Clinical manifestations

Presentation and course

Clinical dementia is central to the clinical diagnosis of dementia with Lewy bodies (Table 1). Cognitive impairment largely involves problems with frontal executive functioning and visuospatial abilities; however, there may also be episodic memory loss (62). Executive impairments include difficulty with following multi-task commands, problems with working memory, and inhibition of incorrect responses. Examples of bedside cognitive testing that may be helpful include digit span (ie, how many digits can be verbally recited forward and reverse), oral trails (ie, alternating between letters and numbers verbally or graphically), verbal fluency tasks for phonemic deficits (ie, letter fluency; for example, the number of words beginning with a specific letter, such as “F” generated in 60 seconds) or categorical lexical retrieval targets (ie, number of words corresponding to a semantic category, such as “animals” or “tools” generated in 60 seconds). Visuospatial abilities may be probed either using constructional tasks, such as drawing a clock face or complex figure, or other measures of perceptual ability. Episodic memory impairments may be tested through use of list-learning tasks or structured narratives for delayed verbal recall and also through visual recall of a previously constructed design. Language impairments, in the form of difficulty with sentence processing and production, can be present and are likely related to involvement of frontal lobes in dementia with Lewy bodies (25). Cognitive impairments must be progressive (through serial examinations or historical report by caregiver) and reach severity sufficient to interfere with activities of daily living to consider a diagnosis of dementia with Lewy bodies. The first clinical symptoms of mild cognitive impairment, delirium, or psychiatric symptoms may precede the onset of dementia by 15 years or more (63). Patients with dementia with Lewy body who have positive CSF biomarkers for amyloid or tau show faster cognitive decline over 5 to 6 years than those whose biomarkers fall in the normal range (84).

Table 1. Diagnostic Criteria for Dementia with Lewy Bodies

Parkinsonism. Over 80% of autopsy-confirmed patients with dementia with Lewy bodies eventually develop extrapyramidal symptoms consistent with Parkinson disease during the progression of dementia with Lewy bodies (36). However, parkinsonism is not necessary to meet formal dementia with Lewy bodies criteria if two or more other core features are present (Table 1). At the time of clinical presentation, parkinsonism was present in only 22% of Lewy body patients who reported to a large Italian memory clinic (19). Parkinsonism may take the form of bradykinesia, postural instability, rigidity, or tremor and should not be attributed to medication or other etiology (ie, spontaneous) (62). The rest tremor in early dementia with Lewy bodies is more likely to be bilaterally symmetrical and less likely to be unilateral, as it is in early Parkinson disease (19).

Fluctuations in cognition. These fluctuations are another core feature of dementia with Lewy bodies and range in expression from periods of excessive daytime sleepiness or periods of reduced attention (including being lost in a train of thought), to prolonged periods of unresponsiveness. If prolonged, these episodes of unresponsiveness can be mistaken for a transient ischemic attack or a complex-partial seizure. Cognitive fluctuations may be elicited through history provided by the caregiver, but they can be difficult to ascertain. Detection of fluctuations may be aided through the use of structured interview questionnaires, such as the Dementia Cognitive Fluctuations Scale (87; 56).

Visual hallucinations. These phenomena often occur in patients with dementia with Lewy bodies and include complex, vivid, well-formed hallucinations of people, animals, or children. They were reported in 42% of Lewy body patients at their first consultation in one large Italian series (19). The patient’s responses to these hallucinations are variable, but often they are not disturbing to them. Hallucinations in other modalities are less common but can occur, such as those involving auditory or tactile modalities. It is important to distinguish true hallucinations from delusions through careful history-taking. Indeed, systematized delusions are supportive for a diagnosis of dementia with Lewy bodies. It is not uncommon for patients with dementia with Lewy bodies to have delusions of strangers invading the home or delusional misidentification syndrome (eg, Capgras syndrome) (63). Some patients with dementia with Lewy bodies and Parkinson disease dementia experience minor visual hallucinations, such as “passage hallucinations,” which consist of shadows or the brief appearance of someone passing through the periphery of one’s visual field (51). Other examples of minor hallucinations are “presence hallucinations,” where the patient feels a vivid sense of another person’s presence in the room. Minor visual hallucinations in dementia with Lewy bodies are not associated with severity of global cognitive impairment but with impairment of visuoperceptual processes and abstract reasoning (10). In one longitudinal study of 488 patients with dementia with Lewy bodies, visual hallucinations developed earlier in women than in men (08).

REM sleep behavior disorder. Active sleep, including loud vocalizations and extreme motor movements of punching and kicking, is characteristic of rapid eye movement sleep behavior disorder (07), which is now considered a core feature of dementia with Lewy bodies (62). The prevalence of this parasomnia in the general population is 0.4% to 0.5%, whereas the prevalence among Lewy bodies patients is 40% (07). Often patients with REM sleep behavior disorder may report a dream where they are fighting off an attacker or an animal. Bed partners may complain of being hit in the middle of the night or becoming injured, and it is not uncommon for a patient to report waking up on the floor due to the aberrant motor behavior. It is important to differentiate true rapid-eye movement sleep behavior disorder from other parasomnias. Formal polysomnogram displaying lack of atonia during REM sleep stages can help to confirm the diagnosis of REM sleep behavior disorder as an indicative biomarker of dementia with Lewy bodies. Interestingly, many patients may have idiopathic REM sleep behavior disorder years prior to developing symptoms of dementia with Lewy bodies. Most patients with idiopathic REM sleep behavior disorder followed longitudinally eventually develop clinical Parkinson disease or dementia with Lewy bodies with alpha-synuclein pathology at autopsy (33; 08; 11). In a large, longitudinal study of patients with idiopathic REM sleep disorder, 73.5% converted to either Parkinson disease or dementia with Lewy bodies by the end of a 12-month follow-up period (71). In another longitudinal study, men were more likely to develop REM sleep behavior disorder earlier in the course of dementia with Lewy bodies than women (08).

Other clinical features considered suggestive for a clinical diagnosis of dementia with Lewy bodies include severe sensitivity to neuroleptic agents. Patients may become excessively somnolent for prolonged periods after exposure to low doses of typical neuroleptics (especially typical agents with high D2 receptor affinity), and there is risk of worsening parkinsonism and serious autonomic impairments similar to neuroleptic malignant syndrome; thus, a trial of neuroleptic medication should not be considered for diagnostic purposes. Clinical dementia with Lewy bodies may also have varying degrees of other non-motor symptoms related to deposition of alpha-synuclein pathology in the peripheral autonomic nervous system, including constipation, rhinorrhea, orthostatic hypotension, and erectile dysfunction (71; 02). Finally, depression and anxiety commonly occur near the onset of cognitive difficulties and are supportive features of dementia with Lewy bodies. When mild cognitive impairment groups were compared (those preceding Lewy body disease and those preceding Alzheimer disease), patients with mild cognitive impairment with Lewy bodies were shown to have more neuropsychiatric symptoms than those with mild cognitive impairment with Alzheimer disease (84).

Prodromal dementia with Lewy bodies. A current goal of research in dementia with Lewy bodies is identifying patients with presymptomatic disease who are in an early stage of dementia with Lewy bodies, including patients with mild cognitive impairment at risk for dementia, with the presence of these clinical features suggestive and supportive of dementia with Lewy bodies to improve diagnosis (15; 62; 63). One group of investigators identified a group of 148 patients with prodromal dementia with Lewy bodies who had either subjective cognitive impairment or mild cognitive impairment and two core features of dementia with Lewy bodies (02). Compared to a control group of subjective cognitive impairment and mild cognitive impairment patients with only one core dementia with Lewy bodies feature, these patients had slower verbal processing, more apathy, and more autonomic complaints.

Prognosis and complications

Dementia with Lewy bodies is an incurable illness with no disease-modifying therapies currently available to alter the progression. Prognosis varies between individuals with a disease duration ranging from less than 1 year to over a decade in some cases. There are currently no prognostic markers validated for clinical use, and serial examinations for progression of cognitive and motor function are useful to help prepare families for next steps in supportive care through increased supervision and assistance with activities of daily living. Prevention of falls and aspiration and safety issues from cognitive impairment, such as wandering or leaving the stove on, are important to help reduce morbidity.

Neuropsychological changes. At baseline, patients in the mild cognitive impairment stage of Lewy body disease had fewer memory problems than an age-matched and cognitively matched group of patients with mild cognitive impairment who had prodromal Alzheimer disease (85; 30). Copying abilities are equally reduced in patients with Alzheimer disease and dementia with Lewy bodies (43), but perception of fragmented letters by patients in the mild to moderate stages of dementia with Lewy bodies is more impaired than in those who are in similar stages of Alzheimer disease (74). The fragmented letters test proved to be a useful tool to gauge the severity of alpha-synuclein pathology in patients with dementia with Lewy bodies. Patients with mild cognitive impairment with Lewy bodies progressed faster over 3 years on attention tasks than patients with mild cognitive impairment with Alzheimer disease, whereas patients with mild cognitive impairment with Alzheimer disease declined faster on memory tasks and on a global cognitive task (MMSE) (85). In a similarly designed study, Hamilton and colleagues found that the mild cognitive impairment with Lewy bodies patients had a more rapid decline in visuospatial skills, whereas both groups progressed similarly with regard to language, memory, and executive functions (30). Those who have dementia with Lewy bodies progress on the MMSE at a rate of about 2.7 points per year and on the Dementia Cognitive Fluctuations Scale at about 2.6 points per year (56).

Clinical vignette

A 68-year-old male developed difficulty with memory and multitasking over the course of the past 2 years and presented to the clinic for cognitive evaluation. The symptoms had been causing significant anxiety and frustration and were reported to interfere with his ability to maintain appointments and pay bills. Doing simple calculations and organizational tasks in the home took much longer than they did previously. His wife had noticed these changes and found errors in his record-keeping for their finances and had taken over this responsibility as well as supervising his medication administration. He also noted that he had difficulty finding words and finishing sentences at times. The patient had been less motivated for social activities and his hobbies and was more content to stay home and watch TV for most of the day. Near the onset of these difficulties, he reported seeing shadows moving at night in the room when there was nothing there. At the time of presentation, he reported occasionally seeing children playing in their living room; he noted that this was not particularly disturbing to him and that he did not believe they were truly present.

The patient’s wife reported that he could separately have episodes of agitation due to the perception of invaders in their home and that his cognitive symptoms could wax and wane throughout the day (not just in the evening) such that he experienced extreme confusion with incoherent speech for periods of time ranging from a few minutes to hours. His wife also noticed in the past few months that his walking had become slow and that he had been off-balance. On review of systems, he had experienced active sleep for the past 10 years. This included sudden jerking movement of his limbs, loud vocalizations, and punching behavior. This had been concerning to his wife as she had been hit by him in the past. The patient underwent a sleep polysomnogram confirming rapid-eye movement sleep behavior disorder.

On examination, the patient had slow hypophonic speech with word-finding pauses and circumlocutions. He largely maintained attention throughout the exam with good effort, but there were periodic fluctuations in concentration during tasks that often required repetition of instructions to maintain set. There was reduced verbal fluency (6 “F” words in 60 seconds without a clear phonetic or semantic strategy) and digit span and poor performance on an oral trail task. His delayed recall of a list of six words was four with fair recognition. There was difficulty with visual construction of a complex figure and impaired perception of line orientation.

Elemental neurologic examination revealed bradykinesia with decrement on fine movements and rare myoclonic jerks. There was increased tone in the arms and legs with some cog-wheeling. There was no rest tremor, but a fine postural tremor. There was a parkinsonian gait with anteroflexed posture and short steps. Pull-back test found evidence of postural instability with three to four steps correction.

The diagnosis of dementia with Lewy bodies was considered, as the patient had dementia in addition to all four of the core features (parkinsonism, visual hallucinations, cognitive fluctuations, and rapid eye movement sleep behavior disorder, which is sufficient for the diagnosis of probable dementia with Lewy bodies (Table 1). An MRI of the brain, lumbar puncture, and blood tests for common etiologies that could contribute to cognitive impairment or mimic dementia with Lewy bodies in this age range were performed. MRI of the brain revealed mild diffuse cortical atrophy with largely preserved hippocampal volumes. Laboratory tests revealed normal TSH, B12, LYME, ESR, RPR, and ANA from serum and normal CSF protein, glucose, IgG, and cytology helping to exclude non-neurodegenerative mimics of this disorder.

The cognitive and motor difficulties progressed over the course of 4 years with increasing confusion, cognitive impairment, apathy, and motor disability. There was some stabilization of cognitive testing for approximately 1 year with use of an acetylcholinesterase inhibitor. There was a mild response of motor symptoms to levodopa. He also developed orthostatic hypotension and syncopal episodes, some of which lasted several hours and were likely to be cognitive fluctuations. In the fourth year of disease, he had reduced oral intake and complete disorientation. He entered hospice care for failure to thrive. At autopsy, there was a high burden of alpha-synuclein-positive Lewy bodies and Lewy neurites in the neocortex, consistent with a primary neuropathological diagnosis of Lewy body disease or dementia with Lewy bodies along with high levels of Alzheimer disease-associated tau tangles and amyloid plaques consistent with a secondary diagnosis of Alzheimer disease.

* This vignette is a composite of the history, evaluation, and cause of several patients to protect identity of the patients.

Biological basis

Etiology and pathogenesis

Pathology. Postmortem findings of cortical and limbic Lewy bodies and Lewy neurites in neurons composed of pathological alpha-synuclein protein are the gold standard for diagnosis of dementia with Lewy bodies (62). Alpha-synuclein is a presynaptic protein thought to play a role in vesicular transport under normal conditions, but this protein undergoes several post-translational modifications and aggregates into Lewy bodies and Lewy neurites in dementia with Lewy bodies. Alpha-synuclein propagates across interconnected networks throughout the nervous system in a prion-like manner (16). Diagnostic accuracy appears to be affected by the degree of comorbid Alzheimer disease pathology and also the degree of cortical alpha-synuclein pathology (78; 20). Braak and colleagues examined the distribution of alpha-synuclein pathology in serial autopsies of patients with Parkinson disease and controls and hypothesized a rostral-to-caudal spread from the dorsal motor nucleus of the vagus in the medulla to the neocortex within an individual over the progressive course of the disease (04). Exceptions to this paradigm have been described (52), including Lewy bodies or Lewy neurites restricted to the amygdala in patients with clinical Alzheimer disease, and efforts to develop a staging of alpha-synuclein pathology have not been reported for dementia with Lewy bodies. Because patients with dementia with Lewy bodies do not universally present with extrapyramidal motor symptoms, it is likely that this pattern of progression may differ from Parkinson disease and perhaps originate in the neocortex. Interestingly, low levels of alpha-synuclein pathology have been found in cognitively normal subjects without motor symptoms (ie, “incidental Lewy pathology”) of unclear significance. Autopsy findings of early dopaminergic degeneration in asymptomatic cases suggest a subclinical prodromal state of alpha-synuclein pathology (12), and experimental studies strongly link Lewy body formation to the degeneration of neurons in the substantia nigra (55). Furthermore, some patients with incidental Lewy pathology appear to have cortical distributions that deviate from Parkinson disease Braak stages, suggesting a preclinical state of dementia with Lewy bodies (22). Comparative autopsy studies of Parkinson disease dementia and dementia with Lewy bodies largely show similar distributions of alpha-synuclein pathology involving both subcortical and cortical regions at end-stage disease (37; 36), reflecting the high association of clinical dementia with cortical alpha-synculein pathology (38; 36). Approximately 80% of patients with clinical dementia with Lewy bodies and 40% of patients with Parkinson disease dementia have sufficient amyloid-beta plaques and tau neurofibrillary tangles to meet pathological diagnostic criteria for a secondary diagnosis of medium to high level Alzheimer disease, and these patients also have a higher burden of cortical alpha-synuclein pathology compared to patients with alpha-synuclein pathology alone (36; 41). Patients who have mixed Lewy body disease and Alzheimer disease have additional cortical thinning throughout the association cortices, compared to the thinning seen in either disease alone (43). Forty percent of patients with dementia with Lewy bodies have cerebral microbleeds that are identifiable on MRI, compared to 50% of Alzheimer patients and 15% of age-matched controls (14). At autopsy, signs of cerebral amyloid angiopathy are significantly higher in patients with dementia with Lewy bodies (99%) than in those with Parkinson disease with dementia (50%) (41). Patients with dementia with Lewy bodies who have increased amyloid deposition on PET show signs of lower grey matter volumes in the inferior temporal cortices compared to those without increased amyloid (20). Despite these group-wide differences, Parkinson disease dementia and dementia with Lewy bodies appear to have no pathological substrates at end-stage disease that clearly substantiate the differentiation of these two clinical syndromes from one another during life; thus, these diseases are best considered a spectrum of synucleinopathy associated with dementia. It is possible that aging and Alzheimer disease pathology may influence the onset and spread of alpha-synuclein pathology (28; 68), but future work using in vivo markers of alpha-synuclein pathology are needed to test this hypothesis.

Alpha-synuclein. Novel experimental models have shown that preformed fibrils formed by recombinant alpha-synuclein alone can propagate and spread through anatomically connected regions of the CNS in a time- and dose-dependent manner in both transgenic mice harboring human disease-associated alpha-synuclein transgene (55) and nongenetically-altered mice (54) (ie, wild-type mice), resulting in reduced survival and a motor phenotype; thus, recapitulating human Parkinson disease-like synucleinopathy. Further, cell culture models demonstrate the ability of pathological misfolded alpha-synuclein seeds or pre-formed fibrils to propagate from neuron to neuron with toxic consequences (86; 16). Finally, preparations of recombinant alpha-synuclein preformed fibrils have been shown to have varying resistance to protease treatment and propensities for transducing both pathological alpha-synuclein and tau pathology in cell models suggestive of strain-like properties of different species of pathological alpha-synuclein (28). These data suggest that alpha-synuclein misfolding and cell-to-cell transmission is central to the disease pathogenesis in Lewy body dementia and that other mechanisms of cell toxicity such as oxidative stress, synaptic dysfunction, disruption of axonal transport, and inhibition of protein degradation pathways are likely down-stream responses to aggregation and spread of pathological species of alpha-synuclein (37). Furthermore, these data suggest a mechanism for observations or stereotypical spread of alpha-synuclein pathology by Braak and colleagues (04) and possibly the findings of alpha-synuclein pathology occurring in grafted fetal neurons in the striatum of patients with Parkinson disease years after implantation (49). The transmission hypothesis of alpha-synuclein pathology is reminiscent of the pathogenic mechanism of prion disease; however, there is no clear evidence of clinical infectivity of Parkinson disease, dementia with Lewy bodies, or Alzheimer disease (34), which is in sharp contrast to the definition of a prion (ie, proteinacious infectious particle). Current research strategies for therapeutic development include immunotherapy or other mechanisms to slow or halt the progression of pathological alpha-synuclein aggregation within the CNS (67; 83).

Beta-amyloid and tau. There is accumulating evidence to suggest that cognitive decline in those who have dementia with Lewy bodies is not primarily due to alpha-synuclein-driven neurodegeneration but that beta-amyloid and tau may also play a role (40; 90; 68; 20). In a study, higher rates of hospitalization were seen in patients with dementia with Lewy bodies who had more neurofibrillary tangle pathology (40). In another study, patients with amyloid-positive Lewy bodies had a younger age at diagnosis and worse performance on tests of attention and visuospatial function (90). They also had greater anxiety and total neuropsychiatric burden.

Genetics. Most cases of dementia with Lewy bodies are sporadic. Rare familial forms of dementia with Lewy bodies have been linked to pathogenic mutations and duplications or triplications of the SNCA gene encoding the alpha-synculein protein, but these are more likely to present as Parkinson disease. Genetic risk factors for dementia with Lewy bodies appear to include both Parkinson disease- and Alzheimer disease-associated genes (27). A genome-wide analysis showed that patients with familial dementia with Lewy bodies could develop the disease based on an Alzheimer disease risk factor (an APOE-e4 allele), or one of several Parkinson disease risk factors (glucocerebrosidase A1, GBA1; alpha-synuclein, SNCA) (66; 82; 27). Not all Parkinson disease-associated genes appear to confer risk for dementia with Lewy bodies, suggesting that there are other genetic influences on the clinical expression of this alpha-synucleinopathy (05). Homozygous mutations in the glucocerebrosidase A1 (GBA1) gene are associated with the lysosomal storage disease, Gaucher disease. Parkinsonism and postmortem alpha-synuclein pathology were noted in many patients surviving to adulthood with GBA mutations that led to findings of increased frequency of heterozygous GBA mutation carriers in clinical and pathological Parkinson disease and dementia with Lewy bodies populations (66). Based on these and other observations, it has been suggested that altered lysosomal autophagy pathways are important in the pathogenesis of various alpha-synucleinopathies. Interestingly, heterozygous GBA mutation carriers are more frequently associated with dementia with Lewy bodies patients without secondary Alzheimer disease pathology (81; 36). In one dementia with Lewy bodies study where CSF real time quaking-induced conversion (RT-QIC) assays were performed, 100% of the GBA mutation carriers showed alpha-synuclein seeding activity, whereas this activity was only documented in 79% of the wild-type participants (06). The authors advocated for using this CSF assay to stratify newly enrolled Lewy body patients into future clinical trials of disease modifying therapies.

Epidemiology

Difficulties in diagnostic accuracy, often requiring evaluation at a tertiary medical center, and clinical and pathological overlap with Alzheimer disease and Parkinson disease make traditional epidemiology studies of dementia with Lewy bodies challenging. Thus, most estimates are likely lower than the true occurrence of dementia with Lewy bodies (75). Postmortem findings of alpha-synuclein pathology in dementia patients suggest that Lewy body dementia is the second most common neurodegenerative dementia diagnosis after Alzheimer disease. Population-based studies for clinical dementia with Lewy bodies estimate a range in prevalence of 0.1% to 2% of the general population and between approximately 3% and 30% of dementia populations. The incidence of clinical dementia with Lewy bodies is estimated to be 3.5 per 100,000 person-years, which increases rapidly with age to more than 30 per 100,000 person years in those older than 65 (76); thus, age is a strong risk factor for dementia with Lewy bodies. Dementia with Lewy bodies has been associated with increased frequency in male patients for reasons that are currently unclear, but this could be related to potential protective effects of estrogen on the development of synucleinopathy. Indeed, studies of environmental risk factors for dementia with Lewy bodies are scant, but some report that oophorectomy prior to the age of 45 is associated with increased risk of dementia with Lewy bodies (03). Other potential environmental risk factors included caffeine abstinence and previous diagnosis of anxiety or depression (03). In a European autopsy study, Jellinger found that the mean age at death among patients with dementia with Lewy bodies (79.8 years) was significantly lower than that seen in Parkinson disease with dementia (83.9 years) (41). Disease duration from the time of diagnosis was also shorter in dementia with Lewy bodies (6.7 years) than in Parkinson disease with dementia (9.2 years).

Prevention

There are no known preventative measures for dementia with Lewy bodies. Strategies for healthy aging, including cognitive and social stimulation, exercise, and heart-healthy diet reducing cardiovascular risk, have been attributed to delaying the onset of age-associated dementias in general, but more studies are needed to understand the significance of these factors for dementia with Lewy bodies.

Differential diagnosis

The differential diagnosis of dementia with Lewy bodies largely is influenced by observations about the onset and rate of progression of disease by patients and families. For those patients with dementia with Lewy bodies who report a slow and subtle progression of cognitive and motor impairments over the course of years, it is important to exclude alternative age-associated neurodegenerative diseases such as Alzheimer disease, multiple system atrophy, and frontotemporal degeneration. Patients with Alzheimer disease may have more prominent episodic memory loss early in the course of their disorder, whereas prominent Parkinsonism is less common in Alzheimer disease (30). Frontotemporal degeneration is a heterogeneous disorder (35) and includes atypical Parkinsonian syndromes (progressive supranuclear palsy or corticobasal syndrome), which can clinically resemble dementia with Lewy bodies. In a pathological study of 126 frontotemporal lobe dementia cases, coexisting Lewy body disease was identified at autopsy in nine brains (7%), and three of these patients had parkinsonism (21). Progressive supranuclear palsy typically has a characteristic oculomotility deficit for vertical saccades along with severe postural instability and axial rigidity, although there is significant heterogeneity in clinical presentation. Corticobasal syndrome usually can be distinguished from dementia with Lewy bodies by the presence of prominent lateralization of extrapyramidal signs and motor apraxia. Multiple system atrophy can also be mistaken for dementia with Lewy bodies, especially if cognitive difficulties are prominent early in the disease, which is not common in multiple system atrophy (48). Findings of severe autonomic dysfunction or prominent cerebellar signs are useful to differentiate multiple system atrophy from dementia with Lewy bodies.

Confusing conditions

Other causes of visual hallucinations. Charles Bonnet syndrome can cause formed or unformed visual hallucinations (people, faces, animals, flowers) in those who have had visual loss from macular degeneration, cataracts, or other chronic eye conditions (47). Complex hallucinations can occur with focal seizures in the presence of occipital lobe tumors or vascular malformations (EEG and MRI are needed to detect these findings). Hallucinogenic substances are also to be suspected as the cause of visual hallucinations, but onset is usually acutely tied to use of the hallucinogenic substance. Psychiatric illnesses, such as schizophrenia, are usually earlier in onset than dementia with Lewy bodies, and the hallucinations are auditory rather than visual (47).

Diagnostic workup

Structural imaging. MRI is a useful examination tool for vascular disease, structural changes (eg, tumor, hippocampal atrophy suggestive of Alzheimer disease, hot-cross bun sign suggestive of multiple system atrophy, hummingbird sign suggestive of progressive supranuclear palsy, pronounced frontotemporal atrophy associated with frontotemporal degeneration), cortical ribbon or thalamic hyper-intensities (suggestive of prion disease), and subcortical hyperintensities suggestive of inflammatory conditions or demyelination. Preservation of hippocampal integrity is supportive of dementia with Lewy bodies diagnosis, but due to the high rate of Alzheimer disease co-morbidity, hippocampal volume loss does not exclude a diagnosis of dementia with Lewy bodies. The presence of cerebral microbleeds in patients with dementia with Lewy bodies should not exclude the diagnosis (14). In patients with dementia with Lewy bodies who had microbleeds, the systolic blood pressure was higher on average (156 mmHg) than in those without microbleeds (135 mmHg). In prodromal dementia with Lewy bodies, the MRI showed evidence of widening of sulci in the occipital lobes, frontoinsular cortices, and olfactory sulci (02). Large areas of white matter hyperintensities should not exclude the diagnosis of dementia with Lewy bodies because patients with dementia with Lewy bodies with increased age and absence of the APOE-e4 allele have been shown to have higher white matter intensity volumes (20).

Laboratory testing. Routine serum studies for common metabolic and infectious etiologies contributing to cognitive impairment in this age range are useful, including a complete metabolic profile, sedimentation rate, and thyroid function studies. Additional laboratory studies should be tailored to the patient’s medical history and review of symptoms (eg, history of rheumatoid arthritis may prompt an expanded autoimmune serology).

CSF studies. In cases in which the disease course is rapidly progressive, a diagnostic lumbar puncture is essential to help differentiate dementia with Lewy bodies from rapid progressive dementia etiologies (44) and routine cell count, protein, glucose, IgG index, gram-stain, culture, and cytology. Further investigations may be useful, depending on the specific rapid progressive dementias suspected in the differential based on a thorough history and physical examination (eg, protein 14-3-3 or real time quaking-induced conversion (RT-QuIC) assay for prion disease [16], anti-NMDA receptor antibody for limbic encephalitis). CSF analysis for Alzheimer disease-associated Abeta and tau protein level changes is still considered a research adjuvant study supporting Alzheimer disease diagnostic criteria (39). Many patients with dementia with Lewy bodies have high CSF tau and low Abeta levels, usually intermediate to the elevated levels of Tau and low levels of Abeta in Alzheimer disease and normal levels in Parkinson disease (29; 84), likely reflecting the high rate of Alzheimer disease co-pathology in dementia with Lewy bodies. Thus, the presence of positive Alzheimer disease CSF biomarkers does not preclude a diagnosis of dementia with Lewy bodies. RT-QuIC assays have been shown to have high sensitivity and specificity for detecting misfolded alpha-synuclein in CSF in Parkinson disease, multiple system atrophy, and dementia with Lewy bodies (06; 16). The latter assay (the same assay that is used in prion diseases) has been shown to be accurate in the MCI stages of dementia with Lewy bodies (73).

EEG. An EEG may be useful to help detect complex-partial seizures or periodic discharges consistent with some forms of rapidly progressing dementias. Diffuse slowing of the background rhythm is common to all dementias but may be more prominent in dementia with Lewy bodies and coincide with cognitive fluctuations (62).

FDG-PET. PET CT imaging using fluorodeoxyglucose may be helpful to detect patterns of cortical hypometabolism suggestive of synaptic dysfunction in dementia with Lewy bodies, which includes prominent posterior parietal and occipital hypometabolism (24). Besides posterior hypometabolism, there are two other distinct patterns that distinguish patients with prodromal dementia with Lewy bodies from those with prodromal Alzheimer disease (45; 58). The “cingulate island sign” is highly specific (but not sensitive) for making a diagnosis of prodromal dementia with Lewy bodies. This sign means that there is relative sparing of metabolism (creating an “island”) in the posterior cingulate cortex compared to surrounding hypometabolism in occipital cortical areas. A more sensitive sign is the ratio of medial temporal/substantia nigra metabolism (the ratio is higher in prodromal dementia with Lewy bodies compared to the MCI that precedes Alzheimer disease). Hypermetabolic areas on FDG-PET (in amygdala and entorhinal cortices) have also been identified in other prodromal patients (those with isolated REM sleep behavior disorder who were classified as being “progressors” because they either developed parkinsonism or mild cognitive impairment over time). These areas of hypermetabolism were hypothesized to represent either the recruitment of compensatory mechanisms or the activation of microglia (11).

Dopamine transporter imaging. Abnormalities in the striatum on DAT scans are a biomarker for dementia with Lewy bodies (Table 1) and reflect presynaptic neuronal degeneration in striatal projections from the substantia nigra. In the setting of possible dementia with Lewy bodies, a positive scan can be useful to differentiate dementia with Lewy bodies from Alzheimer disease (61; 62), which would have a normal signal due to the absence of nigral pathology early in the disease. Of note, dopamine transporter imaging is not specific for synucleinopathies and can be seen in other forms of parkinsonism, including progressive supranuclear palsy and corticobasal syndrome. Furthermore, due to the potential differences in spread of alpha-synculein pathology in dementia with Lewy bodies, not all patients may have sufficient nigral pathology at onset to produce an abnormal DAT scan. Thus, a negative scan does not preclude the diagnosis of dementia with Lewy bodies, but a positive scan in the setting of other key clinical characteristics can be useful (62). Lewy body patients who are amyloid positive have lower DAT activity levels in the anterior putamen, ventral putamen, and ventral striatum (90).

Cardiac innervation scintigraphy. Based on the postmortem findings of pathological alpha-synuclein in postganglionic sympathetic cardiac innervation in dementia with Lewy bodies patients, cardiac imaging using iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy finds abnormalities in dementia with Lewy bodies (79; 72; 57); however, caution in interpretation should be used in the setting of exposure to specific medications and cardiac disease, such as cardiomyopathy, that can influence results (62). A study showed that cardiac MIBG distinguished mild cognitive impairment with Lewy bodies from mild cognitive impairment with Alzheimer disease patients, with a specificity of 88% (72).

Amyloid PET. Finally, Abeta amyloid-PET imaging using an Abeta amyloid-specific radioligand is currently FDA-approved to aid in the diagnosis of Alzheimer disease through in vivo visualization of neuritic amyloid plaques (09). Due to the frequency of amyloid plaque formation in healthy aging, with advanced age the significance of a positive test result for a patient with normal cognition or mild cognitive impairment is unclear but considered to increase risk of progression to dementia (42). Furthermore, most patients with dementia with Lewy bodies have moderate to severe burden of plaque pathology at autopsy (36), and in vivo studies find that imaging with Abeta amyloid-PET and emerging tau specific PET tracer is frequently positive in dementia with Lewy bodies (46; 91; 20); therefore, a positive PET Abeta scan does not preclude the diagnosis of dementia with Lewy bodies. Further studies of these imaging ligands in combination with other emerging biomarkers for Alzheimer disease and synucleinopathies will likely be helpful for diagnosis and prognosis of dementia with Lewy bodies and help reduce the need for ancillary tests described above to rule out alternative diagnoses.

Management

Cholinesterase inhibitors. There are no FDA-approved medications for dementia with Lewy bodies currently, and management is largely symptomatic or supportive. Implementation of increased supervision and structured activities throughout the day are critical to help keep patients engaged with cognitively stimulating activities and reduce agitation and risk of safety issues. Clinical trials suggest acetylcholinesterase inhibitors such as rivastigmine (60), galantamine (17), and donepezil (64) may help to improve attention and concentration, as well as to reduce fluctuations, visual hallucinations, and caregiver burden. There also are data to suggest efficacy of memantine, a glutamate antagonist used for symptomatic treatment of Alzheimer disease, for global functioning in patients with dementia with Lewy bodies (18); the common co-occurrence of Alzheimer disease pathology in dementia with Lewy bodies also suggests there could be potential benefit of these Alzheimer disease symptomatic therapies that restore deficient neurotransmitters in dementia with Lewy bodies, but further studies are needed to confirm this. Wang and colleagues provide a systematic review of therapeutic trials in dementia with Lewy bodies (89).

Antipsychotic drugs. Agitation can often be managed without drugs through the use of behavior-modification strategies to help keep patients oriented and engaged in structured activities. For example, visual hallucinations can often be handled by reassuring the patient that the “visitors” are “our friends,” and that they mean no harm. An unstructured environment can lead to disorientation and promote agitation. Nevertheless, Walker and colleagues demonstrated that patients with dementia with Lewy bodies have higher psychiatric symptom scores than Alzheimer patients (88). They found that in the mild dementia stage, 16% needed neuroleptic medications for agitation, compared to only 4% of mild Alzheimer patients. Refractory visual hallucinations or agitation that creates a safety hazard can potentially be cautiously treated with second-generation neuroleptics with minimal D2 receptor activity (eg, quetiapine or clozapine). The starting dose of quetiapine is usually 25 mg every night at bedtime to avoid excessive daytime sedation or dizziness (32). Kurlan and colleagues performed a small clinical trial to find the mean dose of quetiapine that would be most effective for managing agitation in patients with dementia (23 of their 40 patients had dementia with Lewy bodies) (50). They found that a mean dose of 120 mg/d was well tolerated and did not worsen the parkinsonism in the Lewy bodies patients. Families need to know about the current black box warning associated with neuroleptics in the elderly (because of increased risk of stroke and overall mortality) (59). Typical neuroleptics, such as haloperidol or injectable neuroleptics, are absolutely contraindicated in dementia with Lewy bodies due to risk of severe hypersensitivity reaction (62).

Valproic acid. If patients with dementia with Lewy bodies on cholinesterase inhibitors continue to become agitated while they are taking low doses of quetiapine, the dose of quetiapine can be slowly increased. If increasing the dose of quetiapine causes the patient to experience more parkinsonism, then another way to manage the agitation is to add a low dose of oral valproic acid (32). Several trials have been done with valproic acid in agitated Alzheimer disease patients, but the drug has not been shown to be effective as monotherapy. When it is used in combination with other psychotropic drugs, on the other hand, low doses (250 mg bid) of divalproex have been demonstrated to be useful in preventing agitation in patients with dementia (13). Higher maintenance doses of intravenous valproic acid (1500 mg/day) are sometimes needed to manage agitation in patients who are critically ill and in the ICU (23).

Carbidopa-levodopa. A trial of carbidopa-levodopa may be useful in some patients with dementia with Lewy bodies to improve parkinsonism and alertness during the day (19; 32). An important consideration for patients with dementia with Lewy bodies when using levodopa is the risk of worsening agitation and visual hallucinations with high doses of levodopa. In the large outpatient clinic series of Farina and colleagues, the mean dose of levodopa for patients with dementia with Lewy bodies was low for this reason (303 mg/day), compared to the usual dose needed to treat Parkinson disease (19).

Zonisamide. A new adjunct to levodopa for managing the parkinsonism of dementia with Lewy bodies is the antiepileptic drug, zonisamide. It has been shown in a randomized, double-blind phase 2 study to be effective at a dose of 50 mg/day as an adjunct to levodopa; it carries little risk of producing agitation or visual hallucinations (65). The Lewy body patients enrolled in this trial had had motor symptoms for 3.5 years on average, and their mean dose of levodopa at the time of enrollment was 279 mg/day.

Melatonin. This supplement is effective for treatment of rapid-eye movement sleep behavior disorder in dementia with Lewy bodies patients. Melatonin carries less risk of cognitive, motor, and respiratory side effects, compared to the first-line therapy, clonazepam (01).

Outcomes

Dementia with Lewy bodies is currently an incurable condition that culminates in end-stage dementia and associated sequelae that include systemic infections, injury from falls, or aspiration due to neurogenic dysphagia. Prognosis is variable between individuals, with a mean duration of disease for autopsy-confirmed dementia with Lewy bodies roughly 6 years from the onset of symptoms, ranging from 1 to 14 years in one large study (36; 26). Variability in disease course may be influenced by the difficulties in making a diagnosis early in the disease, socioeconomic factors, genetic modifiers, or other medical comorbidities. In addition, the disease course may depend on whether dementia with Lewy bodies appears in its pure form or whether it is mixed with Alzheimer disease (patients with mixed disease have increased hospitalization rates) (40). Patients with dementia with Lewy bodies have double the rate of functional deterioration in activities of daily living at the end of life, compared to Alzheimer patients (26).

Special considerations

Pregnancy

Pregnancy in the setting of dementia with Lewy bodies is very uncommon as this is an age-associated neurodegenerative condition, and the majority of female patients are not of child-bearing potential at the time of onset.

Anesthesia

Patients with dementia with Lewy bodies are often sensitive to psychoactive medications and can have prolonged delirium after major medical procedures and anesthesia exposure (69). Other factors that can lead to postoperative cognitive dysfunction include postoperative infection, hypotension, or prolonged duration of surgery.