Dementia with Lewy Bodies

1. Dementia with Lewy Bodies Leonard Griffiths Thursday 22nd Nov 07

2. Case: Mrs ME • 86♀ • Admitted 2/10/07 with 2/12 Hx worsening mobility • Leg weakness • No altered sensation of pain • Fall noted 6/52 prior to admission • ‘mechanical sounding’ • No LOC/HI/CP/palpitations/SOB • Recalled incident

3. Case: Mrs ME • Intermittent confusion for 5/52 prior to admission • Treated for UTI (although no urinary signs or symptoms)

4. Case: Mrs ME • PMH • ‘Registered blind’ • Osteoporosis • Angina • Hypertension • Asthma • Episode of jaundice 40 yrs ago

5. PTWR • Diagnosed ‘weakness of legs’ • ?musuloskeletal • ?UTI

6. Abnormal results • WBC 11.5; Neut 8.2 • Na+ 128 • U Osmo 566 • U Na+ <20 • P Osmo 282 • P Na+ 132 •  not SIADH

7. Abnormal results • Urine dip • Blood + • Leuk +++ • Protein + • Nitrites + • Lab +ve for nitrites and leukocytes • Culture  ‘mixed growth suggesting contam.’

8. Abnormal results • AMSE • 8/10 • MMSE 20/28 • GDS 3/15 • i.e. not depressed • CT brain • Moderate small vessel disease • Small L occipital infarct

9. SHO WR 6/10/07 • Thought pt had low mood  d/w consultant  ref to Ψ liaison • Felt that ‘new environment and poor eyesight a significant factor in agitation’

10. Consultant WR 9/10/07 • Cogwheeling • Tremor • Short shuffling gait • ‘Leans backwards’ • Impression: Parkinsonism • 1/52 domperidone commenced • Ref. to PD consultant

11. SHO WR 11/10/07 • Hallucinating • “Horse woman of the year” • Believed someone gave her eye drops (not prescribed)

12. PD consultant review • “Tricky mixed picture which is difficult to disentangle” • Hallucinations • Although ?Charles Bonnet in relation to reduced eyesight • Some reduced memory • ?DLB but has cerebrovascular disease • Parkinsonism – but not typical PD • ‘tremor rather fine’ • ‘balance  back’ • Try madopar, ‘but suspect little to be gained from medication’

13. SHO WR 15/10/07 • Hallucinating • Relatives • Monkey

14. Progress… • 18/10/07 madopar commenced • 22/10/07 more confused and hallucinations worsening  madopar stopped & rivastigmine commenced • 30/10/07 – paranoia and aggressive

15. Progress… • 6/11/07 – hallucinations worse at night  quetiapine added • 16/11/07 – mood even lower  venlafaxine added • Now awaiting community hospital bed

16. Diagnosis • Clinical features reflect anatomical distribution of pathology rather than its nature • Therefore subtle clinical features not helpful

17. What is Dementia? ICD-10 definition • 1. A decline in memory to an extent that it interferes with everyday activities, or makes independent living either difficult or impossible. • 2. A decline in thinking, planning and organizing day-to-day things, again to the above extent. • 3. Initially, preserved awareness of the environment, including orientation in space and time. • 4. A decline in emotional control or motivation, or a change in social behaviour, as shown in one or more of the following: emotional lability, irritability, apathy or coarsening of social behaviour, as in eating, dressing and interacting with others. • Maj, M.. 2002., Dementia, Second Edition [online]. 2nd Edition. Wiley. Available from: http://mil.ingramdigital.com/Browse/open.asp?ID=10147&loc=Cover 15 November 2007

18. Wikipedia definition • Dementia is the progressive decline in cognitive function due to damage or disease in the brain beyond what might be expected from normal ageing. • http://en.wikipedia.org/wiki/Dementia

20. Dementia • Alzheimer's • Vascular • Lewy body • Alcohol • Pure vascular • Frontotemporal lobar degenerations • Creutzfeldt-Jakob disease • Dementia pugilistica • Moyamoya disease

21. Nomenclature • Diffuse Lewy body Disease • Cortical Lewy body Disease • Lewy Body Dementia • Senile Dementia Of Lewy Type • Lewy Body Variant of Alzheimer's Disease • Dementia with Lewy Bodies (preferred)

22. Dementia with Lewy Bodies • Describes several common disorders causing dementia • The main features of these conditions are: • development of dementia with features overlapping with those of Alzheimer's disease • development of features of Parkinson's disease • fluctuation in severity of condition on a day-to-day basis • early development of hallucinations

23. Neuropathology • Degeneration of substantia nigra • Degeneration of the cortical areas of the brain with many or all of the features seen in Alzheimer's disease • Remaining nerve cells contain abnormal structures called ‘Lewy bodies’

24. Lewy Bodies • Abnormal aggregation of proteins, including • alpha-synuclein, neurofilament and ubiquitin • PD • Dementia with Lewy bodies • MSA • Amyotrophic lateral sclerosis • Hallervorden-Spatz syndrome • Core, body, halo • Variations in shape Synucleopathies

26. www.saigata-nh.go.jp/.../SN295LEWYSYNUCLX100.JPG

27. www.saigata-nh.go.jp/.../SN295LEWYSYNUCLX100.JPG

28. Tonus und Bewegund (Muscle Tone and Movement)

29. Frederich Heinrich Lewy

30. opm.phar.umich.edu/images/proteins/1xq8.gif

31. Alpha-synuclein • Abundant CNS protein • Composed of 140 amino acids • Alpha form of synuclein is the only form capable of aggregating into fibrillar structures in vitro • Beta-synuclein is not localized in Lewy bodies, it may have a role in regulating alpha-synuclein metabolism or aggregation

32. faculty.uncfsu.edu/shan/0728%2020c%20006a.gif

33. Normal role of alpha-synuclein • Synaptic plasticity • Negative regulation of dopamine neurotransmission • Protection at nerve terminals during injury • Trafficking of cargo in the ER/Golgi complex

34. Alpha-synuclein in disease • ‘Ubiquitinated’ with no loss of proteasome function, suggesting there is an excessive accumulation of alpha-synuclein that overwhelms the proteolytic machinery (Tofaris, et al. 2003). This may promote the formation of Lewy bodies

35. Presenting Features DLB • Dementia normally presenting feature • Minority present with parkinsonism • Some with psychiatric disorder without dementia • Others with orthostatic hypotension, falls or transient disturbances of consciousness • Sporadic (rarely familial)

36. Common Features • Fluctuation in cognitive performance and functional ability • Variations in attention and level of consciousness • Visual hallucinations in two-thirds

37. Gelder, Michael G.; Lopez-Ibor, Juan Jose; Andreasen, Nancy C.. 2003., New Oxford Textbook of Psychiatry, Volume 1 [online]. New Edition. Oxford University Press. Available from: http://www.myilibrary.com/Browse/open.asp?ID=14714&loc=416 15 November 2007

38. Sensitive signs for ‘bedside’ diagnosis • Psychiatric vs. cognitive symptoms • Hallucinations • Delusions • Fluctuant cognitive state

39. Hallucinations • Repeated visual hallucinations are present in about two-thirds of patients • vivid, colourful, and sometimes fragmented figures of people and animals • often complex, detailed and rapidly moving • can involve scenes and bizarre situations • can start with misinterpretations and are usually short • often occur at night • usually not distressing to the patient

40. Treatment • No cure • Cognitive symptoms  acetylcholinesterase inhibitors, such as donepezil and rivastigmine • May reduce psychiatric and motor symptoms • Rigidity  levodopa

41. Summary • Third most common dementia • Central feature is progressive cognitive decline • Pronounced fluctuations • Recurrent visual hallucinations • Parkinsonism • Symptoms caused by Lewy Bodies comprised of bits of alpha-synuclein