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The diagnosis and treatment of dementia with Lewy bodies

An accurate diagnosis is needed to develop an appropriate treatment plan. Revisions in the diagnostic criteria for DLB help PAs to distinguish it more easily from other dementias.

Stacey Josif, MSBS, PA-C; Karen Graham, MPAS, PA-C

Stacey Josif is a recent graduate of the University of Toledo PA program, Toledo, Ohio. Karen Graham is assistant professor at the University of Toledo PA program and practices in neurology at the Center for Neurological Disorders, University of Toledo Medical Center. The authors have indicated no relationships to disclose relating to the content of this article.

Approximately 7% of persons older than 65 years and 30% of those older than 80 years have dementia.¹ Furthermore, the incidence of dementia will certainly rise as the elderly population increases. Not all dementia is Alzheimer’s disease (AD), and it is becoming increasingly important for primary care PAs to be able to distinguish among the dementias. An accurate diagnosis is needed before an appropriate treatment plan can be determined.

The term dementia with Lewy bodies (DLB) was developed in 1996 during the First International Consortium on Dementia with Lewy Bodies,² more than a decade after researchers first noted the presence of Lewy bodies in the cortex of some patients with dementia.³ After AD, DLB is the second most common form of late-onset degenerative dementia, responsible for 20% of all cases of dementia.¹ DLB occurs more frequently in males, with the average onset at age 75 to 80 years.⁴ Clinically, distinguishing DLB from AD or Parkinson’s disease with dementia (PDD) can be difficult because these conditions have a number of features in common (see Table 1).

PATHOLOGY

DLB is a neurodegenerative condition in which alpha-synuclein proteins accumulate in the cytoplasm of neurons and neuroglia. These accumulations, called Lewy bodies, are predominantly found in the deep cortical layers, particularly the anterior frontal and temporal lobes, and in the nuclei of the brainstem (see Figure 1). Many patients with DLB also have cortical amyloid plaques, such as those seen in AD.⁵ DLB is also associated with neurochemical changes, which include a reduction in choline acetyltransferase, resulting in decreased levels of acetylcholine in the cortex. Compared to patients with AD, patients with DLB have an increased number of functioning cortical postsynaptic muscarinic receptors. These receptors are more responsive to acetylcholine in patients with DLB than in patients with AD.⁶ Dopaminergic deficits are also typical of DLB.

DIAGNOSTIC CRITERIA

The diagnosis of DLB is primarily clinical, with no definitive laboratory or diagnostic testing available. The diagnostic criteria for DLB, first published in 1996 by the Consortium on DLB, were updated in 2005 in an attempt to increase their sensitivity.⁷ The revised criteria divide dementia features into four categories: central, core, suggestive, and supportive.

Central features Dementia, defined as a progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function, is essential for a probable diagnosis of DLB.⁷ Furthermore, the dementia develops within 1 year of the onset of clinical signs of parkinsonism.⁴ Early signs of memory loss are often absent, whereas deficits in attention, executive function, and visuospatial ability are more apparent. Patients with DLB usually score poorly in the areas of attention, construction, and clock drawing on the Mini-Mental State Examination (MMSE).⁴

Core features Cognitive fluctuations, visual hallucinations, and parkinsonism are the core features of DLB.⁷ The presence of two core features is necessary for a probable diagnosis of DLB. Fluctuations in attention and alertness may last minutes, hours, or even days and, when present, are highly suggestive of DLB. This pseudodelirium occurs in 50% to 75% of patients with DLB.¹ Clinicians should perform at least one formal assessment of cognitive fluctuation, based on their level of training.

A diagnosis of DLB is probable if caregivers answer “Yes” to three or more questions on the Mayo Fluctuations Composite Scale. This scale consists of structured questions about the presence of daytime drowsiness and lethargy, daytime sleeping for more than 2 hours, staring into space for long periods, and episodes of disorganized speech.⁷ Visual hallucinations occur in 80% of patients with DLB⁸ and are associated with decreased levels of acetylcholine.⁷ Patients often experience recurrent, vivid, colorful, three-dimensional hallucinations of people or animals.¹ The hallucinations are almost always benign and may even be pleasurable.⁹ Parkinsonism occurs in approximately 75% of patients.¹⁰ The signs are mostly axial, including postural and gait instability. Bradykinesia, rigidity, and falls are common; unlike patients with PDD, those with DLB usually do not exhibit a resting tremor.³

Suggestive features Clinical features suggestive of DLB include rapid eye movement (REM) sleep behavior disorder, neuroleptic sensitivity, and low dopamine transporter activity. The presence of one or more suggestive features with one or more core features is necessary for a probable diagnosis of DLB. REM sleep behavior disorder is characterized by REM sleep without muscle atonia; as a result, patients “act out” their dreams by vocalizing and moving around violently. Because patients do not remember such events upon awakening, questions about this feature should be addressed to the patients’ partners or caregivers.⁷ REM sleep behavior disorder occurs in about 50% of patients with DLB and typically precedes the dementia symptoms.¹¹ Neuroleptic sensitivity to treatment with D₂-receptor blocking agents such as haloperidol is suggestive of DLB. However, these agents should never be used as a clinical challenge for diagnosing DLB.¹² Another suggestive feature of DLB is low striatal dopamine transporter activity on nuclear imaging scans, although these scans are not currently routinely performed in the evaluation of DLB.⁷

Supportive features Autonomic dysfunction, depression, nonvisual hallucinations, repeated falls and syncope, and transient loss of consciousness are common supportive features of patients with DLB. Autonomic dysfunction occurs early in the disease and produces orthostatic hypotension, neurocardiovascular instability, urinary incontinence, constipation, impotence, and swallowing difficulties.¹³ Forty percent of patients with DLB experience a major depressive episode.¹² Supportive features are common in patients with DLB but not specific enough for a diagnosis of DLB. Caregivers often do not associate these symptoms with the dementing process; therefore, PAs need to ask specifically about these symptoms.

PROGNOSIS

Definitive information on the prognosis of patients with DLB is not yet available. Some studies show that patients with DLB experience a decline similar to that in patients with AD.^14,15 Others suggest a worse prognosis for patients with DLB,³ indicating a need for further research. Symptom progression occurs in both diseases over time, with the average survival approximately 8 years from onset.¹⁶ Currently, no prognostic symptoms have been identified.¹

TREATMENT

Current research on the pharmacologic treatment of DLB has focused on the effectiveness of acetylcholinesterase inhibitors. These agents are now considered by many to be first-line therapy for DLB.¹ Acetylcholinesterase inhibitors increase the amount of acetylcholine in nerve synapses by blocking acetylcholinesterase, the predominant enzyme that breaks down acetylcholine in the brain. Four acetylcholinesterase inhibitors are currently available, although all are FDA-approved only for the treatment of AD. When making therapeutic decisions for patients with DLB, clinicians should have an understanding of the current evidence regarding the efficacy of this treatment for both the cognitive and psychiatric features of the disease.

Tacrine was the first agent to be approved. Side effects, in particular hepatotoxicity, were cause for concern. As a result, tacrine has been replaced by a new generation of acetylcholinesterase inhibitors.¹⁷

Donepezil, the first of the new generation of these drugs, is a highly selective reversible acetylcholinesterase inhibitor. The drug does not cause hepatotoxicity, and its once-a-day regimen encourages patient adherence. However, donepezil is metabolized by the cytochrome P450 enzyme system and eliminated by the liver, which increases the risk of drug interactions.¹⁷

Four small studies and numerous case reports have been published regarding the efficacy of donepezil in patients with DLB. The earliest was an open-label study comparing the efficacy of donepezil therapy in 4 patients with DLB compared with 12 patients with AD.¹⁸ A significant improvement was seen in the MMSE scores of the patients with DLB compared to the scores of the patients with AD when treated with donepezil, 5 mg daily, for 6 months.¹⁸ Two more recent studies of 12 and 20 weeks’ duration noted 3-point increases in MMSE scores in patients with DLB treated with donepezil. This result has been described as a gain of approximately 1 year of cognitive decline.^19,20 However, a third study failed to show cognitive improvements in 12 patients with DLB who were treated with donepezil for 12 weeks.²¹

All these studies also evaluated the efficacy of donepezil for treating the psychiatric and behavioral symptoms of DLB using the Neuropsychiatric Inventory (NPI). The NPI consists of 10 subscales: delusions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability/lability, and aberrant motor behavior.²¹ Three of the studies compared patients’ baseline NPI scores with their scores after donepezil treatment. All reported significant improvement, particularly in the subscales of hallucinations and delusions.^19-21 Of note, all of these small studies were open-label with varying eligibility criteria and varying baseline test scores.

Rivastigmine is the second of the new-generation acetylcholinesterase inhibitors. Unlike tacrine and donepezil, rivastigmine is pseudoirreversible because acetylcholinesterase continues to be inhibited for some time after the drug has been discontinued.¹⁷ Rivastigmine, which is not metabolized by the P450 system, has a lower risk of drug interaction. The drug has a shorter half-life and, therefore, must be taken twice a day and with food to minimize nausea and other GI effects commonly associated with its use.¹⁷ A transdermal formulation of rivastigmine that may simplify dosing and reduce GI side effects received FDA approval in July 2007.²²

Although there are case reports of treating DLB with rivastigmine, only one clinical trial has been conducted to date. McKeith and colleagues performed a randomized, double-blind, placebo-controlled international study of 120 patients with DLB who were randomly assigned to rivastigmine or placebo.⁶ The treatment group initially received 1.5 mg twice a day for 2 weeks. This dose was then titrated to a maintenance dose of 6 mg twice a day. Patients received this dose for the remainder of the 20-week study. All subjects were evaluated at baseline and at weeks 12 and 20 using the MMSE and NPI.⁶

Improvements in psychiatric symptoms and a trend toward improvement in cognitive symptoms were seen in those patients treated with rivastigmine. At the end of 20 weeks, the treatment group experienced better MMSE scores than the placebo group, but the results were not statistically significant. A significantly higher percentage of patients had at least 30% improvement in NPI scores at 20 weeks in the treatment group compared to the placebo group. Patients on ri-vastigmine also had significant improvement in the areas of apathy, indifference, anxiety, delusions, hallucinations, and aberrant motor behavior.⁶

Galantamine, the newest reversible acetylcholinesterase inhibitor, is metabolized by the P450 system.¹⁷ Galantamine is typically taken twice a day, although an extended-release form is available.

Galantamine has been evaluated for DLB treatment in only one small, open-label study. Twenty-five patients received galantamine twice a day for 12 weeks. A significant mean improvement of 1.58 points in MMSE scores was seen at 12 weeks. NPI scores showed significant improvement in the areas of delusions, hallucinations, apathy, and depression; half the patients had an 80% improvement in these areas. Seven patients, however, had worse NPI scores following treatment.²³

Adverse effects were prevalent in all these studies and resulted in several subject withdrawals.^6,20,21,23 In one study of patients treated with donepezil, 46% of patients receiving 5 mg daily and 69% of patients receiving 10 mg daily had adverse effects. Hypersalivation, nausea/vomiting, urinary frequency/incontinence, and increased lacrimal secretions were the most frequently reported side effects.²⁰ Nausea, vertigo, anorexia, dyspepsia, diarrhea, and fatigue were the most frequently reported side effects of galantamine.²³ Adverse effects were a particular problem in the rivastigmine trial, with 92% of patients in the treatment group and 75% of patients in the placebo group reporting problems. Nausea, vomiting, anorexia, and somnolence were reported significantly more often by patients taking rivastigmine.⁶

OTHER PHARMACOLOGIC TREATMENTS

Although research on the pharmacologic treatment of DLB has focused on acetylcholinesterase inhibitors, patients with DLB may benefit from other medications, including levodopa, atypical antipsychotics, and antidepressants. The old dosing adage, start low and go slow, particularly applies to patients with DLB because they can be very sensitive to neuropharmacologic agents. Improvements in motor function in patients with DLB in response to treatment with levodopa have been reported.^1,24 If levodopa is used, it should be given at the lowest effective dose to avoid worsening of psychiatric symptoms, particularly hallucinations and somnolence.⁷

Older typical D₂-antagonist antipsychotics, such as haloperidol, should never be administered because up to 50% of patients with DLB treated with these medications suffer from severe sensitivity reactions.¹ Symptoms include sedation, rigidity, postural instability, falls, increased confusion, and neuroleptic malignant syndrome; a twofold to threefold increase in mortality has also been reported.¹ When necessary, low doses of atypical antipsychotics, particularly quetiapine, may be used, but instances of sensitivity reactions and an increased risk of stroke have been reported.⁸ Further research is needed to determine the risks and benefits of atypical antipsychotic use in patients with DLB.

Anxiety, depression, and REM sleep behavior disorder may also require pharmacologic treatment. Selective serotonin reuptake inhibitors may be used for the treatment of anxiety and depression but have not yet been studied in patients with DLB.⁵ REM sleep behavior disorder can be treated with low doses of clonazepam.³

The effectiveness of nonpharmacologic interventions on patients with DLB has yet to be examined. Interventions that are helpful in patients with other forms of dementia are likely to improve the quality of life for patients with DLB, including glasses, hearing aids, environmental structuring, and behavioral interventions.³ Patients with DLB should have regular follow-up and review of medications. As with all patients with dementia, the use of anticholinergic medications should be avoided and the initiation of any new medications should be monitored closely for adverse effects.

Caregiver support is crucial. The care of patients with dementia can be exhausting, and caregivers, who often have their own medical problems, are at risk for depression and other morbidity. PAs should encourage an open line of communication with the caregiver. It is important that caregivers understand the uniqueness of DLB, particularly that cognitive fluctuations and visual hallucinations are common. These issues may make the patient with DLB vulnerable to elder abuse caused by caregiver frustration. The PA needs to be aware of this, educate the caregiver, and screen for elder abuse in this population. Referral to social support organizations, such as Alzheimer’s Association, may be beneficial.¹⁶

LIMITATIONS OF CURRENT RESEARCH

Only one study on the use of acetylcholinesterase inhibitors in DLB is a randomized, double-blind, placebo-controlled trial. The other data come from open-label trials and case reports, which provide a less-than-ideal basis for clinical decisions. The small sample sizes and short study durations may also negatively impact the validity of the data. Further limitations include lack of randomization, lack of control groups, absence of blinding, lack of a controlled research environment, and failure to account for confounding variables.

However, preliminary data suggest that acetylcholinesterase inhibitors may play a significant role in the treatment of patients with DLB. To increase understanding of the role of these agents, more randomized double-blind, placebo-controlled studies are necessary. In addition to the assessment of changes in cognitive, psychiatric, and behavioral symptoms, these studies should also determine whether acetylcholinesterase inhibitors have a role in slowing the progression of the disease. Studies examining the efficacy of other treatment options, such as antidepressants and atypical antipsychotics, alone or in combination with acetylcholinesterase inhibitors are also needed.

CONCLUSION

DLB is a common but only recently recognized form of dementia. The condition shares many clinical features with both AD and PDD. Preliminary evidence suggests that initiating acetylcholinesterase inhibitor therapy may improve cognitive, psychiatric, and behavioral symptoms in patients with DLB. As always, treatment should be tailored to the individual patient, with risk factors weighed against possible benefits. As diagnostic criteria and treatment recommendations continue to evolve, it is important that primary care PAs include DLB in their differential diagnosis of the patient with dementia. JAAPA

DRUGS MENTIONED

Clonazepam (Klonopin)
Donepezil (Aricept)
Galantamine (Razadyne)
Haloperidol (Haldol, Haloperidol Intensol)
Levodopa (Parcopa, Sinemet)
Quetiapine (Seroquel)
Rivastigmine (Exelon)
Tacrine (Cognex)

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