Lewy Body Dementia Case File

Lewy Body Dementia Case File

Eugene C. Toy, MD, Ericka Simpson, MD, Pedro Mancias, MD, Erin E. Furr-Stimming, MD

CASE 21

A 64-year-old woman was admitted for a possible seizure and progressive cognitive decline. The patient states that she has been having vivid nightmares and dreams for months and often wakes up screaming or falling out of bed. She was brought to the hospital because of “thrashing around” and screaming “stop” as witnessed by her niece. Her niece also stated that her aunt has shown a decline for the past year. She was previously an outgoing, active person who lived independently. In the past 6 months, she has become more reclusive, and her son has had to take over her finances as a result of an accumulation of unpaid bills. Her primary care physician had placed her on a psychotropic medicine a few months earlier, with marked worsening. It was discontinued. The patient also admits to seeing images of animals and people, primarily at night. Neurologic examination is significant for mild bradykinesia, decreased bilateral arm swing, and small, shuffling steps. There is also mild bilateral arm rigidity without tremor. A neuropsychological examination revealed changes in executive functioning (behavior, attention, judgment) and difficulties performing previously learned tasks (apraxia).

▶ What is the most likely diagnosis?

▶ What is the next diagnostic step?

▶ What is the next step in therapy?

ANSWERS TO CASE 21:

Lewy Body Dementia                                                    

Summary: The patient is a 64-year-old woman with progressive alteration in personality, daily function, and cognition. The patient’s history is also significant for acting out her dreams during rapid eye movement (REM) sleep (REM sleep behavior disorder [RBD]) and visual hallucinations. Her examination reveals impairment of the extrapyramidal system and a mix of subcortical and cortical cognitive dysfunction, consistent with parkinsonism with cognitive decline.

• Most likely diagnosis: Lewy body dementia (LBD)
• Next diagnostic step: Magnetic resonance imaging (MRI) of the brain; neuropsychological evaluation
• Next step in therapy: Anticholinesterase medications

ANALYSIS

Objectives

1. Describe the common clinical presentation of LBD.
2. Recognize the differential diagnosis of conditions with parkinsonism and dementia.
3. Understand the evaluation and management of LBD.

Considerations

This is a woman who has insidiously developed cognitive, behavioral, and motor dysfunction that is most likely consistent with a diagnosis of LBD. Her history is significant for onset of cognitive and behavioral decline characterized by social isolation, inability to handle personal affairs, RBD, and hallucinations. LBD is characterized by prominent executive dysfunction and parkinsonism in addition to a number of features such as fluctuating cognition, hallucinations, sensitivity to neuroleptics, and sleep disorders. Her examination is highly suggestive of parkinsonism characterized by a shuffling gait (short, small steps), bilateral decreased arm swing, and rigidity. Formal neurocognitive testing confirmed subcortical dysfunction, including impaired concentration, judgment, and apraxia. Her history is also significant for clinical worsening with an empiric trial of a psychotropic, presumably a dopamine blocker.

The differential diagnosis for dementia with parkinsonism includes both degenerative disease, like Parkinson disease dementia (PDD) and the Parkinson plus syndromes or atypical parkinsonian syndromes (Table 21–1). The primary distinguishing factor between LBD and PDD is the duration of cognitive symptoms in relation to parkinsonism. In general, patients with PDD have a relatively long history of motor symptoms or parkinsonism prior to the onset of cognitive decline, whereas patients with LBD usually have parkinsonism and cognitive decline within the first year of symptom onset. Atypical parkinsonian syndromes may have motor symptoms that mimic PD but also include other symptoms and are caused by different pathologies.

Patients with Alzheimer disease (AD) can occasionally have parkinsonian features, but these features tend to develop only in advanced disease when cognitive impairment is severe. Alternatively, patients with AD may require treatment with antipsychotics for associated behavioral disturbances and develop drug-induced parkinsonism.

Normal-pressure hydrocephalus can be confused with LBD, as patients may have mild evidence of parkinsonism, cognitive decline (subcortical dementia), gait disturbance (a magnetic or apraxic gait), and urinary symptoms (urgency or incontinence). This can be distinguished from LBD using neuroimaging and assessing the response to a high-volume lumbar puncture (removal of 30-40 cc of cerebrospinal fluid [CSF]).

APPROACH TO:

Lewy Body Dementia                                        

DEFINITIONS

ALPHA SYNCLEIN: A protein abundant in the human brain mainly at the presynaptic terminals and may have a role in clustering synaptic vesicles.

APRAXIA: Difficulty with motor planning to perform previously learned tasks or movements in the absence of significant impairment of language, motor, or sensory deficits sufficient to explain disorder.

EXECUTIVE FUNCTION: Mental capacity to control and plan mental activity, the ability to sustain or direct attention, the ability to suppress inappropriate behavioral responses, the planning of future actions, the initiation and execution of these strategies, and the ability to flexibly switch among problem-solving strategies. It is mediated by the prefrontal lobes of the cerebral cortex.

REM SLEEP BEHAVIOR DISORDER: A parasomnia involving dissociation of the characteristic stages of sleep. The major feature is loss of muscle atonia during REM sleep leading to a dream enactment during REM sleep. RBD is a common feature of all neurodegenerative diseases with the pathologic hallmark or alpha-synuclein protein aggregates in neurons. (PD, multiple system atrophy [MSA], and LBD) and often precedes their diagnosis.

CLINICAL APPROACH

LBD is the second most common type of dementia behind AD. Pathologic and clinical features can overlap between LBD and AD, and in fact, 40% of AD patients have pathologic alterations felt specific for LBD. Epidemiologic studies are limited but they suggest that men are more affected than women and that the usual onset is in the late 50s and older.

EEG, electroencephalogram; LBD, Lewy body dementia; MIBG, metaiodobenzylguanidine; PET, positron emission tomography; REM, rapid eye movement; SPECT, single-photon emission computed tomography.

CLINICAL HISTORY AND FEATURES

LBD is a progressive neurodegenerative dementia that can overlap clinically and pathologically with other parkinsonian dementias, primarily PDD and occasionally Alzheimer dementia. (See Table 21–1 for an overview of the parkinsonian dementias and Table 21–2 for diagnostic features of LBD.) If the onset of dementia is prior to or in conjunction with motor signs, particularly with visual hallucinations and episodes of reduced responsiveness, the diagnosis of LBD should be considered.

The following clinical features help distinguish LBD from Alzheimer dementia: (1) fluctuations in cognitive function with varying levels of alertness and attention, (2) visual hallucinations, and (3) parkinsonian motor features that appear relatively early in LBD. Other suggestive features include RBD, severe neuroleptic sensitivity, and low dopamine transporter uptake on functional brain scans. Cognitive impairment in LBD is characterized by more executive dysfunction and visual-spatial impairment rather than the anterograde memory loss of AD. It is not unusual for someone with LBD to have a relatively severe cognitive impairment by history but with a relatively preserved delayed recall with severe constructional apraxia with neuropsychological testing. This combination is virtually never seen in AD.

PATHOLOGY

Frederick Lewy first described Lewy bodies (LBs) in 1912 as cytoplasmic inclusions in the substantia nigra of patients with PD. LBs were first reported to be a rare finding associated with dementia in the early1960s. It was not until the mid-1980s, when sensitive immunocytochemical methods to identify LBs were developed, that identified alpha-synuclein inclusions within LBs and dementia with LBs (LBD) was recognized as being far more common than previously thought. However, there is considerable controversy as to whether LBD and PD should be described as two different conditions or as being on the same spectrum, with the latter being more likely as they share common neuropathologic features. The synucleinopathies include PD, MSA, and LBD. In LBD, alpha-synuclein deposition is present not only in the brainstem, but also in limbic and neocortical regions.

DIAGNOSTIC STUDIES

Laboratory studies should include the routine laboratory studies to evaluate for treatable causes of dementia, including a comprehensive metabolic panel, complete blood count (CBC), thyroid studies, vitamin B12 levels, syphilis serology, Lyme disease serology, and HIV testing, when appropriate. Imaging studies are important to evaluate for other conditions that can mimic this disorder (vascular dementia, tumor, normal pressure hydrocephalus, etc). Patients with LBD usually have less hippocampal atrophy than patients with AD (but more than control subjects). Whether this difference is clinically useful is under investigation, as is the diagnostic utility of functional imaging. Single-photon emission computed tomography (CT) scanning or positron emission tomography scanning can show decreased occipital lobe blood flow or metabolism in LBD but not in AD. Reduced dopamine transporter activity in the basal ganglia is seen with positron emission tomography scanning or single-photon emission CT scanning.

Neurocognitive testing can be helpful to differentiate LBD from AD and to establish a baseline for future comparison. CSF examination is not required in routine cases; however, it has recently been found that patients with AD have higher levels of tau protein in their CSF than patients with LBD. CSF levels of beta-amyloid are lower than normal in LBD and AD. Polysomnography should be considered in these patients for evaluation of RBD, especially early in the disease process when parkinsonism and/or cognitive signs are mild to absent.

TREATMENT

It is important to rule out and treat reversible causes of cognitive decline or confusion such as delirium, medication toxicity, and seizures. There are no medications that have been shown to delay the progression of LBD. Symptomatically, the anticholinesterase medications (ie, rivastigmine, donepezil, and galantamine) have been demonstrated to have cognitive/behavioral symptom improvement. Disabling parkinsonism can be treated cautiously with titrated doses of levodopa or other PD medications while monitoring for increased psychosis. Conversely, if psychotic symptoms are present, atypical neuroleptic agents such as quetiapine can be used with extreme caution, and close monitoring for worsening of parkinsonism. RBD can be treated, if necessary, with melatonin or clonazepam.

CASE CORRELATION

• See also Case 20 (Alzheimer Dementia) and Case 24 (Multiple Sclerosis)

COMPREHENSION QUESTIONS

21.1 A 68-year-old woman is diagnosed with dementia with Lewy bodies. Which of the following is the least appropriate initial treatment?

A. Rivastigmine

B. Donepezil

C. Haloperidol

D. Galantamine

21.2 A 61-year-old man is brought into the physician’s office for memory loss and confusion. Which of the following symptoms is most suggestive of AD as opposed to dementia with Lewy bodies?

A. Visual hallucinations

B. Dramatic fluctuations in clinical condition

C. Early anterograde memory loss

D. Early shuffling gait

21.3 A 73-year-old man is noted to have a slow onset of cognitive deficits. The physical examination reveals no obvious etiology. Which of the following imaging findings is most suggestive of dementia with Lewy bodies, using either structural or functional neuroimaging?

A. Medial temporal lobe atrophy

B. Parietal temporal hypometabolism

C. Atrophy of the midbrain

D. Occipital lobe hypometabolism

ANSWERS

21.1 C. Haloperidol is a typical neuroleptic (dopamine receptor antagonist) that can have severely deleterious consequences in this disorder. The other three drugs are cholinesterase inhibitors, and evidence for their use in LBD can be found in the literature.

21.2 C. Cognitive impairment in LBD is characterized by executive dysfunction and visuospatial impairment more than the anterograde memory loss

of AD.

21.3 D. Occipital lobe hypometabolism is most typical of LBD. Medial temporal lobe atrophy and parietal temporal hypometabolism are characteristic of AD. Atrophy of the midbrain is characteristic of progressive supranuclear palsy.

    CLINICAL PEARLS    

▶ LBD is the second most common cause of dementia behind AD. ▶ The classic clinical syndrome of LBD includes cognitive decline with fluctuations in the level of awareness, parkinsonism, and visual hallucinations. ▶ RBD can be one of the first symptoms of LBD, prior to the onset of significant cognitive or motor disturbance. ▶ Levodopa can be effective for the parkinsonism but can exacerbate hallucinations. ▶ Typical antipsychotics should be avoided in patients with LBD, given their sensitivity to neuroleptics.

REFERENCES

Ballard C, Grace J, McKeith I, et al. Neuroleptic sensitivity in dementia with Lewy bodies and Alzheimer’s disease. Lancet. 1998;351:1032-1033. 

Bonner LT, Tsuang DW, Cherrier MM, et al. Familial dementia with Lewy bodies with an atypical clinical presentation. J Geriatr Psychiatry Neurol. 2003;16:59-64. 

Geser F, Wenning GK, Poewe W, et al. How to diagnose dementia with Lewy bodies: state of the art. Mov Disord. 2005;20(suppl 12):S11-S20. 

Gomberts S. Lewy body dementias: dementia with Lewy bodies and Parkinson disease dementia. Continuum (Minneap Minn). 2016;22(2):435-463. 

Korczyn AD, Reichmann H. Dementia with Lewy bodies. J Neurol Sci. 2006;248:3-8. 

Kurlan R, Cummings J, Raman R, Thal L; Alzheimer’s Disease Cooperative Study Group. Quetiapine for agitation or psychosis in patients with dementia and parkinsonism. Neurology. 2007;68: 1356-1363. 

McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005;65:1863-1872. 

Miyasaki JM, Shannon K, Voon V, et al; Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;66:996-1002. 

Vann Jones SA, O’Brien JT. The prevalence and incidence of dementia with Lewy bodies: a systematic review of population and clinical studies. Psychol Med. 2014;44:673-683. 

Wang HF, Yu JT, Tang SW, et al. Efficacy and safety of cholinesterase inhibitors and memantine in cognitive impairment in Parkinson’s disease, Parkinson’s disease dementia, and dementia with Lewy bodies: systematic review with meta-analysis and trial sequential analysis. J Neurol Neurosurg Psychiatry. 2015;86:135-143.

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