Can We Propose Rational Clinical Trials for Lewy Body Dementia?

Can We Propose Rational Clinical Trials for Lewy Body Dementia?

Quinn Joseph
Published: BTG - FUTURE DIRECTIONS IN NEUROLOGY
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A report on a recent consortium meeting on dementia with Lewy bodies (DLB) noted: “Virtually unrecognized 20 years ago, DLB could within this decade be one of the best characterized and potentially treatable neurodegenerative disorders of late life.”1 Despite this level of optimism regarding treatment, clinical trials for DLB are rare and the standard of care is uncertain. For example, Clinicaltrials.gov lists no investigational drugs in clinical trials for DLB at present, and the American Academy of Neurology (AAN) does not have a practice parameter dealing specifically with Lewy body dementia. This situation is due in part to the fact that the US Food and Drug Administration (FDA) has served notice that they will not grant a drug indication for DLB because it is a heterogeneous syndrome with insufficiently sensitive and specific diagnostic criteria. The result has been a general inhibition of clinical trials for DLB, with some effort to gain drug indications for more discrete types of dementia associated with Lewy bodies, such as Parkinson’s disease dementia (PDD).

In this article, we will consider the clinical, neurochemical, and pathological features of the various types of DLB, review therapeutic strategies based on these characteristics, and conclude with suggestions for developing a more potent therapeutic armamentarium for this challenging condition.

The Spectrum of Lewy Body Dementia
According to the most recent consensus criteria,2 a diagnosis of probable DLB requires the presence of dementia, in association with either two core features—fluctuating cognition with pronounced variations in attention and alertness, recurrent visual hallucinations, and spontaneous features of parkinsonism—or one core feature and one suggestive feature—including rapid eye movement (REM) sleep behavior disorder, severe neuroleptic sensitivity, and low dopamine transporter uptake in basal ganglia demonstrated by single photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. A diagnosis of possible DLB is made in the case of one core feature or one or more suggestive features. Features that are supportive but are not used in the diagnostic algorithm include repeated falls and syncope, transient unexplained loss of consciousness, severe autonomic dysfunction, hallucinations in other modalities, systematized delusions, depression, relative preservation of medial temporal lobe structures on CT/magnetic resonance imaging (MRI) scan, generalized low uptake on SPECT/PET perfusion scan with reduced occipital activity, abnormal (low uptake) metaiodobenzylguanidine (MIBG) myocardial scintigraphy, and prominent slow wave activity on electroencephalography (EEG) with temporal lobe transient sharp waves. Features that are considered as evidence against a diagnosis of DLB include the presence of cerebrovascular disease (focal neurological signs or brain imaging), the presence of any other physical illness or brain disorder sufficient to account in part or in total for the clinical picture, or the appearance of parkinsonism for the first time at a stage of severe dementia. Among patients with DLB, there is considerable heterogeneity. Some patients are recognizable from the time of clinical presentation with spontaneous parkinsonism and visual hallucinations; other patients present looking like typical Alzheimer’s disease (AD), but develop Lewy body symptomatology over time.

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