Dementiawith Lewy bodies (DLB) is the second most common neurodegenerative dementiaafter Alzheimer’s disease (AD) in people over 65 years of age. DLB differs fromAD as early cognitive symptoms include deficits in visuospatial and executivefunction, rather than memory. DLB is characterized by parkinsonism,fluctuations in mental status, visual hallucination, and hypersensitivity toneuroleptics.
Therefore, it is difficult to discriminate between DLB andParkinson’s disease with dementia (PDD). Both diseases also share a similarpathologic finding, Lewy bodies. Generally, if cognitive impairments appearwithin a year of parkinsonism, DLB is diagnosed, while patients withparkinsonism for at least a year prior to cognitive impairment are classifiedas PDD.
Early amyloid deposition in DLB relative to PDD may explain thedifference in the timing of dementia and parkinsonism. Qualityof life (QoL) is a key outcome measure of health and social serviceinterventions. Currently, patient-reported outcome measures (PROMs) areincreasingly used in evaluating health and social care. Definitions ofhealth-related QoL include physical, mental, social and role functioning, andhealth perceptions 1. Because agingis a global issue, it is critical to identify QoL determinants in the elderlywho suffer from chronic disease.
A recent study from Southern Taiwan showedAlzheimer disease-8 (AD-8), a screening tool, had the strongest associationwith total QoL score in 115 old age adults suffering from chronic disease. Itis important for geriatric health care providers to realize that cognitiveimpairment among old age adults with chronic disease is a critical determiningfactor of poor QoL 2. AssessingQoL in people with dementia is crucial for evaluating their outcomes; however,it is challenging to interview patients who have a limited ability to expressthemselves and may lack insight. Meanwhile, there are questions concerning thevalidity of generic measures of QoL, which are not specific to dementia.
Currently,evaluations of QoL largely focus on general dementia or AD. A systematic review3 regarding QoLin dementia strongly suggests that depression is consistently related todecreased QoL. Surprisingly, there is no convincing evidence indicating thatlower cognitive ability or greater limitations in activity are associated with alower QoL. Evidenceconcerning QoL in DLB patients is limited 4. In acomparison study, QoL was measured using the Alzheimer Disease Related Quality of Life (ADRQL) evaluation , aproxy-rated, dementia-specific instrument.
The authors concluded that DLBpatients 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 atleast two years. Patients with DLB scored significantly lower on the SF-12Physical and Mental Health Summary than patients with HD and AD.
The authorsconcluded that, when adjusted for age, cognition, comorbidity, and depression,patients with DLB had the poorest QoL 6. Thereis only one study whose primary aim was to compare the QoL in patients with DLBand AD 7. 34 DLBpatients and 34 cognitive-matched AD patients were evaluated using two QoLinstruments: EQ-5D and QoL-AD.
The results showed both patient-rated andproxy-rated QoL was poorer in patients with DLB than those with AD. Due to manydifferences in clinical symptoms, it is reasonable to predict differences inQOL between diseases. Herein, we elaborate on studies related to QoL in DLBpatients. MethodsStudieswere selected from the PubMed database using keywords “quality of life” and”dementia with Lewy bodies”. All languages (with an English abstract) wereincluded. Articles spanned the period between June 1986 and December 2017.Searches yielded 102 citations of which 21 were included as relevant. Otherdata were collected through references from selected articles and searchingrelevant journals offline.
Dementia-specificQoL measurement scalesUnfortunately,there are no instruments available to specifically evaluate QoL in DLB patients.Therefore, we herein discuss QOL measurement scales for dementia. Thereis some debate regarding whether to use the patient’s or caregiver’s reportedQoL as the measurement. Typically, QoL is rated higher by patients than bycaregiver proxy measures. The differences are associated with increased levelsof caregiver burden and caregiver depression, rather than lower levels ofpatients’ cognitive performance 8. Therefore, itis reasonable to directly assess subjective QoL in patients with mild to moderate dementia.
Interestingly, Karlawish et al. proposed a method to minimize the discrepancy betweenpatient’s and caregiver’s QoL scores: caregivers should rate using substitutedjudgment as if they were the patients 9. Issues regardingthe exclusion of patients with severe dementia from self-reportedquestionnaires and weak reliability of proxy versions remain unresolved. Thereis limited knowledge regarding the standard instruments used to evaluate QoL in dementia patients. In a recently published review10, the mostfrequently used dementia-specific instrument was Quality of Life in Alzheimer’s Disease (QOL-AD) and Dementia Quality of Lifequestionnaire (DEMQOL). As for generic measures, EuroQol 5-dimension (EQ-5D)and Short Form surveys (SF-36 or SF-12) were widely used. The authorsrecommended dementia-specific DEMQOL, genericSF-12, and health utility EQ-5D-5L, based on both self- and proxy-report 10.
In the followingparagraphs, we will briefly introduce each widely-used measurement scale. Quality of Life inAlzheimer’s Disease (QOL-AD) TheQOL-AD 11 is an instrument specifically developed for mild to severe dementia.It includes 13 items, including physical health, energy, mood, livingsituation, memory, family, marriage, friends, self, ability to do chores,ability to do things for fun, money, and life as a whole. Each domain is ratedfrom 1 (poor) to 4 (excellent).
As for the caregiver version, which contains 15items, marriage and money are removed, while people who work here, ability totake care of oneself, ability to live with others, and ability to make choicesin one’s life are added. Dementia Quality of Life questionnaire (DEMQOL)TheDEMQOL 12 aims to assess QoL in mild to moderate dementia. It includes 5domains including daily activities and looking after self, health andwell-being, cognitive functioning, social relationships, self-concept, and a totalof 28 items.
Each item is scored from 1 to 4. A proxy version has been developedfor caregivers, DEMQOL-Proxy, which contains 31 items. EuroQol5-dimension (EQ-5D-5L)TheEQ-5D-5L 13 is a genericinstrument. Respondents are asked to rate their current health status on 5dimensions: mobility, hygiene, usual activities, pain/discomfort, andanxiety/depression.
For each dimension, the respondent gives 1 of 5 possibleratings including having no problems, slight problems, moderate problems,severe problems, and being unable to do/having extreme problems. Thequestionnaire also includes a visual analog scale (VAS), ranging from 0 (death)to 100 (perfect health). Thus, two QoL values are acquired with thisinstrument. ShortForm-36 and Short Form-12(SF-36 and SF-12) TheSF-36 14 is a genericmeasurement 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 minimizerespondent burden if only physical and mental health summary scores are ofinterest. Reportedsymptoms that may affect QoL in DLB patientsOnestudy compared QoL in patients with DLB and AD as its primary aim and demonstratedthat the following are important determinants of QoL in DLB patients: theirNeuropsychiatric Inventory (NPI)score, level of independency in instrumental activities of daily living, whetherthe patient lives with the caregiver, apathy and delusion 7.
Similar tomost findings in overall dementia, cognitive function has no strong relation toQoL in this study. Caregiversplay an important role in affecting a patient’s QoL. In a cross-sectional study15 of 161 patientswith dementia (including 13 DLB patients), QoL was measured using the ADRQL.
Theresults indicated that some predictors of reduced QoL include behavioral anddepressive symptoms, dependency in basic activities of daily living, poorercognitive function, use of antipsychotic medication, caregiver burden, andcaregiver not being an adult child. The role of cognitive function on QoL isstill controversial. Here we will discuss some reported causative factors for poorerQoL in DLB patients.
VisualhallucinationsVisualhallucinations occur in 60 to 70% of DLB patients, usually beginning in thefirst 2 or 3 years of the disease 16. The presentation of visual hallucinations inthe first 4 years following the onset of dementia has a positive and negativepredictive 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 areusually reported in DLB. Capgras syndrome, adelusion 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 visualhallucinations and anxiety 19.
A recently published postmortem study 20 showed DLBcases had reduced neuronal density in the intermediategray layer of the superior colliculus tissue, a structure important for directingattention toward visual targets. This finding may provide pathologic evidence forvisual hallucinations in DLB. Across-sectional and retrospective study of 1025 patients with dementia in Spainfound that delusion and hallucinations were more prevalent in DLB patients thanthose with AD and PDD. A high prevalence of non-diagnosed behavioral andpsychological symptoms in DLB leads to a negative impact on QoL and socialenvironment 21. In across-sectional study, 21 DLB and 35 PDD patients with recurrent visualhallucinations were evaluated. Most patients had complex hallucinations daily, usuallylasting minutes. The study showed that neuropsychiatric symptoms that coexistwith hallucinations are apathy, sleep disturbance, and anxiety 22. Treatmentof psychosis is challenging in DLB, since many patients are hypersensitive to neurolepticdrugs, therefore non-pharmacologic treatment approaches should be consideredfirst.
Typical antipsychotic agents should be avoided, while the evidence foratypical antipsychotics is controversial. At present, quetiapine and clozapineare usually prescribed. Pimavanserin, a selective serotonin 5-HT2A inverseagonist, has beneficial effects on treating psychosis in PDD 23, while similarresults are expected in DLB patients. Depressionand apathyThepresence of depression and other behavioral and psychological symptoms ofdementia (BPSD) may worsen the QoL of dementia patients and their caregivers 24. The BPSD canbe classified into four clusters: depression, aggressive behaviors, psychosis,and euphoria. In AD and DLB patients, a cross-sectional analysis determinedthat depressive symptoms in patients may be the most important BPSD symptom asit was the only one shown to cause depression in caregivers 25. Previousliterature revealed that DLB is associated with higher scores on the GeriatricDepression Scale compared to AD, and a higher rate of depression is found inearly stages of the disorder 26. Kurisu et al.
compared the QoL of 279degenerative dementia patients with different subtypes by using the QOL Questionnaire for Dementia (QOL-D) as an evaluationscale. The QOL-D comprises six domains: positive affect, negative affect andactions, communication, restlessness, attachment to others, and spontaneity.Results showed that apathy in frontotemporal dementia (FTD) and DLB patientsand depression in DLB patients might cause the reduced positive affect in FTDand DLB patients compared to AD patients 27. Apathy alsoplays an important role in evaluating QoL in DLB patients. In a DLB and ADcomparison study, DLB patients are less able to complete the QoL questionnaire 4. InDLB, the presence of Lewy bodies in limbic, paralimbic, and neocortical regionsmay account for the appearance of depressive symptoms 24. Earlydetection of depression in DLB patients is important as these symptoms aretreatable. In a recently published review, the authors concluded that neuropsychiatricsymptoms, especially psychosis and depression, are priority targets forintervention to improve the outcome of patients with DLB 4.
SleepdisordersSleep disorders are common in DLB patients, with both rapid eye movement sleep behavior disorder (RBD) and fluctuating cognitionbeing part of the clinical diagnostic criteria. In acontemporary review in sleep medicine, the authors concluded that appropriatemanagement of sleep-related symptoms can improve QoL in patients withneurodegenerative disorders 28. Orexins (alsoknown as hypocretins) are secreted in neurons in the lateral hypothalamus thatare related to sleep regulation and attention 29. Lower levelsof orexin-1 were detected in the cerebrospinal fluid of DLB patients comparedto AD patients and control subjects 30. 76% of DLB patients had RBD 31, which is characterized by acting out dreams, resulting in vocalizationsand even violent behavior. Other nocturnal symptoms such as anxiety, periodicleg movements, urinary dysfunction, and difficulty turning over in bed can contribute to sleep problems 28.
In a retrospective study of 78 patients with DLB andsleep disorders who underwent polysomnography (PSG), approximately threequarters experienced many arousals not accounted for by a movement or breathingdisturbance. Among patients who did not show evidence of significantlydisordered 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 beenpreviously studied. DysautonomiaIna study of the prevalence 33 of autonomicsymptoms in dementia, the authors concluded that total autonomic symptom scores34, urinarysymptoms, constipation, and postural dizziness were significantly higher in DLBpatients than in AD patients. By using the SF-36 35 as a measurement,higher autonomic symptom scores were related to lower QoL. The authors proposedthat the effect of autonomic symptoms upon QoL may be due to the limitations inactivities of daily living.
A systematic review of autonomic dysfunction in ?-synucleinopathies revealed that cardiovascular autonomic failure has significant impact ondaily activities and QoL. Cerebral whitematter changes in image and cognitive decline may be related to altered cerebralperfusion, vascular pressure stress, and associated disruption of the blood–brain barrier 36. In ?-synucleinopathies, autonomic dysfunction is more severe in DLB than PDpatients 37. Both preganglionic and postganglionic dysfunction may be presentin DLB patients 38. In a retrospective examination of DLB patients, urinary incontinence and constipationwere the most commonly presented autonomic symptoms, occurring in 97 and 83% ofpatients, respectively, while syncope occurred in 28% of patients 39. Orthostatic hypotension (OH) has been reported in around 50% of DLBpatients 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 notpresent with classic postural dizziness, but instead non-specific malaise orlethargy, which can markedly increase the risk of falls or syncope. Managementmay include salt supplementation, compression stockings, or oral medicationsuch as midodrine or fludrocortisones 42. Furthermore, a higher prevalence of carotidsinus syndrome, an altered arterial sinus response to baroceptive stimulation resulting in syncope, was found in 32% ofDLB patients compared to 11.
1% of AD patients 43. Reportedmanagement that may improve QoL in DLB patientsItcan be helpful to divide the symptoms of DLB into five categories: cognitive,neuropsychiatric, movement, autonomic, and sleep. It is important to take a detailedhistory and form a comprehensive treatment strategy to improve a patient’s QoL 44. There islittle published data regarding the effect of management of symptoms on QoL inDLB patients. ArmodafinilBecausearmodafinil has a longer half-life thanmodafinil, wemay predict its better effect at treating patients with excessive daytime sleepiness 45. In a 12-weekpilot trial of oral armodafinil therapy (120-250 mg daily), DLB patients withhypersomnia showed improved scores on the Epworth Sleepiness Scale, Maintenanceof Wakefulness Test, and Clinical Global Impression of Change. Moreover,caregivers’ overall QoL improved at week 12 46.
It should benoted that the effect of armodafinil on patients’ QoL was not analyzed in thistrial. MemantineMemantine,an NMDA receptor antagonist, has been widely used in treating moderate tosevere AD. A randomized controlled study was conducted on 70 patients with PDDor DLB over 24 weeks using caregiver-rated QOL-AD as a measurement. A secondaryanalysis of this study showed that memantine improved the total QoL, bodyfunction, physical health, energy, mood, and memory when compared to the placebogroup 47. Large-scaletrials 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 ADpatients. The multi-symptom nature of the DLB (parkinsonism, cognitive, andpsychiatric) results in these patients often being excluded from clinical trialsto avoid confounding results. A recent systematic review confirms a scarcityof research investigating exercise as a potential therapy in DLB patients 48. The authorsconcluded 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.
ConclusionsThisis, to our knowledge, the first review article focusing on QoL in patients withdementia with Lewy bodies. Our review may not be fully comprehensive due to thelimited literature available regarding this topic. Physicians should keep thepatient’s QoL in the forefront when managing their symptoms. The following are reportedfactors leading to poorer QoL in DLB patients: independency in instrumentalactivities of daily living, whether the patient is living with the caregiver,the presence of depression, apathy, delusion, visual hallucination, anddysautonomia. First,we concluded that it is important to develop a specific instrument to assessQoL in DLB patients.
Second, we hope that with the advent of more diagnosticcriteria and advances in biomarkers, there will be well-defined DLB cohorts forclinical trials. Further studies may be facilitated by international ormulticenter cooperation. For example, a large longitudinal cohort of 5624 DLBpatients has been developed recently in 135 dementia centers in Italy (theDLB-SINdem study group) 49. There is an urgentneed for large, cross-sectional, and longitudinal trials to determine otherfactors associated with QoL, such as sleep and movement disorders. Finally,considering the poor prognosis and high socioeconomic burden of DBL, new drugdevelopment, particularly focused on improving QoL, is warranted.
As with otherneurodegenerative diseases, early diagnosis, even prior to clinical symptoms,is crucial for developing disease-modifying therapies. This relies on thedevelopment of sensitive and specific biomarkers as diagnostic tools andtherapeutic endpoints.