Symptomatic approach using acetylcholine-esterase inhibitors (AChEIs).
The therapeutic benefits of different pharmacologic approaches on the cholinergic system have been evaluated in both AD and LBD. While acetylcholine precursors and postsynaptic receptor agonists had poor results in clinical trials in AD, inhibition of acetylcholineesterase has demonstrated to provide symptomatic benefits. Acetylcholinesterase inhibitors (AChEIs) approved by the FDA for the treatment of AD include tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne). To date, there is no compelling evidence that any one AChEI is better than the others. Three independent clinical studies of AChEI treatment using donepezil, galantamine or rivastigmine in patients with LBD suggest that all AChEIs improve cognitive and neuropsychiatric measures. Usually there is no significant increase in Parkinsonism with AChEI use.
a. Rivastigmine: Rivastigmine is a noncompetitive and reversible inhibitor of both acetylcholinesterase and butylcholinesterase available as a tablet, oral solution and transdermal patch. In the treatment of AD, it has been associated with improvement in cognition, behavioral symptoms, and functional abilities including activities of daily living (ADLs). In a double-blind, placebo-controlled, multi-center trial of DLB patients, treatment with rivastigmine 12 mg/day for 20 weeks was completed. On discontinuation of the drug, the differences between rivastigmine and placebo tended to disappear. The rivastigmine group had better performance on tests of attention, working memory and episodic memory compared to placebo. Patients given placebo showed a significant deterioration in attentional functions from baseline scores at 12 and 20 weeks, whereas patients on rivastigmine performed significantly above their baseline levels. Three weeks after discontinuation of rivastigmine, most parameters of cognitive performance returned to pretrial levels. Rivastigmine received FDA indications for the treatment of dementia associated with Parkinson’s disease in 2007.
b. Donepezil: Donepezil is a reversible noncompetitive AChEI. It has a favorable pharmacokinetic profile available as once per day oral dosing either as tablet or oral-disintegrating forms with high specificity to acetylcholinesterase in brain tissue. Most of the side effects reported with donepezil are mild, dose-related and involve the gastrointestinal system and the central nervous system. An open label trial of donepezil compared treatment in 12 AD patients and 4 DLB patients. There was an improvement by 4.8 in MMSE scores in LBD, compared to 0.6 in AD. A randomized clinical trial of 5 mg/day of donepezil in patients with mild to moderate LBD reported marked improvements in behavioral and psychological symptoms of dementia but was not associated with cognitive improvement. The NPI-11 (behavioral) scores were significantly improved at weeks 8 and 12 compared with baseline. This dose was tolerated with no motor deterioration in the treatment group.
c. Galantamine: Galantamine is a reversible and competitive inhibitor of acetylcholinestase and can amplify the actions of other receptors such as glutamate, serotonin, dopamine and GABA. The efficacy and safety of galantamine in LBD has been demonstrated in a 24 week open label study in 50 patients. There were beneficial effects in the NPI and the Clinician’s Global assessment of change with mild side effects. In particular, there was improvement in visual hallucinations, nighttime behavior, and fluctuating cognitive deficits. There was also a benefit in sleep abnormalities and REM sleep behavior disorder.
NMDA antagonists (memantine): The excitatory neurotransmitter glutamate plays important roles in memory and learning. Glutaminergic dysfunction is well documented in AD and possibly contributes to the cognitive dysfunction. Overstimulation of NMDA receptors by glutamate results in calcium mediated excitotoxicity and cell death. Memantine (Namenda) is a noncompetitive voltage dependent antagonist with moderate affinity for the NMDA receptor. The efficacy and safety of memantine in moderate to severe AD have been reported in clinical trials and use of memantine in combination with donepezil has been reported to be more effective than the use of donepezil alone. It was approved by the FDA for the treatment of moderate to severe AD in 2003 but has not been adequately studied in LBD.
Do all Alzheimer’s medications have a role to play in treatment of the cognitive decline in LBD?
AChEI’s have been considered by LBD experts to be the gold standard in treating cognitive and psychiatric symptoms of LBD. A recent comparative analysis of independent clinical studies of AChEI’s in LBD demonstrated all AChEI’s significantly improved cognitive and neuropsychiatric measures and that there was no significant increase in United Parkinson’s Disease Rating Scale (UPDRS-III) scores. However, the study revealed no compelling evidence that supports any one AChEI as better than any other in treating DLB.
There is little published data on the use of memantine in LBD patients. Given that both AChEIs and memantine are often considered by various prescribers, until more research demonstrates clear benefits, a cholinesterase inhibitor would be preferable to memantine.
There are no clinical trials on the best treatment of motor features in LBD. However, levodopa is generally the first-line treatment of PD and some improvement is seen in motor function with levodopa therapy in most cases of LBD. There is a risk, however of provoking behavioral or psychotic symptoms.
Dopamine agonists are associated with more side effects especially drug induced psychosis even at low doses. In head to head trials comparing levodopa to dopamine agonists in early PD, dopamine agonists have been found to be less effective and less well tolerated with a higher incidence of drug induced psychosis than levodopa. However, there is some suggestion that early treatment of PD with dopamine agonists, versus levodopa, may lower the risk of drug-induced dyskinesias. There are no direct head to head trials comparing dopamine agonists with levodopa in LBD. However, in the LBD patient the best risk-benefit ratio (motor improvement versus psychosis and dyskinesias) for treatment of motor features likely is achieved with levodopa. Therefore, a trial of levodopa is recommended in LBD with slow titration of the dose to produce symptomatic benefit.
Other PD medications such as amantadine, COMT inhibitors, MAO inhibitors and anticholinergics have the risk of exacerbating cognitive impairment and should be avoided if possible. Furthermore, the cognitive impairment in LBD makes those patients poor candidates for deep brain stimulation. AChEIs can potentially worsen parkinsonism. In a study of rivastigmine in PDD, approximately 10% of patients experienced worsening of tremor but it was not usually associated with significant medical concern.
How early should treatment of parkinsonism in LBD begin?
Some LBD patients may not demonstrate overt or disabling parkinsonism for years. Given the potential negative side effects, physicians should be conservative when treating parkinsonism in LBD, and start with a slow titration of levodopa only if pharmacological intervention is necessary.
The first line intervention in treating problematic behaviors in LBD patients should be non-pharmacologic measures including evaluating for physical ailments that may be provoking behavioral disturbances (e.g. fecal impaction, pain, decubitus ulcers, urinary tract infection). Avoidance of, or reduction of doses of other medications that can potentially cause agitation should also be attempted. Affective disorders (anxiety and depression) are common in LBD and anecdotally, LBD patients respond to antidepressants and anxiolytics, although they have not been rigorously studied. A general rule is that when medications are needed to modify behaviors, they should be used for the shortest duration possible. Benzodiazepines should not be first-line agents given their risk of sedation and paradoxical agitation.
a. Antipsychotics. Visual hallucinations occur in up to 80% of patients with LBD and are considered one of the core features. Cholinergic deficits appear to be related to psychosis in LBD correlating with low CHAT activity and increased muscarinic receptor binding. Visual hallucinations have been suggested as predictors of a good response to the AChEI rivastigmine.
The management of psychosis in LBD has been mostly based on results of trials in AD and follows the general guidelines of pharmacotherapy in geriatric populations. In addition, some recommendations for the use of antipsychotics in LBD are based on studies in PD patients without dementia. Treatment can be very challenging given the sensitivity of these patients to even low doses of antipsychotics.
Typical neuroleptics (such as haloperidol) and atypical neuroleptics with D2 receptor antagonism (such as olanzapine and risperidone) should be avoided due to the risk of severe neuroleptic sensitivity reactions, neuroleptic malignant syndrome, parkinsonism, somnolence and orthostatic hypotension. Experience with atypical antipsychotics in LBD has been mixed. Risperidone and olanzapine have been shown to control psychosis and agitation in AD in randomized trials. Although low doses of risperidone (0.5 mg) and olanzapine (2.5 mg) are usually well tolerated and do not usually result in motor deterioration, in advanced LBD patients motor deterioration can still be seen.
Quetiapine and clozapine may be preferred when psychosis warrants treatment. Clozapine has been demonstrated to be effective for PD psychosis in a randomized clinical trial. However, due to the potentially fatal adverse event of agranulocytosis and need for blood monitoring, it is not first-line. Aripiprazole has not been studied in LBD. Quetiapine has become a popular treatment of psychosis in LBD given the low incidence of motor deterioration and its ability to control visual hallucinations with low doses. Tolerability has been documented in both PD and DLB. However, measures of efficacy have had mixed results and most data is from either unblinded, open-label studies or small placebo-controlled studies
b. AChEI for behavioral symptoms. A meta-analysis of six large trials in AD showed a small but significant benefit for AChEI in treating neuropyschiatric symptoms. There also appears to be a differential effect of AChEI on different psychiatric symptoms, with psychosis, agitation, wandering, and anxiety being the most consistently responsive while negative symptoms of depression, apathy and eating behaviors are less responsive. Similarly, a few reports are available for behavioral improvement with the use of the AChEI rivastigmine in LBD. In a large multicenter trial, rivastigmine resulted in improvement by 30% from baseline in psychiatric symptoms. In a recent case control study of rivastigmine, treatment was associated with reduction in total behavioral scores, hallucinations and sleep disturbance compared to AD. There were lower rates of apathy, anxiety, delusions and hallucinations in the treatment group compared to controls. It is not clear whether this preferential effect on behavior is due to drug effect or more severe behavioral pathology already present in LBD.
How does the ‘black box warning’ on atypical antipsychotic medications relate to LBD? According to the FDA, “in analyses of seventeen placebo-controlled studies of four drugs in this class (atypical antipsychotics), the rate of death for those elderly patients with dementia was about 1.6 to 1.7 times that of placebo. Although the causes of death were varied, most seemed to be either heart-related (such as heart failure or sudden death) or from infections (pneumonia).”
The FDA’s ‘black box warning’ indicates these drugs are not approved for the treatment of behavioral symptoms in elderly patients with dementia. Physicians should discuss the risks and benefits of these types of medications, so that LBD patients and caregivers can consider issues of quality of life against the risks associated with these medications.
REM sleep behavior disorder and insomnia
Clonazepam has been the mainstay of medical therapy for REM behavior sleep disorder (RBD), usually effective at 0.25-0.5 mg/night, but doses above 1 mg are necessary in some patients. Melatonin may also offer some benefit either as monotherapy or in conjunction with clonazepam, particularly considering the lower risk of side-effects with melatonin compared to clonazepam. Melatonin may reduce the percentage of REM sleep without muscle atonia and decrease the number of stage shifts in REM sleep, suggesting it has a more direct mode of action on RBD pathophysiology. Other drugs reported to improve RBD include pramipexole, donepezil, levodopa, carbamazepine, triazolam, clozapine and quetiapine. For insomnia, treatment can be attempted with low doses of benzodiazepines or with agents such as zolpidem, trazodone, or chloral hydrate. These medications have not been extensively studied in LBD and daytime sedation is a potential side effect.
Initial management of orthostatic hypotension consists of simple measures such as leg elevation, elastic stockings, increasing salt and fluid intake, and if possible avoiding medications that can exacerbate orthostasis. If simple measures fail, medications such as midodrine and fludrocortisone can be used. Midodrine is a vasoconstrictor and side effects include urine retention and supine hypertension. Fludrocortisone has mineralocorticoid activity and causes fluid retention.
Medications with anticholinergic activity such as oxybutynin, tolterodine tartrate, bethanechol chloride, propantheline can be used to treat urinary urgency, frequency and urge incontinence. They should be used cautiously however, given their risk of exacerbating cognitive problems. As LBD is more common in males, the risk of producing urine retention in the setting of prostatic hypertrophy should be considered.
Constipation can usually be treated by exercise and dietary modifications. Laxatives, stool softeners and mechanical disimpaction may be needed. The prokinetic effect of cholinergic stimulation by AChEIs might improve the symptoms in some patients.
Impotence in LBD is likely multifactorial. While autonomic dysfunction plays a major role, often there is contribution from other factors such as depression and motor impairment with nocturnal akinesia. Treatment is complex and often requires specialized care and a urologic consultation should be considered. Options include sildenafil, tadalfil, vardenafil, yohimbine, or a small bedtime dose of levodopa. If mood disturbances are associated with the sexual dysfunction, therapy with antidepressants can be considered.
Is there a role for neutraceuticals (herbal supplements) in the treatment of LBD symptoms?
To date, there is very little information in the scientific literature on the use of neutraceuticals in LBD and none are recommended by LBD experts as part of standard treatment.
Caution should always be taken when considering herbal supplements. Neutraceuticals do not go through the same rigorous testing for FDA approval as prescription medications and some can interact with other medications, lessening the effects of important medications or even creating a toxic reaction. Patients and caregivers should inform their physicians of every medication (including prescriptions, over-the-counter medications and herbal supplements) they are taking.
Optimum management of LBD includes both pharmacological and non-pharmacological treatments for the patient, as well as education and support for the primary caregiver.
Physical therapy options include gait training, and cardiovascular, strengthening, and flexibility exercises. Physicians may also recommend exercise programs such as aerobic exercise, strengthening program, or water exercise.
LBD patients may be responsive to speech therapy for low voice volume and poor enunciation. Speech therapy may also improve inspiratory muscular strength and swallowing difficulties.
Occupational therapy may help maintain skills and promote function and independence.
Education of and support for the primary caregiver is essential to maintain optimum quality of life for both the patient and caregiver. Caregivers need to be educated about the symptoms of LBD, standard treatment options, and how to find the supportive services they will likely need during the course of LBD.
Source: "Current Issues in LBD Diagnosis, Treatment and Research" by James E. Galvin, MD, Bradley F. Boeve, MD, John E. Duda, MD, Douglas R. Galasko, MD, Daniel Kaufer, MD, James B. Leverenz, MD, Carol F. Lippa, MD, Oscar L. Lopez, MD, representing the Scientific Advisory Council of the Lewy Body Dementia Association. May, 2008