Dementia with Lewy bodies

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By Ann Marie Hake MD

Pharmacologic. There have been a small number of double-blind, placebo-controlled clinical trials of medications to treat patients with dementia with Lewy bodies. One area of focus has been on enhancing cholinergic neurotransmission in patients with dementia to stabilize or improve cognitive symptoms. There is post-mortem evidence of a significant decrease in neocortical cholinergic enzymatic activity, which is greater than that seen in Alzheimer disease patients. This supported a clinical trial of the cholinesterase inhibitor rivastigmine for the treatment of patients with a clinical diagnosis of dementia with Lewy bodies. This study randomized 120 patients to placebo or rivastigmine for 20 weeks and examined their performance on neuropsychological tests and a computerized cognitive assessment system and measured their neuropsychiatric symptoms (McKeith et al 2000). Twice as many patients on rivastigmine (63%) than on placebo (30%) showed at least a 30% improvement from baseline on the computerized cognitive assessment program and neuropsychological tests, especially tasks with a substantial attentional component. MMSE scores at the end of the trial were not significantly different between the groups, but there was a trend toward improvement in the MMSE score in the rivastigmine group (1.5 point improvement vs. 0.1 point decline, p=0.072). There was a significant improvement in neuropsychiatric symptoms as measured by the total Neuropsychiatric Inventory score (NPI-10) at study end in those receiving rivastigmine (3.8 point improvement, p=0.048), with significant improvements in apathy, anxiety, delusions, and hallucinations. Side effects that were significantly more common in the treatment group included nausea, vomiting, anorexia, and somnolence, as has been seen in other trials of cholinesterase inhibitors. Another double-blind, multicenter study assessed the efficacy of donepezil, 3, 5, or 10 mg compared to placebo, for 12 weeks in 140 Japanese subjects over 50 years of age with clinical diagnoses of probable dementia with Lewy bodies (Mori et al 2012). Efficacy outcomes included measures of cognition, behavior, global function, and caregiver burden. At 12 weeks, all 3 donepezil-treated groups demonstrated statistically significant improvements in the MMSE, attention and concentration, and global function. The 5 mg donepezil group also showed a benefit in behavior as assessed by the NPI-4 compared to placebo. No differences were seen in verbal fluency or visuoperception amongst the groups. Safety and tolerability was similar to what has been seen in previous clinical trials and general clinical use. Open-label trials of cholinesterase inhibitors (eg, donepezil, galantamine) for the treatment of patients with dementia with Lewy bodies have suggested similar benefits..

Memantine, an N-methyl D-aspartate (NMDA) receptor antagonist that is approved in the United States for the treatment of moderate to severe-stage Alzheimer disease, was also tested in dementia with Lewy bodies in a small parallel-group, 24-week, randomized, placebo-controlled study (Aarsland et al 2009). Seventy-two patients were randomized to either memantine or placebo; 56 subjects completed the trial (withdrawals were due to side effects, with similar proportions in both treatment groups). The memantine group performed better than the placebo group on the study’s primary outcome measure, the Clinical Global Impression of Change (CGI-C), by 0.7 point (p=0.03); and on 1 of the secondary outcome measures, a quick test of cognition (AQT) form, which measures improved speed on attentional tasks (difference 12.4, p=0.004). The authors concluded that memantine may be of benefit in dementia with Lewy bodies, that it seemed to be well tolerated, and that larger-scale studies were warranted. An analysis of secondary outcome measures in this same study evaluated memantine's effect on REM sleep behavior disorder. Of 42 subjects with REM sleep behavior disorder and excessive daytime sleepiness, the memantine-treated group was physically less active during sleep than the placebo group (p=0.006) but there was no significant change in the severity of excessive daytime sleepiness. Another randomized, double-blind, placebo-controlled study of 199 subjects with mild to moderate dementia with Lewy bodies or Parkinson dementia was 24 weeks, with 159 completers. Among the dementia with Lewy body subjects, those assigned to memantine showed greater improvement in global function and behavioral/psychiatric measures compared to the placebo group, whereas no differences were seen between the memantine and placebo groups in the Parkinson dementia population (Larsson et al 2010). Multiple other case reports have conveyed mixed results, including worsening of symptoms in some patients.

Modafinil and armodafinil, dopamine reuptake inhibitors thought to promote wakefulness through the hypocretin/orexin system, have been reported in case reports and in small retrospective and open-label studies to reduce sleepiness, increase alertness, and improve attention in some individuals with dementia with Lewy bodies or Parkinson disease dementia (Varanese et al 2013).

Psychiatric symptoms, including hallucinations, delusions, anxiety, and depression, are a source of significant morbidity for patients with dementia with Lewy bodies, but there has been little research into the most effective medications to treat these symptoms. In patients with severe psychotic symptoms, including delusions and hallucinations, an antipsychotic medication trial can be considered. Neuroleptic antipsychotics should be avoided because of the risk of worsening parkinsonism and the risk of neuroleptic hypersensitivity reactions. When antipsychotics cannot be avoided, the atypical antipsychotic class (eg, clozapine, quetiapine, aripiprazole, risperidone, olanzapine, ziprasidone, paliperidone) is associated with less risk of worsening parkinsonism than the traditional antipsychotics. Placebo-controlled trials of atypical antipsychotics for the treatment of psychosis in patients with parkinsonism have not shown a significant benefit, although positive responses have been seen in some individual patients (Friedman and Fernandez 2002; Miyasaki et al 2006). The potential benefits of atypical antipsychotic medications need to be weighed against potential side effects of these drugs, including agranulocytosis (seen rarely with clozapine) and the potential for somnolence, worsening of gait or parkinsonism, cognitive decline, and the increase in risk of cerebrovascular events or death that has been reported with drugs in the class when used to treat patients with dementia (Schneider et al 2005; 2006). There have been no placebo-controlled trials of medications to treat symptoms of depression and anxiety specifically in patients with dementia with Lewy bodies, despite the common occurrence of these symptoms. Clinical experience and open-label studies suggest that selective serotonin reuptake inhibitor and serotonin-norepinephrine reuptake inhibitor drugs are safe and effective for the treatment of symptoms of depression and anxiety in patients with dementia with Lewy bodies.

A trial of levodopa should be considered in patients with dementia with Lewy bodies, if parkinsonism is causing significant functional disability. However, the clinical response to levodopa is often less dramatic in patients with dementia with Lewy bodies than in patients with idiopathic Parkinson disease (Molloy et al 2005; Lucetti et al 2010). The dose of levodopa should be kept low, because dopaminergic stimulation may worsen neuropsychiatric symptoms, especially psychosis. Similarly, dopamine agonists should be avoided because of a higher risk of exacerbating neuropsychiatric symptoms, and anticholinergic medications should be avoided because of a high risk of causing confusion and memory loss in patients with dementia with Lewy bodies. Low-dose clonazepam (0.25 to 0.5 mg at bedtime) can be used to help improve symptoms related to REM sleep behavior disorder but may cause sedation and gait instability in some patients (Boeve et al 2004). For autonomic system dysfunction such as orthostatic hypotension, fludrocortisone, midodrine, or droxidopa can be used; if the latter is used in patients who are also taking carbidopa-levodopa, dosing adjustments of the droxidopa may need to take into account the reduced metabolism of this drug in the presence of carbidopa; in addition, supine hypertension is a potential serious risk with any of these agents (Boeve 2004, Metzler et al 2013). Concomitant medications should also be carefully monitored, and those that contribute to undesirable symptoms should be adjusted or discontinued when possible.

Behavioral strategies. Not all symptoms of dementia with Lewy bodies will require pharmacologic intervention. Modifying daily tasks to encourage personal interaction may help reduce agitation and aggression (for example, sponge bathing a person in bed rather than having them take a bath or shower). Other management options include physical therapy, massage therapy, and aromatherapy. Difficulties with sleep disturbances may be improved by reducing daytime naps and caffeine intake. Keeping patients stimulated throughout the day until bedtime may be helpful and necessary. Maintaining a predictable routine and avoiding overstimulating environments and situations can help decrease confusion and agitation. Exercise should be encouraged, as it gives opportunity for the patient and caregiver to spend time together. Exercise improves strength and cardiovascular health, helps with depression, and helps in daily motor functioning. It also helps sustain strength, flexibility, and balance, which can lessen the injuries associated with possible falls (Lingler and Kaufer 2002). There is evidence supporting the use of psychological treatments for disruptive behaviors that occur in individuals with dementia. These can include behavioral problem-solving therapies that identify and modify antecedents and consequences of problem behaviors and individualized interventions based on progressively lowered stress threshold models that include problem solving and environmental modification (Logsdon et al 2007).

Caregivers. Currently there is no cure for patients with dementia with Lewy bodies, so once dementia is apparent, it can be assumed that progressively increasing levels of care will be required. For family members, caregiving can become challenging and overwhelming. Recent studies have also suggested that higher levels of caregiver stress are associated with patient mood disturbances, cognitive fluctuations, daytime sleep, and psychosis, all of which occur commonly in individuals with dementia with Lewy bodies (Lee et al 2012; Ornstein et al 2013). Specific education about dementia with Lewy bodies and its associated symptoms is important for caregivers to better understand support and management needs and treatment options and to anticipate future problems. Educational materials and support groups are available through national caregiver support organizations for Lewy body disease, as well as for Alzheimer disease and Parkinson disease. In addition, in many regions of the country there are psychologists or social workers who can provide individual counseling and education concerning behavioral management strategies that are specific to dementia caregivers. There is evidence-based support for several forms of psychological treatments to lower distress in family caregivers of older adults with dementia, including skill training programs focused on behavioral management, cognitive behavioral therapy for the caregiver, and combinations of individual caregiver counseling and support group attendance (Gallagher-Thompson and Coon 2007). These approaches may all be used to help lower stress in caregivers of patients with dementia with Lewy bodies, especially those that focus on behavioral symptoms that are very common in patients with dementia with Lewy bodies are one of the greatest sources of distress to caregivers (Leggett et al 2011).

As with all patients with dementia, caregivers should ensure that the environment is safe for someone with dementia. Medicines, toxic household chemicals, alcohol, weapons, and power tools should be locked up. The environment should be well lighted and potential obstacles such as throw rugs and cords should be eliminated to reduce the risk of falls. Wandering can become a problem; adjustments to the environment, such as adding latches or locks to doors in non-habitual spots (such as near the top of the frame), painting doors to make them less visually obvious, and adding bells, alarms, or alerts to doors or the patient’s phone that are triggered by movement or by the patient being outside a set perimeter, can assist caregivers in the event of wandering. The patient should also carry a card with his or her home phone number or phone number of a loved one and wear a bracelet with his or her name and phone number and identified with "Memory impaired." The Alzheimer's Association offers a 24-hour helpline (800-272-3900) and a Safe Return® program in association with MedicAlert®. The Lewy Body Disease Association also offers a toll-free Caregiver Link (800-539-9767 or 800-LEWYSOS).

Legal and financial issues should be discussed with the patient, their family, social workers, and an attorney. These include assigning a durable power of attorney to help with medical and financial decisions in the future if the patient is unable to make decisions. Courts can appoint a guardian if the patient has progressed to moderate-to-severe dementia. Patients and families should discuss and record advanced directives for end-of-life care.

In This Article

Historical note and nomenclature
Clinical manifestations
Clinical vignette
Pathogenesis and pathophysiology
Differential diagnosis
Diagnostic workup
Prognosis and complications
References cited