Dementia with Lewy bodies (DLB) is a neurodegenerative dementia occurring concurrently with or within 1 yr (either before or after) of the onset of parkinsonism. DLB also has other core features, including fluctuations in attention and alertness and recurrent vivid visual hallucinations. Diagnostic criteria for dementia syndrome associated with Lewy body pathology are described in Table E1. Patients generally respond to cholinesterase inhibitors, are very sensitive to the adverse effects of neuroleptics, and are less responsive to levodopa compared with Parkinson disease (PD) patients.

DLB

Lewy body dementia

Diffuse Lewy body disease

Lewy body type senile dementia

Cortical Lewy body disease

• Importance of recognizing DLB relates to its pharmacologic management, including responsiveness to cholinesterase inhibitors, sensitivity to the adverse effects of neuroleptics, and relative unresponsiveness to levodopa.
• The diagnostic criteria for DLB have been revised several times. The latest revision, the Fourth Consensus Report of the DLB Consortium, was published in 2017 and is the basis for the diagnostic information outlined later. ¹
• The presence of dementia is absolute requirement for the diagnosis. The dementia is insidious in onset with a neuropsychologic profile of early impairments in visuoperceptual, attentional, and executive functions, with relative sparing early on of episodic memory (in contradistinction to ADs, in which impairment in episodic memory is a hallmark early finding). Memory impairment typically ensues as the disease progresses.
• In addition to dementia, DLB has four core clinical features. For the diagnosis of probable DLB, the patient should have dementia plus either two core clinical features or one core clinical feature and one indicative biomarker. Possible DLB can be diagnosed in a patient with dementia who manifests only one core clinical feature or has no core clinical features but has one or more indicative biomarkers of the disease.
• Core clinical features
  1. Fluctuations in cognition with marked variations in attention and alertness level
  2. Recurrent well formed, vivid visual hallucinations
  3. Rapid eye movement (REM) sleep behavior disorder (RBD), which may precede the cognitive decline by several years
  4. Parkinsonian motor features, which include at least one of the following: bradykinesia, rest tremor, or rigidity
     1. a. NB: The dementia either precedes the onset of parkinsonism or begins at the same time. For research purposes, 1 yr is used as the time in which dementia and parkinsonism should be appear. Because the first three core features often precede the onset of parkinsonism, at the time of diagnosis, parkinsonian may not have yet manifested.
• Supportive clinical features include:
  1. Severe neuroleptic sensitivity
  2. Repeated falls
  3. Unexplained syncope or other episodes of nonresponsiveness
  4. Severe autonomic dysfunction
  5. Hyposmia
  6. Hallucinations other than visual
  7. Systematized delusions
  8. Apathy, anxiety, and depression
• Biomarkers
  1. Indicative biomarkers
     1. a. Reduced dopamine transporter uptake in the basal ganglia demonstrated by single-photon emission computerized tomography (SPECT) or PET.
     2. b. Low uptake on ¹²³iodine-MIBG myocardial scintigraphy
     3. c. Polysomnographic confirmation of REM sleep without atonia
  2. Suggestive biomarkers
     1. a. Relative preservation of medial temporal lobe structures on computed tomography/MRI scan.
     2. b. Generalized low uptake on SPECT/PET perfusion/metabolism scan with reduced occipital activity ± the cingulate island sign on fluorodeoxyglucose (FDG)-PET imaging.
     3. c. Prominent posterior slow-wave activity on electroencephalogram (EEG) with periodic fluctuations in the pre-alpha/theta range.

• SNCA encodes for a protein normally found at the synapse with a role in vesicle production. In its insoluble form, SNCA aggregates into Lewy bodies found at the cortical and subcortical levels.
• Lewy bodies (Fig. E1) are round, eosinophilic, intracytoplasmic inclusions in the nuclei of neurons.
• Cortical Lewy bodies are found in deep cortical layers of the anterior frontal and temporal lobes, the cingulate gyrus, and insula.
• As in PD, Lewy bodies aggregate in the following structures: Substantia nigra, locus ceruleus, raphe nuclei, nucleus basalis of Meynert, and brain stem nuclei.
• Fig. E2 shows the relationships among the subtypes of dementia.
• Many patients with DLB also have evidence of amyloidosis typical of AD. These patients often have a worse cognitive profile than pure DLB, with a cognitive phenotype typical of both AD (episodic memory loss) and DLB (inattention, executive dysfunction, and visuospatial dysfunction).

• Diagnosis of DLB when dementia occurs before or concurrently with extrapyramidal features-arbitrarily set as the “1-yr rule” vs. PD with dementia, which occurs in the setting of well-established PD.
• Dementia: AD, vascular dementia, frontotemporal dementia. However, some patients have pathologic overlap of AD and DLB or DLB and vascular dementia.
• Parkinsonian features: Parkinson disease dementia, progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multisystem atrophy (MSA).
• Rapidly progressive form: Creutzfeldt-Jakob disease (CJD). Lack of cerebellar signs and lack of typical CJD MRI may help distinguish DLB from classic CJD (but not variant form of CJD).
• Psychiatric features: Late-onset psychosis or depression with psychotic features.
• Hallucinations with fluctuations in consciousness: Temporal lobe epilepsy (TLE) or delirium due to toxic/metabolic or autoimmune derangement.

• MRI of the brain to evaluate for structural causes of dementia and exclude MRI features of vascular dementia or CJD.
• Lumbar puncture to rule out underlying chronic infections, only if there are atypical features.
• EEG if there is concern about TLE. However, both DLB and TLE may show nonspecific slowing or periodic complexes (see supportive biomarkers above).
• DaTscan [Ioflupane (123I)] imaging is a SPECT scan preceded by injection of a radiopharmaceutical that detects the loss of functional dopaminergic neuron terminals in the striatum, reflecting underlying PD or DLB.

Rule out other potential reversible causes for dementia, including CBC, complete metabolic panel, thyroid-stimulating hormone, and B₁₂. Consider RPR and HIV testing as well.

• MRI typically shows a relative preservation of the hippocampi and medial temporal lobe volumes (in contrast to AD) but generalized atrophy and white matter changes may be present.
• Generalized low uptake on SPECT/PET perfusion/metabolism scan with reduced occipital activity ± the cingulate island sign on FDG-PET imaging.

• Social interaction and environmental novelty may improve cognitive dysfunction and psychiatric features often exacerbated by low levels of arousal and attention
• Behavioral methods, such as avoiding previously exposed environmental triggers known to cause anxiety, agitation, or aggression
• Physical therapy, mobility aids, and daily exercise

Atypical neuroleptic for disabling, persistent, bothersome (to the patient) psychotic features despite initiation of a cholinesterase inhibitor. A very low dose of an atypical antipsychotic (quetiapine 12.5 mg/day) may be started after patient/caregiver education regarding the sensitivity to neuroleptics. However, all neuroleptics do carry a boxed warning from the FDA about the increased mortality risk associated with neuroleptic use in patients with dementia. Patients and/or caregivers should be informed of this risk and allowed to balance the risk against the perceived benefit.

• Cholinesterase inhibitors for cognitive and behavioral symptoms. Rivastigmine (6 to 12 mg/day PO or 9.5 mg/day by transdermal patch) has shown in a randomized controlled trial (RCT) to significantly reduce anxiety, delusions, and hallucinations, as well as significantly improved performance on neuropsychologic testing.
• PD medications for disabling parkinsonian features. Carbidopa/levodopa is reported to be more effective with fewer side effects than dopamine agonists, which have higher rates of psychotic symptoms. Begin at a low dose-25/100 mg three times a day-and slowly titrate over several weeks as tolerated and according to response.
• Selective serotonin reuptake inhibitors are commonly used for depression.
• If REM sleep disorder remains disabling (or patient has not responded to an atypical antipsychotic initiated for psychosis), a trial of low-dose clonazepam (0.25 to 0.5 mg) or melatonin (3 mg) at bedtime remains an option.
• Orthostatic hypotension may be aided by nonpharmacologic therapy such as supportive stockings or pharmacologically by midodrine, fludrocortisone, or droxidopa.
• Memantine demonstrated an improvement in clinical global measure and remains well tolerated but may worsen hallucinations or delusions.
• Avoid anticholinergics (including tricyclic antidepressants), benzodiazepines, and typical neuroleptics, as they can trigger delirium and worsen symptoms.

• Survival resembles the progression of AD, but a minority of cases may have a rapid disease course.
• Progression in cognitive decline, similar to AD, by approximately 10%/yr on cognitive testing.

DLB requires a multidisciplinary approach including the general practitioner, neurologist, neuropsychologist, and/or neuropsychiatrist.

• Clinical presentation helps differentiate DLB from AD. AD presents with early signs of anterograde episodic memory loss without the benefit of cues on neuropsychologic testing because of cortical atrophy at the medial temporal lobe region.
• Vascular dementia may also present with evidence of frontal-subcortical features but typically without the core features listed in the criteria above.
• Bed partners may report that individuals with DLB “act out their dreams,” sometimes violently, leading to sleeping in separate beds. This history may indicate REM sleep behavior disorder. A history of REM sleep behavior may precede the diagnosis by many years. However, REM sleep behavior does not necessarily lead to DLB, but can be premonitory of any alpha synucleinopathy, including PD and multiple system atrophy.

• Visual hallucinations (VHs) typically consist of innocuous, well-formed, detailed images of animate figures. These are classically labeled Lilliputian, because the hallucinatory images are often relatively small. Unless VH lead to a potential threat to self or others, avoid antipsychotics due to the sensitivity of neuroleptics. Family/friends are often more alarmed by the VH than the patient with DLB.
• Apathy is a common clinical feature of DLB and mimics changes in mood, including depression or excessive daytime somnolence. These features are often noticed by family/friends.