Lewy Body Dementia: Diagnosis, Management and Future Directions

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1 Lewy Body Dementia: Diagnosis, Management and Future Directions Bradley F. Boeve, M.D. Divisions of Behavioral Neurology and Movement Disorders Center for Sleep Medicine Department of Neurology Mayo Clinic Rochester, Minnesota

2 Disclosures Financial/Other Investigator for clinical trials sponsored by Cephalon, Inc., Allon Pharmaceuticals, and GE Healthcare Royalties from the publication of a book entitled Behavioral Neurology Of Dementia (Cambridge Medicine, 2009) Honoraria from the American Academy of Neurology Research support from the NIA, NINDS, Alzheimer's Association, and Mangurian Foundation Off-label and/or Investigational Use Will discuss use of many medications which are not FDA-approved for the indications to be reviewed

3 Dementia with Lewy Bodies/Lewy Body Dementia Outline Nomenclature Diagnostic Features Management Options Future Directions

4 The Syndrome Dementia With Lewy Bodies Nomenclature Dementia with Lewy bodies (DLB)/Lewy body dementia (LBD) Clinically probable DLB Clinically possible DLB The Disease Lewy body disease (LBD) brainstem limbic neocortical

5 Clinical Features and Diagnostic Criteria Core features Dementia syndrome plus: Spontaneous parkinsonism (unrelated to drugs) Recurrent fully formed visual hallucinations Fluctuating arousal/cognition 2 or 3 of above = clinically probable DLB 1 of above = clinically possible DLB McKeith et al, Neurology 1996 McKeith et al, Neurology 1999 McKeith et al, Neurology 2005

6 Clinical Features and Diagnostic Criteria Suggestive features (one or more present in addition to one or more core features is sufficient for a diagnosis of probable DLB, and in the absence of any core features is sufficient for possible DLB) REM sleep behavior disorder (which may precede onset of dementia by several years) Severe neuroleptic sensitivity Abnormal (low uptake) in basal ganglia on SPECT dopamine transporter scan Boeve et al, Neurology 1998 McKeith et al, Neurology 2005

7 Clinical Features and Diagnostic Criteria Ferman et al, Neurology 2012 Core features Dementia syndrome plus: Spontaneous parkinsonism (unrelated to drugs) Recurrent fully formed visual hallucinations Fluctuating arousal/cognition RBD Any 2 of the following c/w DLB RBD plus 1 of the other features - >90% accurate

8 Video Example - RBD

9 Hypersomnia The data confirms subjective (ESS) and objective evidence of EDS (MSLT) is present in DLB and not in AD. Ferman et al, AAN 2010

10 Neuropsychiatric Features The most frequent neuropsychiatric features in DLB: Visual hallucinations Illusions Delusions (including Capgras syndrome) Depression Apathy

11 Neuropsychological Features Ferman et al, Neurology 1999 Ferman et al, Clin Neuropsych 2006 Cognitive Domains Learning & Memory Language Executive Functions Visuospatial Functions Impairment 0 to ++ 0 to + + to to +++

12 Neuropsychological Features Evaluation 2 14 AD Impaired on: Memory measures BNT and/or Cat Flu 2 0 DRS WMS- LM WMS- VR AVLT-PR BNT COWAT CAT FLU TMT-A TMT-B WAIS- DS WAIS- BD WAIS- PC REY-O Global Memory Language Attention/Executive Visuospatial Evaluation 1 DLB Impaired on: TMT, Dig Symbol WAIS-BD, -PC Rey-O CFT 0 DRS WMS-LM WMS-VR AVLT-PR BNT COWAT CAT FLU TMT-A TMT-B WAIS- DS WAIS- BD WAIS- PC Global Memory Language Attention/Executive Visuospatial REY-O Ferman et al, Neurology 1999 Ferman et al, Clin Neuropsych 2006

13 Please draw this figure: Dementia With Lewy Bodies Neuropsychological Features Please draw this figure: Draw a clock showing the time of 11:10:

14 Neuroimaging Features MRI Normal AD DLB normal hippocampi hippocampal atrophy normal hippocampi

15 Neuroimaging Features MRI VBM Whitwell et al, Brain 2007

16 Neuroimaging Features FDG-PET Normal

17 Neuroimaging Features FDG-PET Kantarci et al, Neurobiol Aging 2011 AD Posterior cingulate Temporoparietal Frontal DLB Occipital

18 Neuroimaging Features - DaTscan caudate Ioflupane putamen DaTscan - meaures nigrostriatal uptake of dopamine transporter in the caudate and putamen Normal

19 Neuroimaging Features - DaTscan AD DLB

20 Neuropathologic Features A B C A Ach DA 5-HT HCT-1 Ach? (RBD) B C

21 Neuropathologic Features H&E -synuclein Photomicrographs courtesy Dennis Dickson, M.D.

22 Clinical Tools - ESS

23 Clinical Tools - MSQ 1. Have you ever seen the patient appear to act out your dreams while sleeping? (punched or flailed arms in the air; shouted or screamed) SN: 100% SP: 97% Olmsted County

24 Clinical Tools - MFS Nl AD DLB Ferman et al, Neurology 2004

25 Clinical Tools - Friedman Friedman Palate Position Friedman Tonsil Grading Friedman et al, Laryngoscope 2004;114:

26 Management Consider symptoms as they relate to: cognitive impairment neuropsychiatric features motor features sleep disorders autonomic dysfunction Ask patient/family to prioritize the most troublesome issues they seek to change Boeve BF. AAN Continuum 2004

27 Management Cognitive impairment Varying degrees of memory impairment Verbal blocking Executive dysfunction Bradyphrenia Spatial/geographic disorientation Visual misidentification Fluctuations Management Education and counseling Therapies: Aricept, Razadyne, Exelon Sinemet, Mirapex Provigil, Nuvigil, methylphenidate, Adderall

28 Cognition issues Dementia With Lewy Bodies Brain-Behavior Relationships Mainly due to reduced Ach Reductions in other brain chemicals contributes to cognitive impairment Some degree of neuron cell loss too A A B C HCT B Ach DA 5-HT C

29 Management Neuropsychiatric features Visual hallucinations Illusions Delusions Capgras syndrome Depression Anxiety Agitation/aggressive behavior Management Education and counseling Therapies: Aricept, Razadyne, Exelon SSRIs, melatonin Seroquel, Zyprexa Provigil, Nuvigil, methylphenidate, Adderall NO HALDOL

30 Brain-Behavior Relationships Neuropsychiatric issues Hallucinations and delusions related to DA imbalance Depression related to low 5-HT Apathy many causes A B C A B Ach DA 5-HT C

31 Management Motor dysfunction Tremor Bradykinesia Rigidity Myoclonus Shuffling gait Stooped posture Difficulty with fine motor skills Masked facies Sialorrhea Management Education and counseling Therapies: Sinemet Mirapex, Requip, Neupro patch (when available) Clonazepam, Neurontin

32 Motor issues Dementia With Lewy Bodies Brain-Behavior Relationships The Parkinson s disease-like features (parkinsonism) primarily relate to the reduction in DA A A B C B DA C

33 Management Sleep disorders REM sleep behavior disorder Excessive daytime somnolence Insomnia Obstructive sleep apnea Central sleep apnea Restless legs syndrome Periodic limb movement in sleep Management Education and counseling Therapies: Clonazepam, Melatonin Provigil, Nuvigil, methylphenidate, Adderall Trazodone, Ambien, chloral hydrate nasal CPAP oxygen, temazepam Mirapex, Sinemet

34 Sleep issues Dementia With Lewy Bodies Brain-Behavior Relationships Daytime sleepiness, insomnia, and fragmented sleep relate in part to the loss in HCT Acting out dreams (RBD) relates to changes in the dorsal pons Reduced DA and 5-HT also affects sleep A A B C HCT B DA 5-HT? C

35 Management Autonomic dysfunction Orthostatic hypotension Impotence Urinary incontinence Constipation Management Education and counseling Therapies: Midodrine, Florinef, salt Viagra, etc. Enablex, Gelnique, Sanctura Senokot, MiraLAX

36 Autonomic issues Many autonomic changes related to changes in the spinal cord and peripheral nerves in and around the: heart stomach intestines bladder sex organs Dementia With Lewy Bodies Brain-Behavior Relationships

37 Management Initial evaluation Follow-up evaluation donepezil levodopa CPAP MMSE: 21 ESS: 14 MMSE: 28 ESS: 4 Boeve BF. AAN Continuum 2004

38 Initial evaluation Dementia With Lewy Bodies Management Follow-up evaluation donepezil levodopa modafinil MMSE: 7/30 STMS: 21/38 DRS: 52/144 ESS: 15 MMSE: 25/30 STMS: 31/38 DRS: 129/144 ESS: 6

39 Future Directions

40 Future Directions Braak et al, Cell Tiss Res 2004 Boeve BF. Ann NY Acad Sci 2010

41 Functioning Dementia With Lewy Bodies Future Directions Assessment Tools RBD onset MCI MPS DLB PD Age

42 Future Directions Boot et al, Ann Neurol 2012

43 Future Directions 15/44 subjects developed MCI/PD (14 MCI, 1 PD) HR 2.2 Boot et al, Ann Neurol 2012

44 Future Directions Iranzo et al, Lancet Neurol 2011

45 Future Directions Normal RBD RBD RBD Boeve et al, unpublished data

46 Functioning Dementia With Lewy Bodies Future Directions Assessment Tools RBD onset Delay the onset and slow the course of symptoms MCI MPS DLB PD Rx Age

47 Resources Lewy Body Dementia Association Please access this website and check it at least monthly, review the newsletter

48 Resources

49 Resources

50 Collaborators/Support Ronald Petersen, PhD, MD David Knopman, MD Daniel Drubach, MD Keith Josephs, MD Laura Allen, RN, CNP Sue Kennebeck, RN Angela Lunde, MA Tanis Ferman, PhD Glenn Smith, PhD Robert Ivnik, PhD Julie Fields, PhD John Lucas, PhD Cliff Jack, Jr., MD Kejal Kantarci, MD Val Lowe, MD Jennifer Whitwell, PhD David Jones, MD Mike Silber, MBBS Erik St. Louis, MD Maja Tippmann-Peikert Mithri Junna, MD Joseph Parisi, MD Dennis Dickson, MD Departments of Neurology, Psychiatry and Psychology, Diagnostic Radiology, Pathology and Laboratory Medicine, Community Internal Medicine, and Health Sciences Research, Mayo Clinic Rochester, Mayo Clinic Jacksonvile, and Mayo Clinic Scottsdale; Neuropathology Laboratory, Mayo Clinic Jacksonville; Mayo Alzheimer s Disease Research Center, Mayo Foundation; and M.H. Udall PD Center of Excellence Grant, Mayo Foundation Supported by grants AG006786, AG016574, and AG from the NIA; Mangurian Foundation

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