lewy body disease - uci mind©2014 mfmer | 3351930-10 clinical features core features parkinsonism...

©2014 MFMER | 3351930-1

Lewy Body Disease Neill R Graff-Radford, MBBCh, FRCP (London)

©2014 MFMER | 3351930-2

Disclosure

• Dr. Graff-Radford receives funding from several NIA grants

• He is also funded for several multicenter studies by Lilly, TauRx, Biogen, Axovant

• He has also consulted for Cytox

[email protected]

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History of DLB •  In 1912, Fritz Jakob Heinrich Lewy (1885-1950)

described the cellular inclusions that are characteristic of Parkinson disease

• Konstantin Nikolaevich Tretiakoff (1892-1956) named them after Lewy (‘corps de Lewy’, or Lewy bodies) in 1919

Goedert M et al: Nat Rev Neurol 9:13, 2013

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Lewy Body Disease • Consensus Criteria • Clinical Features •  Imaging

•  18F-FDG PET •  123I-β-CIT SPECT • PIB

• Pathology • Management

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Clinical Features Core Features

Parkinsonism

•  Parkinsonism is common in community •  15% of people 65 to 74 years of age, 30% of those

75 to 84, and 52% of those 85 and older

•  Fewer than half of DLB cases have parkinsonism at presentation

•  A fourth continue to have no evidence of them throughout their illness

•  Compared to PD less resting tremor and myoclonus, greater symmetry and worse response to levodopa

Bennett DA et al: NEJM 334:71, 1996 Louis ED et al: Neurology 48:376, 1997

Gnanalingham KK et al: JNNP 62:243, 1997

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Hallucinations (fully formed) • Occur in 32-85% of autopsy-confirmed cases • 11-38% of those with AD without concomitant α-synucleinopathy

• When visual hallucinations developed within the first 5 years of dementia, the odds were 4-5 times greater for autopsy-confirmed LBD

Ferman TJ et al: Parkinsonism & Related Disorders, 2013

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Fluctuations in cognitive performance and alertness, either in the form of • Episodic confusional states resembling

delirium or • Transient periods of reduced or loss

of consciousness

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Clinical Features Core Features (cont)

Fluctuations may be misinterpreted as • Vascular events • Sundowning • Confusional states • Toxic metabolic processes

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Clinical Features Suggestive Features

Rapid Eye Movement (REM) sleep behavior disorder

•  REM Behavior Disorder (RBD) increased the odds by 6-fold of autopsy-confirmed DLB

•  More than core LBD features

•  The National Alzheimer’s Coordinating Center registry reported the sensitivity of clinical diagnoses of DLB compared to subsequent pathologic examination to be 32.1%

•  172 Path confirmed RBD cases LBD(n=138), MSA (n=19), AD (n=6), PSP(n=2)

Boeve BF, Silber MH, Ferman TJ et al: Neurology, 1998 Nelson PT, et al: J Neurol 257:359, 2010

Boeve BF: Sleep Med (8):754, 2013

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Boeve et al: Sleep Med 12(5): 445, 2011

The core question on recurrent dream enactment behavior yielded a sensitivity of 98% and specificity of 74% for the diagnosis of RBD

Please mark “Yes” if the described event has occurred at least 3 times

1.  Have you ever seen the patient appear to “act out his/her dreams” while sleeping? (punched of flailed arms in the air, shouted or screamed)

0 no 1 yes

•  If Yes a.  How man months or years has this been going on?

year(s) months

b.  Has the patient ever been injured from these behaviors (bruises, cuts, broken bones)?

c.  Has a bed partner ever been injured from these behaviors (bruises, blows, pulled hair)?

No Yes No bed partner

d.  Has the patient told you about dreams of being chased, attacked or that involve defending himself/herself?

No Yes Never told you about dreams

e.  If the patient woke up and told you about a dream, did the details of the dream match the movements made while sleeping?

0 no 1 yes

No Yes Never told you about dreams

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Clinical Features Suggestive Features

Neuroleptic sensitivity • Neuroleptic sensitivity, detected in 61% of all

DLB patients who receive neuroleptics but in only 15% of AD patients

McKeith I et al: Br Med J 1992;305:673, 1992

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Clinical Features Supportive Features •  Repeated Falls (up to a third of DLB cases)

•  Autonomic dysfunction •  Urinary incontinence (97%) and constipation (83%)

most common; urinary retention and syncopal attacks were less common (28% each)

•  Hallucinations in other modalities/Delusions

•  Depression

•  Abnormal Scintigraphy

•  Abnormal EEG (abnormal in up to 90% of DLB patients; loss of alpha rhythm and transient slow-wave activity in the temporal lobe areas are the most common changes)

•  Relative preservation of medial temporal lobe structures on CT/MRI scan Horimoto Y: J Neurol 250(5):530, 2003

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Background on Imaging (18FDeoxy Glucose)

• Numerous studies have reported occipital hypoperfusion and hypometabolism in DLB patients, and parietotemporal reduction is common to both AD and DLB Kantarci Neurobiol . Aging 2012 33:2091 -05

• The cingulate cortex in DLB, compared with that in AD, appears to be relatively spared Journal of Nuclear Medicine 50:1638, 2009

• One study comparing autopsy results with PET findings found that glucose hypometabolism in the primary visual cortex distinguished DLB from AD with 90% sensitivity and 80% specificity Journal of Nuclear Medicine 50:1638, 2009

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•  18F-FDG PET (top row) and β-CIT SPECT images (middle row) overlaid on MRI in patient with DLB (left column) and patient with AD (right column) who had diagnosis confirmed at autopsy

•  Immunohistochemical stain for – synuclein demonstrates frequent Lewy bodies in DLB patient (black arrows) but none in AD patient; white arrow points to posterior cingulate cortex on 18F-FDG PET study, demonstrating cingulate island sign of DLB

Journal of Nuclear Medicine 50:1638, 2009

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Background on Imaging the Dopamine Transporter (DAT) •  The pathologic feature can be studied via neuroimaging

using radioligand binding to the DAT (dopamine transporter)

•  SPECT with 123I-b-carbomethoxy-3β-(4-iodophenyl) tropane (123I-β-CIT) examining the ratio of binding in the striatum to binding in the occipital cortex has been shown to reliably quantify DAT density

•  FDA approved DaTscan (Ioflupane I 123 injection, also known as phenyltropane), a radiopharmaceutical agent which is injected into a patient’s veins in a procedure referred to as SPECT imaging

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0 1 2 3 4 5 6 7 8 9

DLB AD

•  Box plot of median and interquartile range of DAT binding parameter obtained from 123I-β-CIT scans

•  Results are calculated as V3, ratio of mean striatum to occipital cortex

•  Values in brackets are mean and SD

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0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0

AD DLB PDD PDD NCS

Dis

tribu

tion

volu

me

ratio

Amyloid Deposition in Lewy Body Diseases

Gomoperts et al: Neurology 71:903, 2008

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Amyloid Burden (PIB)

Gomoperts et al: Neurology 71:903, 2008

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PIB and LBD •  Cortical amyloid burden was higher in the DLB group

than in the PDD group, comparable to the AD group

•  Amyloid deposition in the PDD group was low, comparable to the PD and NC groups

•  Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups

•  For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/ posterior cingulate region was related to visuospatial impairment

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•  Kantarci K Neurobiol . Aging 2012 33:2091 -05 •  Three-dimensional view of the imaging variables in patients with Alzheimer's disease (AD) and Dementia

with Lewy bodies (DLB) •  Red plots represent the DLB subjects while blue plots represent the AD subjects •  Observations that appear larger represent data points that are closer to the viewer •  The ellipsoids for the 2 groups are concentration ellipsoids •  For each group, assuming normality, the dimensions have been set to contain half of the expected values •  Except for 1 DLB patient, all AD and DLB patients are separated using multimodality imaging measures

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Probability of Lewy-Related Cognitive Disorder Dickson Lancet Neurology 2009 8:1150

Kosaka criteria NFT stage 0-2/

CERAD possible NFT stage 3-4/

CERAD probable NFT stage 5-6/ CERAD definite

Brainstem Low Low Low Transitional High Intermediate Low Diffuse High High Intermediate

Data based on NIA–Reagan criteria1 for Alzheimer’s disease-type pathology. The probability matrix is shown as proposed by the third Consortium of Dementia with Lewy Bodies,2 in which Lewy pathology and Alzheimer’s disease-type pathology determines the likelihood of a Lewy-related cognitive disorder (dementia with Lewy bodies or Parkinson’s disease with dementia). Distribution of Lewy bodies and Alzheimer’s disease-type pathology are the two major axes in the matrix. CERAD=Consortium to Establish a Registry for Alzheimer’s Disease. NFT=neurofi brillary tangles. NIA=National Institute on Aging.

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Management • Cognitive • Motor • Neuropsychiatric/Mood • Sleep • Autonomic • Lifestyle

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Management: Cognitive (Memory/Attention) •  Randomized, controlled double blind trial

of donepezil in DLB

•  Responder rate (MMSE change >3) was significantly higher in all donepezil groups (3mg, 42.9%, 5mg, 65.6%, 10 mg, 44.4%) compared to placebo (12.9%)

•  On the WMS-R attention/concentration and WAIS-III symbol digit tests, significant improvements were also noted in each dose group compared to placebo

•  No improvement in category fluency, letter fluency, or visual-spatial functioning

Mori E. Donepezil for Dementia with Lewy Bodies: A Randomized, Placebo-Controlled Trial ANN NEUROL 2012

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Management: Motor • Parkinsonism

•  Less responsive to levodopa but still responsive

•  Slow titration •  In UK study, 12/16

DLB and 15/15 PD responded

•  Falls •  PT/OT •  Prescribe

exercise plan Louis ED et al: Neurology 48:376, 1997

Gnanalingham KK et al. J Neurol Neurosurg Psychiatry 62:243, 1997

DLBD PD Cases (no.) 31 34 Gender Male (%) 22 (71.0%) 22 Female (%) 9 (29.0) 12 Mean age at onset (yr) 67.9 62.0 Mean disease duration (yr) 9.5 14.5 Mean age at death (yr) 77.3 76.0 Presenting signs Parkinsonism (%) 7 (24.1) 31 (93.9) Cognitive or psychiatric (%) 21 (72.4) 2 (6.1) Both (%) 1 (3.5) 0 Not known 2 1 Clinical diagnoses Parkinsonism (%) 4 (12.9) 30 (83.3) AD or dementia (%) 17 (54.8) 2 (5.6) Both (%) 10 (32.3) 4 (11.1) Rest tremor (%) 11/20 (55.0) 17/20 (85) Any tremor (%) 19/25 (76.0) 23/26 (88.5) Rigidity (%) 24/26 (92.3) 20/21 (95.2) Bradykinesia (%) 17/19 (89.5) 19/20 (95.0) Dystonia (%) 2/29 (6.9) 1/26 (3.8) Myoclonus (%) 5/27 (18.5) 0/26 (0) Gaze palsy (%) 1/28 (3.6) 0/26 (0) Trial of levodopa (%) 10/24 (41.7) 14/15 (93.3) Clinical response to levodopa (%) 7/10 (70.0) 14/14 (100)

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Management: Neuropsychiatric Apathy, indifference, anxiety, delusions, hallucinations, and aberrant motor behavior significantly improved on Rivastigmine

McKeith I et al: Lancet 356: 2031, 2000

Mean Changes (95% CIs) of Individual NPI Items – Observed-Cases Analysis

-3.00

-2.00

1.00

0

1.00

2.00 Det

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ratio

n Im

prov

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Mea

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from

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eek

20)

Rivastigmine Placebo

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Management: Neuropsychiatric Hallucinations/Delusions •  Improve with cholinesterase inhibitors • Remove medications that may induce

• Dopamine Agonists, Anticholinergics • Neuroleptics

• Avoid typical antipsychotics

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Management: Neuropsychiatric Depression • Lack of randomized control data in DLB • Avoid TCA (Anticholinergic) • Can consider SSRI (May worsen RBD/Tremor)

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Management-Autonomic Dysfunction Constipation • Occurs in 89% of PD patients • 16% hospitalized with bowel obstruction • Treat with psyllium/high fiber diet • 42% complained of social isolation due to fear

of fecal incontinence

MDS 17th International Congress of Parkinson's Disease and Movement Disorders, Volume 28, June 2013 Abstract Supplement. Lawrence J.

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Management-Autonomic Dysfunction Orthostatic hypotension • Remove unnecessary vasodilators • Encourage hydration • Salt tablets • Thigh high stockings/abdominal binders • Refractory cases may need

Fludrocortisone or Midodrine

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Management-Autonomic Dysfunction Incontinence in 90% • Trospium is an anti-cholinergic that

does not cross BBB • Avoid Oxybutinin Erectile dysfunction • Phosphodiesterase-5 inhibitors

Sakakibara R: JNNP 76(5):729, 2005

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Management-Sleep RBD

•  Non-pharmacological •  Remove sharp objects,

create barriers •  Bed alarms to detect

significant movement

•  Pharmacological •  Melatonin is safe and

effective •  Clonazepam can be

added second line but can increase risk of confusion/falls

88

48

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20

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20

94

44

67

33

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33

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20

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60

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100 Melatonin Clonazepam

Pre treatment

DEB

Post treatment

DEB

Pre treatment

falls

Post treatment

falls

Pre treatment

injury

Post treatment

injury

Pat

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s (%

)

Percentage of RBD patients reporting dream enactment behaviors, falls, and injury before and after treatment with melatonin or clonazepam; statistically significant improvements were seen for melatonin in RBD DEB, falls, and injury; trends toward similar improvements were seenwith clonazepam treatment

McCarter SJ et al: Sleep Med, 2013

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Management-Sleep Excessive daytime sleepiness • Good sleep history, overnight PSG •  Stimulants can be effective but have risk of

psychosis and addiction • Modafinil and Armodafinil have safer profiles

although only covered if documented OSA • Open-label pilot study using armodafinil 250 mg

taken orally every morning in patients with hypersomnia associated with DLB; 90% reported improvement

Kuntz K et al: Neurology 25:78(Meeting Abstracts 1): P04.192, 2012

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Lifestyle Physical Activity and Future Risk of

Parkinson Disease

• 213,701 participants in AARP-NIH diet and healthy study age range 50-71

• Physical activities over 4 periods (ages 15-18, 19-29, and 35-39, and in the past 10 yr) were noted in 1996-1997

• 767 incident case after 2000, age range • Recall of more exercise between age 35-39

0.62 (95% CI 0.48-0.81, P=0.005); last 10 yr 0.65 (95% CI 0.51-0.83, P=0.0001) associated with lower number of cases

Xu Neurology 75:341, 2010

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Meta-Analysis of Prospective Studies on Physical Activities and Risk of Parkinson Disease

Xu et al: Neurology 75:341, 2010

Gender/study OR (95% CI) OR (95% CI) Men Shen, 2005 0.40 (0.20, 1.20) Thacker, 2008 0.70 (0.50, 1.10) Logrosinco, 2006 0.63 (0.36, 1.12) Current 0.68 (0.51, 0.90) Subgroup 0.66 (0.53, 0.82) Women Shen, 2005 1.00 (0.50, 1.80) Thacker, 2008 0.40 (0.20, 1.00) Current 0.60 (0.37, 0.85) Subgroup 0.67 (0.48, 0.94) Total 0.67 (0.56, 0.80)

0.1 0.2 0.5 1 2

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Effectiveness of Exercise Interventions for People With Parkinson's Disease

Movement Disorders 23:631,2008

Study (outcome) F-U weeks

Standardized mean diff. (95% CI) Weight (%)

Comella, 1994 (UPDRS) 4

-0.07 (-0.87, 0.73) 11.5

Ellis, 2005 (UPDRS) 6

-0.85 (-1.35, -0.36) 18.3

Bridgewater, 1997 (NUDS) 16

-1.15 (-1.98, -0.32) 10.9

Burini, 2006 (UPDRS) 22

-0.50 (-1.31, 0.31) 11.3

Miyai, 2002 (UPDRS) 26

-0.99 (-1.93, -0.05) 9.4

Ashburn, 2007 (SAS) 26

-0.10 (-0.45, 0.24) 22.5

Schmitz-Hubsch, 2005 (UPDRS) 52

-0.04 (-0.61, 0.53) 16.2

Ocerall (95% CI) -0.47 (-0.82, -0.12)

1 0 -1 -2

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MD

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Nonmotor Experiences of Daily Living eg, Cognition, Sleep, Hallucinations

Motor Aspects of Experiences of Daily Living eg, Drooling,

Swallowing Motor Examination

Time (mo) Time (mo) Time (mo)

Tango Control

* * *


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15 16 17 18 19 20 21 22 23

-3 0 3 6 9 12 Time (mo)

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In Summary • Lewy Body Disease is common • Parkinsonism, visual hallucinations, fluctuations

and REM sleep disorder help with the diagnosis • Many aspects are treatable • Avoid typical antipsychotics

lewy body disease - uci mind©2014 mfmer | 3351930-10 clinical features core features parkinsonism...

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