Dr. Ken Madden Associate Professor

Division of Geriatric Medicine Department of Medicine

University of British Columbia

abnormal intracytoplasm inclusions

Noted in 1912

In a patient with Parkinson’s Disease

In 1961, Okazaki first described a relationship between the presence of cortical Lewy bodies and dementia

In 1984, Dr. Kosaka

Suggested new disease entity, which they termed ‘diffuse Lewy body disease’

Epidemiology of DLB

―Standard‖ Presentation, why problematic

Examples of Nonstandard presentations (―Actually Standard‖)

Diagnositic Criteria and Evidence

Case-based Examples of Presentations

Evidence for Treatments

Dementia of Lewy Body (DLB) is the second most common neurodegenerative dementia

Range of 10 to 22 percent of dementia cases

Prevalence of 0.7 percent of subjects over 65 years of age

J Neurol Neurosurg Psychiatry 2003;74:720-724

Mean age at presentation—75 years

Possible predilection for men

Up to 66 percent

Often overlooked due to heterogeneous presentation

J Neurol Neurosurg Psychiatry 2003;74:720-724

76 year old woman

Presents with slowly progressive decrease in short term memory over 3 years

3 year history of difficulty walking

Course seems quite variable

Fluctuates up and down throughout the day, becoming quite confused occasionally

Family physician gave a ―pill to calm‖and patient became very confused

Physical exam shows extrapyramidal signs

Increased tone

Shuffling, unsteady gait

No tremor

The problem with classic presentations is that they aren’t as common as one would like

Criteria are useful

Mixed bag of symptoms makes DLB diagnosis difficult

Progressive dementia

deficits in attention and executive function are typical. Prominent memory impairment may not be evident in the early stages.

Fluctuating cognition with pronounced variations in attention and alertness

Recurrent complex visual hallucinations

Spontaneous features of Parkinsonism.

REM sleep behaviour disorder (RBD), which can appear years before the onset of dementia and Parkinsonism

Severe sensitivity to neuroleptics occurs in up to 50% of LBD patients who take them

Low dopamine transporter uptake in the brain's basal ganglia as seen on SPECT and PET imaging scans

Repeated falls and syncope (fainting)

Transient, unexplained loss of consciousness

Autonomic dysfunction

Hallucinations of other modalities

Visuospatial abnormalities like depth perception, object orientation, directional sense and illusions

Other psychiatric disturbances like systematized delusions, aggression and depression.

A probable LBD diagnosis requires:

Dementia plus two or more core features

Dementia plus one core feature and one or more suggestive features.

A possible LBD diagnosis requires:

Dementia plus one core feature

Dementia plus one or more suggestive features

Dementia and Geriatric Cognitive Disorders, Volume 32, Issue 3, pp. 202 - 208

Litvan et al., Mov Desord 2003; 18:467-86

Fluctuating levels of consciousness over a background of progressive deterioration

Easier said than recognized

combination of cortical and subcortical

substantial attentional deficits

frontosubcortical and visuospatial dysfunction

Memory complaints less

DLB do better than those with Alzheimer’s disease on tests of verbal memory but worse on visuospatial performance tasks

Late stages impossible to tell

Can be over minutes, hours or days

In 50 to 75% of patients

Caregiver reports

Formal testing

I honestly have a hard time outside of inpatient unit

70 year old man who lives on a ranch outside of Burns’ Lake

Progressively started ―acting weirder‖ over the last year

Started seeing people and animals that weren’t there

2 days ago had hallucination wild dogs were attacking his family and biting his hands

Ran around his farmhouse shooting at the dogs with a shotgun

RCMP called, scene from Chuck Norris movie ensues

Admitted to hospital (obviously)

Physical exam shows cogwheeled rigidity, shuffling gait

Mild cognitive dysfunction

25/30

Temporal spatial, attention

Usually visual

3-dimensional

Detailed and vivid

Often frightening

Usually patient believes they are real

Generally mute

Visual hallucinations are associated with greater deficits in cortical acetylcholine

Predicts better responses to cholinesterase inhibitors (abstract only)

hallucinators (n=66) and non-hallucinators (n=23)

Lewy bodies in the posterior temporal lobes and amygdale are associated with hallucinations

These areas involved in emotion and visual processing

A.J. Harding, et al. Brain, 125 (Pt. 2) (2002), pp. 391–403

Postulated irritant effect?

A.J. Harding, et al. Brain, 125 (Pt. 2) (2002), pp. 391–403

30–50% of DLB patients

Ninety-four patients were included (15 with DLB, 36 with PDD, 26 with PD, 17 with Alzheimer's disease

A.J. Harding, et al. Brain, 125 (Pt. 2) (2002), pp. 391–403

Severe neuroleptic sensitivity only occurred in patients with Lewy body disease: DLB (8 [53%]), PDD (14 [39%]), and PD (7 [27%])

did not occur in Alzheimer's disease

(p = .006)

Family brings to family doctor

9 month history of memory issues

Losing objects

Also hallucinations of dead relatives

Delusions of theft

Cognitive testing shows mild memory impairment

Prominent inattention and temporalspatial issues

Cognition fluctuates, according to caregivers

Physical exam shows no extrapyramidal signs

Gait normal

Can this be DLB?

Presesentation is subjectively quite different

Poorly studied

Retrospective analysis of case notes of 21 autopsy patients with DLB and 37 cases with AD

McKeith IG, et al. Psychol Med. 1992 Nov;22(4):911-22.

At the time of diagnosis

50% of DLB patients have extrapyramidal motor symptoms

75% developing them during some stage of the disease course

McKeith IG, et al. Psychol Med. 1992 Nov;22(4):911-22.

Arbitrary rule

Patients with DLB must develop motor symptoms within 1 year of cognitive symptoms

Otherwise, need to consider parkinson’s associated dementia

Rule is neat and tidy

Unfortunately from the book of made up medicine in the sky

Wife bring in to doctor

―Driving her crazy at night‖

Numerous night time issues

Moving around

Flailing arms

Sleep walking

Sleepy during the daytime

Patient denies any of this

REM behavioural disorder is the most common one

A lack of muscle atonia in combination with vivid dreams

Usually diagnosed on history

Another option is increased EMG activity during sleep study

To date, no RCTs to guide us

Numerous agents suggested

Cholinesterase inhibitors

Sedatives (danger)

Melatonin

Quetiapine

Modify sleep environment for safety!

DLB association website has excellent suggestions for caregivers

His wife brings him back, and says he is falling down

Feels light headed when standing up

Physical exam shows orthostatic hypotension

DLB has been associated with autonomic instability

Most common manifastation is orthostatic hypotension or urinary incontinence

39 patients with AD

30 with VAD

30 with DLB

40 with PDD

38 elderly controls

Ewing’s battery of autonomic function tests

HRV testing

Kenny et al, J Neurol Neurosurg Psychiatry 2007;78:671–677

Based on limited evidence

Symptomatic

Targeted at specific symptoms

No disease-modifying agents

Survival time in DLB is a mean of 7.7 years (compared with 9.3 years with AD)

Shorter time to institutionalization

First line therapy

Limited evidence for

Rivastigmine

Donepezil

Benefits reported for

Cognition

Fluctuations

Apathy, indifference

Psychotic symptoms

McKeith, et al. Lancet 356(9247), 2000:2031–2036.

ITT=intent to treat dataset LOCF=last observation carried forward OC=observed cases dataset.

Improvement in NPI-4

Case reports of worsening

Cognitive function

REM sleep disorder

Parkinsonism

Ballard, C et al. Neurology. 68(20) 2010:1726 - 9

Improved outcomes on primary outcome measure

Clinical global impression of change

No improvements on any other secondary outcomes

Recruited DLB or PD-related dementia

Case reports of worsening

Delusions

Hallucinations

What about neuroleptics?

Severe neuroleptic reactions are characteristic of the disease

Exacerbation of: Parkinsonism

Confusion

Autonomic Dysfunction

Consider Cholinesterase inhibitor first or lower dose of dopaminergic agent

Use only atypical antipsychotics and at lowest possible dose

Quetiapine

Olanzapine

Risperidone

Cloazapine (neutropenia)

Switch agents instead of raising dose

Nonpharmacological interventions

Anticholinesterase inhibitors

Atypical Antipsychotics

NEVER:

Benzodiazapines (except maybe REM sleep disorder)

TCAs

Treatment is similar to PD but less successful

15-25% success rate

May exacerbate psychotic symptoms

Conservative approach

Carbidopa-levodopa 25/100 mg

One-half tablet po tid

Titrate slowly over several weeks as tolerated

Dopamine agonists tend to be poorly tolerated

Anticholinergic agents are contraindicated

Standard therapies

High salt

Leg stockings

Fludrocortisone

Midodrine

Avoid anticholinergic agensts