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Next, let’s look at a 2019 review article by a pair of neurologists in the journal Drugs and Aging that presents general information about dementia with Lewy bodies with an emphasis on treatment options. This article and a few other resources that I’ve listed in the references provided me—and I hope for you—some background on dementia with Lewy bodies that I found useful. Though, if you’re a geriatric specialist, this is probably routine information for you.
First, dementia with Lewy bodies is the third most common neurodegenerative disorder, right behind Alzheimer’s and Parkinson’s. As a reminder of the mechanism, Lewy bodies are clumps of the protein alpha-synuclein. If they’re in the brainstem, the symptoms are primarily autonomic, like blood pressure and heart rate instability or temperature fluctuations and sweating, but also depression. If the Lewy bodies are in the substantia nigra, they cause parkinsonism. If they’re in the cortex, they cause cognitive impairment that includes both executive (planning and multitasking) as well as visuospatial, like navigating and constructing, and then memory as well.
A quick note on nomenclature: If the Parkinson’s happens first and then dementia later, it’s called Parkinson’s disease with dementia. But if the dementia occurs before Parkinson’s symptoms or very early in Parkinson’s, then it would be called dementia with Lewy bodies because one of the symptoms is parkinsonism.
Diagnostically, there are 4 cardinal symptoms of dementia with Lewy bodies, according to the neurology group called the Dementia with Lewy Bodies Consortium. In their 2017 report, they summarized the 4 cardinal symptoms. Fluctuating cognition with variations in attention and alertness. Secondly, recurrent visual hallucinations that are detailed and well formed. Third, REM sleep behavior; these are acting-out movements in sleep, like thrashing and kicking or punching that shouldn’t be happening in REM because, usually, that is a state of relative paralysis. And then finally, fourthly, Parkinson’s symptoms, like bradykinesia, tremor, and rigidity. I’ll repeat those 4 in just a moment. So, diagnosis is based primarily on history, the presence of 2 or more of those cardinal findings. And severe autonomic disturbance like you would expect in brainstem involvement are supportive as well. Again, those 4—fluctuating cognition, visual hallucinations, REM sleep behavior, and parkinsonism.
What about imaging? Can that help us? Well, MRI, CT, SPECT scan or PET scan, functional MRI, and others have been used, but none from what I could gather, including that Neurology 2017 report, none are clearly routine. A 2014 summary from Health Quality Ontario looking at how much we spend in order to get good healthcare summarized that thus, and I thought this was useful: “It’s not well understood which patients will most benefit from a brain scan and which type of scan works best to diagnose dementia. Scans have the most value when doctors are uncertain as to the type of dementia despite monitoring the patient for a while, e.g., 2 years.” So, moreover, co-pathology with Alzheimer’s, meaning both the tau proteins and neurofibrillary tangles are also present as well as the Lewy bodies, co-pathology with Alzheimer’s is very common and in varying degrees. So, trying to nail down which you’re dealing with can often be challenging and maybe not particularly fruitful. You’ll end up focusing on treatment options.
So, let’s have a look there. In terms of treatment, of course, one should begin with: What medications could be causing these symptoms like agitation, excessive daytime sedation like loss of attentiveness, and fluctuating levels of consciousness? So, think, like delirium, opioids, anticholinergics, benzodiazepines, and tricyclics would all be potential culprits. And so, remembering that list of anticholinergics is huge. You should cross-check the patient’s medication list with something like the Beers criteria or some such resource.
Now, because neurodegeneration in the basal forebrain occurs in dementia with Lewy bodies, just as in Alzheimer’s, the acetylcholinesterase inhibitors can be helpful: Donepezil, rivastigmine, and galantamine. These have not been tested against one another. The sample sizes in these studies are better for donepezil and rivastigmine. And then memantine, the NMDA receptor antagonist, was found in 1 review to also be helpful but only for global clinical improvement, not for cognitive function, where the acetylcholinesterase has actually led to a significant short-term improvement.
What about the hallucinations? Well, actually, these may improve with acetylcholinesterase inhibitors. So, that is pretty clearly a better place to start. You might end up not needing an antipsychotic. And of course, some of these hallucinations are very detailed but not necessarily distressing for the patient and may not need treatment. But if you do end up considering an antipsychotic, then, of course, remembering that neuroleptic malignant syndrome is more common in dementia with Lewy bodies patients and, of course, these dopamine blockers can exacerbate Parkinson’s, then you likely already know that low-dose quetiapine is preferred. Actually, the randomized trials for that in dementia are not very encouraging, but it’s a common practice. There are some alternatives, though. For example, for agitation, valproate. Now, a Cochrane meta-analysis some years ago found it was no better than placebo as monotherapy in dementia for agitation. But 2 subsequent studies found benefit as an adjunct for the management of agitation and dementia without specifying the type of dementia.
Two more considerations to go, here. How about the REM sleep behavior? Well, if it hasn’t already happened, how about separate beds? But then to pharmacologically treat it, the standard recommendation includes clonazepam. The quality of evidence was nearly as good for melatonin, but I was struck by the size of the doses that were used in these studies—3 mg to 12 mg—and these were just open trials, not randomized trials.
And then finally, what about the parkinsonism? Well, as you know, the problem is that dopamine agonists for Parkinson’s can make the hallucinations worse. So, levodopa is used with caution and at low doses. There is 1 randomized trial. It was zonisamide for the motor problems associated with Parkinson’s, and it did have some benefit for the motor symptoms. You might remember zonisamide is an anticonvulsant once examined for weight loss and occasionally used in bipolar disorder. I confess, everyone I ever tried on it—that was about 10 people—had cognitive impairment. It was the same story as topiramate. They only stayed on it as long as they were losing weight and not having to take care of children or go to school or work.
In conclusion, dementia with Lewy bodies is a different condition than Alzheimer’s. It’s managed differently, particularly with respect to use of antipsychotics. There are multiple alternatives. We begin by looking for medications that could be exacerbating the problem, particularly anticholinergics. If you’re going to use an antipsychotic, it’s cautioned with low-dose quetiapine. And remember to consider valproate for agitation and melatonin as well as clonazepam for the REM sleep behavior.
Abstract
Pharmacological Management of Dementia with Lewy Bodies
Linda A Hershey, Rhonda Coleman-Jackson
Dementia with Lewy bodies (DLB) is a complex disease that involves a variety of cognitive, behavioral and neurological symptoms, including progressive memory loss, visual hallucinations, parkinsonism, cognitive fluctuations and rapid eye movement sleep behavior disorder (RBD). These symptoms may appear in varying combinations and levels of severity in each patient who is seen in the clinic, making diagnosis and treatment a challenge. DLB is the third most common of all the neurodegenerative diseases behind both Alzheimer’s disease and Parkinson’s disease (PD). The median age of onset for DLB (76.3 years) is younger than that seen in PD dementia (81.4 years). New pathological studies have shown that most DLB patients have variable amounts of Alzheimer’s changes in their brains, explaining the wide variability in this disease’s clinical presentation and clinical course. This review discusses the three cholinesterase inhibitors that have been shown to be effective in managing the cognitive and behavioral symptoms of DLB: rivastigmine, galantamine and donepezil. Memantine is able to improve clinical global impression of change in those with mild to moderate DLB. Levodopa can treat the parkinsonism of some DLB patients, but the dose is often limited due to the fact that it can cause agitation or worsening of visual hallucinations. A recent phase 2 clinical trial showed the benefit of zonisamide when it is added as an adjunct to levodopa for treating DLB parkinsonism. While atypical antipsychotic drugs may not always be helpful as monotherapy in managing the agitation associated with DLB, low doses of valproic acid can be effective when added as an adjunct to drugs like quetiapine. Pimavanserin may prove to be a useful treatment for psychosis in DLB patients, but like other antipsychotic drugs that are used in dementia patients, there is a small increased risk of mortality. RBD, which is a common core clinical feature of DLB, can be managed with either melatonin or clonazepam. Two agents targeting alpha-synuclein (NPT200-11 and ambroxol) currently hold promise as disease-modifying therapies for DLB, but they are yet to be tested in clinical trials. An agent (E2027) that offers hope of neuroprotection by increasing central cyclic guanosine monophosphate (cGMP) levels is currently being examined in clinical trials in DLB patients.
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Reference
Hershey, L. A., & Coleman-Jackson, R. (2019). Pharmacological management of dementia with Lewy bodies. Drugs & Aging, 36(4), 309-319
