also seen. On subjective
measures, caregiver ratings of sleep quality showed
improvement in the 2.5 mg sustained-release mela-
tonin group relative to placebo.

Thus, melatonin might need a longer time to
exert an effect on sleep and other relevant
symptoms of dementia. This supports the study of
Cardinali et al. (2002), who found a positive in-
fluence on sundowning and sleep under the applica-
tion of 6 mg of melatonin in the 4-month follow-up.

Another interesting aspect in this context is the
fact that music therapy increases the melatonin
levels in AD patients and possibly has a soothing
effect by means of the latter mechanism (Kumar et
al. 1999).

In general, after exclusion of sleep disturbances
due to PMLS and before applying other drugs, non-
pharmacological approaches in order to physiolo-
gically stimulate the chronobiological and homeo-
static regulation of rest-activity rhythms should be
primarily used. The remaining dynamic usedepen-
dent neuronal processing/connecting capacity
should be reinforced by sufficient light exposure a
well-directed day-structure with meals, stimulating
coffee and physical activity on a regular basis. The
caregivers should be asked for a description of the
daily routine and given the respective advice (Teri
et al. 2002).

However, studies provide evidence that in some
nursing home environments only a light intensity
of a median of 54 lux was measured, and the resi-
dents only spent approximately 10 minutes in light
of more than 1000 lux (Shochat et al. 2000). In
comparison with that we reach 300-500 lux in our
illuminated workspaces. Even on cloudy days dur-
ing winter the light intensity reaches 3000-4000 lux
outdoors. The positive effect of daylight on sleep
could be proven in a study on elderly with sleep
disorders (Mishima et al. 2001). In this study an
exposure to daylight for two hours in the morning
and for two hours in the afternoon resulted in
increased melatonin levels and sleep amelioration.
In demented patients light therapy during the
evening hours reduces nocturnal motoric agitation
(Satlin et al. 1992, Haffmans et al. 2001), but light
therapy during the morning hours is also effective
(Okumoto et al. 1998, Lyketsos et al. 1999) and
even an amelioration of cognition in the Mini
Mental State Examination can be achieved
(Yamadera et al. 2000, Graf et al. 2001). Also indi-
rect light therapy with increased light intensity in
the living room stabilizes the sleep-wake cycle (van
Someren et al. 1997). Stimulation exerted by sun-
rise and sunset also had positive effects on sleep
onset latency, nocturnal agitation states and sleep
duration in elderly patients with advanced demen-
tia (Fontana Gasio et al. 2003). According to the
available data and the routines of (nursing) homes,
we recommend for demented patients a 30-minute
light therapy of 10,000 lux which in consideration
of the load on the time schedule can be easily fitted
into the ward routine. Alternatively 2500 lux can be
applied for two hours. However, it has to be noted
that severely demented patients with substantial
degeneration of the SCN can only benefit to a
limited extent (Ancoli-Israel et al. 2003).


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___
Prof. Dr. J. STAEDT,
Griesingerstr. 27-33,
13589 Berlin (Germany).
E-mail : juergen.staedt@vivantes.de