Clinical features and diagnosis of dementia with Lewy bodies

INTRODUCTION — 

Dementia with Lewy bodies (DLB) is one of the most common types of degenerative dementias, second to Alzheimer disease (AD). In addition to dementia, distinctive clinical features include visual hallucinations, parkinsonism, cognitive fluctuations, rapid eye movement (REM) sleep behavior disorder (RBD), dysautonomia, and neuroleptic sensitivity.

The pathological hallmark of DLB is the presence of eosinophilic intracytoplasmic inclusions called Lewy bodies that contain aggregated alpha-synuclein. Lewy bodies are typically present in the deep cortical layers throughout the brain, especially in anterior frontal and temporal lobes, cingulate gyrus, and insula.

"Lewy body dementia" is an umbrella term that includes DLB and Parkinson disease with (Lewy body) dementia (PDD). There is increasing consensus that DLB is a clinically distinct disorder, distinguished by early onset of dementia and more rapid progression. By contrast, dementia occurs much later in patients with PDD, sometimes as much as 10 years after the onset of Parkinson disease (PD). While both disorders share similar clinical features and pathology, DLB is comparatively underrecognized and harbors a poorer prognosis, with an average disease duration of five to eight years from symptom onset.

Clinical diagnostic criteria for DLB are continually being refined to improve specificity and sensitivity. Appropriate diagnosis is critical in order to provide the best treatment in regard to maximizing efficacy and limiting adverse effects.

This topic reviews the clinical and radiologic features and diagnosis of DLB. The epidemiology, neuropathology, pathogenesis, prognosis, and treatment of this disorder are discussed separately:

●(See "Epidemiology, pathology, and pathogenesis of dementia with Lewy bodies".)

●(See "Prognosis and treatment of dementia with Lewy bodies".)

Other dementia syndromes are described separately:

●(See "Cognitive impairment and dementia in Parkinson disease".)

●(See "Etiology, clinical manifestations, and diagnosis of vascular dementia".)

●(See "Clinical features and diagnosis of Alzheimer disease".)

●(See "Frontotemporal dementia: Clinical features and diagnosis".)

●(See "Normal pressure hydrocephalus".)

CLINICAL FEATURES — 

Consensus criteria for the clinical diagnosis of DLB, developed by the DLB Consortium, were most recently revised in 2017 to improve diagnostic sensitivity and specificity (table 1) [1,2].

Dementia is essential to the diagnosis of DLB. Other clinical manifestations of DLB are organized into a hierarchy of core and supportive diagnostic features and biomarkers that provide strong or suggestive evidence for the diagnosis.

Dementia — Dementia is defined as a progressive cognitive decline that interferes with normal social and occupational functions or with usual daily activities; this is an essential feature of DLB [2]. Cognitive dysfunction is often the presenting symptom in DLB.

Prominent and early features of cognitive impairment include deficits in attention, executive function, and visuoperceptual function. Unlike Alzheimer disease (AD), which typically presents with memory loss as its first and most prominent cognitive deficit, DLB is characterized by early impairments in attention and executive and visuospatial function, with memory affected later in the course of the disease [3-9]. Early symptoms include driving difficulty (eg, getting lost, misjudging distances, or failing to see stop signs or other cars) and impaired job performance.

Bedside tests of cognitive function (eg, the Mini-Mental State Examination [MMSE] or Montreal Cognitive Assessment [MoCA]) do not reliably differentiate among dementia types [10]. However, the early appearance of impaired figure copying (overlapping pentagon), clock drawing, and serial sevens (or spelling "WORLD" backward) can be suggestive of DLB, while patients with AD generally show impaired short-term memory and orientation as the earliest deficits on the MMSE [11,12]. In one study with neuropathological confirmation, absence of visuospatial impairments in the early stages of disease helped to exclude DLB with a negative predictive value of 90 percent [8].

Early signs on neuropsychological testing may include deficiencies in tests of visuospatial and visuoperceptual ability [5,9,13-15]. Measures of executive function and attention (eg, Stroop, trail-making tasks, Wisconsin Card Sorting Test, phonemic fluency) may also be impaired early on [16]. When memory does become impaired in DLB, memory retrieval may be more affected than acquisition [17]. DLB patients with prominent AD pathology (eg, neurofibrillary tangles) may have a cognitive profile that is more characteristic of AD.

Prodromal DLB may be associated with mild cognitive impairment that may go unrecognized [18,19]. In one series of patients with idiopathic rapid eye movement (REM) sleep behavior disorder (RBD), evidence of cognitive decline, particularly in attention and executive function, was a predictor of subsequent dementia (either DLB or Parkinson disease dementia [PDD]) [20].

These evaluations are described separately. (See "The mental status examination in adults" and "Mental status scales to evaluate cognition".)

Core clinical features — In addition to dementia, a patient with probable DLB must have at least two "core clinical features" of DLB: cognitive fluctuations, visual hallucinations, RBD, and parkinsonism (table 1). These typically appear early and may persist throughout the disease course [2].

Cognitive fluctuations — Fluctuations in cognition, attention, and arousal are estimated to be a feature in 60 to 80 percent of cases and may occur early in the course of DLB [21].

The severity, duration, and type of symptoms involved in fluctuations are quite varied, even for a given patient. Episodes can be subtle, as in a brief decline in ability to perform an activity of daily living, or they may be dramatic enough to raise the question of a stroke or seizure. Caregivers often describe episodes in which patients appear to "zone out," lose consciousness or awareness, become unresponsive, have speech or motor arrest, or become excessively somnolent. Alternatively, they may become confused and behave in a bizarre manner. These episodes can last for seconds to several days, and they can be interspersed with periods of near-normal function.

This feature of DLB has been considered the most difficult of the core clinical features for inexperienced clinicians to evaluate. Family members may not volunteer this history. At the same time, questions to elicit a history of fluctuations, if too general, are likely to obtain false-positive responses in patients with other forms of dementia [22,23]. Structured questionnaires (eg, Clinician Assessment of Fluctuation, One Day Fluctuation Assessment Scale) appear to more specifically elicit the symptoms of fluctuations in DLB [24]. These share, as a common feature, the solicitation of more than one example of a fluctuation episode with specific descriptive details regarding symptoms, severity, and duration. These scales are available separately [24].

Episodes that include at least three of the four following features are more likely to occur in patients with DLB than with AD: daytime drowsiness, daytime naps lasting more than two hours, prolonged staring spells, and episodes of disorganized speech [22]. By contrast, fluctuations in AD are usually described vaguely as "good days and bad days" and are often explained by external stressors. In DLB, fluctuations are more often spontaneous and episodic (ie, waxing and waning), seemingly related to an interruption of awareness or attention that impacts functional ability [23].

An objective measure of fluctuations in DLB using computerized assessments of reaction time and vigilance has been shown to distinguish patients with DLB from those with vascular dementia and AD, but this is not a generally available clinical assessment tool [25].

Visual hallucinations — Visual hallucinations occur in up to 70 percent of patients with DLB; they are an early sign in DLB and may precede parkinsonism. Among patients with DLB, those with visual hallucinations appear to have more severe deficits in visual attention and executive function compared with those without visual hallucinations, but similar degrees of visuospatial and visual-perceptual impairment [26].

By contrast, visual hallucinations are relatively rare in AD [27-29]. In one study with neuropathological confirmation, having visual hallucinations at presentation was the most useful clinical feature to distinguish DLB from AD, with 83 percent positive predictive value [8]. Visual hallucinations are somewhat less common in PDD than in DLB [30]. While in Parkinson disease (PD) hallucinations arise frequently in the setting of dopaminergic therapy, in DLB they may occur spontaneously [1,31].

Visual hallucinations are typically well-formed and detailed. Typical descriptions range from images of people, children, or small animals, to more abstract visions such as shapes or colors. Patients report simple hallucinations such as seeing something briefly out of the corner of their eye, or extremely complex hallucinations, such as having an ongoing dialog with a deceased loved one.

Patients may also describe visual illusions or misperceptions (eg, mistaking a tree for a person) [32]. Others report a "sense of presence" hallucination or delusion (a sensation that someone is present nearby when no one is there) or passage hallucinations, which consist of a brief vision of a person passing [33].

If not specifically solicited, visual hallucinations are often unreported.

Patients may or may not have insight into the nature of the hallucinations or illusions, and reactions may vary from fear, to indifference, to enjoyment. Some patients may also confuse vivid dreams (occurring during sleep) with hallucinations. (See "Approach to the patient with visual hallucinations", section on 'Neurodegenerative disease'.)

REM sleep behavior disorder — RBD is a parasomnia characterized by dream enactment behavior that emerges after a loss of the atonia that occurs in REM sleep. RBD is commonly associated with DLB, occurring in up to 90 percent of individuals [2,34-37]. Isolated RBD is recognized as a prodromal symptom and may occur 6 to 10 years, even as long as 20 years, before the clinical diagnosis of DLB [38,39]. RBD may become less apparent or "burn out" later in the disease.

RBD is not specific to DLB and occurs frequently in patients with PD and other synucleinopathies. It can also be seen in patients with narcolepsy or structural lesions in the brainstem, and as a side effect of certain medications, most notably the selective serotonin reuptake inhibitor (SSRI) antidepressants. (See "Rapid eye movement sleep behavior disorder", section on 'Etiology' and "Rapid eye movement sleep behavior disorder", section on 'Epidemiology'.)

Individuals with RBD have recurrent sleep-related vocalization and/or complex motor behaviors during REM sleep, correlating with dreams. The movements of RBD are short in duration (less than 60 seconds) and appear purposeful, such as throwing a ball or flailing to protect oneself. They range in severity from benign hand gestures to violent thrashing, punching, and kicking. (See "Rapid eye movement sleep behavior disorder", section on 'Clinical features'.)

Sleep-related injuries can arise from jumping or falling out of bed, or striking a bed partner. All patients with RBD and their bed partners should be counseled on ways to modify the sleeping environment to prevent injury. Most patients respond to treatment with melatonin or clonazepam. (See "Rapid eye movement sleep behavior disorder", section on 'Management'.)

Parkinsonism — Parkinsonian symptoms including bradykinesia, rest tremor, rigidity, and/or gait disorder are seen in approximately 70 to 90 percent of patients with DLB [28,40]. While the parkinsonism in DLB can be as severe as that in idiopathic PD, the symptoms are usually milder and more symmetric [41]. Tremor is less common and less severe than in PD [42,43]. Despite these observed clinical trends, no specific feature reliably distinguishes the motor parkinsonism of PD versus DLB. (See "Bradykinetic movement disorders in children", section on 'Parkinson disease'.)

Supportive clinical features — These features include severe sensitivity to antipsychotic drugs, among others (table 1). Supportive clinical features lack diagnostic specificity on their own but can help support the diagnosis of DLB, especially if persistent, or if several features are present in combination.

Antipsychotic sensitivity — Approximately 30 to 50 percent of individuals with DLB have marked sensitivity to antipsychotic drugs [44-46]. Acute reactions include severe, sometimes irreversible parkinsonism and impaired consciousness, sometimes with other features suggestive of neuroleptic malignant syndrome. This can occur in individuals without baseline parkinsonism.

Adverse reactions are more common with first-generation antipsychotics (eg, haloperidol), but reactions to second-generation antipsychotics have also been described [47]. (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and "Second-generation and other antipsychotic medications: Pharmacology, administration, and side effects".)

The phenomenon is not dose related. Antipsychotic medications may also precipitate or worsen confusion or autonomic dysfunction, and their use has been associated with a two- to threefold increase in mortality. (See "Management of neuropsychiatric symptoms of dementia", section on 'Mortality risk'.)

Severe reactions to antipsychotics are less common in patients with PD (with or without dementia), but such reactions have not been described in AD [46]. Despite the high specificity of this finding, deliberate pharmacologic challenge as a diagnostic strategy is obviously unwise.

A history of neuroleptic tolerance does not exclude DLB or future antipsychotic sensitivity.

Postural instability and falls — Recurrent falls occur in up to one-third of patients with DLB and may be among the earliest symptoms [48,49]. Falls may occur with or without provocation and may be related to parkinsonism, to cognitive fluctuations, or to orthostatic hypotension.

Syncope or transient loss of consciousness — Episodes of altered or loss of consciousness are commonly described in DLB.

Patients may transiently lose consciousness, or they may be awake but mute and stare blankly. Episodes may even resemble cataplexy, in which patients develop sudden atonia and fall to the floor.

Episodes can occur as a result of orthostatic hypotension, which has been reported in 28 to 50 percent of patients, and which can be severe enough to mimic multiple system atrophy [50,51]. In one series, 6 of 20 patients with DLB followed for three years required medication for blood pressure maintenance [51]. Carotid sinus sensitivity has also been described in association with DLB and may underlie episodes of syncope, or may be a general marker of autonomic dysfunction [52].

Episodes may also represent an extreme cognitive fluctuation or may be analogous to the motor "freezing" seen in idiopathic PD. Other etiologies such as seizures, stroke, transient ischemic attack, or cardiac arrhythmia should also be ruled out.

Autonomic dysfunction — Autonomic symptoms are common in the synucleinopathy disorders, including DLB, occurring in approximately 60 percent of patients [53]. Symptoms may be prodromal and occur prior to cognitive impairment [54-57].

In addition to orthostatic hypotension and neurocardiovascular instability discussed in the section above, autonomic dysfunction in DLB may include urinary incontinence or retention, erectile dysfunction (in males), constipation, and other gastrointestinal symptoms [50,51,58].

Autonomic symptoms are more prevalent and severe in DLB than in PD, but less so than in multiple system atrophy [51]. Urinary incontinence occurs at late stages of AD when dementia is severe but is often an early sign in DLB [59,60].

In small case series, tests of autonomic dysfunction (eg, sympathetic sweat responses, skin vasomotor reflexes, head-up tilt, ventilatory response to hypercapnia, and heart rate variability) were markedly abnormal in patients with DLB and may help differentiate these patients from individuals with other neurodegenerative dementias [61,62]. However, this diagnostic approach still requires independent, prospective validation.

Hypersomnia — Hypersomnia, also referred to as "excessive daytime sleepiness," is common in patients with DLB and may be multifactorial. In addition to RBD, other sleep disorders that may contribute to daytime sleepiness in DLB include insomnia, sleep apnea (obstructive or central), periodic limb movements of sleep, and restless legs syndrome/Willis-Ekbom disease [63]. Using multiple sleep latency testing, one study demonstrated daytime sleepiness in 81 percent of patients with DLB versus 39 percent of patients with AD dementia [64].

Hyposmia — Decreased olfactory function is common in patients with DLB and other neurodegenerative dementias, including AD and PD. Whether poor performance on bedside tests of olfactory function is useful in distinguishing DLB from AD is uncertain, as deficits have been observed in patients with presymptomatic or early-stage forms of both diseases [65,66]. One study found that a combination of a brief smell assessment with a specific cognitive test was useful to discriminate DLB from AD, but this requires independent confirmation [67].

Hallucinations in other modalities — In addition to visual hallucinations, patients with DLB may also experience hallucinations in other modalities.

●Auditory hallucinations may be well-formed, such as hearing identifiable speech or music, or they may be less distinct, such as having the impression of hearing a television, voice, or telephone ringing in another room.

●Olfactory hallucinations can be pleasant (eg, flowers or food) or unpleasant (eg, burning rubber).

●Patients have also described tactile hallucinations such as the feeling of insects on their skin or a cat brushing against their leg.

The presence of these hallucinations may prompt a workup for partial seizures, psychotic disorders, or substance intoxication or withdrawal.

Systematized delusions — Delusions (false, fixed beliefs) are common in DLB (in as much as 75 percent of cases); they may be elaborate, specific, and systematic [68]. They are often rooted in hallucinations or visual misperceptions that the patient has experienced. Common themes include that the spouse or caregiver is an impostor (Capgras syndrome), the house is not their home, or people in the television or mirror are speaking to them or following them.

Somatoform disorder (characterized by a high frequency of medically unexplained symptoms) is a related but distinct psychiatric syndrome that may be observed in patients with DLB. In one study, 12 percent (15 of 124) of patients with DLB exhibited symptoms of somatization [69]. The observed symptoms often took on delusional qualities (body deformation, requests for invasive medical procedures) and were associated with motor catatonic signs in eight patients.

Apathy, anxiety, and depression — Most patients with DLB experience depressive symptoms at some point in their illness, and up to 40 percent have a major depressive episode [2,70-74]. Some but not all studies suggest that rates of depression are higher in DLB than in AD or PD [2,70-73,75-77]. Depression is less likely than other features of DLB to persist over time [68].

Anxiety is also common and affects 50 percent or more of patients in all stages of DLB [70,73,78]. In one study, anxiety was reported more frequently in patients with DLB than in those with AD (63 versus 27 percent) [77]. Anxiety preceded the diagnosis of DLB by up to four to five years and was associated with depression and living at home. Anxiety in DLB was characterized as intermittent panic attacks without a clear cause or occurring during delirium, and, in contrast to patients with AD, was often severe enough to require medical treatment or psychiatric care.

Apathy, manifesting as lack of motivation, energy, or interest, occurs in nearly 55 percent of patients with DLB and may be present with or without depression [70].

IMAGING AND OTHER TEST FEATURES

Indicative biomarkers — Although diagnostic biomarkers of DLB are not yet clinically available, several indirect measures of Lewy body pathology are indicative or supportive of the diagnosis in the proper clinical context (table 1) [2].

Indicative biomarkers, in combination with one or more core features, can be used to diagnose probable DLB. Dementia plus one or more indicative biomarker, but without a core feature, suggests possible DLB.

Dopamine transporter imaging — Using specific ligands for the dopamine transporter (DAT), both single-photon emission computed tomography (SPECT) and positron emission tomography (PET) studies have demonstrated low dopaminergic activity in the striatum in patients with DLB (image 1) [79-86]. DAT SPECT imaging is considered an indicative biomarker in the diagnosis of probable or possible DLB (table 1).

This finding is also seen in Parkinson disease (PD), multiple system atrophy, and progressive supranuclear palsy, but not in Alzheimer disease (AD). A study in 326 patients with dementia reported a sensitivity of 78 percent and a specificity of 90 percent of ioflupane I-123 DAT SPECT imaging (DaTscan) for the diagnosis of DLB [87]; a smaller study with autopsy-based pathological confirmation reported a sensitivity and specificity of 80 and 90 percent, respectively, among 55 patients with DLB and AD [88]. In 2022, the US Food and Drug Administration (FDA) approved ioflupane I-123 DaTscan for use in the diagnosis of DLB [89].

Myocardial scintigraphy — Cardiac autonomic denervation is observed in Lewy body disorders including PD, DLB, and pure autonomic failure. The presence of this phenomenon can be assessed using metaiodobenzylguanidine (MIBG), a noradrenaline analogue that binds to postganglionic sympathetic receptors present in the heart.

In DLB, 123-I-MIBG myocardial scintigraphy demonstrates low uptake, representing reduced sympathetic cardiac innervation (image 2) [90,91]. Studies suggest high sensitivity and specificity of MIBG scintigraphy for DLB [92], especially when distinguishing it from AD [93,94]. A multicenter study in DLB found the sensitivity and specificity of MIBG to be 69 and 89 percent, respectively, [95], which increased with three-year follow-up [96].

Importantly, MIBG scintigraphy may be limited by comorbid conditions and medications that can reduce uptake. Studies have typically excluded participants with common conditions like heart failure, ischemic heart disease, and poorly controlled diabetes.

Polysomnography — Formal sleep testing, or polysomnography, allows for objective measurement of rapid eye movement (REM) sleep behavior disorder (RBD) and other parasomnias by measuring electroencephalography (EEG), eye and limb movements, and oxygen saturation during sleep. (See "Rapid eye movement sleep behavior disorder", section on 'Video polysomnography'.)

RBD confirmed by polysomnography has a high diagnostic specificity of 98 percent for Lewy body disorders [97] and sensitivity of 84 percent in postmortem DLB [35], and is classified as an indicative biomarker for DLB.

Supportive biomarkers — While supportive biomarkers lack diagnostic specificity, these features are noteworthy and, when consistent, can be helpful in the diagnostic evaluation of DLB.

Neuroimaging — Generalized atrophy and white matter lesions are nonspecific findings in dementia; however, magnetic resonance imaging (MRI) may identify patterns of regional atrophy that are more specific to DLB (image 1). As examples:

●Volumetric analyses of MRI scans in patients with DLB show more pronounced cortical atrophy than in patients with PD dementia (PDD) [98]. However, this observation alone is not sufficiently sensitive or specific to aid in the diagnosis of DLB versus PDD in individual patients [99].

●Volumetric analyses of MRI scans also demonstrate atrophy of the putamen and dorsal mesopontine gray matter in DLB compared with that in AD [98-101]. Hippocampal atrophy in DLB as seen on coronal MRI sections is not as prominent compared with AD (image 3) [100,102,103].

In patients with DLB, SPECT and PET scans show generalized decreased perfusion and metabolism most marked in the occipital areas [104-110]. In contrast to AD, there is often relative preservation of posterior cingulate metabolism on 18-F fluorodeoxyglucose-PET (FDG-PET), referred to as the "cingulate island sign" (image 4) [111]. Relative hypoperfusion in the occipital lobe in DLB appears, at least in small series, to have potential diagnostic utility in DLB, with a sensitivity and specificity for SPECT of 65 and 87 percent, respectively, and for PET of 90 and 80 percent, respectively [105,112]. In another series, reduced metabolism, frequently seen in the occipital lobes, correlated with the frequency and severity of visual hallucinations [113]. Despite the changes in the occipital lobe on SPECT and PET, regional occipital atrophy is generally not observed on MRI in DLB. However, one study did report a finding of reduced fractional anisotropy in the parieto-occipital white matter tracts on diffusion tensor imaging was associated with DLB and not AD [114].

Amyloid PET shows increased binding in a significant subset of patients with DLB and may correlate with cognitive impairment; however, more studies are needed [115].

Electroencephalography — Increasing evidence supports the use of quantitative EEG as a potential biomarker for DLB.

Prominent posterior slow-wave activity and temporal slow-wave activity are characteristic [116-118]. Frontal intermittent rhythmic delta activity (FIRDA) has also been described [119,120]. The normal dominant alpha rhythm appears slowed toward pre-alpha/fast theta and is more variable over time [117,118,121]. Single-center studies report good to excellent discrimination of DLB from AD using quantitative EEG [118], whereas multicenter studies are more equivocal [122,123].

Investigational biomarkers

Alpha-synuclein — Abnormal deposition of alpha-synuclein can be detected peripherally in the gastrointestinal tract, cardiac sympathetic nerve fibers, and skin in patients with DLB [124].

●Skin biopsy – Pathological detection of abnormal phosphorylated alpha-synuclein deposits in skin nerve fibers is a sensitive biomarker for DLB. Similar deposits can be detected in PD, multiple system atrophy, and pure autonomic failure, but they are most abundant in DLB [125]. In one study, phosphorylated alpha-synuclein was present in all DLB cases (including 11 with autonomic dysfunction) but absent in healthy controls and patients with AD or frontotemporal dementia [126]. In a subsequent multicenter study, phosphorylated alpha-synuclein was detected by skin biopsy in 96 percent of patients with DLB, and there was a very low frequency of false positives (3.3 percent of controls) [127].

Phosphorylated alpha-synuclein deposits were also found in skin biopsies of 75 percent of patients with idiopathic RBD, suggesting a potential biomarker for early or prodromal DLB [128].

●Cerebrospinal fluid evaluation – In cerebrospinal fluid (CSF), reduced total levels of alpha-synuclein and increased oligomeric alpha-synuclein have been reported in DLB, but these overlap with those of healthy controls [129].

Use of real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA) methods, however, now allow for the amplification of pathological, misfolded alpha-synuclein aggregates in biofluids such as CSF with high sensitivity and specificity in DLB and PD [130-134]. Further studies are needed to confirm the utility of CSF assays using standardized seed amplification methods.

●Blood testing – Blood plasma measurement of alpha-synuclein remains limited and fraught with technical challenges [135-137].

Alzheimer disease biomarkers — AD biomarkers are commonly used in dementia evaluations, particularly for patients with suspected AD. (See "Clinical features and diagnosis of Alzheimer disease", section on 'Role of biomarkers'.)

CSF biomarkers for AD, such as tau and amyloid-beta (Aβ) 42 ratio (as well as PET markers), can be detected antemortem in DLB. Such AD markers are increased in DLB compared with PD and PDD, but are lower than in AD, and reflect concomitant AD pathology (ie, DLB-AD). AD biomarkers in DLB also correlate with dementia severity, progression, and survival [138]. Patients with DLB-AD may also respond differently to treatment. (See 'Differential diagnosis' below.)

●Amyloid-beta 42 ratio – CSF Aβ1-42 levels are low in both DLB and AD compared with healthy controls, but they are not significantly different between the disorders [130]. Whereas Aβ1-40 levels show a moderate decrease in DLB, they rise sharply in the prodromal stage of AD. The Aβ42 to Aβ40 ratio is thus relatively lower in AD than in DLB, especially early in the disease, helping to distinguish it from DLB and other forms of dementia, with a reported sensitivity range of 73 to 94.7 percent and specificity of 78 to 100 percent.

●Total tau (t-tau) and phosphorylated tau (p-tau) – T-tau levels in CSF are normal or slightly lower in DLB patients than in AD patients, but they overlap; thus, t-tau levels are unreliable.

Elevated p-tau at threonine-181 (p-tau181) levels appear to be specific to AD and can help discriminate it from other dementias, such as DLB, in which it is largely unchanged. P-tau at threonine-217 (p-tau217) measurements can also help identify individuals with underlying AD tau pathology [139,140].

●Plasma neurofilament light chain (NfL) – NfL, in contrast, is a nonspecific marker of neurodegeneration and is elevated in both AD and DLB but is not established as a marker of clinical progression [130].

Genetic markers — Although most cases are sporadic, multiple studies indicate that DLB has a strong genetic component. Indeed, the presence of a family history of dementia or DLB increases the risk of DLB in siblings of affected individuals by more than twofold [141,142]. Despite this, family pedigrees with multiple affected members are quite rare.

Currently, genetic testing does not have an established role in the evaluation or diagnosis of DLB. However, with the increasing availability of genetic testing and knowledge of risk variants, genetics may play a role in understanding disease etiology, risk, and potentially even prognosis.

Genetic markers of DLB are discussed separately. (See "Epidemiology, pathology, and pathogenesis of dementia with Lewy bodies", section on 'Genetics'.)

EVALUATION AND DIAGNOSIS

●Evaluation – The evaluation of a patient with dementia first establishes the presence of cognitive impairment and provides a measure of its severity. Treatable conditions are excluded. In general, this evaluation includes a cognitive assessment (Mini-Mental State Examination [MMSE], Montreal Cognitive Assessment [MoCA], or formal neuropsychological testing), a neuroimaging study (usually magnetic resonance imaging [MRI]), and laboratory evaluations (vitamin B12 level and thyroid function tests). This topic is discussed in more detail elsewhere. (See "Evaluation of cognitive impairment and dementia".)

Other ancillary studies are not routinely indicated but may be needed depending on the clinical picture:

•Electroencephalography (EEG) may be helpful if there is a question of seizures or of Creutzfeldt-Jakob disease (CJD). Video-monitored EEG may be useful to rule out seizures in the evaluation of cognitive fluctuations or staring spells.

•Polysomnography is useful in evaluating sleep disorders, especially to confirm rapid eye movement (REM) sleep behavior disorder (RBD), which has high specificity for DLB. (See 'Polysomnography' above.)

•Other tests to evaluate the possibility of transient ischemic attack or syncope may be indicated in some patients with severe fluctuations or episodic loss of consciousness. (See "Initial evaluation and management of transient ischemic attack and minor ischemic stroke" and "Syncope in adults: Clinical manifestations and initial diagnostic evaluation".)

•Single-photon emission computed tomography (SPECT) scanning using the dopamine transporter (DAT) ligand ioflupane I-123 (DaTscan) can provide support for the diagnosis of DLB (indicative biomarker) in cases when the clinical features are suggestive but not diagnostic [143]. (See 'Dopamine transporter imaging' above.)

•Skin and fluid biomarker tests are increasingly available and used. Skin biopsy to detect pathological phosphorylated alpha-synuclein may be useful to detect synucleinopathy but is not specific for DLB. Cerebrospinal fluid (CSF) and plasma Alzheimer disease (AD) biomarkers such as amyloid-beta (Aβ) 42 to Aβ40 and tau may be useful to detect comorbid AD pathology and to help stratify DLB versus DLB-AD. (See 'Investigational biomarkers' above.)

●Diagnosis – The biggest barrier to the diagnosis of DLB is a low index of suspicion. The cardinal features of DLB that suggest the diagnosis may not be volunteered by patients or caregivers and often require specific solicitation by the clinician.

A positive diagnosis of DLB in a patient with dementia is primarily based upon the presence of core clinical features by history and examination (table 1). (See 'Core clinical features' above.)

Several autopsy-confirmed studies have shown that clinical diagnostic criteria provide high specificity (87 to 100 percent) but low sensitivity (22 to 65 percent) for the pathological diagnosis of DLB [41,144-150]. The revised criteria of the fourth report of the DLB Consortium are an effort to improve the sensitivity of the clinical diagnosis (table 1) [2]. These have not yet been validated.

The clinical and radiologic features that distinguish DLB from AD and other dementias are most useful earlier in the course of the disease. In late stages, the clinical features of most dementia syndromes are more similar than different.

DIFFERENTIAL DIAGNOSIS — 

The primary considerations in the differential diagnosis for DLB are AD and Parkinson disease (PD). Other considerations include vascular dementia, other degenerative dementias, and certain psychiatric diseases [119]. The clinical features that are useful in distinguishing among these disorders are discussed above. (See 'Clinical features' above.)

●Parkinson disease dementia – The differentiation of PD dementia (PDD) and DLB is somewhat arbitrary [31]. In PDD, dementia occurs in the setting of well-established parkinsonism, while in DLB, dementia usually occurs concomitantly with or before the development of parkinsonian signs. If parkinsonism is present for more than one year before the onset of dementia, it is officially classified as PDD. This arbitrary "one-year rule" may be an artificial distinction; the length of time that parkinsonism precedes other symptoms in otherwise similar patients does not correlate with pathological differences [119].

On the other hand, in one quantitative morphometric magnetic resonance imaging (MRI) study, patients with DLB had more pronounced cortical atrophy compared with patients with PDD, despite a similar severity of dementia in both groups [98]. Another study also found that patients with PDD and DLB with similar severities of dementia could be distinguished by patterns of fractional anisotropy on diffusion tensor MRI [151]. By contrast, a positron emission tomography (PET) study using dopaminergic and cholinergic tracers found that PDD and DLB appeared similar [152].

Other features that may help distinguish between DLB and PDD are an older age of onset, faster clinical decline, and decreased levodopa responsivity for DLB compared with PDD [153]. Other clinical characteristics don't clearly distinguish well between DLB and PDD [29]. PDD is discussed separately. (See "Cognitive impairment and dementia in Parkinson disease".)

●Alzheimer disease (AD) and other degenerative dementias – When superimposed on AD or other degenerative dementias, delirium (from medication effects, systemic illness, or other metabolic abnormalities) may mimic some symptoms of DLB, including fluctuations and hallucinations. Fluctuations in an individual with dementia may be due to transient ischemic attack, seizure, or cardiac arrhythmia, rather than a manifestation of DLB. Similarly, extrapyramidal side effects of medications should be considered as a potential cause of parkinsonism in patients with dementia. There is substantial clinical as well as pathological overlap between AD and DLB. (See "Epidemiology, pathology, and pathogenesis of dementia with Lewy bodies", section on 'Clinicopathologic correlation'.)

●Mixed DLB and AD (DLB-AD) – Mixed DLB-AD, as defined by the presence of AD biomarkers compared with "pure" DLB, is distinguished by more rapid clinical progression and mortality [154]. Studies also indicate later onset (increased age), as well as higher prevalence in females and of APOE ε4 genotype, memory impairment, delusions, and hallucinations in DLB-AD [138,155]. By contrast, parkinsonism and rapid eye movement (REM) sleep behavior disorder (RBD) are less common. There are also some limited data to suggest that patients with DLB-AD are less likely to improve with cholinesterase inhibitor treatment [156].

●Creutzfeldt-Jakob disease – Creutzfeldt-Jakob disease (CJD) and DLB can have similar presentations. Prominent visual disturbances can present as an early sign in some forms of CJD (the Heidenhain variant), and myoclonus, a frequent manifestation of CJD, is sometimes a feature of DLB. (See "Creutzfeldt-Jakob disease".)

●Normal pressure hydrocephalus – Normal pressure hydrocephalus (NPH) presents with cognitive decline, urinary incontinence, and gait disorder; all of these are features of DLB. Psychiatric symptoms, sleep disorder, and other dysautonomic manifestations are absent in NPH. (See "Normal pressure hydrocephalus".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cognitive impairment and dementia".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Dementia with Lewy bodies (The Basics)")

●Beyond the Basics topic (see "Patient education: Dementia (including Alzheimer disease) (Beyond the Basics)").

SUMMARY AND RECOMMENDATIONS

●Clinical features – Dementia is an essential clinical feature of dementia with Lewy bodies (DLB) and is characterized by deficits in attention and visuospatial function. (See 'Dementia' above.)

Other core clinical features of DLB include fluctuating cognition, recurrent visual hallucinations, rapid eye movement (REM) sleep behavior disorder (RBD), and spontaneous motor features of parkinsonism (table 1). (See 'Core clinical features' above.)

Other common associated symptoms include repeated falls, syncope, autonomic dysfunction, antipsychotic drug sensitivity, delusions, hallucinations in other modalities, and depression (table 1). (See 'Supportive clinical features' above.)

●Diagnosis – The diagnosis of DLB is made primarily by clinical criteria (table 1). The diagnosis requires a high index of suspicion and specific solicitation of cardinal features, which may not be volunteered by patients or caregivers. (See 'Clinical features' above.)

Radiologic features and other testing may also aid in the diagnosis but are not required when clinical criteria are met. For any individual feature, the specificity is greater than the sensitivity for DLB. (See 'Evaluation and diagnosis' above.)

●Differential diagnosis – The differential diagnosis of DLB includes other degenerative dementias, especially if complicated by superimposed delirium, medication toxicity, or seizures. (See 'Differential diagnosis' above.)

Additional testing (blood work, electroencephalography [EEG]) is frequently indicated to rule out delirium or seizure as a cause of or contributor to a patient's symptoms. (See 'Evaluation and diagnosis' above.)

ACKNOWLEDGMENTS — 

The UpToDate editorial staff acknowledges Ann Marie Hake, MD, and Martin R Farlow, MD, who contributed to earlier versions of this topic review.