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LEWY BODY DEMENTIA/ PARKINSON’S DISEASE DEMENTIA. Insights Into a Common Spectrum Disorder. Dr. Albert Chen Clinical Gerontologist June 29 th 2012.

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Page 1: Lewy Body Dementia Slides

LEWY BODY DEMENTIA/ PARKINSON’S DISEASE

DEMENTIA.

Insights Into a Common Spectrum Disorder.

Dr. Albert ChenClinical Gerontologist

June 29th 2012.

Page 2: Lewy Body Dementia Slides

"From the brain and the brain alone arise our pleasures, joys, laughter and jests, as well as our

sorrows, pains and griefs" Hippocrates

“By their benevolant labours it’s real nature may be ascertained, and appropriate modes of relief, or

even of cure, pointed out.” James Parkinson 1817.

Page 3: Lewy Body Dementia Slides

CONTENTS Why discuss dementia now? What’s behind brain degeneration

with aging? History & Epidemiology of LBD Clinico-Pathological insight into LBD Differential Diagnosis & Treatment Current & Future Challenges What did we just talk about?

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THATS WHY WE NEED TO DISCUSS DEMENTIA!

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9

Aetiology of Primary Degenerative Dementia.

Alzheimer’s disease (AD)

Frontotemporal lobar degeneration

– Behavioural, frontotemporal dementia

– Progressive, non fluent aphasia

– Semantic dementia

Dementia with Lewy bodies (DLB)

Prion diseases

Parkinson’s disease dementia (PDD)

Corticobasal degeneration syndrome / Progressive supranuclear palsy (PSP)

Huntington’s disease (HD)

Motor neuron disease (ALS), Multiple Systemic Atrophy (MSA)

Other

Page 10: Lewy Body Dementia Slides

FREE RADICAL PROLIFERATIO

N

INCREASED IONIZING

RADIATION

OBESITY

DIABETES

PESTICIDES & INSECTICIDES

INCREASED RADIOACTIVITY

EXPOSURE

METABOLIC SYNDROME

FOOD PREPARATION

METHODS

PROCESSED FOOD

Chen A.W. (2008)

O2-

O2- OH.

ALCOHOL &TOBACCO

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DEMENTIA

Fronto-temporal

DegenerationSubcortical

Disease

ALZHEIMER’S DISEASE(~65%)

CVD & STROKESmall Vessel

DiseaseCADASIL

OTHER non-CNS DISEASES

Unknown Factors???

LEWY BODY DEMENTIA(PDD/DLB)(~15-20%)

Page 14: Lewy Body Dementia Slides

Frequency of Various Dementias

Dementia Type Various Rabins Barker et al.

AD 60-70 %

66% 42%

LBD 20-30%

8-15% 8%

VascularDementia

15-30% 15-20%

3%

FTD 13.3-21.9%

5% 4%

Mixed 42%

Page 15: Lewy Body Dementia Slides

LEWY BODY DEMENTIA/PARKINSON DISEASE

DEMENTIA.A SPECTUM DISORDER

COMPREHENSIVE OVERVIEW

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Dr Friedrich Heinrich Lewy (1885-1950)

Konstantin Nikolaevitch Tretiakoff (December 26, 1892 – 1958)

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Recent History of LBD Late identification due to difficulty visualizing

Lewy bodies in cortex. AD with rigidity and rapid progression, or

with plaques but no tangles. LBD first reported by Kosaka et. al. 1978 Type I (LB in midbrain, eg. Parkinson’s disease)

Type II (transitional form)

Type III (LB’s in cortex, eg. LBD)

Page 19: Lewy Body Dementia Slides

DEMENTIA WITH LEWY BODIES.IAN McKEITH

Every 7 s a new case of dementia worldwide. Pathological studies suggest that 15-20% are due

to DLB, a condition unrecognised 15 yrs ago. The functional impairments and cost of managing

DLB is twice that of AD. Correct management can bring significant benefits. DLB is part of a spectrum of disease, including

Parkinson’s and Autonomic Failure. To beat it we must talk more with colleagues,

cutting across specialities boundaries

Page 20: Lewy Body Dementia Slides

LEWY BODY DEMENTIA IS NOT A RARE DISEASE…

It accounts for up to 20% of dementia cases in the U.S. — that’s up to 1.3

million cases in the U.S. alone, with only 30%-50%

of LBD cases being accurately diagnosed, even

in dementia centres.

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Lewy Bodies Round, eosinophilic cytoplasmic

inclusion bodies with pale halo. irregular shape, halo less prominent

in cortical LB’s, difficult to visualize.Easier to visualize with newer

immunofluourescent stains. Composed of abnormal neurofilaments

(mostly polymerized alpha-synuclein and ubiquitin).

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What’s in a Name? Lewy Body disease (LBd) Diffuse Lewy Body disease (DLBd) Lewy Body Dementia (LBD) Dementia with Lewy bodies (DLB) Alzheimer’s disease, Lewy body

variant (ADLBv) Senile Dementia, Lewy body type

Parkinson’s Disease Dementia (PDD)

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LEWY BODY DISEASE SPECTRUM

PARKINSON’S DISEASE

LEWY BODY DEMENTIA

SUBCLINICAL PHENOTYPE

Chen A.W 2012

Progression

PAF

Sub. Nigra

CORTEX

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LEWY BODY DEMENTIA

PARKINSONS’ DISEASE DEMENTIA

(PDD)

DEMENTIA WITH LEWY BODIES

(DLB)

Chen A.W. 2012

Lets get the

classification right!

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Lewy Body Disease Presenting Features.

Dementia alone Parkinsonism alone Parkinsonism with dementia Psychiatric disorder, absent dementia Orthostatic hypotension Altered consciousness... transient Falls Primary autonomic failure

Age: 50 -83 yrs. M>F ~ 10% decline per annum

(McKeith et al. 1992., Byrnes et al 1989.)

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Dementia With Lewy Bodies (DLB)

Heyman A et al. Neurology. 1999;52:1839-1844. Ballard CG et al. Dement Geriatr Cogn Disord. 1999;10:104-108.

Barber R et al. Neurology. 1999;52:1153-1158.

DEMENTIA FLUCTUATING

COGNITION

PARKINSONISM

VISUAL HALLUCINATION

S

LBD

Chen A.W 2008

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Dementia With Lewy Bodies (DLB)

Heyman A et al. Neurology. 1999;52:1839-1844. Ballard CG et al. Dement Geriatr Cogn Disord. 1999;10:104-108.

Barber R et al. Neurology. 1999;52:1153-1158.

DEMENTIA

FLUCTUATING COGNITION

PARKINSONISM

VISUAL HALLUCINATION

S

LBDVisuospatia

l Deficit

RBD

Autonomic Dysfunctio

n

NEUROLEPTIC SENSITIVITY

depressive

Chen A.W 2012

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DEMENTIA“de..... mentia”

An acquired deterioration of global cognitive functions in previously unimpaired persons... Severe enough to impair their normal functioning.

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POSTROLANDICFRONTAL/SUBCORTICAL

Memory deficits Aphasia Apraxia Agnosia Personality

preserved MMSE valid

Memory deficits Loss of goal-oriented

behavior, behavioral plasticity.

Personality Changes - Disinhibition - Abulia Incontinence MMSE useless

Two Types of Dementia

Chen A.W 2008

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LBD is a Post-Rolandic Dementia

Similar to Alzheimer’s disease in presentation.

Neuropsychological testing similar to AD (may be a bit more executive and visiospatial deficit)

SPECT, PET findings like AD (parieto-temporal hypo-metabolism)

Similar, or slightly earlier, age of onset, but more rapid progression (mean survival 5-8 years).

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Subcortical Dementias

Parkinson's disease (PD);

Huntington's disease (HD);

multiple system atrophy; idiopathic basal ganglia calcification;

multi-infarct dementia; and,

AIDS dementia complex

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DEMENTIA SYNDROMES

• Wandering

• Pacing• Repititive

• Apraxia• ADL• IADL

• Depression• Psychosis• Hallucination

• Apathy• Agitation• anxiety

• Memory• Judgment• Attention• Executive functions.

• Visuospatial• Language

Cognitive NeuroPsychiatric

Behavioural

Functional

Chen A.W 2010

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Alzheimer Warning Signs

Top TenAlzheimer’s disease Outreach Programme (Jamaica) 1. Recent memory loss affecting

job 2. Difficulty performing familiar

tasks 3. Problems with language 4. Disorientation to time or place 5. Poor or decreased judgment 6. Problems with abstract

thinking 7. Misplacing things 8. Changes in mood or behavior 9. Changes in personality 10. Loss of initiative

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Lewy Body Dementia Dementia similar to that of Alzheimer’s.

Significantly greater fluctuation in condition from day to day, compared to AD.

81% have periods of marked unexplained confusion, mimicking delirium.

Twice as common in men. (1.6-2:1)

Generally non-familial, but a few autosomal dominant cases reported

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Acta Neuropathol. 1998 Aug;96(2):207-10.

Autosomal dominant diffuse Lewy body disease.

Wakabayashi K, Hayashi S, Ishikawa A, Hayashi T, Okuizumi K, Tanaka H, Tsuji S, Takahashi H.Source: Brain Disease Research Center, Brain Research Institute, Niiata University, Japan. [email protected]

Abstract: We describe a Japanese family with parkinsonism and later-onset dementia. The proband developed parkinsonism at the age of 61 years, followed by dementia starting when she was 67. Her uncle, who was also her husband, died at the age of 78 years after 7- and 5-year histories of parkinsonism and dementia, respectively. Pathological examination of these two patients showed marked neuronal loss with Lewy bodies (LBs) in the brain stem pigmented nuclei and numerous cortical LBs and ubiquitin-positive hippocampal CA2/3 neurites were observed. The proband also had many amyloid plaques. Their two sons developed similar parkinsonism at the ages of 39 and 28 years and also suffered later-on-set dementia. These findings strongly suggest that this family has autosomal dominant diffuse LB disease

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Journal of Neuropathology & Experimental Neurology:January 2009 - Volume 68 - Issue 1 - pp 73-82

Early-Onset Familial Lewy Body Dementia With Extensive Tauopathy: A Clinical, Genetic, and Neuropathological

Study.

Clarimón, Jordi PhD; Molina-Porcel, Laura MD; Gómez-Isla, Teresa MD, PhD; Blesa, Rafael MD, PhD; Guardia-Laguarta, Cristina BSc; González-Neira, Anna PhD; Estorch, Montserrat MD, PhD; Ma Grau, Josep MD, PhD; Barraquer, Lluís MD, PhD; Roig, Carles MD, PhD; Ferrer, Isidre MD, PhD; Lleó, Alberto MD, PhDAbstract: We describe a Spanish family in which 3 of 4 siblings had dementia with Lewy bodies, 2 of them starting at age 26 years and the other at 29 years. The father has recently been diagnosed with Lewy body disease, with onset at 77 years. Neuropathological examination of the brain of the index patient disclosed unusual features characterized by diffuse Lewy body disease and generalized neurofibrillary tangle pathology but with no amyloid deposits in any region. Moreover, Lewy body pathology colocalized with neurofibrillary tangles in most affected neurons.

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Cognitive Symptoms Common to AD and LBD.

Behavioral changesDecreased judgmentConfusion and temporal/spatial disorientation

Difficulty following directionsDecreased ability to communicate

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DLB COURSE The course of DLB is progressive, with

cognitive test scores declining about 10% per annum, similar to AD.

Cognitive fluctuations may contribute to large variability in repeated test scores, eg, by five

Mini-Mental State Examination (MMSE) points difference over the course of a few days or weeks, making it difficult to be sure of the severity of cognitive impairment by single examination.

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Neurotransmitter Changes in LBD. AcetylCholine 90-95% Dopamine 30-50%

No Serotonergic deficit.

Ach 5HT NE Glu Chen A.W

2008

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Dementia patients with LBP may respond more favorably to treatment with cholinesterase inhibitors………… but are more likely

to develop hypersensitivity reactions to

antipsychotic medications.

Liberini P, Valerio A, Memo F, Spano P. Lewy-body dementia and responsiveness to cholinesterase inhibitors: a paradigm for heterogeneity of Alzheimer’s disease? Trends Pharmacol Sci 1996;

1996:155-160.

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

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CLINICAL COMPARISON

LBD vs. DAT

James E. Gavin et. al. 2008. Current Issues in Lewy Body Dementia

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LBD Places High toll on Families

A cross-sectional study evaluated 84 patients with DLB or AD in a secondary care setting.

Bristol Activities of Daily Living Scale (BADLS) to assess functional impairments,

Unified Parkinson‘s Disease Rating Scale (UPDRS) to assess motor impairments,

Neuropsychiatric Inventory (NPI) and Mini-Mental Status Examination (MMSE) to assess cognitive function.

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Results The study concluded that patients with LBD

were more functionally impaired than patients with AD with similar cognitive scores.

LBD patients also had more motor difficulties than AD patients.

Total score on motor difficulties was highly correlated to functional impairment in areas of dressing, hygiene, teeth cleaning, bath/shower, toilet, transfers and mobility.

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Results II

AD patients were not shown to be significantly more impaired

than LBD patients in any of the functional areas studied.

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LBD vs AD DLB were 2 times more likely to die

at comparable ages compared with people with AD.

The average survival time for DLB was 78 years of age and for AD was 85 years of age.

Men were 1.5 times more likely to die sooner than women.

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Survival From Diagnosis

Individuals with DLB had an average survival of 7 years.

AD individuals lived 8.5 years.

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Comparative Level of Care

LBD patients used more than double the amount of resources compared to AD patients.

Specifically, DLB patients used greater resources in accommodations.

Required more outpatient care, informal care, community services and pharmacological therapy.

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Apathy: LBD vs. AD Apathy, along with other

neuropsychiatric features, was measured and found to be higher in DLB patients than AD patients.

Cost of care for DLB patients with apathy was almost three times as high as in AD patients with apathy.

Page 51: Lewy Body Dementia Slides

FLUCTUATING COGNITION

LEWY BODY DEMENTIA

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What Fluctuates?Alertness

AttentionMemoryThinkingExecutive FunctionsCommunicative SkillsApraxia, Agnosia

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Clinician Assessment of Fluctuation Scale One Day Fluctuation Assessment Scale.

Frequency and Severity of occurrence are the main aspects of FC that differentiate DLB from AD and other dementias.

“the marked amplitude between best and worst performance”

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‘‘Does the patient ever have spontaneous impaired

alertness and concentration,—that is, appear drowsy but awake, look dazed, not

be aware of what is going on around?’’

‘‘Has the level of confusion experienced by the patient tended to vary a lot recently

from day to day or week to week?’’

‘‘Has the patient had a period (or periods) today when he or she seemed to be

confused and muddled and then a period (or periods) when he or she seemed to be

improved and functioning better? Give examples of the worst and best period of

function.’’

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Fluctuating CognitionLBD

FC unrelated to situational demands.

Confabulatory or fleeting delusional quality.

short lived alterations in cognitive and functional abilities.

lapse in the stream of awareness or attention

Can’t focus properly. Blank staring during which the

patient appeared to disengage from the ongoing flow of activity or conversation

DAT Situational confusion Persisting or enduring

quality to FC Actions or thoughts are

deflected onto another task or question as a result of memory failure

Repetitiveness in conversation

Forgetfulness

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PARKINSONISM

LEWY BODY DEMENTIA

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Parkinsonian Features Relatively mild, onset usually at time of dementia (+ or – 1 year). Mostly gait changes and rigidity, tremor is rare - postural instability worse than PD (Burn et al. 2006)

Response to L-dopa not very robust -Slightly better response in younger patients

-usually doesn't worsen hallucination

Rule out recent, up to 3 months, neuroleptic exposure.

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VISUAL HALLUCINATION

LEWY BODY DEMENTIA

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Psychotic SymptomsMay be first symptomPresent in 75 to 80% of cases of LBD

Usually visual hallucination (phantom boarder, at times years before dementia)

More prominent, appears earlier than in AD

Hallucinations usually not distressing

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PVH in LBDUsually of people or animals but may be inanimate objects such as statues or pieces of furniture.

Occurs in most (> 60%) LBD cases.

Usually without emotional content.

Usually vivid, colourful... Detailed...

Related or unrelated auditory hallucinations may co-exist.

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Visual hallucinations in DLB are associated with greater

deficits in cortical acetylcholine and predict betterresponse to cholinesterase inhibitors.

Perry EK, McKeith I, Thompson P, et al. Topography, extent, and clinical relevance

of neurochemical deficits in dementia of Lewy body type, Parkinson's disease and Alzheimer's disease. Ann N Y Acad Sci. 1991;640:197-202.

McKeith IG WK, Perry E, Ferrara, R. Hallucinations predict attentional improvements with rivastigmine in dementia with Lewy bodies. Dement Geriatr Cogn Disord. 2004;18:94-100.

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TREATMENT DILEMMA

PSYCHOSISEPS

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TREAT HALLUCIANTIONS.......

HALLUCINATIONS& PSYCHOSIS

EPS

Chen A.W. (2012)

Page 65: Lewy Body Dementia Slides

TREAT ESP.............HALLUCINATIONS

& PSYCHOSIS

EPS

Chen A.W.

(2012)

Page 66: Lewy Body Dementia Slides

Management of Psychotic Symptoms. Caregiver education, benign neglect

Increased socialization, lighting

Avoid anticholinergics

Minimize/optimize antiparkinsonians

Atypicals at times. -avoid risperidone and

aripripazole

Page 67: Lewy Body Dementia Slides

NEUROLEPTIC SENSITIVITY

LEWY BODY DEMENTIA

Page 68: Lewy Body Dementia Slides

Neuroleptics and LBD

Most patients have severe reaction to typical (and atypical) neuroleptics, including severe akinesia, dystonia and NMS-like symptoms. > 50% affected

Greater sensitivity than in PD. Prolongs hospitalization in 81%, reduces

lifespan in 50% (McKeith et al 1992) Doubles rate of cognitive decline (McShane

et al. 1997) A severe , unexpected reaction to low dose

antipsychotic strongly suggests LBD

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Neuroleptics et. al.

Dopamine Blockers Not restricted to anti-psychotics. Anti-emetics Chlorpromazine Prochlorperazine. Promethazine.

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Neuroleptic sensitivity in Parkinson's disease and parkinsonian dementias.

Aarsland et at. J Clin Psychiatry 2005 May;66(5):633-7. Background: Severe sensitivity to neuroleptic agents is a major clinical problem in dementia with Lewy bodies (DLB), but has not been determined in Parkinson's disease (PD) and PD with dementia (PDD).

Method: Severe neuroleptic sensitivity reactions (NSRs) were evaluated according to an operationalized definition blind to clinical and neuropathologic diagnoses in prospectively studied patients exposed to neuroleptics from 2 centers. The study was conducted from June 1995 to May 2003.

Results: Ninety-four patients were included (15 with DLB, 36 with PDD, 26 with PD, 17 with Alzheimer's disease, all diagnosed with various operational criteria). Severe NSR only occurred in patients with Lewy body disease: DLB (8 [53%]), PDD (14 [39%]), and PD (7 [27%]), but did not occur in Alzheimer's disease (p = .006). Severe NSR was not associated with other clinical or demographic features. In DLB, severe NSR was not associated with neuropathologic indices (Consortium to Establish a Registry for Alzheimer's Disease staging, Braak staging, or cortical distribution of Lewy bodies).

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Possible Signs of NSR  Excessive initial sedation Sudden onset of rigidity Postural instability, Falls. Rapid general deterioration, Increased confusion, Immobility, rigidity, Fixed flexion posture, Decreased food intake

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NEUROLEPTIC MALIGNANT SYNDROME

 FALTER F – Fever A – Autonomic instability L – Leukocytosis T – Tremor E – Elevated enzymes (elevated CPK) R – Rigidity of muscles

Altered consciousnessTachypnoeaElevated arterial pressure

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Treatment & Management

Discontinue all antipsychotics. Supportive measures: circulatory and

ventilatory support as needed. Cooling blankets and antipyretics can be used

to control temperature. Aggressive fluid resuscitation and alkalization

of urine can help prevent acute renal failure and enhance excretion of muscle breakdown products.

Benzodiazepines and physical restraints may be useful.

The value of other interventions, such as dantrolene, amantadine, bromocriptine, and electroconvulsive therapy, is uncertain

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Current Clinical Experience  Olanzapine appears to be poorly

tolerated. Risperidone has been associated with

high risk of neuroleptic malignant syndrome.

Clozapine use remains controversial because of its potent anticholinergic action and risk of agranulocytosis. Established efficacy in PDD/LDB

Quetiapine has been shown to reduce psychiatric manifestations of DLB without causing neuroleptic sensitivity or increasing EPS.

Hence, quetiapine is an attractive candidate for the treatment of psychoses in DLB and other dementias.

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AUTONOMIC DYSFUNCTION

LEWY BODY DEMENTIA

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Autonomic Dysfunction

Approximately 62% of patients with DLB experience significant autonomic failure,

and dysautonomia is observed in up to 80% of

patients with PD

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Autonomic Dysfunction: Blood pressure fluctuations (e.g.

postural/orthostatic hypotension). Heart rate variability (HRV), Constipation, Sialorrhea , Sleep disturbances Urinary problems, Hyperhidrosis, decreased sweating/heat

intolerance. Syncope (fainting),  Temperature dysregulation. Dry eyes/mouth, and difficulty

swallowing which may lead to aspiration pneumonia.

Sexual disturbances/impotence,

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Primary Autonomic Failure/dysfunction of CVS in LBD

OH

Supine or nocturnal hypertensi

onPostprandi

al hypotension, (PPH)

60%Carotid Sinus

Syndrome 40%

QTcBradyarrhythm

iasChen A.W.

(2012)

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Potential inducers of OH in LBD

Antiparkinsonian medications, Diuretics, alpha-blockers, Oral nitrates, Tricyclic antidepressants, beta-blockers, alpha-1 adrenergic receptor

antagonists, Calcium channel blockers, monoamine oxidase inhibitors, ethyl alcohol abuse.

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Autonomic dysfunctions in dementia with Lewy bodies.

Horimoto et. al. J Neurol. 2003 May;250(5):530-3. 29 DLB were retrospectively examined for

autonomic symptoms. Twenty-eight cases showed some kind of

autonomic dysfunction. (96.5%) Urinary incontinence (97 %) , urinary retention

28% Constipation (83 %) . Episodic hypotension

28% There were 18 cases (62 %) with severe

autonomic failure. LBD of all pathological subtypes exhibits some kind and level of autonomic

symptoms.

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Treating OH Compression stockings Frequent, small meals, High-salt diet, Increased fluid intake Fludrocortisone, Midodrine, Ephedrine. SSRI’s

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REM SLEEP BEHAVIOR DISORDER

(RBD)

LEWY BODY DEMENTIA

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Anatomy of SleepN-REM SLEEP

REM SLEEP Dreaming Irregular Breathing Muscular Atonia Elevated Blood Pressure Rapid Movement of Eyes

Stage 1 1Stage II

Stage III

Stage IV

Che n A. W (2012)

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REM-Sleep Behavior Disorder (RBD). (Parasomnia)

Characterized by loss of muscle atonia during dreaming, producing “acting out” of dream (e.g., punching, kicking, rolling off bed, yelling, screaming)

RBD is characterized by the acting out of dreams that are vivid, intense, and violent.

Highly sensitive & specific for “synucleopaties” (PD, DLB, MSA.)

An acute form may occur during withdrawal from alcohol or sedative-hypnotic drugs.

Very responsive to low dose clonazepam.

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Clinical Correlates of RBD

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DEPRESSIVE PHENOTYPE

LEWY BODY DEMENTIA

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Depressive Symptoms Increased irritability,

Poor concentration, lack of attention during

interactions, Sadness or a negative mood, Poor appetite or sleep, or the

opposite over-eating and sleeping too much

Withdrawal from normal activities General apathy

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NEUROIMAGING

LEWY BODY DEMENTIA

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ImagingComparis

on

Alzheimer’s

LBD

CT/MRI Generalized atrophy. > MTL

Generalized atrophy. Sparing MTL

Deep WM lesions on MRI

Moderate increase relative to normal

Moderate increase relative to normal

Peri-venricular WM on MRI

Comparable to normal Comparable to normal

SPEC (blood flow) Global reduction. > posterior P-T, MTL

Global reduction. > occipital. MTL normal

SPEC (dopamine transporter)

~ Normal for age Reduced in putamen, similar to PD

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90

Functional imaging (PET) in other dementias:

Dementia with Lewy Bodies

PET image provided by, and used with the kind permission of, Dr Pablo Martínez-Lage

Normal control DLB

18F-Glucose

18F-Dopa

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SPECT control vs. LBD

control LBD

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 D2 receptors in striatum - DLB neuroleptic tolerant

 D2 receptors in striatum - neuroleptic sensitive

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Guidelines for Diagnosis of DLB(McKeith et al., Neurology 1996;47:1113-1124)

Mandatory: Dementia

Core features:1. cognitive & behavioral fluctuations,

2. Parkinsonism, 3. visual hallucination, also 4.REM-sleep behavior disorders.

Supporting features: 1.syncope (often due to orthostatic

hypotension), 2.repeated falls, 3.transient loss of consciousness, 4.paranoid delusions, 5.neuroleptic sensitivity, 6.non-visual hallucinations.

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ALZHEIMER’S DISEASE ASSESSMENT & TREATMENT CENTRE

CHEN LEWY BODY DISEASE QUESTIONNAIREPatient Name: ………………………………… Age:…………

Address: ……………………………………… Date: ………..

Please answer the following questions, yes or no!1. Is there evidence of Cognitive Impairment? YES / NO 4 2. Is there shuffled gait or rigidity? YES / NO 4 3. Is there evidence/history of vivid visual hallucinations? YES / NO 44. Is there fluctuation of cognition or attention? YES / NO 45. Is there a history of sensitivity to neuroleptics? YES / NO 46. Is there complains of sleeping disorder, acting out dreams? YES / NO 27. Is there a history of frequent falls or black-outs? YES / NO 28. Is memory relatively intact? YES / NO 29. Is there hypotension, constipation or excessive sweating? YES / NO 2 10. Is there an evident tremor? YES / NO 211. Did motor signs and cognitive impairment occur within 18 months of each other? YES / NO 212. Are there false ideas about other persons or situations? YES / NO 2

TOTAL SCORE: /34 Interpretation: 20 or more Lewy Body Dementia

12-20 Probable LBD

8-12 Possible LBD

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Hypothetical Treatment Model LBD.Neuro-Chemical Deficit/

SyndromeMechanism of interaction

Proposed Treatment

ACETYLCHOLINEDEFICIT

DELAY BRAKEDOWN OF ACETYLCHOLINE IN SYNAPTIC CLEFT BY INHIBITING ACETYL- AND BUTYL CHOLINESTERASE

DONEPEZILRIVASTIGMINE

GALANTAMINE HCL

PARKINSONISM INCREASE DOPAMINE LEVEL

Sinemet ?? ??Benign neglect, PT

NO SEROTONIN DEFICITYet Depressed Affect

INHIBIT REUPTAKE OF 5HT ??

SSRI’S NOT NEEDED??AChEI may help

REM SLEEP BEHAVIOR DISORDER

SYNUCLEOPATHIES MELATONINCLONAZEPAM

PSYCHOSIS/HALLUCINATION BENIGN NEGLECTCAREGIVER TRAINING

SEROQUEL

GLUTAMATE NMDA- RECEPTOR INHIBITION

MEMANTINE HCL

Autonomic Dysfunction OH, PPH, Constipation, CSS

Salt & fluid intake, SSRI, Elevate bed head,

laxatives

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WISH LIST Better understanding of free radical brain

interaction. Develop new drugs to prevent FR brain

damage. New drugs to chelate cross-linked protein

aggregate from brain. Cross the new BBB frontier. nitromemantines

Improved awareness of LBD & other dementias.

Increased willingness of PCP to diagnose early, and treat persons with dementia.

Better tolerated, safer, more effective drugs to treat the various neurotransmitter deficits.

Combination drugs to address multiple deficits.

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“we are like dwarfs on the shoulders of giants, so

that we can see more than they, and things at a

greater distance, not by virtue of any sharpness of sight on our part, or any physical distinction, but because we are carried high and raised up by

their giant size." John of Salisbury, 1159

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THANK YOU!

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A woman in her early 50s was admitted to a hospital because of increasingly odd

behavior.

Her family reported that she had been showing memory problems and strong

feelings of jealousy. She also had become disoriented at home and was hiding objects. During a doctor's examination, the woman

was unable to remember her husband's name, the year, or how long she had been at

the hospital. She could read but did not seem to understand what she read, and she

stressed the words in an unusual way. She sometimes became agitated and

seemed to have hallucinations and irrational fears.

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“You have dementia, none of the drugs work so there’s is little to do, so get your

finances in order and plan for a

painful next few years when you won't recognize your family, will need to live in a

nursing home..... "

Frustrated doctor

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FREE RADICAL THEORY OF AGEING.

Organisms age because cells accumulate free radical damage over time.

A free radical is any atom or molecule that has a single unpaired electron in an outer shell.

Cross linkage between proteins. Free radicals: superoxide ( O2

- ), H2O2, OH. Antioxidants: Vit. A, Vi. C, Vit. E, SOD

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Queries What governs the type of precipitate

formed by free radical induced protein aggregation?

How do we reduce CNS free radical proliferation?

How do we remove free radicals and cross-linked protein aggregates from the brain?

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LBD Prevalence LBD accounts for 15-20% of dementia

cases in hospital autopsy series.

UK community-based dementia case register studies confirms.

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Dementia with Lewy bodiesIan McKeith,MD, FMedSci

A recent community study of 85+ year olds found 5.0% to meet clinical diagnostic criteria for DLB, representing 22% of all demented Cases.

Rahkonen T, Eloniemi-Sulkava U, Rissanen S, Vatanen A, Viramo P, Sulkava R. Dementia with Lewy bodies according to the consensus criteria in a general population aged 75 years or older. J Neurol Neurosurg Psychiatry. 2003;74:720-724.

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Prevalence of LBD7 to 30% of all dementias at autopsy.

Possibly more common than vascular dementia.

Most common incorrect diagnosis in brain bank programs.

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 Neuropathology In DLBA. Substantial nigra hematoxylin-eosin stain, arrows -- Lewy bodies.B. Cerebral cortex hematoxylin-eosin stain, arrows -- Cortical Lewy body.C. Basal forebrain synuclein stain, arrow -- Lewy body, arrowhead -- Lewy neuriteD. Cerebral cortex synuclein stain, arrow -- Cortical Lewy body, arrowhead -- Lewy neurite

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Dementia with Lewy Bodies