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Dementia with Lewy bodies

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Template:Short description Template:Cs1 config Template:Redirect Template:Distinguish Template:Featured article Template:Use mdy dates Template:Infobox medical condition (new) Dementia with Lewy bodies (DLB) is a type of dementia characterized by changes in sleep, behavior, cognition, movement, and regulation of automatic bodily functions. Unlike some other dementias, memory loss may not be an early symptom. The disease worsens over time and is usually diagnosed when cognitive impairment interferes with normal daily functioning. Together with Parkinson's disease dementia, DLB is one of the two Lewy body dementias. It is a common form of dementia, but the prevalence is not known accurately and many diagnoses are missed. The disease was first described on autopsy by Kenji Kosaka in 1976, and he named the condition several years later.

REM sleep behavior disorder (RBD)—in which people lose the muscle paralysis (atonia) that normally occurs during REM sleep and act out their dreams—is a core feature. RBD may appear years or decades before other symptoms. Other core features are visual hallucinations, marked fluctuations in attention or alertness, and parkinsonism (slowness of movement, trouble walking, or rigidity). A presumptive diagnosis can be made if several disease features or biomarkers are present; the diagnostic workup may include blood tests, neuropsychological tests, imaging, and sleep studies. A definitive diagnosis usually requires an autopsy.

Most people with DLB do not have affected family members, although occasionally DLB runs in a family. The exact cause is unknown but involves formation of abnormal clumps of protein in neurons throughout the brain. Manifesting as Lewy bodies (discovered in 1912 by Frederic Lewy) and Lewy neurites, these clumps affect both the central and the autonomic nervous systems. Heart function and every level of gastrointestinal function—from chewing to defecation—can be affected, constipation being one of the most common symptoms. Low blood pressure upon standing can also occur. DLB commonly causes psychiatric symptoms, such as altered behavior, depression, or apathy.

DLB typically begins after the age of fifty,<ref name=NINDS2020Book/> and people with the disease have an average life expectancy, with wide variability, of about four years after diagnosis.Template:Sfn There is no cure or medication to stop the disease from progressing, and people in the latter stages of DLB may be unable to care for themselves. Treatments aim to relieve some of the symptoms and reduce the burden on caregivers. Medicines such as donepezil and rivastigmine can temporarily improve cognition and overall functioning, and melatonin can be used for sleep-related symptoms. Antipsychotics are usually avoided, even for hallucinations, because severe reactions occur in almost half of people with DLB,Template:Sfn and their use can result in death. Management of the many different symptoms is challenging, as it involves multiple specialties and education of caregivers. Template:TOC limit

Classification and terminologyEdit

Dementia with Lewy bodies (DLB) is a type of dementia, a group of diseases involving progressive neurodegeneration of the central nervous system.Template:Sfn It is one of the two Lewy body dementias, along with Parkinson's disease dementia.Template:Sfn

Dementia with Lewy bodies can be classified in other ways. The atypical parkinsonian syndromes include DLB, along with other conditions.Template:Sfn Also, DLB is a synucleinopathy, meaning that it is characterized by abnormal deposits of alpha-synuclein protein in the brain. The synucleinopathies include Parkinson's disease, multiple system atrophy, and other rarer conditions.Template:Sfn

The vocabulary of diseases associated with Lewy pathology causes confusion.Template:Sfn Lewy body dementia (the umbrella term that encompasses the clinical diagnoses of dementia with Lewy bodies and Parkinson's disease dementia) differs from Lewy body disease (the term used to describe pathological findings of Lewy bodies on autopsy).Template:Sfn Because individuals with Alzheimer's disease (AD) are often found on autopsy to also have Lewy bodies, DLB has been characterized as an Alzheimer disease-related dementia; the term Lewy body variant of Alzheimer disease is no longer used because the predominant pathology for these individuals is related to Alzheimer's disease.Template:Sfn Even the term Lewy body disease may not describe the true nature of this group of diseases; a unique genetic architecture may predispose individuals to specific diseases with Lewy bodies, and naming controversies continue.Template:Sfn

Signs and symptomsEdit

DLB is dementia that occurs with "some combination of fluctuating cognition, recurrent visual hallucinations, rapid eye movement (REM) sleep behavior disorder (RBD), and parkinsonism", according to Armstrong (2019),Template:Sfn when Parkinson's disease is not well established before the dementia occurs.<ref name=McKeithConsensus2017Table1/> DLB has widely varying symptoms and is more complex than many other dementias.Template:Sfn<ref name=NIH2018Bas>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Several areas of the nervous system (such as the autonomic nervous system and numerous regions of the brain) can be affected by Lewy pathology,Template:Efn in which the alpha-synuclein deposits cause damage and corresponding neurologic deficits.Template:Sfn

In DLB, there is an identifiable set of early signs and symptoms; these are called the prodromal, or pre-dementia, phase of the disease.Template:SfnTemplate:Sfn These early signs and symptoms can appear 15 years or more before dementia develops.Template:Sfn The earliest symptoms are constipation and dizziness from autonomic dysfunction, hyposmia (reduced ability to smell), RBD, anxiety, and depression.Template:SfnTemplate:Sfn RBD may appear years or decades before other symptoms.Template:Sfn Memory loss is not always an early symptom.Template:Sfn

Manifestations of DLB can be divided into essential, core, and supportive features.<ref name=McKeithConsensus2017Table1/> Dementia is the essential feature and must be present for diagnosis, while core and supportive features are further evidence in support of diagnosis (see diagnostic criteria below).Template:Sfn

Essential featureEdit

A dementia diagnosis is made after cognitive decline progresses to a point of interfering with normal daily activities, or social or occupational function.Template:Sfn While dementia is an essential feature of DLB, it does not always appear early on, and is more likely to be present as the condition progresses.Template:SfnTemplate:Sfn

Core featuresEdit

While specific symptoms may vary, the core features of DLB are fluctuating cognition, alertness or attention; REM sleep behavior disorder; one or more of the cardinal features of parkinsonism, not due to medication or stroke; and repeated visual hallucinations.<ref name=McKeithConsensus2017Table1/>

The 2017 Fourth Consensus Report of the DLB Consortium determined these to be core features based on the availability of high-quality evidence indicating they are highly specific to the condition.Template:Sfn

Fluctuating cognition and alertnessEdit

Fluctuations in cognitive function are the most characteristic feature of the Lewy body dementias.Template:SfnTemplate:Sfn They are the most frequent symptom of DLB, and are often distinguishable from those of other dementias by concomitant fluctuations of attention and alertness,Template:Sfn described by Tsamakis and Mueller (2021) as "spontaneous variations of cognitive abilities, alertness, or arousal".Template:Sfn They are further distinguishable by a "marked amplitude between best and worst performances", according to McKeith (2002).Template:Sfn These fluctuations vary in severity, frequency and duration; episodes last anywhere from seconds to weeks,Template:SfnTemplate:Sfn interposed between periods of more normal functioning.Template:Sfn When relatively lucid periods coincide with medical appointments, cognitive testing may inaccurately reflect disease severity,Template:Sfn with subsequent assessments of cognition showing improvements from baseline.Template:Sfn

Unlike the deficits in memory and orientation that are characteristic of Alzheimer's disease,Template:Sfn the distinct impairments in cognition seen in DLB are most commonly in three domains: attention, executive function, and visuospatial function.Template:SfnTemplate:Sfn These fluctuating impairments are present early in the course of the disease.Template:Sfn Individuals with DLB may be easily distracted, have a hard time focusing on tasks,Template:Sfn or appear to be "delirium-like", "zoning out", or in states of altered consciousnessTemplate:SfnTemplate:Sfn with spells of confusion, agitation or incoherent speech.Template:Sfn They may have disorganized speech and their ability to organize their thoughts may change during the day.Template:SfnTemplate:Sfn

Executive function describes attentional and behavioral controls, memory and cognitive flexibility that aid problem solving and planning.Template:Sfn Problems with executive function surface in activities requiring planning and organizing.Template:Sfn Deficits can manifest in impaired job performance, inability to follow conversations, difficulties with multitasking, or mistakes in driving, such as misjudging distances or becoming lost.Template:Sfn

The person with DLB may experience disorders of wakefulness or sleep disorders (in addition to REM sleep behavior disorder) that can be severe.Template:Sfn These disorders include daytime sleepiness, drowsiness or napping more than two hours a day, insomnia, periodic limb movements, restless legs syndrome and sleep apnea.Template:Sfn

REM sleep behavior disorderEdit

Template:Quote box REM sleep behavior disorder (RBD) is a parasomnia in which individuals lose the paralysis of muscles (atonia) that is normal during rapid eye movement (REM) sleep, and consequently act out their dreams or make other abnormal movements or vocalizations.Template:Sfn About 80% of those with DLB have RBD.Template:Sfn Abnormal sleep behaviors may begin before cognitive decline is observed,Template:Sfn and may appear decades before any other symptoms, often as the first clinical indication of DLB and an early sign of a synucleinopathy.Template:Sfn

On autopsy, 94 to 98% of individuals with polysomnography-confirmed RBD have a synucleinopathy—most commonly DLB or Parkinson's diseaseTemplate:SfnTemplate:Sfn in about equal proportions.Template:Sfn More than three out of four people with RBD are diagnosed with a neurodegenerative condition within ten years,Template:Sfn but additional neurodegenerative diagnoses may emerge up to 50 years after RBD diagnosis.Template:Sfn RBD may subside over time.Template:Sfn

Individuals with RBD may not be aware that they act out their dreams.Template:Sfn RBD behaviors may include yelling, screaming, laughing, crying, unintelligible talking, nonviolent flailing, or more violent punching, kicking, choking, or scratching.Template:SfnTemplate:Sfn The reported dream enactment behaviors are frequently violent,Template:Sfn and involve a theme of being chased or attacked.Template:Sfn People with RBD may fall out of bed or injure themselves or their bed partners,Template:SfnTemplate:SfnTemplate:Sfn which may cause bruises, fractures, or subdural hematomas.Template:Sfn Because people are more likely to remember or report violent dreams and behaviors—and to be referred to a specialist when injury occurs—recall or selection bias may explain the prevalence of violence reported in RBD.Template:Sfn

ParkinsonismEdit

Parkinsonism is a clinical syndrome characterized by slowness of movement (called bradykinesia), rigidity, postural instability, and tremor;Template:SfnTemplate:Sfn it is found in DLB and many other conditions like Parkinson's disease, Parkinson's disease dementia, and others.Template:Sfn Parkinsonism occurs in more than 85% of people with DLB, who may have one or more of these cardinal features,Template:Sfn although tremor at rest is less common.Template:Sfn

Motor symptoms may include shuffling gait, problems with balance, falls, blank expression, reduced range of facial expression, and low speech volume or a weak voice.<ref name=NINDS2020Book/> Presentation of motor symptoms is variable, but they are usually symmetric, presenting on both sides of the body.Template:Sfn Only one of the cardinal symptoms of parkinsonism may be present,<ref name=McKeithConsensus2017Table1/> and the symptoms may be less severe than in persons with Parkinson's disease.Template:Sfn

Visual hallucinationsEdit

Up to 80% of people with DLB have visual hallucinations, typically early in the course of the disease.Template:SfnTemplate:Sfn They are recurrent and frequent; may be scenic, elaborate and detailed;Template:Sfn and usually involve animated perceptions of animals or people, including children and family members.Template:Sfn Examples of visual hallucinations "vary from 'little people' who casually walk around the house, 'ghosts' of dead parents who sit quietly at the bedside, to 'bicycles' that hang off of trees in the back yard".Template:Sfn

These hallucinations can sometimes provoke fear, although their content is more typically neutral.Template:Sfn In some cases, the person with DLB has insight that the hallucinations are not real.Template:Sfn Among those with more disrupted cognition, the hallucinations can become more complex, and they may be less aware that their hallucinations are not real.Template:Sfn Visual misperceptions or illusions are also common in DLB but differ from visual hallucinations. While visual hallucinations occur in the absence of real stimuli, visual illusions occur when real stimuli are incorrectly perceived;Template:Sfn for example, a person with DLB may misinterpret a floor lamp for a person.Template:Sfn

Supportive featuresEdit

Supportive features of DLB have less diagnostic weight, but they provide evidence for the diagnosis.Template:Sfn Supportive features may be present early in the progression, and persist over time; they are common but they are not specific to the diagnosis. The supportive features are:<ref name=McKeithConsensus2017Table1/>

File:Haloperidol (Haldol).jpg
People with DLB are very sensitive to antipsychotic medications like haloperidol,Template:Sfn which carry an increased risk of morbidity and mortality in DLB.Template:SfnTemplate:SfnTemplate:Sfn

Partly because of loss of cells that release the neurotransmitter dopamine, people with DLB may have neuroleptic malignant syndrome, impairments in cognition or alertness, or irreversible exacerbation of parkinsonism including severe rigidity,Template:Sfn and dysautonomia from the use of antipsychotics.Template:Sfn

Dysautonomia (autonomic dysfunction) occurs when Lewy pathology affects the peripheral autonomic nervous system (the nerves dealing with the unconscious functions of organs such as the intestines, heart, and urinary tract).Template:Sfn The first signs of autonomic dysfunction are often subtle.Template:Sfn Manifestations include blood pressure problems such as orthostatic hypotension (significantly reduced blood pressure upon standing) and supine hypertension (significantly elevated blood pressure when lying horizontally);Template:Sfn constipation,Template:Sfn urinary problems,Template:Sfn and sexual dysfunction;Template:Sfn loss of or reduced ability to smell;Template:SfnTemplate:Sfn and excessive sweating, drooling, or salivation, and problems swallowing (dysphagia).Template:SfnTemplate:Sfn

Alpha-synuclein deposits can affect cardiac muscle and blood vessels.Template:Sfn "Degeneration of the cardiac sympathetic nerves is a neuropathological feature" of the Lewy body dementias, according to Yamada Template:NowrapTemplate:Sfn Almost all people with synucleinopathies have cardiovascular dysfunction, although most are asymptomatic.Template:Sfn Between Template:Nowrap of individuals with DLB have orthostatic hypotension due to reduced blood flow, which can result in lightheadedness, feeling faint, and blurred vision.Template:Sfn

From chewing to defecation, alpha-synuclein deposits affect every level of gastrointestinal function.Template:SfnTemplate:Sfn Almost all persons with DLB have upper gastrointestinal tract dysfunction (such as gastroparesis, delayed gastric emptying) or lower gastrointestinal dysfunction (such as constipation and prolonged stool transit time).Template:Sfn Persons with Lewy body dementia almost universally experience nausea, gastric retention, or abdominal distention from delayed gastric emptying.Template:Sfn Problems with gastrointestinal function can affect medication absorption.Template:Sfn Constipation can present a decade before diagnosis,Template:Sfn and is one of the most common symptoms for people with Lewy body dementia.Template:Sfn Dysphagia is milder than in other synucleinopathies and presents later.Template:Sfn Urinary difficulties (urinary retention, waking at night to urinate, increased urinary frequency and urgency, and over- or underactive bladder) typically appear later and may be mild or moderate.Template:Sfn Sexual dysfunction usually appears early in synucleinopathies, and may include erectile dysfunction and difficulty achieving orgasm or ejaculating.Template:Sfn

Among the other supportive features, psychiatric symptoms are often present when the individual first comes to clinical attention and are more likely, compared to Alzheimer's disease, to cause more impairment.Template:Sfn About one-third of people with DLB have depression, and they often have anxiety as well.Template:Sfn Anxiety leads to increased risk of falls,Template:Sfn and apathy may lead to less social interaction.<ref name=NINDS2020Book/>

Agitation, behavioral disturbances,Template:Sfn and delusions typically appear later in the course of the disease.Template:Sfn Delusions may have a paranoid quality, involving themes like a house being broken in to, infidelity,Template:Sfn or abandonment.Template:Sfn Individuals with DLB who misplace items may have delusions about theft.Template:Sfn Capgras delusion may occur, in which the person with DLB loses knowledge of the spouse, caregiver, or partner's face,Template:Sfn and is convinced that an imposter has replaced them.Template:Sfn Hallucinations in other modalities are sometimes present, but are less frequent.Template:Sfn

Sleep disorders (disrupted sleep cycles, sleep apnea, and arousal from periodic limb movement disorder) are common in DLB and may lead to hypersomnia.Template:Sfn Loss of sense of smell may occur several years before other symptoms.Template:Sfn

CausesEdit

File:ApoE 22k fragment 2001.png
A ribbon diagram of apolipoprotein E. Variants of this protein influence the risk of developing DLB.Template:Sfn

The exact cause of DLB is unknown.Template:Sfn Synucleinopathies are typically caused by interactions of genetic and environmental influences.Template:Sfn Most people with DLB do not have affected family members, although occasionally DLB runs in a family.<ref name=NINDS2019/> The heritability of DLB is thought to be around 30% (that is, about 70% of disease severity is due to external factors or chance).Template:Sfn

There is overlap in the genetic risk factors for DLB, Alzheimer's disease (AD), Parkinson's disease, and Parkinson's disease dementia.Template:SfnTemplate:Sfn The APOE gene has three common variants. One, APOE ε4, is a risk factor for DLB and AD, whereas APOE ε2 may be protective against both.Template:SfnTemplate:Sfn Mutations in GBA, a gene for a lysosomal enzyme, are associated with both DLB and Parkinson's disease.Template:Sfn Rarely, mutations in SNCA, the gene for alpha-synuclein, or LRRK2, a gene for a kinase enzyme, can cause any of DLB, AD, Parkinson's disease or Parkinson's disease dementia.Template:Sfn This suggests some shared genetic pathology may underlie all four diseases.Template:Sfn

The greatest risk of developing DLB is being over the age of 50. Having REM sleep behavior disorder or Parkinson's disease confers a higher risk for developing DLB. The risk of developing DLB has not been linked to any specific lifestyle factors.<ref name=NINDS2020Book/> Risk factors for rapid conversion of RBD to a synucleinopathy include impairments in color vision or the ability to smell, mild cognitive impairment, and abnormal dopaminergic imaging.Template:Sfn

PathophysiologyEdit

File:Immunostaining (brown) of alpha-synuclein in Lewy Bodies and Lewy Neurites in the neocortex of a patient with Lewy Body Disease.jpg
This photomicrograph shows brown-immunostained alpha-synuclein in Lewy bodies (large clumps) and Lewy neurites (thread-like structures) in the neocortical tissue of a person who died with Lewy body disease.

DLB is characterized by the development of abnormal collections of alpha-synuclein protein within diseased brain neurons, manifesting as Lewy bodies and Lewy neurites.Template:Sfn When these clumps of protein form, neurons function less optimally and eventually die.<ref name=NIH2018Bas/> Neuronal loss in DLB leads to profound dopamine dysfunctionTemplate:Sfn and marked cholinergic pathology;Template:Sfn other neurotransmitters might be affected, but less is known about them.Template:Sfn Damage in the brain is widespread, and affects many domains of functioning.<ref name=NIH2018Bas/>Template:Efn

Loss of acetylcholine-producing neurons is thought to account for degeneration in memory and learning, while the death of dopamine-producing neurons appears to be responsible for degeneration of behavior, cognition, mood, movement, motivation, and sleep.<ref name= NINDS2020Book/> The extent of Lewy body neuronal damage is a key determinant of dementia in the Lewy body disorders.Template:SfnTemplate:Sfn

The precise mechanisms contributing to DLB are not well understood and are a matter of some controversy.Template:Sfn The role of alpha-synuclein deposits is unclear, because individuals with no signs of DLB have been found on autopsy to have advanced alpha-synuclein pathology.Template:Sfn The relationship between Lewy pathology and widespread cell death is contentious.Template:Sfn It is not known if the pathology spreads between cells or follows another pattern.Template:Sfn The mechanisms that contribute to cell death, how the disease advances through the brain, and the timing of cognitive decline are all poorly understood.Template:Sfn There is no model to account for the specific neurons and brain regions that are affected.Template:Sfn

Autopsy studies and amyloid imaging studies using Pittsburgh compound B (PiB)Template:Sfn indicate that tau protein pathology and amyloid plaques,Template:Sfn which are hallmarks of Alzheimer's disease,Template:Sfn are also common in DLBTemplate:Sfn and more common than in Parkinson's disease dementia.Template:Sfn Amyloid-beta (Aβ) deposits are found in the tauopathies—neurodegenerative diseases characterized by neurofibrillary tangles of hyperphosphorylated tau proteinTemplate:SfnTemplate:SfnTemplate:Sfn—but the mechanism underlying dementia is often mixed, and Aβ is also a factor in DLB.Template:Sfn

A proposed pathophysiology for REM sleep behavior disorder (RBD) implicates neurons in the reticular formation that regulate REM sleep. RBD might appear decades earlier than other symptoms in the Lewy body dementias because these cells are affected earlier, before spreading to other brain regions.Template:Sfn

DiagnosisEdit

Dementia with Lewy bodies can only be definitively diagnosed after death with an autopsy of the brain (or in rare familial cases, via a genetic test),<ref name=NINDS2020Book/> so diagnosis of the living is referred to as probable or possible.Template:Sfn

Diagnosing DLB can be challenging because of the wide range of symptoms with differing levels of severity in each individual.Template:Sfn DLB is often misdiagnosedTemplate:Sfn or, in its early stages, confused with Alzheimer's disease (AD).Template:Sfn The majority of individuals with Lewy body dementias receive an inaccurate initial diagnosis—such as AD, parkinsonism, other dementias or a psychiatric diagnosis—resulting in reduced support and increased fear and uncertainty, sometimes for many years.Template:Sfn Comparing the rates of detection of DLB in autopsy studies to those diagnosed while in clinical care indicates that as many as one in three diagnoses of DLB may be missed.Template:SfnTemplate:Sfn Another complicating factor is that DLB commonly occurs along with AD; autopsy reveals that half of people with DLB have some level of changes attributed to AD in their brains, which contributes to the wide-ranging variety of symptoms and diagnostic difficulty.Template:SfnTemplate:SfnTemplate:Sfn

Living with an uncertain diagnosis and prognosis is a concern expressed by both individuals with DLB and their caregivers and difficulty gaining a diagnosis and differing interactions with healthcare professionals are common experiences; once diagnosed, there are still difficulties finding a doctor knowledgeable in treating DLB.Template:Sfn Despite the difficulty in diagnosis, a prompt diagnosis is important because of the serious risks of sensitivity to antipsychotics and the need to inform both the person with DLB and the person's caregivers about those medications' side effects.Template:SfnTemplate:Sfn The management of DLB is difficult in comparison to many other neurodegenerative diseases, so an accurate diagnosis is important.Template:Sfn

CriteriaEdit

The 2017 Fourth Consensus Report established diagnostic criteria for probable and possible DLB, recognizing advances in detection since the earlier Third Consensus (2005)Template:Sfn version.Template:Efn The 2017 criteria are based on essential, core, and supportive clinical features, and diagnostic biomarkers.<ref name=McKeithConsensus2017Table1/>

The essential feature is dementia; for a DLB diagnosis, it must be significant enough to interfere with social or occupational functioning.Template:Sfn

File:CSIRO ScienceImage 9370 Amyloid beta plaque in the brain follows specific patterns as detected by CSIROs analysis technique from PiB PET scans here an AIBL volunteer is receiving a PiB PET scan.jpg
Positron emission tomography, for example, using PiB is helpful in the diagnosis of DLB.Template:SfnTemplate:Sfn

The four core clinical features (described in the Signs and symptoms section) are fluctuating cognition, visual hallucinations, REM sleep behavior disorder, and signs of parkinsonism. Supportive clinical features are marked sensitivity to antipsychotics; marked autonomic dysfunction; nonvisual hallucinations; hypersomnia (excessive sleepiness); hyposmia (reduced ability to smell); false beliefs and delusions organized around a common theme; postural instability, loss of consciousness and frequent falls; and apathy, anxiety, or depression.<ref name=McKeithConsensus2017Table1/>Template:Sfn

Direct laboratory-measurable biomarkers for DLB diagnosis are not known, but several indirect methods can lend further evidence for diagnosis.Template:Sfn The indicative diagnostic biomarkers are: reduced dopamine transporter uptake in the basal ganglia shown on PET or SPECT imaging; low uptake of 123iodine-metaiodobenzylguanidine Template:Nowrap shown on myocardial scintigraphy; and loss of atonia during REM sleep evidenced on polysomnography. Supportive diagnostic biomarkers (from PET, SPECT, CT, or MRI brain imaging studies or EEG monitoring<ref>Template:Cite journal</ref>) are: lack of damage to medial temporal lobe (damage is more likely in Alzheimer's diseaseTemplate:Sfn); reduced occipital activity; and prominent slow-wave activity on EEG.Template:Sfn

Probable DLB can be diagnosed when dementia and at least two core features are present, or when one core feature and at least one indicative biomarker are present. Possible DLB can be diagnosed when dementia and only one core feature are present or, if no core features are present, then at least one indicative biomarker is present.Template:SfnTemplate:Sfn

DLB is distinguished from Parkinson's disease dementia by the time frame in which dementia symptoms appear relative to parkinsonian symptoms. DLB is diagnosed when cognitive symptoms begin before or at the same time as parkinsonian motor signs. Parkinson's disease dementia would be the diagnosis when Parkinson's disease is well established before the dementia occurs (the onset of dementia is more than a year after the onset of parkinsonian symptoms).<ref name=McKeithConsensus2017Table1/> Known as the one-year rule, the distinction is acknowledged to be arbitrary; it recognizes overlap between the conditions along with key differences, while allowing for variations in treatment and prognosis and providing a framework for research.Template:Sfn

DLB is listed in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) as major or mild neurocognitive disorder with Lewy bodies.Template:Sfn The differences between the DSM and DLB Consortium diagnostic criteria are: 1) the DSM does not include low dopamine transporter uptake as a supportive feature, and 2) unclear diagnostic weight is assigned to biomarkers in the DSM.Template:Sfn Lewy body dementias are classified by the World Health Organization in its ICD-11, the International Statistical Classification of Diseases and Related Health Problems, in chapter 06, as neurodevelopmental disorders, code 6D82.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Clinical history and testingEdit

Diagnostic tests can be used to establish some features of the condition and distinguish them from symptoms of other conditions. Diagnosis may include taking the person's medical history, a physical exam, assessment of neurological function, brain imaging, neuropsychological testing to assess cognitive function,<ref name=NINDS2020Book/><ref name=NIADiagDem2017>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> sleep studies, myocardial scintigraphy,Template:Sfn or laboratory testing to rule out conditions that may cause symptoms similar to dementia, such as abnormal thyroid function, syphilis, HIV, and vitamin deficiencies.<ref name=NIADiagDem2017/>Template:Sfn

Typical dementia screening tests used are the mini-mental state examination (MMSE) and the Montreal Cognitive Assessment (MoCA).Template:Sfn The pattern of cognitive impairment in DLB is distinct from other dementias, such as AD; the MMSE mainly tests for the memory and language impairments more commonly seen in those other dementias and may be less suited for assessing cognition in the Lewy body dementias, where testing of visuospatial and executive function is indicated.Template:Sfn The MoCA may be better suited to assessing cognitive function in DLB,Template:Sfn and the Clinician Assessment of Fluctuation scale and the Mayo Fluctuation Composite Score may help understand cognitive decline relative to fluctuations in DLB.Template:Sfn For tests of attention, digit span, serial sevens, and spatial span can be used for simple screening, and the Revised Digit Symbol Subtest of the Wechsler Adult Intelligence Scale may show defects in attention that are characteristic of DLB.Template:Sfn The Frontal Assessment Battery, Stroop test and Wisconsin Card Sorting Test are used for evaluation of executive function, and there are many other screening instruments available.Template:Sfn

File:Polysomnography connections.jpg
Adult connected to wires from sensors for polysomnography

If DLB is suspected when parkinsonism and dementia are the only presenting features, PET or SPECT imaging may show reduced dopamine transporter activity. A DLB diagnosis may be warranted if other conditions with reduced dopamine transporter uptake can be ruled out.Template:Sfn

REM sleep behavior disorder(RBD) is diagnosed either by sleep study recording or, when sleep studies cannot be performed, by medical history and validated questionnaires.Template:SfnTemplate:SfnTemplate:Efn In individuals with dementia and a history of RBD, a probable DLB diagnosis can be justified (even with no other core feature or biomarker) based on a sleep study showing REM sleep without atonia because it is so highly predictive.Template:Sfn Conditions similar to RBD, like severe sleep apnea and periodic limb movement disorder, must be ruled out.Template:Sfn Prompt evaluation and treatment of RBD is indicated when a prior history of violence or injury is present as it may increase the likelihood of future violent dream enactment behaviors.Template:Sfn Individuals with RBD may not be able to provide a history of dream enactment behavior, so bed partners are also consulted.Template:SfnTemplate:Sfn The REM Sleep Behavior Disorder Single-Question Screen offers diagnostic sensitivity and specificity in the absence of polysomnography with one question:Template:Sfn "Have you ever been told, or suspected yourself, that you seem to 'act out your dreams' while asleep (for example, punching, flailing your arms in the air, making running movements, etc.)?"Template:Sfn Because some individuals with DLB do not have RBD, normal findings from a sleep study cannot rule out DLB.Template:Sfn

Since 2001, 123iodine-metaiodobenzylguanidine Template:Nowrap myocardial scintigraphy has been used diagnostically in East Asia (principally Japan),Template:SfnTemplate:SfnTemplate:Sfn but not in the US.Template:Sfn MIBG is taken up by sympathetic nerve endings, such as those that innervate the heart, and is labeled for scintigraphy with radioactive 123iodine.Template:Sfn Autonomic dysfunction resulting from damage to nerves in the heart in patients with DLB is associated with lower cardiac uptake of Template:NowrapTemplate:Sfn

There is no genetic test to determine if an individual will develop DLB<ref name=NINDS2020Book/>Template:Sfn and, according to the Lewy Body Dementia Association, genetic testing is not routinely recommended because there are only rare instances of hereditary DLB.<ref name=LBDAGenetics>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

DifferentialEdit

Many neurodegenerative conditions share cognitive and motor symptoms with dementia with Lewy bodies. The differential diagnosis includes Alzheimer's disease; such synucleinopathies as Parkinson's disease dementia, Parkinson's disease, and multiple system atrophy; vascular dementia; and progressive supranuclear palsy, corticobasal degeneration, and corticobasal syndrome.Template:Sfn

The symptoms of DLB are easily confused with delirium,Template:Sfn or more rarely with psychosis;Template:Sfn prodromal subtypes of delirium-onset DLB and psychiatric-onset DLB have been proposed.Template:Sfn Mismanagement of delirium is a particular concern because of the risks to people with DLB associated with antipsychotics.Template:Sfn A careful examination for features of DLB is warranted in individuals with unexplained delirium.Template:Sfn PET or SPECT imaging showing reduced dopamine transporter uptake can help distinguish DLB from delirium.Template:Sfn

Lewy pathology affects the peripheral autonomic nervous system; autonomic dysfunction is observed less often in AD, frontotemporal, or vascular dementias, so its presence can help differentiate them.Template:Sfn MRI scans almost always show abnormalities in the brains of people with vascular dementia, which can begin suddenly.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Alzheimer's diseaseEdit

Dementia with Lewy bodies (DLB) is distinguishable from Alzheimer's disease (AD) even in the prodromal phase.Template:Sfn Short-term memory impairment is seen early in AD and is a prominent feature, while fluctuating attention is uncommon; impairment in DLB is more often seen first as fluctuating cognition.Template:Sfn In contrast to AD—in which the hippocampus is among the first brain structures affected, and episodic memory loss related to encoding of memories is typically the earliest symptom—memory impairment occurs later in DLB.Template:SfnTemplate:Sfn People with amnestic mild cognitive impairment (in which memory loss is the main symptom) may progress to AD, whereas those with non-amnestic mild cognitive impairment (which has more prominent impairments in language, visuospatial, and executive domains) are more likely to progress towards DLB.Template:Sfn Memory loss in DLB has a different progression from AD because frontal structures are involved earlier, with later involvement of temporoparietal brain structures.Template:Sfn Verbal memory is not as severely affected as in AD.Template:Sfn

Template:Multiple image

While 74% of people with autopsy-confirmed DLB had deficits in planning and organization, they show up in only 45% of people with AD.Template:Sfn Visuospatial processing deficits are present in most individuals with DLB,Template:Sfn and they show up earlier and are more pronounced than in AD.Template:Sfn Hallucinations typically occur early in the course of DLB,Template:Sfn are less common in early AD, but usually occur later in AD.Template:Sfn AD pathology frequently co-occurs in DLB and is associated with more rapid decline; cerebrospinal fluid (CSF) testing may reveal an "Alzheimer's disease pattern" of higher tau and lower amyloid beta.Template:Sfn

PET or SPECT imaging can be used to detect reduced dopamine transporter uptake and distinguish AD from DLB.Template:SfnTemplate:Sfn Severe atrophy of the hippocampus is more typical of AD than DLB.Template:Sfn Before dementia develops (during the mild cognitive impairment phase), MRI scans show normal hippocampal volume. After dementia develops, MRI shows more atrophy among individuals with AD, and a slower reduction in volume over time among people with DLB than those with AD.Template:Sfn Compared to people with AD, FDG-PET brain scans in people with DLB often show a cingulate island sign.Template:Sfn

In East Asia, particularly Japan,Template:Nowrap is used in the differential diagnosis of DLB and AD, because reduced labeling of cardiac nerves is seen only in Lewy body disorders.Template:SfnTemplate:Sfn Other indicative and supportive biomarkers are useful in distinguishing DLB and AD (preservation of medial temporal lobe structures, reduced occipital activity, and slow-wave EEG activity).Template:Sfn

SynucleinopathiesEdit

Dementia with Lewy bodies and Parkinson's disease dementia are clinically similar after dementia occurs in Parkinson's disease.Template:Sfn Delusions in Parkinson's disease dementia are less common than in DLB,Template:Sfn and persons with Parkinson's disease are typically less caught up in their visual hallucinations than those with DLB.Template:Sfn There is a lower incidence of tremor at rest in DLB than in Parkinson's disease, and signs of parkinsonism in DLB are more symmetrical.Template:Sfn In multiple system atrophy, autonomic dysfunction appears earlier and is more severe,Template:Sfn and is accompanied by uncoordinated movements, while visual hallucinations and fluctuating cognition are less common than in DLB.Template:Sfn Urinary difficulty is one of the earliest symptoms with multiple system atrophy, and is often severe.Template:Sfn

Frontotemporal dementiasEdit

Corticobasal syndrome, corticobasal degeneration and progressive supranuclear palsy are frontotemporal dementiasTemplate:Sfn with features of parkinsonism and impaired cognition. Similar to DLB, imaging may show reduced dopamine transporter uptake. Corticobasal syndrome and degeneration, and progressive supranuclear palsy, are usually distinguished from DLB by history and examination. Motor movements in corticobasal syndrome are asymmetrical. There are differences in posture, gaze and facial expressions in the most common variants of progressive supranuclear palsy, and falling backwards is more common relative to DLB. Visual hallucinations and fluctuating cognition are unusual in corticobasal degeneration and progressive supranuclear palsy.Template:Sfn

ManagementEdit

Palliative care is offered to ameliorate symptoms, but there are no medications that can slow, stop, or improve the relentless progression of the disease.Template:SfnTemplate:SfnTemplate:Sfn No medications for DLB are approved by the US Food and Drug Administration (FDA) as of 2023,Template:Sfn although donepezil is licensed in Japan and the Philippines for the treatment of DLB.Template:Sfn As of 2020, there has been little study on the best management for non-motor symptoms such as sleep disorders and autonomic dysfunction; most information on management of autonomic dysfunction in DLB is based on studies of people with Parkinson's disease.Template:Sfn

Management can be challenging because of the need to balance treatment of different symptoms: cognitive dysfunction, neuropsychiatric features, impairments related to the motor system, and other nonmotor symptoms.Template:Sfn Individuals with DLB have widely different symptoms that fluctuate over time, and treating one symptom can worsen another; suboptimal care can result from a lack of coordination among the physicians treating different symptoms.Template:Sfn A multidisciplinary approach—going beyond early and accurate diagnosis to include educating and supporting the caregivers—is favored.Template:SfnTemplate:Sfn

MedicationEdit

Template:Quote box Pharmacological management of DLB is complex because of adverse effects of medicationsTemplate:Sfn and the wide range of symptoms to be treated (cognitive, motor, neuropsychiatric, autonomic, and sleep).Template:SfnTemplate:Sfn Anticholinergic and dopaminergic agents can have adverse effects or result in psychosis in individuals with DLB,Template:Sfn and a medication that addresses one feature might worsen another.Template:Sfn For example, acetylcholinesterase inhibitors (AChEIs) for cognitive symptoms can lead to complications in dysautonomia features; treatment of movement symptoms with dopamine agonists may worsen neuropsychiatric symptoms; and treatment of hallucinations and psychosis with antipsychotics may worsen other symptoms or lead to a potentially fatal reaction.Template:Sfn

Extreme caution is required in the use of antipsychotic medication in people with DLB because of their sensitivity to these agents.<ref>"The use of antipsychotics ... comes with attendant mortality risks ... and they should be avoided whenever possible, given the increased risk of a serious sensitivity reaction." Template:Harvnb As cited in Template:Harvnb</ref> Severe and life-threatening reactions occur in almost half of people with DLB,Template:SfnTemplate:Sfn and can be fatal after a single dose.Template:Sfn Antipsychotics with D2 dopamine receptor-blocking properties are used only with great caution.Template:Sfn According to Boot (2013), "electing not to use neuroleptics is often the best course of action".Template:Sfn People with Lewy body dementias who take neuroleptics are at risk for neuroleptic malignant syndrome, a life-threatening illness.Template:Sfn There is no evidence to support the use of antipsychotics to treat the Lewy body dementias,Template:Sfn and they carry the additional risk of stroke when used in the elderly with dementia.Template:Sfn

Medications (including tricyclic antidepressants and treatments for urinary incontinence) with anticholinergic properties that cross the blood–brain barrier can cause memory loss.<ref name=GompTable4.6/> The antihistamine medication diphenhydramine (Benadryl), sleep medications like zolpidem,<ref name=GompTable4.6>Gomperts 2016, Table 4-6, p. 457. Template:Webarchive</ref> and benzodiazepines may worsen confusionTemplate:Sfn or neuropsychiatric symptoms.Template:Sfn Some general anesthetics may cause confusion or delirium upon waking in persons with Lewy body dementias, and may result in permanent decline.<ref name=NINDS2020Book/>

Cognitive symptomsEdit

There is strong evidence for the use of acetylcholinesterase inhibitors (AChEIs) to treat cognitive problems; these medications include rivastigmine and donepezil.Template:SfnTemplate:Sfn Both are first-line treatments in the UK.Template:Sfn Even when the AChEIs do not lead to improvement in cognitive symptoms, people taking them may have less deterioration overall,Template:Sfn although there may be adverse gastrointestinal effects.Template:Sfn The use of these medications can reduce the burden on caregivers and improve activities of daily living for the individual with DLB.Template:Sfn The AChEIs are initiated carefully as they may aggravate autonomic dysfunction or sleep behaviors.Template:Sfn There is less evidence for the efficacy of memantine in DLB,Template:Sfn but it may be used alone or with an AChEI because of its low side effect profile.Template:Sfn Anticholinergic drugs are avoided because they worsen cognitive symptoms.Template:Sfn

To improve daytime alertness, there is mixed evidence for the use of stimulants such as methylphenidate and dextroamphetamine; although worsening of neuropsychiatric symptoms is not common, they can increase the risk of psychosis.Template:Sfn Modafinil and armodafinil may be effective for daytime sleepiness.Template:Sfn

Motor symptomsEdit

Motor symptoms in DLB appear to respond somewhat less to medications used to treat Parkinson's disease, like levodopa, and these medications can increase neuropsychiatric symptoms.Template:SfnTemplate:Sfn Almost one out of every three individuals with DLB develops psychotic symptoms from levodopa.Template:Sfn If such medications are needed for motor symptoms, cautious introduction with slow increases to the lowest possible dose may help avoid psychosis.Template:Sfn

The anticonvulsant zonisamide has been approved in Japan since 2009 for treating Parkinson's diseaseTemplate:Sfn and since 2018 to treat parkinsonism in DLB.Template:Sfn There is high certainty according to the GRADE certainty rating approach that it is effective for treating motor symptoms in DLB.Template:Sfn

Neuropsychiatric symptomsEdit

Neuropsychiatric symptoms of DLB (aggression, anxiety, apathy, delusions, depression and hallucinations) do not always require treatment.Template:Sfn The first line of defense in decreasing visual hallucinations is to reduce the use of dopaminergic drugs, which can worsen hallucinations.Template:Sfn If new neuropsychiatric symptoms appear, the use of medications (such as anticholinergics, tricyclic antidepressants, benzodiazepines and opioids) that might be contributing to these symptoms is reviewed.Template:Sfn

Among the AChEIs, donepezil and rivastigmine can help reduce neuropsychiatric symptomsTemplate:Sfn and improve the frequency and severity of hallucinations in the less severe stages of DLB.Template:Sfn For treating psychosis and agitation in DLB, there is low evidence for memantine, olanzapine and aripiprazole, and very low evidence for the efficacy of quetiapine.Template:Sfn Although clozapine has been shown effective in Parkinson's disease, there is very low evidence for its use to treat visual hallucinations in DLB, and its use requires regular blood monitoring.Template:SfnTemplate:Sfn

Apathy may be treated with AChEIs, and they may also reduce hallucinations, delusions, anxiety and agitation.Template:Sfn Most medications to treat anxiety and depression have not been adequately investigated for DLB.Template:Sfn Antidepressants may affect sleep and worsen RBD.Template:SfnTemplate:SfnTemplate:Sfn Mirtazapine and SSRIs can be used to treat depression, depending on how well they are tolerated, and guided by general advice for the use of antidepressants in dementia.Template:Sfn Antidepressants with anticholinergic properties may worsen hallucinations and delusions.Template:Sfn People with Capgras syndrome may not tolerate AChEIs.Template:Sfn

Sleep disordersEdit

The first steps in managing sleep disorders are to evaluate the use of medications that impact sleep and provide education about sleep hygiene.Template:Sfn Sleep medications are carefully evaluated for each individual as they carry increased risk of falls, increased daytime sleepiness, and worsening cognition.Template:Sfn

Injurious dream enactment behaviors are a treatment priority.Template:Sfn Frequency and severity of RBD may be lessened by treating sleep apnea, if it is present.Template:Sfn RBD may be treated with melatonin or clonazepam.Template:Sfn Melatonin may be more helpful in preventing injuries,Template:Sfn and it offers a safer alternative, because clonazepam can produce deteriorating cognition,Template:Sfn and worsen sleep apnea.Template:Sfn

Memantine is useful for some people.Template:Sfn Modafinil may be used for hypersomnia, but no trials support its use in DLB.Template:Sfn Antidepressants (SSRIs, SNRIs, tricyclics, and MAOIs), AChEIs, beta blockers, caffeine, and tramadol may worsen RBD.Template:Sfn

Autonomic symptomsEdit

Decreasing the dosage of dopaminergic or atypical antipsychotic drugs may be needed with orthostatic hypotension, and high blood pressure drugs can sometimes be stopped.Template:Sfn When non-pharmacological treatments for orthostatic hypotension have been exhausted, fludrocortisone, droxidopa, or midodrine are options,Template:Sfn but these drugs have not been specifically studied for DLB as of 2020.Template:Sfn Delayed gastric emptying can be worsened by dopaminergic medications, and constipation can be worsened by opiates and anticholinergic medications.Template:Sfn Muscarinic antagonists used for urinary symptoms might worsen cognitive impairment in people with Lewy body dementias.Template:Sfn

OtherEdit

There is no high-quality evidence for non-pharmacological management of DLB,Template:SfnTemplate:Sfn but some interventions have been shown effective for addressing similar symptoms that occur in other dementias.Template:Sfn For example, organized activities, music therapy, physical activity and occupational therapy may help with psychosis or agitation, while exercise and gait training can help with motor symptoms.Template:Sfn Cognitive behavioral therapy can be tried for depression or hallucinations, although there is no evidence for its use in DLB.Template:Sfn Cues can be used to help with memory retrieval.Template:Sfn

For autonomic dysfunction, several non-medication strategies may be helpful. Dietary changes include avoiding meals high in fatTemplate:Sfn and sugary foods, eating smaller and more frequent meals,Template:Sfn after-meal walks, and increasing fluids or dietary fiber to treat constipation.Template:Sfn Stool softeners and exercise also help with constipation.Template:Sfn Excess sweating can be helped by avoiding alcohol and spicy foods, and using cotton bedding and loose fitting clothing.Template:Sfn

Physical exercise in a sitting or recumbent position, and exercise in a pool, can help maintain conditioning.Template:Sfn Compression stockings and elevating the head of the bed may also help, and increasing fluid intake or table salt can be tried to reduce orthostatic hypotension.Template:Sfn To lessen the risk of fractures in individuals at risk for falls, bone mineral density screening and testing of vitamin D levels are used,Template:Sfn and caregivers are educated on the importance of preventing falls.Template:Sfn Physiotherapy has been shown helpful for Parkinson's disease dementia, but as of 2020, there is no evidence to support physical therapy in people with DLB.Template:Sfn

CaregivingEdit

Template:Further Demands placed on caregivers are higher than in Alzheimer's disease (AD) because of the neuropsychiatric symptoms associated with DLB.Template:Sfn Contributing factors to the caregiver burden in DLB are emotional fluctuations,Template:Sfn apathy,Template:Sfn psychosis, aggression, agitation, and night-time behaviors such as parasomnias,Template:Sfn that lead to a loss of independence earlier than in AD.Template:Sfn Caregivers may experience depression and exhaustion, and they may need support from other people.Template:Sfn Other family members who are not present in the daily caregiving may not observe the fluctuating behaviors or recognize the stress on the caregiver, and conflict can result when family members are not supportive.<ref name=NINDS2020Book/>

Teaching caregivers how to manage neuropsychiatric symptoms (such as agitation and psychosis) is recommended,Template:Sfn although education for caregivers has not been studied as thoroughly as in AD or Parkinson's disease.Template:Sfn Caregiver education reduces not only distress for the caregiver, but symptoms for the individual with dementia.Template:Sfn Caregiver training, watchful waiting, identifying sources of pain, and increasing social interaction can help minimize agitation.Template:Sfn Individuals with dementia may not be able to communicate that they are in pain, and pain is a common trigger of agitation.Template:Sfn

Visual hallucinations associated with DLB create a particular burden on caregivers.Template:Sfn Caregivers can be educated to distract or change the subject when confronted with hallucinations, and that this is more effective than arguing over the reality of the hallucination.Template:Sfn<ref name=LBDABehavioral>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Coping strategies may help and are worth trying, even though there is no evidence for their efficacy.Template:Sfn These strategies include having the person with DLB look away or look at something else, focus on or try to touch the hallucination, wait for it to go away on its own, and speak with others about the visualization.Template:Sfn Delusions and hallucinations may be reduced by increasing lighting in the evening, and making sure there is no light at night when the individual with DLB is sleeping.Template:Sfn

With the increased risk of side effects from antipsychotics for people with DLB, educated caregivers are able to act as advocates for the person with DLB.<ref name=LBDACareMeds>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> If evaluation or treatment in an emergency room is needed, the caregiver may be able to explain the risks associated with neuroleptic use for persons with DLB.Template:Sfn Medical alert bracelets or notices about medication sensitivity are available and can save lives.Template:Sfn

Individuals and their caregivers can be counselled about the need to improve bedroom safety for RBD symptoms.Template:Sfn Sleep-related injuries from falling or jumping out of bed can be avoided by lowering the height of the bed,Template:Sfn placing a mattress next to the bed to soften the impact of a fall, and removing sharp objects from around the bed.Template:Sfn Sharp surfaces near the bed can be padded, bed alarm systems may help with sleepwalking, and bed partners may find it safer to sleep in another room.Template:Sfn According to St Louis and Boeve, firearms should be locked away, out of the bedroom.Template:Sfn

A home safety assessment can be done when there is risk of falling.Template:Sfn Handrails and shower chairs can help avoid falls.Template:Sfn Driving ability may be impaired early in DLB because of visual hallucinations, movement issues related to parkinsonism, and fluctuations in cognitive ability, and at some point it becomes unsafe for the person to drive.<ref name=LBDAEarlyCare/> Driving ability is assessed as part of management, and family members generally determine when driving privileges are removed.Template:Sfn<ref name=LBDAEarlyCare>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

PrognosisEdit

As of 2021, no cure is known for Dementia with Lewy bodies (DLB).<ref name= NINDS2020Book/><ref name= NINDS2019/>Template:Sfn The prognosis for DLB has not been well studied; early studies had methodological limitations, such as small sample size and selection bias.Template:Sfn Relative to Alzheimer's disease (AD) and other dementias, DLB generally leads to higher rates of disability, hospitalization and institutionalization, and lower life expectancy and quality of life, with increased costs of care.Template:SfnTemplate:Sfn Depression, apathy, and visual hallucinations contribute to the reduced quality of life.Template:Sfn Decline may be more rapid when the APOE gene is present, or when AD—or its biomarkers—is also present.Template:Sfn The severity of orthostatic hypotension also predicts a worse prognosis.Template:Sfn Visuospatial deficits early in the course of DLB were thought to be a predictor of rapid decline,Template:Sfn but more recent studies did not find an association.Template:Sfn

The trajectory of cognitive decline in DLB is difficult to establish because of the high rate of missed diagnoses; the typical delay of a year in the US, and 1.2 years in the UK, for diagnosis of DLB mean that a baseline from which deterioration can be measured is often absent.Template:Sfn Compared to AD, which is better studied, memory is thought to be retained longer, while verbal fluency may be lost faster,Template:Sfn but the most common tools used to assess cognition may miss the most common cognitive deficits in DLB, and better studies are needed.Template:Sfn There are more neuropsychiatric symptoms in DLB than AD, and they may emerge earlier, so those with DLB may have a less favorable prognosis, with more rapid cognitive decline, more admissions to residential care, and a lower life expectancy.Template:SfnTemplate:Sfn An increased rate of hospitalization compared to AD is most commonly related to hallucinations and confusion, followed by falls and infection.Template:Sfn

Life expectancy is difficult to predict, and limited study data are available.Template:Sfn Survival may be defined from the point of disease onset, or from the point of diagnosis.Template:Sfn There is wide variability in survival times, as DLB may be rapidly or slowly progressing.Template:Sfn A 2019 meta-analysis found an average survival time after diagnosis of 4.1 yearsTemplate:Sfn—indicating survival in DLB 1.6 years less than after a diagnosis of Alzheimer's disease.Template:Sfn A 2017 review found survival from disease onset between 5.5 and 7.7 years, and survival from diagnosis between 1.9 and 6.3 years. The difference in survival between AD and DLB could be because DLB is harder to diagnose, and may be diagnosed later in the course of the disease.Template:Sfn An online survey with 658 respondents found that, after diagnosis, more than 10% died within a year, 10% lived more than 7 years, and some live more than 10 years;Template:Sfn some people with Lewy body dementias live for 20 years.<ref name=NINDS2020Book/> Shorter life expectancy is more likely when visual hallucinations, abnormal gait, and variable cognition are present early on.Template:Sfn

Fear and anxiety feature strongly for both people with Lewy body dementia and their caregivers; a range of emotional responses to living with Lewy bodies includes fear of hallucinations, fear of falls and frightening nightmares as a result of REM sleep behavior disorder, and being fearful of the effects of tiredness and fatigue. The symptoms of fluctuations, depression, delirium and violence are also experienced as frightening.Template:Sfn An immense amount of physical support from friends and family is often required to maintain social and supporting relationships. Individuals with Lewy body dementias describe feeling a burden in the wider social context, as they reduce attending social events due to their increasing physical needs. Frequently reported burden dimensions include personal strain and interference with personal life, which can lead to relationship dissatisfaction and resentment.Template:Sfn

In the late phase of the disease, people may be unable to care for themselves.<ref name=NIH2018Bas/> Falls—caused by many factors including parkinsonism, dysautonomia, and frailness—increase morbidity and mortality.Template:Sfn Failure to thriveTemplate:Sfn and aspiration pneumonia, a complication of dysphagia (difficulty swallowing) that results from dysautonomia, commonly cause death among people with the Lewy body dementias.Template:Sfn Cardiovascular disease and sepsis are also common causes of death.Template:Sfn

EpidemiologyEdit

The Lewy body dementias are as a group the second most common form of neurodegenerative dementia after Alzheimer's disease (AD) as of 2021.Template:Sfn DLB itself is one of the three most common types of dementia, along with AD and vascular dementia.<ref name=NINDS2020Book/>Template:SfnTemplate:Efn

The diagnostic criteria for DLB before 2017 were highly specific, but not very sensitive,Template:Sfn so that more than half of cases were missed historically.Template:Sfn Dementia with Lewy bodies was under-recognized as of 2021,Template:Sfn and there is little data on its epidemiology.Template:Sfn The incidence and prevalence of DLB are not known accurately, but estimates are increasing with better recognition of the condition since 2017.Template:Sfn

About 0.4% of those over the age of 65 are affected with DLB,Template:Sfn and between Template:Nowrap per 1,000 people develop the condition each year.Template:SfnTemplate:Sfn Symptoms usually appear between the ages of 50 and 80Template:Sfn (median 76Template:Sfn), and it is not uncommon for it to be diagnosed before the age of 65.Template:Sfn

DLB is thought to be slightly more common in men than women,Template:Sfn but this finding has been challenged and is inconsistent across studies.Template:Sfn Women may be over-represented in community samples and under-represented in clinical populations, where REM sleep behavior disorder (RBD) is more frequently diagnosed in men; the diagnosis appears to have a higher prevalence for men in those under 75, while women appear to be diagnosed later and with greater cognitive impairment.Template:Sfn Studies in Japan, France and Britain show a more equal prevalence between men and women than in the US.Template:Sfn

An estimated 10 to 15% of diagnosed dementias are Lewy body type, but estimates range as high as 23%Template:Sfn for those in clinical studies.Template:Sfn A French study found an incidence among persons 65 years and older almost four times higher than a US study Template:Nowrap per 100,000 person-years), but the US study may have excluded people with only mild or no parkinsonism, while the French study screened for parkinsonism.Template:Sfn Neither of the studies assessed systematically for RBD, so DLB may have been underdiagnosed in both studies.Template:Sfn A door-to-door study in Japan found a prevalence of 0.53% for persons 65 and older, and a Spanish study found similar results.Template:Sfn

HistoryEdit

Frederic Lewy (1885–1950) was the first to discover the abnormal protein deposits in the early 1900s.Template:SfnTemplate:Sfn In 1912, studying Parkinson's disease (paralysis agitans),Template:Sfn he described findings of these inclusion bodies in the vagus nerve, the nucleus basalis of Meynert and other brain regions.Template:Sfn<ref>Template:Harvnb As cited in Template:Harvnb</ref> He published a book, The Study on Muscle Tone and Movement. Including Systematic Investigations on the Clinic, Physiology, Pathology, and Pathogenesis of Paralysis agitans, in 1923 and except for one brief paper a year later, never mentioned his findings again.Template:Sfn

In 1961, Okazaki et al. published an account of diffuse Lewy-type inclusions associated with dementia in two autopsied cases.Template:SfnTemplate:Sfn Dementia with Lewy bodies was fully described in an autopsied case by Japanese psychiatrist and neuropathologist Kenji Kosaka in 1976.Template:SfnTemplate:Sfn Kosaka first proposed the term Lewy body disease four years later, based on 20 autopsied cases.Template:SfnTemplate:Sfn DLB was thought to be rare until it became easier to diagnose in the 1980s after the discovery of alpha-synuclein immunostaining that highlighted Lewy bodies in post mortem brains.Template:Sfn Template:Nowrap described thirty-four more cases in 1984, which were mentioned along with four UK cases by Template:Nowrap in 1987 in the journal Brain, bringing attention to the Japanese work in the Western world.Template:Sfn A year later, Template:Nowrap published the first general description of diffuse Lewy body disease.Template:Sfn

In the 1990s, with Japanese, UK, and US researchers finding that DLB was a common dementia, there were still no available diagnostic guidelines, with each group using different terminology.Template:Sfn The different groups of researchers began to realize that a collaborative approach was needed if research was to advance.Template:Sfn The DLB Consortium was established, and, in 1996, the term dementia with Lewy bodies was agreed upon,Template:Sfn and the first criteria for diagnosing DLB were elaborated.Template:Sfn

Two 1997 discoveries highlighted the importance of Lewy body inclusions in neurodegenerative processes: a mutation in the SNCA gene that encodes the alpha-synuclein protein was found in kindreds with Parkinson's disease, and Lewy bodies and neurites were found to be immunoreactive for alpha-synuclein.Template:Sfn Thus, alpha-synuclein aggregation was established as the primary building block of the synucleinopathies.Template:Sfn

Between 1995 and 2005, the DLB Consortium issued three consensus reports on DLB.Template:Sfn DLB was included in the fourth text revision of the DSM (DSM-IV-TR, published in 2000) under "Dementia due to other general medical conditions". In the 2010s, the possibility of a genetic basis for LBD began to emerge.Template:Sfn The Fourth Consensus Report was issued in 2017, giving increased diagnostic weighting to RBD and Template:Nowrap myocardial scintigraphy.Template:Sfn

Society and cultureEdit

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}

File:Robin Williams Happy Feet premiere.jpg
According to his widow, Robin Williams (pictured in 2011) was diagnosed during autopsy as having diffuse Lewy bodies.Template:SfnTemplate:SfnTemplate:Sfn

The British author and poet Mervyn Peake died in 1968 and was diagnosed posthumously as a probable case of DLB in a 2003 study published in JAMA Neurology.Template:Sfn Based on signs in his work and letters of progressive deterioration, fluctuating cognitive decline, deterioration in visuospatial function, declining attention span, and visual hallucinations and delusions, his may be the earliest known case where DLB was found to have been the likely cause of death.Template:Sfn

At the time of his suicide on August 11, 2014, Robin Williams, the American actor and comedian, had been diagnosed with Parkinson's disease.Template:Sfn According to his widow, Williams had experienced depression, anxiety, and increasing paranoia.Template:Sfn His widow said that his autopsy found diffuse Lewy body disease,Template:SfnTemplate:SfnTemplate:Sfn while the autopsy used the term diffuse Lewy body dementia.<ref name=LBDA/> Dennis Dickson, a spokesperson for the Lewy Body Dementia Association, clarified the distinction by stating that diffuse Lewy body dementia is more commonly called diffuse Lewy body disease and refers to the underlying disease process.<ref name=LBDA>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> According to Dickson, "Lewy bodies are generally limited in distribution, but in DLB, the Lewy bodies are spread widely throughout the brain, as was the case with Robin Williams."<ref name=LBDA/> Ian G. McKeith, professor and researcher of Lewy body dementias, commented that Williams' symptoms and autopsy findings were explained by DLB.Template:Sfn

Research directionsEdit

The identification of prodromal biomarkers for DLB will enable treatments to begin sooner,Template:Sfn improve the ability to select subjects and measure efficacy in clinical trials,Template:Sfn and help families and clinicians plan for early interventions and awareness of potential adverse effects from the use of antipsychotics.Template:Sfn Criteria were established in 2020 to help researchers better recognize DLB in the pre-dementia phase.Template:SfnTemplate:Sfn Three syndromes of prodromal DLB have been proposed: 1) mild cognitive impairment with Lewy bodies (MCI-LB); 2) delirium-onset DLB; and 3) psychiatric-onset DLB.Template:Sfn The three early syndromes may overlap.Template:Sfn As of 2020, the DLB Diagnostic Study Group's position is that criteria for MCI-LB can be recommended, but that it remains difficult to distinguish delirium-onset and psychiatric-onset DLB without better biomarkers.Template:Sfn Nonetheless, severe late-onset psychiatric disorders can be an indication to consider Lewy body dementia,Template:Sfn and unexplained delirium raises the possibility of prodromal DLB.Template:Sfn

The diagnosis of DLB is made using the DLB Consortium criteria, but a 2017 study of skin samples from 18 people with DLB found that all of them had deposits of phosphorylated alpha-synuclein, while none of the controls did,Template:Sfn suggesting that skin samples offer diagnostic potential.Template:Sfn Other potential biomarkers under investigation are quantitative electroencephalography, imaging examination of brain structures, and measures of synucleinopathy in CSF.Template:Sfn While commercial skin biopsy tests for DLB are available in the US, and the FDA has given a 'breakthrough device' authorization for CSF testing, these tests are not widely available and their role in clinical practice has not been establishedTemplate:SfnTemplate:Sfn as of 2022.Template:SfnTemplate:Sfn Other tests to detect alpha-synuclein with blood tests are under study as of 2021.Template:Sfn

Cognitive training, deep brain stimulation and transcranial direct-current stimulation have been studied more in Parkinson's and Alzheimer's disease than they have in dementia with Lewy bodies, and all are potential therapies for DLB.Template:Sfn Four clinical trials for treating parkinsonian symptoms in DLB have been completed as of 2021, but more studies are needed to assess risk vs. benefits, adverse effects, and longer-term therapeutic protocols.Template:Sfn

Strategies for future interventions involve modifying the course of the disease using immunotherapy, gene therapy, and stem cell therapy, and reducing amyloid beta and alpha-synuclein accumulation. Therapies under study as of 2019 aim to reduce brain levels of alpha-synuclein (with the pharmaceuticals ambroxol, NPT200-11, and E2027), or to use immunotherapy to reduce widespread neuroinflammation resulting from alpha-synuclein deposits.Template:SfnTemplate:Sfn

NotesEdit

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ReferencesEdit

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Works citedEdit

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Further readingEdit

|CitationClass=web }} – lists of typical and atypical antipsychotics

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External linksEdit

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