Dementia With Lewy Bodies

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Dementia with Lewy bodies (DLB) is a progressive, degenerative dementia of unknown etiology. Affected patients generally present with dementia preceding motor signs, particularly with visual hallucinations and episodes of reduced responsiveness.

Symptoms and signs of DLB may result, in part, from disruption of bidirectional information flow from the striatum to the neocortex, especially the frontal lobe.

The following clinical features help to distinguish DLB from Alzheimer disease:

Fluctuations in cognitive function with varying levels of alertness and attention (eg, excessive daytime drowsiness despite adequate nighttime sleep or daytime sleep >2 hours, staring into space for long periods, episodes of disorganized speech)

Visual hallucinations

Parkinsonian motor features

Relatively early extrapyramidal features (vs may occur late in Alzheimer disease)

Anterograde memory loss: May be less prominent (vs prominent early sign in Alzheimer disease)

More prominent executive function deficits and visuospatial impairment (eg, Stroop, digit span backwards)

Other symptoms that may alert clinicians to the diagnosis of DLB (vs Alzheimer disease) include the following:

Nonvisual hallucinations

Delusions

Unexplained syncope

Rapid eye movement sleep disorder

Neuroleptic sensitivity

See Clinical Presentation for more detail.

Examination of cognition and mental status in patients with suspected DLB may include the following findings:

Impaired, but relatively conserved cognition

Fluctuating cognition: Periods of being alert, coherent, and oriented alternating with periods during which the patient is confused and unresponsive to questions

Retrieval from memory: May be relatively worse than memory storage

May do relatively well with confrontation naming tests but poorly on tests of visuospatial skills (eg, drawing a clock, copying figures)

Other findings on physical examination may include the following:

Some parkinsonian signs but usually not enough to meet the criteria for a diagnosis of Parkinson disease

Mild gait impairment: Relatively frequent; should not be ascribed to old age or osteoarthritis.

Resting tremor: Occurs less frequently than in Parkinson disease

May exhibit myoclonus before severe dementia

Orthostatic hypotension: Particularly common in DLB [1]

Testing

No sensitive or specific blood or urine tests are currently available for DLB. Laboratory studies should include those usually ordered in a dementia evaluation, including the following:

Chemistry panel

Complete blood count

Thyroid studies

Vitamin B-12 levels

Syphilis, Lyme disease, or human immunodeficiency virus testing, when appropriate

Cerebrospinal fluid examination is not required in routine cases. In certain circumstances, neuropsychologic testing is helpful in differentiating DLB from Alzheimer disease and in establishing a baseline for future comparison.

Patients with DLB may have changes on electroencephalography earlier than do patients with Alzheimer disease, but whether this difference is diagnostically useful is not clear.

Imaging studies

The following radiologic studies of the brain may be used to evaluate patients with suspected DLB:

Magnetic resonance imaging: To distinguish DLB from vascular dementia

Computed tomography scanning

Single photon emission computed tomography

Positron emission tomography scanning

See Workup for more detail.

Patients who have DLB with mild hallucinations and agitation may not require medical treatment. When medication is used, acetylcholinesterase inhibitors should be tried first. When cholinesterase inhibitors are ineffective, most experts recommend atypical neuroleptics such as clozapine, quetiapine, or aripiprazole. Avoid standard neuroleptics, such as haloperidol, because of neuroleptic sensitivity.

Pharmacotherapy

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

The following medications are used in patients who have DLB:

Cholinesterase inhibitors (eg, donepezil, rivastigmine, rivastigmine patch, galantamine)

2nd-generation antipsychotics (eg, clozapine, quetiapine, aripiprazole)

Antidepressants (eg, venlafaxine, paroxetine, sertraline, fluoxetine)

Benzodiazepines (eg, clonazepam)

Dopamine precursors (eg, levodopa and carbidopa)

See Treatment and Medication for more detail.

Dementia with Lewy bodies (DLB) is a progressive, degenerative dementia. Frederick Lewy first described Lewy bodies (LBs)—cytoplasmic inclusions found in cells of the substantia nigra in patients with idiopathic Parkinson disease —in 1914. (See Etiology.)

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. DLB was then recognized as being far more common than previously thought. (See Workup.)

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

Clinical criteria for DLB were first proposed in 1996 [2] and modified in the subsequent DLB Consortium reports. [3] Several clinicopathologic studies have assessed the sensitivity and specificity of these clinical criteria. (See Presentation and Workup.) [4, 5]

The third report of the DLB Consortium, headed by Ian McKeith, discussed an arbitrary 1-year rule to distinguish DLB from Parkinson disease with dementia. [6] According to the report, if parkinsonism has been present for 12 months or longer before cognitive impairment is detected, the disorder is called Parkinson disease with dementia; otherwise, it is called DLB. The report recognized 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. (See Presentation.)

Postmortem examinations in patients with Parkinson disease and those with DLB have demonstrated LBs in the substantia nigra and possibly in the locus ceruleus, dorsal raphe, substantia innominata, and dorsal motor nucleus of cranial nerve X (CNX, the vagus nerve). LBs are found in the neocortex of many patients with idiopathic Parkinson disease and in all patients with DLB. DLB overlaps parkinsonian dementias. (See Workup.)

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 acetylcholine (ACh), are diminished in DLB. The decrease in ACh may be more severe than in Alzheimer disease. (See Treatment and Medication.)

Up to 40% of patients with Alzheimer disease have concomitant LBs. These mixed cases are sometimes called the LB variant of Alzheimer disease (LBV-AD) and represent an overlap syndrome between DLB and Alzheimer disease. Signs and symptoms of LBV-AD also overlap between DLB and Alzheimer disease. [7]

The etiology of DLB is not known. 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 levels of neuromodulators and/or neurotransmitters (eg, 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 fluctuations in cognitive function, which characterize DLB, is unknown. [8]

Nagahama et al found that different types of psychotic symptoms in patients with DLB correlated with perfusion changes in different parts of the brain. Single-photon emission computed tomography (SPECT) scanning studies in 145 DLB patients revealed the following [9] :

Visual hallucinations – Were related to hypoperfusion of the parietal and occipital association cortices

Misidentifications – Were related to hypoperfusion of the limbic-paralimbic structures

Delusions – Were related to hyperperfusion of the frontal cortices

Rare cases of familial DLB have been reported. Overrepresentation of apolipoprotein E subtype 4 (ApoE4) genotype has been found in patients with DLB, but only in those whose disease has occurred concomitantly with Alzheimer disease.

Findings from autopsy studies suggest that DLB accounts for 10-20% of dementias. However, because the sensitivity and specificity of clinical diagnosis are poor, no good epidemiologic data on the incidence or prevalence of DLB are available.

Autopsy studies in Europe and Japan indicate that the frequency of DLB is comparable with that reported in studies from the United States. A prospective, population-based study in a cohort of persons over the age of 65 years in southwestern France found an incidence of 112 cases per 100,000 person-years for suspected DLB. [10]

DLB has been described in Asian, African, and European races. Data concerning the relative frequency of DLB in different races are not available. Most studies suggest that DLB is slightly more common in men than in women.

DLB is a disease of late middle age and old age. The aforementioned study in southwestern France found that the incidence of DLB increased continuously with advancing age, whereas that of Parkinson disease decreased after age 85 years. [10]

DLB is a disorder of inexorable progression. The rate of progression varies, and some investigators think that progression is faster than that of Alzheimer disease. Patients eventually die from complications of immobility, poor nutrition, and swallowing difficulties.

The following morbidities are associated with DLB:

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

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.

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

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

For patient education information, see the Brain and Nervous System Center, as well as Dementia Overview, Dementia With Lewy Bodies, and Dementia Medication Overview.

Sonnesyn H, Nilsen DW, Rongve A, Nore S, Ballard C, Tysnes OB, et al. High prevalence of orthostatic hypotension in mild dementia. Dement Geriatr Cogn Disord. 2009. 28(4):307-13. [Medline].

McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology. 1996 Nov. 47(5):1113-24. [Medline].

McKeith IG, Perry EK, Perry RH. Report of the second dementia with Lewy body international workshop: diagnosis and treatment. Consortium on Dementia with Lewy Bodies. Neurology. 1999 Sep 22. 53(5):902-5. [Medline].

McKeith IG, Ballard CG, Perry RH, et al. Prospective validation of consensus criteria for the diagnosis of dementia with Lewy bodies. Neurology. 2000 Mar 14. 54(5):1050-8. [Medline].

Verghese J, Crystal HA, Dickson DW, Lipton RB. Validity of clinical criteria for the diagnosis of dementia with Lewy bodies. Neurology. 1999 Dec 10. 53(9):1974-82. [Medline].

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Ferman TJ, Smith GE, Boeve BF, et al. DLB fluctuations: specific features that reliably differentiate DLB from AD and normal aging. Neurology. 2004 Jan 27. 62(2):181-7. [Medline].

Serra L, Cercignani M, Basile B, Spanò B, Perri R, Fadda L, et al. White Matter Damage along the Uncinate Fasciculus Contributes to Cognitive Decline in AD and DLB. Curr Alzheimer Res. 2012 Jan 23. [Medline].

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Perez F, Helmer C, Dartigues JF, Auriacombe S, Tison F. A 15-year population-based cohort study of the incidence of Parkinson’s Disease and dementia with Lewy bodies in an elderly French cohort. J Neurol Neurosurg Psychiatry. 2009 Dec 3. [Medline].

McKeith IG, Rowan E, Askew K, et al. More severe functional impairment in dementia with lewy bodies than Alzheimer disease is related to extrapyramidal motor dysfunction. Am J Geriatr Psychiatry. 2006 Jul. 14(7):582-8. [Medline].

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Howard A Crystal, MD Professor, Departments of Neurology and Pathology, State University of New York Downstate; Consulting Staff, Department of Neurology, University Hospital and Kings County Hospital Center

Howard A Crystal, MD is a member of the following medical societies: American Academy of Neurology, American Neurological Association

Disclosure: Nothing to disclose.

Daniel H Jacobs, MD, FAAN Associate Professor of Neurology, University of Florida College of Medicine; Director for Stroke Services, Orlando Regional Medical Center

Daniel H Jacobs, MD, FAAN is a member of the following medical societies: American Academy of Neurology, American Society of Neurorehabilitation, Society for Neuroscience

Disclosure: Received grant/research funds from Teva Pharmaceutical for consulting; Received grant/research funds from Biogen Idex for independent contractor; Received royalty from Serono EMD for speaking and teaching; Received royalty from Pfizer for speaking and teaching; Received royalty from Berlex for speaking and teaching.

Jasvinder Chawla, MD, MBA Chief of Neurology, Hines Veterans Affairs Hospital; Professor of Neurology, Loyola University Medical Center

Jasvinder Chawla, MD, MBA is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American Medical Association

Disclosure: Nothing to disclose.

Robert A Hauser, MD, MBA Professor of Neurology, Molecular Pharmacology and Physiology, Director, Parkinson’s Disease and Movement Disorders Center, University of South Florida; Clinical Chair, Signature Interdisciplinary Program in Neuroscience

Robert A Hauser, MD, MBA is a member of the following medical societies: American Academy of Neurology, American Medical Association, American Society of Neuroimaging, and Movement Disorders Society

Disclosure: Adamas Pharmaceuticals Consulting fee Consulting

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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