Dementia with Lewy bodies

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Dementia with Lewy bodies
ICD-10 G31.8
ICD-9 331.82
DiseasesDB 3800
MeSH D020961

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Kiran Singh, M.D. [2]
Synonyms and Keywords: Lewy Body dementia (LBD), Diffuse Lewy Body disease (DLBD), Cortical Lewy Body disease (CLBD), and Senile dementia of Lewy type

Overview

Dementia with Lewy bodies (DLB) is the second most common cause of dementia following Alzheimer's disease. It usually affects patients aged > 50 years. The hallmark of DLB is the presence of Lewy bodies, which are intracytoplasmic inclusion bodies that contain synuclein proteins located in the cortical and subcortical neurons. However, these findings are not specific to DLB and may similarly be present in other neurodegenerative diseases. Although the majority of DLB cases are due to sporadic development, DLB may be familial, suggesting a genetic predisposition. Clinically, DLB is characterized by the development of a triad of features, namely cognitive, neurological, and psychiatric symptoms. The diagnosis of DLB is difficult, given the absence of distinguishing features on imaging and neuropathology. Instead, physicians should rely exclusively on the presence of core and suggestive clinical features that may distinguish DLB from other neurodenegerative disorders that cause dementia and symptoms of parkinsonism, such as Alzheimer's disease (AD) and Parkinson's disease with dementia (PDD). Distinguishing features of DLB include the presence of dementia followed by early parkinsonism symptoms within less than 1 year of symptoms-onset, vivid and detailed visual hallucinations, depressive symptoms, REM sleep disorders, neuroleptic sensitivity, early-onset postural instability and falls, and prominent visuospatial and verbal learning impairment. There is currently no cure for DLB, but management is generally aimed at improving quality of life via pharmacologic and non-pharmacologic interventions. Cholinesterase inhibitors, such as rivastigmine and memantine, have demonstrated efficacy in the treatment of behavioral symptoms among patients with DLB, and they are the first-line pharmacologic agents for the management of DLB. The prognosis of DLB is poor with a median survival time comparable to that of AD (3-8 years), but more aggressive forms have also been described.

Historical Perspective

  • Lewy body dementia (LBD) was named after Frederich Heinrich Lewy, a German-American neurologist who discovered the characteristic intracytoplasmic inclusions in 1912.[1][2]
  • In 1961, Okazaki suggested that the presence of cortical Lewy bodies in brain tissue was associated with the development of dementia.[1]
  • In 1984, Kosaka and colleagues hypothesized that the presence of Lewy bodies may correspond to a new disease entity, which was eventually named "diffuse Lewy body disease".[3] The disease name was then changed in 1996 at the First International Workshop of the Consortium on Dementia with Lewy Bodies to become "dementia with Lewy bodies" (DLB).[4]
  • DLB was not considered a diagnosis of dementia in the first 4 versions of the Diagnostic and Statistical Manual (DSM) for Mental Disorders. In 2013, DSM-5 incorporated DLB as a differential diagnosis for dementia.[5][2]

Pathophysiology

Genetics

Familial predisposition to DLB has been frequently described in observational studies, suggesting the role of genetics in the development of DLB. To date, genetic mutations that are exclusively implicated in DLB have not been described; genetic determinants of DLB have also been frequently reported in Parkinson's disease.

SNCA Gene

Predisposition to DLB may be caused by autosomal dominant genetic mutations of the Synuclein gene family.[6][7] Synuclein proteins are members of a pre-synpatic protein family located in the central and peripheral nervous systems. Although the majority of reports describe defects of the α-synuclein protein overexpression in DLB, the β- and γ-synuclein protein variants have also been associated with development of DLB. Mutations of α-synuclein (SNCA) gene have been classically associated with Parkinson's disease with dementia (PDD), but triplication defects and mutations of the E46K and A53T loci within the SNCA gene have been described in patients with DLB.[8][9][10][10]

Other Genes

Mutations of the following genes are also associated with the development of DLB are:

  • LRRK2[11][12]
  • Glucocerebrosidase (GBA) gene mutation among patients with Gaucher's disease and their relatives[13]
  • V70M[10]
  • P123H[10]
  • 2q35-q36 locus on chromosome 2 (adjacent to PARK11 locus whose mutation is associated with PD)[14]

Pathology

The hallmark of dementia with Lewy bodies (DLB) is the presence of Lewy bodies (LB) that are accompanied by dystropic Lewy neurite (LN) in cortical, brainstem, and limbic system neurons. Lewy bodies are eosinophilic, filamentous, intracytoplasmic inclusion bodies composed of the following components:[15][16][17][18][19][20]

Pathology alpha synuclein DLB dementia with lewy bodies autopsy.jpg
Figure: A. Lewy bodies (synuclein-positive, eosinophilic, neuronal inclusions) in brain tissue of patient with dementia with Lewy bodies (DLB); B. Immunohistochemical staining of Lewy Neurites; C. Immunhistochemical staining of frontal cortex in DLB demonstrates alpha-Synuclein positive inclusions (Images courtesy of user:Jensflorian from http://commons.wikimedia.org/ licensed under the Creative Commons Attribution-Share Alike 3.0 Unported under the terms of GNU Free Documentation License)

Classically, Lewy bodies in DLB are initially present in the amygdala. As the disease advances, these bodies spread to the limbic cortex and then to the neocortex. These findings may explain the predominance of dementia in patients with early DLB and the consequent development of parkinsonism symptoms.[21] The clinical features of DLB are directly associated with the severity of Lewy-related pathology. In turn, severity is measured by the pattern of regional involvement of Lewy bodies rather than the number of Lewy bodies.[22]

Classification

DLB may be classified according to the regional involvement of the brain tissue based upon the presence of Lewy bodies:

  • Diffuse neocortical DLB
  • Brainstem predominant DLB
  • Limbic/transitional DLB

Differential Diagnosis

Dementia with Lewy bodies (DLB) should be distinguished from other disorders that cause memory impairment, recurrent hallucinations, and Parkinsonism. The most important differential diagnoses of DLB are Alzheimer's disease (AD) and Parkinson's disease with dementia (PDD) due to the overlapping clinical features with absence of distinguishing radiographic or neuropathological features across the 3 diseases. Generally, the distinction between the 3 disease is exclusively clinical based on key findings during history-taking and physical examination.

Alzheimer's Disease (AD) and Parkinsons's Disease with Dementia (PDD)

Comparison Table Distinguishing Features Dementia with Lewy Bodies vs. Alzheimer's disease and Parkinson's disease with dementia.jpg
Comparison Table: Dementia with Lewy Bodies (DLB) vs. Alzheimer's Disease (AD) and Parkinson's Disease with Dementia (PDD)[23][24][25][26][27][28][29][30][31][32][33][34][35][36][31][37][38][39][40][41]

Other Neurodegenerative Disorders

Other neurodegenerative disorders may also be considered in the differential diagnosis of DLB[23]:

Cause of dementia Clinical features Associated features Nature of progression Histopathological findings
Cognitive impairment
Recall Recollection Cue requirement for recall Infirngement of thoughts Semantic memory Procedural memory Working memory Awareness Attention Executive functioning issues Visuo-spatial skills
Alzheimer's disease +++

(Slow cognitive and functional decline with early loss of awareness)

+++ Not helpful +++ ++ - ++ +++ ++ ++ ++ Has the following clinical stages:
Lewy body dementia ++ - Helpful +++ + + +++ + +++ +++ +++
Frontotemporal lobar degeneration +/- - Helpful +++ + - +++ +++ ++ +++ -
  • Onset in young age
Vascular dementia + (Dysexecutive syndrome) - Helpful + + + ++ - ++ +++ +


Epidemiology and Demographics

DLB is the 2nd most common cause of dementia following Alzheimer's disease (AD) and is the underlying etiology of approximately 1.7-30.5% of dementia cases. DLB generally affects patients older than 50 years of age and has a slight male predilection.

Incidence

  • In the general population, the annual incidence of DLB is 100 per 100,000 persons.[58]
  • Among patients with dementia, the annual incidence of DLB is 3,200 - 5,000 per 100,000 persons.[58]

Prevalence

  • In the general population, the prevalence of DLB is approximately 5,000 per 100,000 persons.[59][60][61][62][63][64]
  • Among patients with dementia, the prevalence of DLB ranges between 1,700 to 30,500 per 100,000 persons.[59][60][61][62][63][64]

Age

  • Age at diagnosis is usually between 50 - 83 years.[65]

Gender

  • DLB has a slight male predilection.[65]

Risk Factors

  • Familial predisposition to DLB has been frequently described in observational studies, suggesting the role of genetics in the development of DLB.[66]

Natural History

Presenting Symptoms

The presenting symptoms of DLB vary and may include any of the following:[67][2][65]

Common Symptoms of Advanced Disease

  • 100% of patients with DLB eventually develop dementia early during the course of the disease.[65]
  • Similarly, the development of parkinsonism symptoms has also been reported in up to 50-100% of patients.[65]
  • In advanced disease, DLB symptoms eventually include cognitive fluctuation (45-90%), depression (12-89%), visual hallucinations (13-80%), and falls (22-50%).[65]

Prognosis

  • In general, the mean survival time in DLB is similar to AD (3-8 years).[65][68]
  • In a minority of patients, the disease progresses aggressively, and patients may die within 1-2 years of symptoms-onset.[65]

Clinical Features

Dementia with Lewy bodies (DLB) is characterized by the triad of progressive cognitive impairment, parkinsonism, and neuropsychiatric disturbances. The diagnosis of the DLB is usually made clinically based on history-taking and findings on physical examination in the absence of metabolic, vascular, and degenerative disoders. Unfortunately, the clinical features of DLB frequently overlap with other neurodegenerative diseases, namely Alzheimer's disease and Parkinson's disease, and some experts consider DLB to be part of the Alzheimer's/Parkinsonism spectrum.

Clinical Pearls: Distinguishing Features

There are several distinguishing clinical features that suggest the diagnosis of DLB:

  1. Dementia in DLB precedes parkinsonism symptoms.
  2. The progression of signs and symptoms in DLB is relatively rapid compared to other neurodegenerative diseases. The occurrence of parkinsonism is frequently observed within less than one year of onset of dementia. Classically, patients with DLB report postural instability (eg. frequent falls and bone fractures) early in the disease compared to the delayed onset of postural instability observed in Parkinson's disease.
  3. Hallucinations in DLB are frequently visual, well-formed, and thoroughly described, compared to auditory hallucinations typically observed in schizophrenia or tactile hallucinations commonly observed in drug-induced disorders and delirium.
  4. Postural instability in DLB manifests early. Unlike patients with Parkinson's disease, patients with DLB report frequent falls that may be present as early as a few months after onset of symptoms.[26]
  5. Sleep disturbances in DLB are often due to REM sleep disorder. While other neurodegenerative diseases are associated with sleep disorders, REM sleep disorders have been frequently associated with DLB.
  6. Sensitivity to neuroleptic agents and to antiparkinsonian drugs. As many patients with DLB are diagnosed with psychosis or Parkinson's disease due to the presence of overlapping features, symptoms in DLB paradoxically exacerbate upon administration of neuroleptics and antiparkinsonian drugs. Patients often experience worse psychotic symptoms (antiparkinsonian drugs) and parkinsonism symptoms (neuroleptics).[69][26]

Main Clinical Features[70]

Motor

Cognitive

Psychiatric

Dysautonomic

Less Common Features

Motor

Psychiatric

Dysautonomic
Sleep Disorders
Others

Diagnostic Criteria

DSM-V Diagnostic Criteria for Major or Mild Neurocognitive Disorder With Lewy Bodies[66]

  • A.The criteria are met for major or mild neurocognitive disorder.

AND

  • B.The disorder has an insidious onset and gradual progression.

AND

  • C.The disorder meets a combination of core diagnostic features and suggestive diagnostic features for either probable or possible neurocognitive disorder with Lewy bodies.

For probable major or mild neurocognitive disorder with Lewy bodies, the individual has two core features, or one suggestive feature with one or more core features.

For possible major or mild neurocognitive disorder with Lewy bodies, the individual has only one core feature, or one or more suggestive features.

  • 1.Core diagnostic features:
  • a.Fluctuating cognition with pronounced variations in attention and alertness.
  • b.Recurrent visual hallucinations that are well formed and detailed.
  • c.Spontaneous features of parkinsonism, with onset subsequent to the development of cognitive decline.
  • 2.Suggestive diagnostic features;
  • a.Meets criteria for rapid eye movement sleep behavior disorder.
  • b.Severe neuroleptic sensitivity.

AND

  • D.The disturbance is not better explained by cerebrovascular disease, another neurodegenerative disease, the effects of a substance, or another mental, neurological, or systemic disorder.

Management

Management Goals

Management consists of a 4-step approach[71]:

  • Establish an accurate and timely diagnosis
  • Identify severity and nature of clinical features
  • Provide non-pharmacologic interventions
  • Administer pharmacologic therapy

Non-pharmacologic Interventions

Non-pharmacologic interventions are the mainstay of DLB management, given the lack of efficacy and at at times, paradoxical responses induced by some pharmacologic agents.[71]

  • Education of patients and caregivers
  • Mobility aid and physiotherapy

Pharmacologic Interventions

Cholinesterase Inhibitors

  • Cholinesterase inhibitors are the first-line pharmacologic agents to treat cognitive and psychiatric symptoms of patients with DLB.[72]
  • Rivastigmine: The efficacy of rivastigmine in DLB was studied in a multi-center, randomized, controlled trial (n=120).[72]
    • Neuropsychiatric assessment was made at baseline and followed by assessments at weeks 12, 20, and 23.[72]
    • Rivastigmine significantly reduced core clinical features of DLB with > 30% improvement in behavioral symptoms.[72]
    • The recommended dose in the trial was rivastigmine 6 - 12 mg once daily.[72]
  • Memantine: The efficacy of memantine in DLB was studied in a randomized, double-blind, placebo-controlled trial (n=34).[73]
    • The trial compared the baseline Alzheimer's disease cooperative study (ADCS)-clinical global impression of change scores to the scores at 24 weeks.[73]
    • Memantine improved global clinical status and behavioral symptoms of patients with mild to moderate DLB.[73]
    • The recommended dose in the trial was memantine 20 mg once daily.[73]
  • Despite efficacy, a minority of patients reported worsening symptoms of parkinsonism when administered cholinesterase inhibitors.[72][72]

Atypical Antipsychotics

  • Based on expert-opinion, atypical antipsychotics are the second-line pharmacologic agents for management of symptoms of DLB.
  • Antipsychotic agents are indicated only if cholinesterase inhibitors have proven ineffective.

Benzodiazepines

Selective Serotonine Receptor Inhibitors (SSRI)

  • SSRI are recommended as first-line agents for the management of depression associated with DLB.

Dopamine Agonists

  • Levodopa-carbidopa has demonstrated efficacy in the treatment of parkinsonism symptoms among one third of patients with DLB (n=14).[69]
  • The mean daily dose in the trial was levodopa-carbidopa 323 mg.
  • Younger patients were more responsive to levodopa-carbidopa therapy.[69]
  • Generally, levodopa-carbidopa was well-tolerated, but a minority of patients experienced exacerbations of confusion.[69]

Other Pharmacologic Agents

  • Neuroleptics (first generation antipsychotic agents) and antiparkinsonian agents are generally not recommended in patients with DLB, given the high rates of sensitivity to these drugs. When administered neuroleptics, patients often report worsening motor symptoms. When administered antiparkinsonian agents, some patients reported exacerbations of hallucinations.

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