DEMENTIA WITH LEWY BODIESARNAUTU SERGIU, HAJEVSCHI ANDREI, MATCAU DIANA, JIANU DRAGOS CATALIN

DEFINITION

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.

ETIOLOGYThe 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.

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 :

• 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

SIGNS AND SYMPTOMSSYMPTOMS 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

DIAGNOSIS

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

TESTINGNo 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.

OTHER TESTS

A new test, called the Lewy body composite risk score (LBCRS), may help determine whether Lewy body pathology is contributing to dementia. The checklist was derived from clinical features in autopsy-verified cases of healthy controls, Alzheimer’s disease (AD), DLB, and PD with and without dementia. It was tested and validated in a cohort of 256 patients. The LBCRS was able to discriminate DLB from other causes of dementia. [20, 21]

The test consists of 10 yes-or-no questions: 4 covering motor symptoms (slow movements, rigidity or stiffness, balance problems with or without falls, and a resting tremor) and 6 covering nonmotor symptoms (excessive daytime sleepiness, episodes of illogical thinking, frequent staring spells, visual hallucinations, acting out dreams, and orthostatic hypotension).

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

MANAGEMENT

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 candecrease the rate of cognitive decline. Medications can beused to treat agitation and hallucinations, as well asdepression, and to improve cognition and/or alertness.

The following medications are used in patients who haveDLB:

• 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)

LOCATION AND COMPOSITION OF LEWY BODIES

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.

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.

DLB AND ALZHEIMER DISEASE

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

GENETICS

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.

PHYSICAL EXAMINATION

Patients with DLB usually have impaired cognition consistent with dementia. Cognitive function, as measured by Mini-Mental State Examination (MMSE) scores, appears to be relatively preserved in DLB compared with Alzheimer disease (AD) or AD+DLB (P< .01). Nelson et al evaluated data from 2 large, multicenter data registries (6,340 cases in total) and found that final MMSE scores were 15.6 (+/- 8.7) in persons with DLB, 10.7 (+/- 8.6) in persons with Alzheimer disease, and 10.6 (+/- 8.6) in those with AD+DLB.

An important observation during mental status testing is that the patient has periods of being alert, coherent, and oriented that alternate with periods during which the patient is confused and unresponsive to questions (despite the fact that the patient is awake). This fluctuation is a relatively specific feature of DLB.

Patients may have some parkinsonian signs but usually not enough to meet the criteria for a diagnosis of Parkinson disease. Mild gait impairment is relatively frequent and should not be ascribed to old age or osteoarthritis. Resting tremor occurs less frequently than in Parkinson disease. Myoclonus may occur before severe dementia.

Orthostatic hypotension appears to be particularly common in patients with DLB, even when dementia is mild

IMAGING STUDIES

Because vascular dementia can cause symptoms and signs similar to those of DLB, brain magnetic resonance imaging (MRI) is indicated to distinguish DLB from vascular dementia. Patients with vascular dementia often have white matter lesions on MRI scans, whereas patients with DLB do not.

Patients with DLB usually have less hippocampal atrophy than do patients with Alzheimer disease (but more than control subjects), although whether this difference is clinically useful is under investigation, as is the diagnostic utility of functional imaging. MRI is superior to computed tomography (CT) scanning in identifying this atrophy.

SPECT or positron emission tomography (PET) scanning may show decreased occipital lobe blood flow or metabolism in DLB but not in Alzheimer disease. SPECT using ligands that bind to the dopamine transporter molecule (eg,123 I-beta-CIT) has been used to suggest the diagnosis of DLB. Abnormal dopamine transporter scans have been shown to have a sensitivity of over 75% and a specificity of over 90% for DLB.

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, and dorsal raphe, as well as in the dorsal motor nucleus of CNX. LBs are found in nonpyramidal cells in layers V and VI of the cortices (especially the limbic and transitional cortex).

Other histologic findings in DLB 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.

DIFFERENTIAL DIAGNOSES

Alzheimer’s Disease Hydrocephalus

Lacunar syndrome

Cortical Basal Ganglionic

Degeneration

FrontotemporalDementia

FrontotemporalLobar Degeneration

Parkinson’s Disease Prion-Related Diseases

Progressive Supranuclear Palsy

PROGNOSIS, MORBIDITY AND MORTALITY

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