Dementia (PROMs) are increasingly used in evaluating health

Dementia
with Lewy bodies (DLB) is the second most common neurodegenerative dementia
after Alzheimer’s disease (AD) in people over 65 years of age. DLB differs from
AD as early cognitive symptoms include deficits in visuospatial and executive
function, rather than memory. DLB is characterized by parkinsonism,
fluctuations in mental status, visual hallucination, and hypersensitivity to
neuroleptics. Therefore, it is difficult to discriminate between DLB and
Parkinson’s disease with dementia (PDD). Both diseases also share a similar
pathologic finding, Lewy bodies. Generally, if cognitive impairments appear
within a year of parkinsonism, DLB is diagnosed, while patients with
parkinsonism for at least a year prior to cognitive impairment are classified
as PDD. Early amyloid deposition in DLB relative to PDD may explain the
difference in the timing of dementia and parkinsonism. Quality
of life (QoL) is a key outcome measure of health and social service
interventions. Currently, patient-reported outcome measures (PROMs) are
increasingly used in evaluating health and social care. Definitions of
health-related QoL include physical, mental, social and role functioning, and
health perceptions 1. Because aging
is a global issue, it is critical to identify QoL determinants in the elderly
who suffer from chronic disease. A recent study from Southern Taiwan showed
Alzheimer disease-8 (AD-8), a screening tool, had the strongest association
with total QoL score in 115 old age adults suffering from chronic disease. It
is important for geriatric health care providers to realize that cognitive
impairment among old age adults with chronic disease is a critical determining
factor of poor QoL 2. Assessing
QoL in people with dementia is crucial for evaluating their outcomes; however,
it is challenging to interview patients who have a limited ability to express
themselves and may lack insight. Meanwhile, there are questions concerning the
validity of generic measures of QoL, which are not specific to dementia. Currently,
evaluations of QoL largely focus on general dementia or AD. A systematic review
3 regarding QoL
in dementia strongly suggests that depression is consistently related to
decreased QoL. Surprisingly, there is no convincing evidence indicating that
lower cognitive ability or greater limitations in activity are associated with a
lower QoL. Evidence
concerning QoL in DLB patients is limited 4. In a
comparison study, QoL was measured using the Alzheimer Disease Related Quality of Life (ADRQL) evaluation , a
proxy-rated, dementia-specific instrument. The authors concluded that DLB
patients have poorer QoL than AD patients 5. Figari et al. compared QoL in 46 AD, 23 DLB,
and 39 Huntington’s disease (HD) patients, all of whom had dementia for at
least two years. Patients with DLB scored significantly lower on the SF-12
Physical and Mental Health Summary than patients with HD and AD. The authors
concluded that, when adjusted for age, cognition, comorbidity, and depression,
patients with DLB had the poorest QoL 6. There
is only one study whose primary aim was to compare the QoL in patients with DLB
and AD 7. 34 DLB
patients and 34 cognitive-matched AD patients were evaluated using two QoL
instruments: EQ-5D and QoL-AD. The results showed both patient-rated and
proxy-rated QoL was poorer in patients with DLB than those with AD. Due to many
differences in clinical symptoms, it is reasonable to predict differences in
QOL between diseases. Herein, we elaborate on studies related to QoL in DLB
patients.  MethodsStudies
were selected from the PubMed database using keywords “quality of life” and
“dementia with Lewy bodies”. All languages (with an English abstract) were
included. Articles spanned the period between June 1986 and December 2017.
Searches yielded 102 citations of which 21 were included as relevant. Other
data were collected through references from selected articles and searching
relevant journals offline.  Dementia-specific
QoL measurement scalesUnfortunately,
there are no instruments available to specifically evaluate QoL in DLB patients.
Therefore, we herein discuss QOL measurement scales for dementia.  There
is some debate regarding whether to use the patient’s or caregiver’s reported
QoL as the measurement. Typically, QoL is rated higher by patients than by
caregiver proxy measures. The differences are associated with increased levels
of caregiver burden and caregiver depression, rather than lower levels of
patients’ cognitive performance 8. Therefore, it
is reasonable to directly assess subjective QoL in patients with mild to moderate dementia. Interestingly, Karlawish et al. proposed a method to minimize the discrepancy between
patient’s and caregiver’s QoL scores: caregivers should rate using substituted
judgment as if they were the patients 9. Issues regarding
the exclusion of patients with severe dementia from self-reported
questionnaires and weak reliability of proxy versions remain unresolved. There
is limited knowledge regarding the standard instruments used to evaluate QoL in dementia patients. In a recently published review
10, the most
frequently used dementia-specific instrument was Quality of Life in Alzheimer’s Disease (QOL-AD) and Dementia Quality of Life
questionnaire (DEMQOL). As for generic measures, EuroQol 5-dimension (EQ-5D)
and Short Form surveys (SF-36 or SF-12) were widely used. The authors
recommended dementia-specific DEMQOL, generic
SF-12, and health utility EQ-5D-5L, based on both self- and proxy-report 10. In the following
paragraphs, we will briefly introduce each widely-used measurement scale. Quality of Life in
Alzheimer’s Disease (QOL-AD) The
QOL-AD 11 is an instrument specifically developed for mild to severe dementia.
It includes 13 items, including physical health, energy, mood, living
situation, memory, family, marriage, friends, self, ability to do chores,
ability to do things for fun, money, and life as a whole. Each domain is rated
from 1 (poor) to 4 (excellent). As for the caregiver version, which contains 15
items, marriage and money are removed, while people who work here, ability to
take care of oneself, ability to live with others, and ability to make choices
in one’s life are added. Dementia Quality of Life questionnaire (DEMQOL)The
DEMQOL 12 aims to assess QoL in mild to moderate dementia. It includes 5
domains including daily activities and looking after self, health and
well-being, cognitive functioning, social relationships, self-concept, and a total
of 28 items. Each item is scored from 1 to 4. A proxy version has been developed
for caregivers, DEMQOL-Proxy, which contains 31 items. EuroQol
5-dimension (EQ-5D-5L)The
EQ-5D-5L 13 is a generic
instrument. Respondents are asked to rate their current health status on 5
dimensions: mobility, hygiene, usual activities, pain/discomfort, and
anxiety/depression. For each dimension, the respondent gives 1 of 5 possible
ratings including having no problems, slight problems, moderate problems,
severe problems, and being unable to do/having extreme problems. The
questionnaire also includes a visual analog scale (VAS), ranging from 0 (death)
to 100 (perfect health). Thus, two QoL values are acquired with this
instrument. Short
Form-36 and Short Form-12(SF-36 and SF-12) The
SF-36 14 is a generic
measurement containing 36 questions across 8 dimensions of health status:
vitality, physical functioning, bodily pain, general health perceptions,
physical role functioning, emotional role functioning, social role functioning,
and mental health. A shorter version, SF-12, was developed to minimize
respondent burden if only physical and mental health summary scores are of
interest.  Reported
symptoms that may affect QoL in DLB patientsOne
study compared QoL in patients with DLB and AD as its primary aim and demonstrated
that the following are important determinants of QoL in DLB patients: their
Neuropsychiatric Inventory (NPI)
score, level of independency in instrumental activities of daily living, whether
the patient lives with the caregiver, apathy and delusion 7. Similar to
most findings in overall dementia, cognitive function has no strong relation to
QoL in this study.  Caregivers
play an important role in affecting a patient’s QoL. In a cross-sectional study
15 of 161 patients
with dementia (including 13 DLB patients), QoL was measured using the ADRQL. The
results indicated that some predictors of reduced QoL include behavioral and
depressive symptoms, dependency in basic activities of daily living, poorer
cognitive function, use of antipsychotic medication, caregiver burden, and
caregiver not being an adult child. The role of cognitive function on QoL is
still controversial. Here we will discuss some reported causative factors for poorer
QoL in DLB patients. Visual
hallucinationsVisual
hallucinations occur in 60 to 70% of DLB patients, usually beginning in the
first 2 or 3 years of the disease 16. The presentation of visual hallucinations in
the first 4 years following the onset of dementia has a positive and negative
predictive value for DLB of 81% and 79%, respectively 17. The most common visual hallucinations are fully formed persons (84%),
animals or bugs (37%), and objects (39%) 18. Early misperceptions and misidentification of family members are
usually reported in DLB. Capgras syndrome, a
delusion where a person has been substituted by an imposter with a similar outward,
is also common in DLB and is associated with higher rates of visual
hallucinations and anxiety 19. A recently published postmortem study 20 showed DLB
cases had reduced neuronal density in the intermediate
gray layer of the superior colliculus tissue, a structure important for directing
attention toward visual targets. This finding may provide pathologic evidence for
visual hallucinations in DLB. A
cross-sectional and retrospective study of 1025 patients with dementia in Spain
found that delusion and hallucinations were more prevalent in DLB patients than
those with AD and PDD. A high prevalence of non-diagnosed behavioral and
psychological symptoms in DLB leads to a negative impact on QoL and social
environment 21. In a
cross-sectional study, 21 DLB and 35 PDD patients with recurrent visual
hallucinations were evaluated. Most patients had complex hallucinations daily, usually
lasting minutes. The study showed that neuropsychiatric symptoms that coexist
with hallucinations are apathy, sleep disturbance, and anxiety 22. Treatment
of psychosis is challenging in DLB, since many patients are hypersensitive to neuroleptic
drugs, therefore non-pharmacologic treatment approaches should be considered
first. Typical antipsychotic agents should be avoided, while the evidence for
atypical antipsychotics is controversial. At present, quetiapine and clozapine
are usually prescribed. Pimavanserin, a selective serotonin 5-HT2A inverse
agonist, has beneficial effects on treating psychosis in PDD 23, while similar
results are expected in DLB patients. Depression
and apathyThe
presence of depression and other behavioral and psychological symptoms of
dementia (BPSD) may worsen the QoL of dementia patients and their caregivers 24. The BPSD can
be classified into four clusters: depression, aggressive behaviors, psychosis,
and euphoria. In AD and DLB patients, a cross-sectional analysis determined
that depressive symptoms in patients may be the most important BPSD symptom as
it was the only one shown to cause depression in caregivers 25.  Previous
literature revealed that DLB is associated with higher scores on the Geriatric
Depression Scale compared to AD, and a higher rate of depression is found in
early stages of the disorder 26. Kurisu et al. compared the QoL of 279
degenerative dementia patients with different subtypes by using the QOL Questionnaire for Dementia (QOL-D) as an evaluation
scale. The QOL-D comprises six domains: positive affect, negative affect and
actions, communication, restlessness, attachment to others, and spontaneity.
Results showed that apathy in frontotemporal dementia (FTD) and DLB patients
and depression in DLB patients might cause the reduced positive affect in FTD
and DLB patients compared to AD patients 27. Apathy also
plays an important role in evaluating QoL in DLB patients. In a DLB and AD
comparison study, DLB patients are less able to complete the QoL questionnaire 4. In
DLB, the presence of Lewy bodies in limbic, paralimbic, and neocortical regions
may account for the appearance of depressive symptoms 24. Early
detection of depression in DLB patients is important as these symptoms are
treatable. In a recently published review, the authors concluded that neuropsychiatric
symptoms, especially psychosis and depression, are priority targets for
intervention to improve the outcome of patients with DLB 4. Sleep
disordersSleep disorders are common in DLB patients, with both rapid eye movement sleep behavior disorder (RBD) and fluctuating cognition
being part of the clinical diagnostic criteria. In a
contemporary review in sleep medicine, the authors concluded that appropriate
management of sleep-related symptoms can improve QoL in patients with
neurodegenerative disorders 28. Orexins (also
known as hypocretins) are secreted in neurons in the lateral hypothalamus that
are related to sleep regulation and attention 29. Lower levels
of orexin-1 were detected in the cerebrospinal fluid of DLB patients compared
to AD patients and control subjects 30.  76% of DLB patients had RBD 31, which is characterized by acting out dreams, resulting in vocalizations
and even violent behavior. Other nocturnal symptoms such as anxiety, periodic
leg movements, urinary dysfunction, and difficulty turning over in bed can contribute to sleep problems 28. In a retrospective study of 78 patients with DLB and
sleep disorders who underwent polysomnography (PSG), approximately three
quarters experienced many arousals not accounted for by a movement or breathing
disturbance. Among patients who did not show evidence of significantly
disordered breathing, 62% of arousals were arousals for no apparent reason
(AFNAR) 32. The direct effect of sleep disorders on QoL in DLB patients has not been
previously studied. DysautonomiaIn
a study of the prevalence 33 of autonomic
symptoms in dementia, the authors concluded that total autonomic symptom scores
34, urinary
symptoms, constipation, and postural dizziness were significantly higher in DLB
patients than in AD patients. By using the SF-36 35 as a measurement,
higher autonomic symptom scores were related to lower QoL. The authors proposed
that the effect of autonomic symptoms upon QoL may be due to the limitations in
activities of daily living.  A systematic review of autonomic dysfunction in ?-synucleinopathies revealed that cardiovascular autonomic failure has significant impact on
daily activities and QoL. Cerebral white
matter changes in image and cognitive decline may be related to altered cerebral
perfusion, vascular pressure stress, and associated disruption of the blood–brain barrier 36. In ?-synucleinopathies, autonomic dysfunction is more severe in DLB than PD
patients 37.  Both preganglionic and postganglionic dysfunction may be present
in DLB patients 38. In a retrospective examination of DLB patients, urinary incontinence and constipation
were the most commonly presented autonomic symptoms, occurring in 97 and 83% of
patients, respectively, while syncope occurred in 28% of patients 39. Orthostatic hypotension (OH) has been reported in around 50% of DLB
patients 40. OH is defined as the reduction in systolic blood pressure (SBP) of at least 20 mmHg or diastolic blood pressure (DBP) of 10 mmHg within 3 minutes of standing from lying position 41. Patients may not
present with classic postural dizziness, but instead non-specific malaise or
lethargy, which can markedly increase the risk of falls or syncope. Management
may include salt supplementation, compression stockings, or oral medication
such as midodrine or fludrocortisones 42. Furthermore, a higher prevalence of carotid
sinus syndrome, an altered arterial sinus response to baroceptive stimulation resulting in syncope, was found in 32% of
DLB patients compared to 11.1% of AD patients 43.  Reported
management that may improve QoL in DLB patientsIt
can be helpful to divide the symptoms of DLB into five categories: cognitive,
neuropsychiatric, movement, autonomic, and sleep. It is important to take a detailed
history and form a comprehensive treatment strategy to improve a patient’s QoL 44. There is
little published data regarding the effect of management of symptoms on QoL in
DLB patients. ArmodafinilBecause
armodafinil has a longer half-life than
modafinil, we
may predict its better effect at treating patients with excessive daytime sleepiness 45. In a 12-week
pilot trial of oral armodafinil therapy (120-250 mg daily), DLB patients with
hypersomnia showed improved scores on the Epworth Sleepiness Scale, Maintenance
of Wakefulness Test, and Clinical Global Impression of Change. Moreover,
caregivers’ overall QoL improved at week 12 46. It should be
noted that the effect of armodafinil on patients’ QoL was not analyzed in this
trial. MemantineMemantine,
an NMDA receptor antagonist, has been widely used in treating moderate to
severe AD. A randomized controlled study was conducted on 70 patients with PDD
or DLB over 24 weeks using caregiver-rated QOL-AD as a measurement. A secondary
analysis of this study showed that memantine improved the total QoL, body
function, physical health, energy, mood, and memory when compared to the placebo
group 47. Large-scale
trials are required to confirm these preliminary findings. On the other hand,
although cholinesterase inhibitors are widely prescribed for patients with DLB,
we found no reported effect of cholinesterase inhibitors on QoL in DLB patients.
 ExerciseExercise may improve functional outcomes in PD and AD
patients. The multi-symptom nature of the DLB (parkinsonism, cognitive, and
psychiatric) results in these patients often being excluded from clinical trials
to avoid confounding results. A recent systematic review confirms a scarcity
of research investigating exercise as a potential therapy in DLB patients 48. The authors
concluded that the effect of exercise on cognitive,
psychiatric, QoL, and physiological outcomes remains unclear in DLB patients. Further clinical trials in larger cohorts are necessary.   ConclusionsThis
is, to our knowledge, the first review article focusing on QoL in patients with
dementia with Lewy bodies. Our review may not be fully comprehensive due to the
limited literature available regarding this topic. Physicians should keep the
patient’s QoL in the forefront when managing their symptoms. The following are reported
factors leading to poorer QoL in DLB patients: independency in instrumental
activities of daily living, whether the patient is living with the caregiver,
the presence of depression, apathy, delusion, visual hallucination, and
dysautonomia. 

First,
we concluded that it is important to develop a specific instrument to assess
QoL in DLB patients. Second, we hope that with the advent of more diagnostic
criteria and advances in biomarkers, there will be well-defined DLB cohorts for
clinical trials. Further studies may be facilitated by international or
multicenter cooperation. For example, a large longitudinal cohort of 5624 DLB
patients has been developed recently in 135 dementia centers in Italy (the
DLB-SINdem study group) 49. There is an urgent
need for large, cross-sectional, and longitudinal trials to determine other
factors associated with QoL, such as sleep and movement disorders. Finally,
considering the poor prognosis and high socioeconomic burden of DBL, new drug
development, particularly focused on improving QoL, is warranted. As with other
neurodegenerative diseases, early diagnosis, even prior to clinical symptoms,
is crucial for developing disease-modifying therapies. This relies on the
development of sensitive and specific biomarkers as diagnostic tools and
therapeutic endpoints. 

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