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:
Other symptoms that may alert clinicians to the diagnosis of DLB (vs Alzheimer disease) include the following:
See Clinical Presentation for more detail.
Examination of cognition and mental status in patients with suspected DLB may include the following findings:
Other findings on physical examination may include the following:
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:
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:
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:
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] :
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:
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.
Dementia with Lewy bodies (DLB) is a progressive, degenerative dementia.The following clinical features help to distinguish DLB from Alzheimer disease:
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
Although extrapyramidal features may occur late in the course of Alzheimer disease, they appear relatively early in DLB.
In addition, whereas patients with Alzheimer disease 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 do patients with Alzheimer disease, whereas patients with Alzheimer disease do better on tests of verbal fluency, visual perception, and performance tasks.[11]
Executive function deficits and visuospatial impairment may be more prominent in persons with DLB than in those with Alzheimer disease (eg, Stroop, digit span backwards).
Other symptoms that may alert clinicians to the diagnosis of DLB (versus Alzheimer disease) include the following:
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.[12]
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.
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 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.[1]
No sensitive or specific blood or urine tests are currently available for DLB. Laboratory studies in patients with dementia with Lewy bodies (DLB) should include those usually ordered in a dementia evaluation, including the following:
Cerebrospinal fluid (CSF) examination is not required in routine cases. However, CSF findings in DLB include the following:
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.
In certain circumstances, neuropsychological testing is helpful in differentiating DLB from Alzheimer disease and in establishing a baseline for future comparison.[14]
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.[15]
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.[16]
A study by Lim et al using SPECT scanning with123 I-beta- carbomethoxy-3beta-(4-fluorophenyl) tropane (123 I-beta-CIT), as well as PET scanning with18 F-fluorodeoxyglucose (18 F-FDG), in 14 patients with a clinical diagnosis of DLB and 10 with Alzheimer disease found that relative preservation of the mid- or posterior cingulate gyrus (cingulate island sign) had 100% specificity for DLB. SPECT and PET scanning each appeared useful for the diagnosis of DLB, but SPECT provided more robust results than did PET.[17]
PET imaging with Pittsburgh Compound B showed that amyloid deposition in clinically diagnosed patients with DLB was similar to that in the patients with Alzheimer disease. However, amyloid binding was less in patients with dementia in Parkinson disease. Findings of these studies suggest that the presence of amyloid accelerates dementia in Lewy body disorders but has little influence on its nature.[18, 19]
Until disease-modifying therapies that are specific to DLB or Alzheimer disease are developed, metabolic imaging studies to enhance the accuracy of the diagnosis are rarely needed.
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.
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).
Hallucinations and agitation are especially troublesome in dementia with Lewy bodies (DLB). When these symptoms are mild, no medical treatment may be necessary. When medication is used, acetylcholinesterase inhibitors should usually be tried first. For example, double-blinded, placebo-controlled studies have demonstrated that the cholinesterase inhibitor rivastigmine may decrease psychiatric symptoms associated with DLB, particularly apathy, anxiety, hallucinations, and delusions.[22]
Studies have also shown that patients with DLB treated with cholinesterase inhibitors do better on neuropsychological tests than do subjects treated with placebo.[23] Cholinesterase inhibitors that may be effective in the treatment of DLB also include donepezil and galantamine. In a small minority of patients, motor features are worsened with cholinesterase inhibitors.
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.
Some experts have tried antiepileptic drugs to treat agitation and hallucinations, but clinical data supporting their use is lacking.
Studies suggest that memantine improves cognitive function and neuropsychiatric features in patients with DLB. A multicenter, double-blinded, placebo-controlled trial revealed significant improvement in 2 important measurement tools in patients who received the drug: the Alzheimer's Disease Cooperative Study clinical global impression of change score (memantine vs placebo, 3.3 vs 3.9) and the Neuropsychiatric Inventory score (memantine vs placebo, -4.3 vs 1.7).[24, 25]
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.
Depression is frequent in patients with DLB; it may occur as a result of damage in the dorsal raphe and locus ceruleus and/or as a psychological response to impaired function. Selective serotonin reuptake inhibitors (SSRIs) are the drugs of choice for treating depression in DLB.
A Cochrane Database review revealed that mild to moderate cognitive stimulation exercises are of benefit for mild and moderate dementia with improvements in memory and quality of life measures.[26]
Spouses, family members, and caregivers of patients with DLB frequently realize that the patient with DLB behaves differently than typical patients with Alzheimer disease. 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.
No dietary restrictions are indicated except for patients with severe disease who have swallowing impairment.
Physical therapy and exercise classes can be useful for maintaining the patient’s mobility. Advise families of potential problems faced by patients with DLB who drive.
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.
Acetylcholinesterase inhibitors should usually be the first drugs used to treat hallucinations and agitation in patients with dementia with Lewy bodies (DLB). Studies also indicate that administering cholinesterase inhibitors to these patients can improve neuropsychological test scores.[23]
Regarding nonspecific partial glutamate antagonists, memantine has been approved in the United States for the treatment of moderate to severe Alzheimer disease. It is not approved for the treatment of Parkinson disease or DLB.
A double-blind, placebo-controlled, multicenter trial of memantine in 72 patients with DLB or Parkinson disease dementia found that after 24 weeks of treatment, patients taking memantine had better clinical global impression of change scores than did those taking placebo.[24, 25] A few case reports have noted that memantine may exacerbate fluctuations.
Although clonazepam has been considered the treatment of choice for rapid eye movement sleep behavior disorder in patients with DLB, melatonin may be beneficial, either alone or in combination with clonazepam. Melatonin may be administered at 3mg at bedtime.[27]
Clinical Context: Donepezil noncompetitively inhibits centrally active acetylcholinesterase, which may increase concentrations of ACh available for synaptic transmission in the central nervous system (CNS).
Clinical Context: This agent is a competitive and reversible inhibitor of acetylcholinesterase. Although the drug's mechanism of action is unknown, it may reversibly inhibit cholinesterase, which may, in turn, increase concentrations of ACh available for synaptic transmission in the CNS and enhance cholinergic function. Rivastigmine's effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. No evidence indicates that acetylcholinesterase inhibitors alter the course of underlying dementia.
Clinical Context: Galantamine is a competitive and reversible inhibitor of acetylcholinesterase. Although its mechanism of action unknown, the drug may reversibly inhibit cholinesterase, which may, in turn, increase concentrations of ACh available for synaptic transmission in the CNS and enhance cholinergic function. Galantamine's effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. No evidence indicates that acetylcholinesterase inhibitors alter the course of underlying dementia. Galantamine is available in extended-release (ER) daily dosing and in immediate-release (IR) form.
Clinical Context: Rivastigmine is a competitive and reversible acetylcholinesterase inhibitor. Although its mechanism of action is unknown, it may reversibly inhibit cholinesterase, which may, in turn, increase concentrations of ACh available for synaptic transmission in the CNS and thereby enhance cholinergic function. Rivastigmine's effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact.
Rivastigmine is available as a 5cm2 patch containing 9 mg (releases 4.6 mg/24 h) and a 10-cm2 patch containing 18 mg (releases 9.5 mg/24 h). The drug is indicated for dementia of Alzheimer disease and for dementia associated with Parkinson disease.
ACh concentrations are decreased in the brains of patients with DLB. Patients with DLB are more likely than patients with Alzheimer disease to improve with cholinesterase inhibitor therapy. Fluctuations in cognition may decrease, alertness may increase, and memory may improve.
Clinical Context: Clozapine is associated with the risk of agranulocytosis when it is used at doses required for the treatment of schizophrenia with symptoms refractory to standard neuroleptics. In the United States, weekly dosing and a weekly CBC are required to dispense the drug. Discontinuing therapy at the first sign of leukopenia decreases, but does not eliminate, the risk of agranulocytosis. Whether agranulocytosis is associated with low doses in elderly patients and in patients with dementia is not clear.
Clinical Context: Quetiapine is an atypical neuroleptic that may act by antagonizing dopamine and serotonin effects. It is also used to treat insomnia.
Clinical Context: Aripiprazole improves positive and negative schizophrenic symptoms. Its mechanism of action unknown, but it has been hypothesized that the drug works differently than other antipsychotics do. Aripiprazole is thought to be a partial dopamine (D2) and serotonin (5HT1A) agonist and to antagonize serotonin (5HT2A). Additionally, no QTc interval prolongation has been noted in clinical trials. Aripiprazole is available as a tablet, an orally disintegrating tablet, and an oral solution.
Patients with DLB frequently have hallucinations that can cause them to engage in unsafe behavior; these patients therefore require treatment. Standard neuroleptics exacerbate parkinsonian motor features and, consequently, are contraindicated.
Clinical Context: Venlafaxine may treat depression by inhibiting neuronal serotonin and norepinephrine reuptake. In addition, it causes beta-receptor down-regulation.
Clinical Context: Paroxetine selectively inhibits presynaptic serotonin reuptake, with minimal or no effect on the reuptake of norepinephrine or dopamine.
Clinical Context: Sertraline selectively inhibits presynaptic serotonin reuptake.
Clinical Context: Fluoxetine selectively inhibits presynaptic serotonin reuptake, with minimal or no effect on the reuptake of norepinephrine or dopamine. The drug may cause more gastrointestinal adverse effects than do other currently available SSRIs, which is why it is not recommended as a first treatment choice. Fluoxetine may be given as a liquid and a capsule.
The drug may be administered in 1 dose or in divided doses. The presence of food does not appreciably alter levels of the medication. Fluoxetine may take up to 4-6 weeks to achieve steady-state levels, as it has the longest half-life (72 h).
Fluoxetine's long half-life is an advantage and a drawback. If the drug works well, an occasional missed dose is not a problem, but if problems occur, eliminating all active metabolites takes a long time. The choice depends on adverse effects and drug interactions. Adverse effects of SSRIs seem to be quite idiosyncratic; thus, relatively few reasons exist to prefer one over another at this point if dosing is started at a conservative level and advanced as tolerated.
Depression is frequent in DLB. Antidepressants with little or no anticholinergic activity are desirable.
Clinical Context: Clonazepam is a long-acting benzodiazepine that increases presynaptic GABA inhibition and reduces monosynaptic and polysynaptic reflexes. It suppresses muscle contractions by facilitating inhibitory GABA neurotransmission and other inhibitory transmitters. Clonazepam has multiple indications, including the suppression of myoclonic, akinetic, or petit mal seizure activity and focal or generalized dystonias (eg, tardive dystonia). The drug reaches peak plasma concentration at 2-4 hours after oral or rectal administration.
In patients who are dependent, clonazepam is used in a manner similar to phenobarbital to smoothly wean patients from short-acting benzodiazepines. The general principle is that sedatives with longer half-lives have less severe withdrawal symptoms. Various schemes are used to individualize the dose to the patient. If symptoms are severe enough to require inpatient treatment, intravenous lorazepam or diazepam is used.
By binding to specific receptor sites, these agents appear to potentiate the effects of gamma-aminobutyric acid (GABA) and to facilitate inhibitory GABA neurotransmission and other inhibitory transmitters.
Clinical Context: Levodopa is a large, neutral amino acid absorbed in the proximal small intestine by the saturable carrier-mediated transport system. Absorption is decreased by meals that include other large, neutral amino acids (although only patients with meaningful motor fluctuations need to consider a low-protein or protein-redistributed diet). The drug's half-life is approximately 2 hours.
Provide at least 70-100 mg/day of carbidopa; if more is required, substitute a 25/100 tablet for each 10/100 tablet. When more levodopa is required, substitute a 25/250 tablet for the 25/100 or 10/100 tablet. The controlled-release (CR) formulation is absorbed more slowly and provides more sustained levodopa levels than IR form does.
When it is initially required, the CR form is as effective as the IR form and may be more convenient. Patients with dissipating motor fluctuations and no dyskinesia often benefit from prolongation of the short-duration response when switched from the IR to the CR form. Patients with meaningful fluctuations and dyskinesia often have increased dyskinesia when switched to the CR form. Doses and intervals for the CR form may be increased or decreased to response.
Most patients are adequately treated with 2-8 tablets daily in doses divided every 4-8 hours when the patient is awake. Allow at least 3 days between dose adjustments. Levodopa/carbidopa may be administered as a whole or half tablet, which should not be crushed or chewed. Motor symptoms and signs may or may not improve.
Patients with DLB have impaired dopaminergic tone due to disease in the substantia nigra and possibly other dopaminergic nuclei. The efficacy of the treatment of motor features in DLB depends on where the patient is on the Parkinson disease ̶ DLB spectrum. Whether or not levodopa influences cognition positively or negatively remains controversial, and its effect on cognition is probably modest.