Mary E. Scott, RN, MSN, FNP-BC
Lawrence W. Elmer, MD, PhD
DESCRIPTION 
Dementia with Lewy bodies (DLB) belongs to a family of disorders termed α-synucleinopathies which include idiopathic Parkinson's disease (IPD) and multiple system atrophy (MSA). In both DLB and PD, α-synuclein inclusions are found in the nucleus, axons, and dendrites of neurons; in MSA the inclusions are found within CNS glial cell cytoplasm. These disorders share common clinical features. However, neither PD nor MSA typically demonstrates significant cognitive abnormalities early in the disease course, while DLB is largely defined by early cognitive changes.
- DLB commonly presents with motor symptoms mimicking PD including bradykinesia and rigidity, as well as tremor and gait disturbances. DLB patients may also experience depression, anxiety, and REM sleep behavior disorder. Postmortem cases of DLB have shown coincident Alzheimer's disease (AD) pathology in over 70% of cases.
- Older literature described patients with dementia and parkinsonism as “Alzheimer's with extrapyramidal features” or diffuse Lewy body disease, consistent with a cortical, rather than brainstem, localization of Lewy bodies (LBs), differentiating DLB from IPD. These terms have been replaced by the current term “dementia with Lewy bodies.”
EPIDEMIOLOGY
Incidence
The incidence, prevalence and other population features of DLB are unknown. DLB is likely the most common form of dementia with extrapyramidal features and may be the second most common dementia after AD.
Prevalence
Estimates suggest that DLB makes up approximately 10–30% of all cases of dementia.
RISK FACTORS
Age is the greatest risk factor for DLB.
Genetics
A number of mutations found in familial PD have also been associated with cases of DLB. Some of these mutations include genes encoding alpha-synuclein and leucine-rich repeat kinase 2.
PATHOPHYSIOLOGY
- 3 different pathological variants associated with a DLB clinical syndrome have been described. All 3 may overlap with pathological features of AD. The likelihood that DLB is the cause of the clinical symptoms is directly related to the severity and distribution of LB pathology and inversely related to the severity of concomitant AD pathology (neurofibrillary tangles)
- Brainstem predominant –LB and Lewy neurite (LN) pathology seen predominantly in the 9th–10th cranial nerves, the locus coeruleus, and the substantia nigra. These findings are usually associated with IPD rather than DLB.
- Limbic (transitional) – in addition to brainstem involvement, LB and LN pathology is seen in the nucleus basalis of Meynert, the amygdala, and transentorhinal and cingulate gyri. Mild AD pathology is generally associated with DLB, while severe AD changes are more commonly seen with clinical features of AD.
- Diffuse neocortical – LB and LN pathology is seen throughout brainstem, limbic, as well as temporal, frontal, and parietal regions. Low or moderate concentrations of coexisting AD pathology correlate with a high chance of DLB clinical syndromes, while high concentrations of AD pathology along with diffuse LB disease may be seen in either AD or DLB.
ETIOLOGY
DLB is thought to be a disorder on a continuum between PD and AD.
[Outline]
HISTORY
- Consensus on diagnostic criteria for DLB includes 3 key features: Parkinsonism, visual hallucinations, and fluctuations/cognitive changes.
- Dramatic fluctuations in motor function and mentation unrelated to medication schedule.
- Patients may have syncope-like spells.
- Visual hallucinations are common in DLB.
- REM sleep behavior disorder is very common in DLB and may precede other features by years.
- Patients may also develop myoclonus.
- DLB and Parkinson's disease with dementia (PDD) have similar cognitive difficulties in attention, visuospatial processing, and executive function with lesser deficits in memory function and orientation early.
PHYSICAL EXAM
A combination of parkinsonian manifestations (bradykinesia, tremor, mask facies, gait disorder, rigidity) and early dementia, within the first year of motor symptom onset, suggest DLB.
Diagnostic Criteria – DLB Consortium 3rd Revision (1)
- Central feature (essential for the diagnosis of possible or probable DLB) – Dementia defined as progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function.
- Prominent or persistent memory impairment may not necessarily occur early on but is usually evident with progression. Deficits in attention, executive function, and visuospatial ability may be especially prominent.
- Core features (2 are sufficient for a diagnosis of probable DLB, 1 for possible DLB)
- Fluctuating cognition with pronounced variations in attention and alertness
- Recurrent visual hallucinations that are typically well formed and detailed
- Spontaneous features of parkinsonism
- Suggestive features
- REM sleep behavior disorder
- Severe neuroleptic sensitivity
- Low dopamine transporter uptake in basal ganglia demonstrated by SPECT or PET imaging
- Supportive features
- Repeated falls and syncope
- Transient, unexplained loss of consciousness
- Severe autonomic dysfunction, e.g., orthostatic hypotension, urinary incontinence
- Hallucinations in other modalities
- Systematized delusions
- Depression
- Relative preservation of medial temporal lobe structures on CT/MRI scan
- Generalized low uptake on SPECT/PET perfusion scan with reduced occipital activity
- Abnormal MIBG myocardial scintigraphy
- Prominent slow wave activity on EEG with temporal lobe transient sharp waves
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
Tests to identify potential underlying secondary causes of parkinsonism: Serum vitamin B12 level, thyroid function tests, ceruloplasmin, 24-hour urine copper excretion.
Imaging
Initial Approach
- Structural imaging studies (CT, MRI) do not assist in the diagnosis of DLB; preservation of medial temporal structures may help differentiate DLB from AD. MRI imaging may reveal evidence of other causes of parkinsonism and/or dementia.
- PET or SPECT scanning is not specific for DLB, although some studies have suggested hypometabolism in parietal and occipital regions of DLB patients contrasts with the parietal and temporal hypometabolism in AD.
Diagnostic Procedures/Other
A therapeutic trial of Sinemet®, a combination of carbidopa and levodopa, at doses of up to 600–800 mg of levodopa equivalents in 24 hours, is sometimes considered diagnostic of true IPD when the patient responds with dramatic symptomatic improvement. Patients with DLB may have only partial response. They may also develop confusion and/or psychosis with this class of medications.
Pathological Findings
DLB consensus guidelines proposed pathological confirmation based on LB density by alpha-synuclein (AS) immunohistochemistry in brainstem, limbic, and 5 cortical regions. AS is a protein that forms the intraneuronal inclusions which, in part, make up LBs. DLB pathology is correlated with accumulation of LBs and apoptotic neurodegeneration. The severity of dementia correlates with the abundance of cortical LBs as well as varying degrees of AD pathology, typically seen in over 70% of DLB post-mortem cases. In contrast, LB deposits in IPD and PDD initially occur in brainstem and motor pathways with evidence suggesting a caudal to rostral accumulation.
DIFFERENTIAL DIAGNOSIS
Includes extrapyramidal and dementing illnesses:
- PDD
- Parkinson's disease (IPD)
- Drug-induced parkinsonism
- MSA
- Progressive supranuclear palsy (PSP)
- Wilson's disease
- Vascular parkinsonism
- Frontotemporal dementia with parkinsonism
- Alzheimer's with extrapyramidal features
[Outline]
ADDITIONAL TREATMENT
General Measures
- The management of DLB is complicated by cognitive decline, behavioral changes, and frequent delusions and hallucinations.
- Parkinsonian manifestations may be managed with anti-parkinsonian agents, which may cause side effects, particularly confusion and visual hallucinations. Low doses of carbidopa/levodopa medications are best tolerated, with relatively increased toxicity from dopamine agonists.
- DLB patients are sensitive to confusion from many medications including anticholinergics, benzodiazepines, antihistamines, and narcotics.
Specific Therapies
- Carbidopa/levodopa (brand name Sinemet®): Doses vary, but patients are usually initiated with 25 mg carbidopa/100 mg L-Dopa t.i.d. and titrated to a total daily dose of dopamine of 300–800 mg.
Cholinesterase inhibitors– these agents may benefit the cognitive and behavioral features in DLB. Oral forms need to be taken with food and titrated to minimize GI side effects.
- Donepezil (Aricept®, 5–10 mg daily). It can cause bradycardia when used with beta-blockers.
- Rivastigmine (Exelon®, 6–12 mg/day) is given twice daily and is also available as a topical skin patch (Exelon® patch 4.6 mg and 9.5 mg) applied daily to the skin for 24 hours. The patch has less GI side effects than the oral formulation.
- Galantamine (Razadyne®, 4, 8, 12 mg tablets and liquid 4 mg/ml) is given twice daily with food. Galantamine ER (Razadyne ER®, 8, 16 and 24 mg) is a daily extended-release formulation.
NMDA receptor antagonists—Memantine (5 mg and 10 mg twice daily).
ADDITIONAL TREATMENT
Psychiatric Measures
- Atypical antipsychotics are used in very low doses to treat associated hallucinations and behavioral disturbances. Judicious use is needed because of an increased risk of death in elderly, especially those with cardiovascular risk factors. Agents with no extrapyramidal side effects include:
- Clozapine (Clozaril®, 12.5–25 mg/day) is the prototypic atypical antipsychotic. A rare, but life-threatening side effect is agranulocytosis. Weekly CBC is required for the first 6 months and every 2 weeks thereafter.
- Quetiapine (Seroquel®, 25–100 mg/day) is another atypical antipsychotic that shows no dose-dependent extrapyramidal side effects.
- ALERT – Conventional neuroleptics are contraindicated in the treatment of DLB psychosis. DLB patients may experience severe, life-threatening rigidity and bradykinesia if administered medications with high affinity for dopamine receptors such as haloperidol.
- Antidepressants such as venlafaxine (75–225 mg/day) and paroxetine (10–20 mg/day) may be required for treatment of depression and/or anxiety but may worsen cognition.
Issues for Referral
Referral to geriatric psychiatry, cognitive or movement disorders neurology is warranted for assistance with medication management.
Additional Therapies
- Physical and occupational therapists to help with mobility issues and activities of daily living.
- Neuropsychologists may assess whether depression and/or anxiety are confounding components.
- Social workers assess caregiver stress and coordinate home health care services.
SURGERY/OTHER PROCEDURES
Deep brain stimulation is contraindicated in DLB due to risk of worsening dementia.
IN-PATIENT CONSIDERATIONS
Admission Criteria
Not uncommonly, concomitant illnesses (e.g., pneumonia, UTI) may lead to an acute exacerbation of parkinsonian or cognitive symptoms, requiring hospitalization for dysphagia, airway management, confusion and issues of decreased mobility. Psychosis frequently precipitates hospitalization/institutionalization.
Nursing
Close observation is needed due to confusion and increased risk of falls from the extrapyramidal symptoms. Attention to sleep/wake cycles, hydration and nutritional status, as well as avoidance of heavily sedating agents is necessary. Treatment with carbidopa/levodopa needs to be dosed on a strict schedule to minimize motor and/or cognitive fluctuations.
Discharge Criteria
Evaluations from physical and occupational therapists, neuropsychologists, and social workers may be necessary to judge whether the patient will require home health care or a subacute rehab stay to return home safely. Persistent psychosis is a common cause of nursing home placement.
[Outline]
PATIENT MONITORING
DLB requires steadily increasing doses of medications for the treatment of dopaminergic deficiency, side effects of dopaminergic therapy and the cognitive/behavioral abnormalities.
DIET
Separating carbidopa/levodopa from meals rich in protein may be required to obtain optimal clinical efficacy (levodopa absorption is impaired by the presence of neutral amino acids).
PATIENT EDUCATION
Support groups for parkinsonian disorders are available. There are several large national organizations that provide educational materials.
PROGNOSIS
DLB is typically more relentless than Parkinson's disease in its progression with significant disability – emotional, cognitive and physical – by 7–10 years after the onset of symptoms.
COMPLICATIONS
Drug-induced psychosis, falls, aspiration pneumonia, severe autonomic dysfunction including orthostatic hypotension and syncope.
[Outline]
ICD9
331.82 Dementia with Lewy bodies
Cognitive deficits seen early in DLB include attention and concentration (serial 7’s, spelling WORLD backwards) and visuospatial skills (intersecting pentagons, clock drawing test) while orientation and memory are largely preserved. This contrasts sharply to AD in which orientation and short-term memory are involved early or in equal proportion to attention/concentration and/or visuospatial skills.