AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Frederick Lewy first described Lewy bodies (LBs), cytoplasmic inclusions found in cells of the substantia nigra in patients with idiopathic Parkinson disease (PD), in 1914. In the 1960s, several pathologists described patients with dementia who had LBs of the neocortex. However, such cases were presumed to be rare until the mid 1980s, when sensitive immunocytochemical methods to identify LBs were developed. Dementia with LBs (DLB) was then recognized as being far more common than previously thought.

The relationship of DLB and PD is an area of considerable controversy, particularly because dementia frequently occurs in PD. Many investigators believe that a spectrum of LB disorders exists.

The third report of the DLB Consortium headed by Ian McKeith discusses an arbitrary 1-year rule to distinguish DLB from PD with dementia.¹ If parkinsonism has been present for 12 months or longer before cognitive impairment is detected, the disorder is called PD with dementia; otherwise, it is called DLB. The report recognizes that this rule may be difficult to apply in clinical practice. When dementia precedes motor signs, particularly with visual hallucinations and episodes of reduced responsiveness, the diagnosis of DLB should be considered. Clinical criteria for DLB were first proposed in 1996² and modified in the subsequent DLB Consortium reports³. Several clinicopathological studies have assessed the sensitivity and specificity of these clinical criteria.^{4, 5} These clinical features are discussed below.

Postmortem examinations in both PD and DLB patients demonstrate LBs in the substantia nigra and possibly in the locus ceruleus, dorsal raphe, substantia innominata, and dorsal motor nucleus of the vagus. LBs are found in the neocortex of many patients with idiopathic PD and in all patients with DLB. DLB overlaps parkinsonian dementias.

Pathophysiology

Symptoms and signs of DLB probably result, in part, from disruption of bidirectional information flow from the striatum to the neocortex, especially the frontal lobe. The cause is multifactorial. Altered neuromodulator and/or neurotransmitter levels (eg, acetylcholine [ACh], dopamine) influence the function of many neuronal circuits. In DLB, nonpyramidal cells in layers V and VI of the neocortex may contain LBs. Their function in neocortical information processing and in relaying data to subcortical regions probably is impaired. The etiology of the fluctuations in cognitive function, which characterize DLB, is unknown.

Frequency

United States

Findings from autopsy studies suggest that DLB accounts for 10-20% of dementias. Up to 40% of patients with Alzheimer disease (AD) have concomitant LBs. These mixed cases are sometimes called the LB variant of AD (LBV-AD) and represent an overlap syndrome between DLB and AD. Signs and symptoms of LBV-AD also overlap between DLB and AD. Because the sensitivity and specificity of clinical diagnosis are poor, no good epidemiologic data on incidence or prevalence of DLB are available.

International

Autopsy studies in Europe and Japan indicate that the frequency of DLB is comparable with that reported in studies from the United States.

Mortality/Morbidity

• Dementing illnesses (including DLB) shorten life expectancy.

• With severe disease, patients may experience swallowing problems that can lead to impaired nutrition.

• Patients are at risk for falls because of impaired mobility and balance.

• Because of prolonged bed rest, patients are at risk for decubitus ulcers.

• Dysphagia and immobility also can lead to pneumonia.

Race

DLB has been described in Asian, African, and European races. Data concerning the relative frequency of DLB in different races are not available.

Sex

Most studies suggest that DLB is slightly more common in men than in women.

Age

DLB is a disease of late middle age and old age.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• DLB is a progressive degenerative dementia.
• The following clinical features that help distinguish DLB from AD:
• • Fluctuations in cognitive function with varying levels of alertness and attention: Clues to the presence of fluctuations include excessive daytime drowsiness (if nighttime sleep is adequate) or daytime sleep longer than 2 hours, staring into space for long periods, and episodes of disorganized speech.
  • Visual hallucinations
  • Parkinsonian motor features


• Although extrapyramidal features may occur late in the course of AD, they appear relatively early in DLB.
• Whereas patients with AD virtually always have anterograde memory loss as a prominent symptom and sign early in the course of the illness, anterograde memory loss may be less prominent in DLB. McKeith et al have suggested that patients with DLB do relatively better on tests of confrontation naming, short and medium recall, and recognition than AD patients, whereas AD patients do better on tests of verbal fluency, visual perception, and performance tasks.⁶
• Executive function deficits and visuospatial impairment may be more prominent in persons with DLB than in those with AD (eg, Stroop, digit span backwards).
• Other symptoms that may alert clinicians to the diagnosis of DLB (versus AD) include the following:
• • Nonvisual hallucinations
  • Delusions
  • Unexplained syncope
  • Rapid eye movement sleep disorder
  • Neuroleptic sensitivity

Physical

• Patients usually have impaired cognition consistent with dementia.
• An important observation during mental status testing is that the patient has periods of being alert, coherent, and oriented that alternate with periods of being confused and unresponsive to questions (although awake). This fluctuation is a relatively specific feature of DLB.
• Retrieval from memory may be relatively worse than memory storage.
• Patients may do relatively well with confrontation naming tests and poorly on tests of visuospatial skills (eg, drawing a clock, copying figures).
• Patients may have some parkinsonian signs but usually not enough to meet the criteria for a diagnosis of PD.
• Mild gait impairment is relatively frequent and should not be ascribed to old age or osteoarthritis.
• Resting tremor occurs less frequently than in PD.
• Myoclonus may occur before severe dementia.

Causes

• The etiology of DLB is not known.
• Rare cases of familial DLB have been reported.
• Apolipoprotein E subtype 4 (ApoE4) genotype is overrepresented only when DLB occurs with concomitant AD.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Dementia in PD
Dementia in progressive supranuclear palsy

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Laboratory studies should include those usually ordered in a dementia evaluation, including tests of the following:
• • Chemistry panel
  • Complete blood cell count
  • Thyroid studies
  • Vitamin B-12 levels
  • Syphilis, Lyme disease, or HIV testing, when appropriate

• No sensitive or specific blood, cerebrospinal fluid (CSF), or urine tests are currently available for DLB.

Imaging Studies

• Because vascular dementia can cause symptoms and signs similar to those of DLB, brain MRI is indicated to distinguish DLB from vascular dementia.
• Patients with vascular dementia often have white matter lesions on MRIs, whereas patients with DLB do not.
• MRI is superior to CT scanning in identifying hippocampal atrophy.
• Patients with DLB usually have less hippocampal atrophy than patients with AD (but more than control subjects). Whether this difference is clinically useful is under investigation, as is the diagnostic utility of functional imaging.
• Single-photon emission CT scanning or positron emission tomography scanning may show decreased occipital lobe blood flow or metabolism in DLB but not in AD
• Reduced dopamine transporter activity in the basal ganglia is seen with positron emission tomography scanning or single-photon emission CT scanning.

Other Tests

• In certain circumstances, neuropsychological testing is helpful to differentiate DLB from AD and to establish a baseline for future comparison.
• Patients with DLB may have changes on electroencephalography earlier than patients with AD, but whether this difference is diagnostically useful is not clear.
• CSF examination is not required in routine cases.
• • Patients with AD have higher levels of tau protein in their CSF than patients with DLB.
  • Patients with both LBV-AD have intermediate values.
  • CSF levels of beta-amyloid are lower than normal in DLB, AD, and LBV-AD. However, CSF beta-amyloid levels in DLB, LBV-AD, and AD do not differ from each other.

Histologic Findings

The characteristic lesion is the LB, an eosinophilic (hematoxylin and eosin staining), round inclusion found in the cytoplasm of substantia nigra cells and in the nucleus basalis of Meynert, locus ceruleus, dorsal raphe, and the dorsal motor nucleus of cranial nerve X. LBs are found in nonpyramidal cells in layers V and VI of the cortices (especially limbic and transitional cortex).

Other findings are minimal atrophy, occasional vacuolization in deep layers of the temporal cortex, and abnormal neurites in cells of CA2/3 of the hippocampus and various brainstem nuclei. The primary constituent of LBs is alpha-synuclein, a presynaptic protein, the function of which is unknown. Neurofilament proteins and ubiquitin are other important constituents of LBs. Numerous neurotransmitters, including ACh, are diminished in DLB. The decrease in ACh may be more severe than in AD.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Double-blinded, placebo-controlled studies have demonstrated that rivastigmine may decrease psychiatric symptoms associated with DLB, particularly apathy, anxiety, hallucinations, and delusions. These studies also demonstrate that patients with DLB treated with cholinesterase inhibitors do better on neuropsychological tests than subjects treated with placebo. Open-label studies suggest that donepezil and galantamine also are effective.
• For the treatment of agitation and hallucinations associated with DLB, acetylcholinesterase inhibitors are the drugs of choice.
• In a small minority of patients, motor features are worsened with cholinesterase inhibitors.

• Levodopa/carbidopa may improve motor function in some patients with DLB; however, in many patients this combination has no effect and may exacerbate psychiatric symptoms or confusion.
• Hallucinations and agitation are especially troublesome in DLB. When these symptoms are mild, no medical treatment may be necessary.
• • Acetylcholinesterase inhibitors should usually be tried first.

  • Most experts recommend atypical neuroleptics such as clozapine, quetiapine, or aripiprazole when cholinesterase inhibitors are ineffective.

  • Avoid standard neuroleptics such as haloperidol because of neuroleptic sensitivity.

• Depression is frequent in DLB patients and may result from damage in the dorsal raphe and locus ceruleus and/or as a psychological response to impaired function. Selective serotonin reuptake inhibitors are the drugs of choice.

Consultations

Spouses, family members, and caregivers of patients with DLB frequently realize that the patient with DLB behaves differently than typical patients with AD. Primary caregivers (or neurologists not specializing in dementia) frequently are unable to adequately explain these differences. In such situations, referral to a dementia specialist can be helpful.

Diet

No dietary restrictions are indicated except for patients with severe disease who have swallowing impairment.

Activity

Physical therapy and exercise classes can be useful to maintain mobility. Additionally, advise families of potential problems faced by patients with DLB who drive.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

As yet, no compelling data indicate that medications can decrease the rate of cognitive decline. Medication can be used to treat agitation and hallucinations, treat depression, and improve cognition and/or alertness.

Regarding nonspecific partial glutamate antagonists, in the United States, memantine (Namemda) is approved for the treatment of moderate-to-severe AD. It is not approved for the treatment of PD or DLB. Although this class of drugs might be useful in DLB, as of November 2006, no results of double-blinded, placebo-controlled comparisons of the efficacy of memantine and placebo in the treatment of DLB have been published. Melatonin may be administered at 3 mg hs.

For further discussion of possible treatment of motor features, see Parkinson Disease.

Drug Category: Centrally acting acetylcholinesterase inhibitors

Ach concentrations are decreased in the brains of patients with DLB. Patients with DLB are more likely than patients with AD to improve with cholinesterase inhibitor therapy. Fluctuations in cognition may decrease, alertness may increase, and memory may improve.

Drug Category: Atypical neuroleptics

Patients with DLB frequently have hallucinations that can cause them to engage in unsafe behavior. Thus, they require treatment. Standard neuroleptics exacerbate parkinsonian motor features and, therefore, are contraindicated.

Drug Category: Antidepressants

Depression is frequent in DLB. Antidepressants with little or no anticholinergic activity are desirable.

Drug Category: Benzodiazepines

By binding to specific receptor-sites, these agents appear to potentiate the effects of GABA and facilitate inhibitory GABA neurotransmission and other inhibitory transmitters.

Drug Category: Dopamine precursors

Patients with DLB have impaired dopaminergic tone due to disease in the substantia nigra and possibly other dopaminergic nuclei. Efficacy of the treatment of motor features in DLB depends on where the patient is on the PD-DLB spectrum. Whether or not levodopa influences cognition positively or negatively remains controversial, and its effect on cognition is probably modest.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Deterrence/Prevention

• Data are not available on deterrence or prevention of this condition.

Prognosis

• DLB is a disorder of inexorable progression.



• The rate of progression varies, and some investigators think that progression is faster than that of AD.



• Patients eventually die from complications of immobility, poor nutrition, and swallowing difficulties.

Patient Education

• Primary caregivers need information about the course of the disease and the management of symptoms such as agitation, hallucinations, and cognitive fluctuations.



• Family members and physicians may mistake fluctuations for transient ischemic attacks.



• Information concerning issues such as daycare and home health aides can be useful.



• Children of patients with DLB may request information concerning genetic risks or neuroprotective treatment regimens.



• For excellent patient education resources, visit eMedicine's Dementia Center. In addition, see eMedicine's patient education articles Dementia Overview, Dementia With Lewy Bodies, and Dementia Medication Overview.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Family members should be made aware that DLB eventually affects job performance.
• Depending on the patient's occupation and level of dysfunction, medical leave of absence or early retirement may be advised.
• Driving privileges need to be addressed by the patient, family, caregivers, primary care physician, and neurologist.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Jul 16, 2007