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Lewy Body Dementia Slides
Lewy Body Dementia Slides
Insights Into a Common Spectrum Disorder. Dr. Albert Chen Clinical Gerontologist June 29th 2012.
"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 its real nature may be ascertained, and appropriate modes of relief, or even of cure, pointed out. James Parkinson 1817.
CONTENTS
Why
discuss dementia now? Whats 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?
OH.
OBESITY
METABOLI C SYNDROM E
PROCESSE D FOOD
DEMENTIA
???
Unknow n Factors
Various
Rabins
Barker et al.
42% 8% 3% 4% 42%
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 Parkinsons and Autonomic Failure. To beat it we must talk more with colleagues, cutting across specialities boundaries
It accounts for up to 20% of dementia cases in the U.S. thats up to 1.3 million cases in the U.S. alone, with only 30%-50%
Round, eosinophilic cytoplasmic inclusion bodies with pale halo. irregular shape, halo less prominent in cortical LBs, difficult to visualize. Easier to visualize with newer immunofluourescent stains. Composed of abnormal neurofilaments (mostly polymerized alpha-synuclein and ubiquitin).
Lewy Bodies
Whats in a Name?
Lewy
Body disease (LBd) Diffuse Lewy Body disease (DLBd) Lewy Body Dementia (LBD) Dementia with Lewy bodies (DLB) Alzheimers disease, Lewy body variant (ADLBv)
Dementia, Lewy body type
Senile
Parkinsons
Disease Dementia
(PDD)
PARKINSON S DISEASE
PAF
Progression
Chen A.W 2012
(PDD)
(DLB)
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.)
FLUCTUATING COGNITION
PARKINSONISM
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.
Chen A.W 2008
VISUAL HALLUCINATIONS
DEMENTIA
LBD
RBD
Autonomic Dysfunctio n
FLUCTUATING COGNITION
PARKINSONISM
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.
VISUAL HALLUCINATIONS
DEMENTIA
depress ive
LBD
Visuospatia l Deficit
NEUROLEPTIC SENSITIVITY
DEMENTIA
de..... mentia
An
acquired deterioration of global cognitive functions in previously unimpaired persons... Severe enough to impair their normal functioning.
deficits
Memory deficits Loss of goal-oriented behavior, behavioral plasticity. Personality Changes - Disinhibition - Abulia Incontinence MMSE useless
Similar
Similar, or slightly earlier, age of onset, but more rapid progression (mean survival 5-8 years).
Subcortical Dementias
Parkinson's
disease (PD); Huntington's disease (HD); multiple system atrophy; idiopathic basal ganglia calcification; multi-infarct dementia; and, AIDS dementia complex
DEMENTIA SYNDROMES
Memory Judgment Attention Executive functions. Visuospatial Language Depression Psychosis Hallucination Apathy Agitation anxiety
Cognitive
Behaviour al
NeuroPs ychiatric
Functional
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
Significantly
greater fluctuation in condition from day to day, compared to AD. 81% have periods of marked unexplained confusion, mimicking delirium.
Twice
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
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.
Clarimn, Jordi PhD; Molina-Porcel, Laura MD; Gmez-Isla, Teresa MD, PhD; Blesa, Rafael MD, PhD; Guardia-Laguarta, Cristina BSc; GonzlezNeira, Anna PhD; Estorch, Montserrat MD, PhD; Ma Grau, Josep MD, PhD; Barraquer, Llus MD, PhD; Roig, Carles MD, PhD; Ferrer, Isidre MD, PhD; Lle, Alberto MD, PhD
Abstract: 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,
changes Decreased judgment Confusion and temporal/spatial disorientation Difficulty following directions Decreased ability to communicate
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.
AcetylCholine
90-95%
Dopamine
30-50%
No Serotonergic deficit.
Ach NE Glu 5HT
Chen A.W 2008
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 Alzheimers disease? Trends Pharmacol Sci 1996; 1996:155-160. Ballard C, Grace J, McKeith I, Holmes C. Neuroleptic sensitivity in dementia with Lewy bodies and
CLINICAL COMPARISON
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 Parkinsons Disease Rating Scale (UPDRS) to assess motor impairments, Neuropsychiatric Inventory (NPI) and Mini-Mental Status Examination (MMSE) to assess cognitive function.
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.
Results II
AD
patients were not shown to be significantly more impaired than LBD patients in any of the functional areas studied.
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.
with DLB had an average survival of 7 years. AD individuals lived 8.5 years.
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.
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.
FLUCTUATING COGNITION
LEWY BODY DEMENTIA
Clinician
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
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
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
Cant focus properly. Blank staring during which the patient appeared to disengage from the ongoing flow of activity or conversation
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
PARKINSONISM
LEWY BODY DEMENTIA
Muscle stiffness Difficulties with balance Shuffling gait Stooped posture PD 100% LBD > Slow movements 70% Restless leg syndrome Tremors
EPS PREVALENCE
Parkinsonian Features
Relatively
VISUAL HALLUCINATION
LEWY BODY DEMENTIA
Psychotic Symptoms
May
be first symptom Present 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
PVH in LBD
Usually
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.
Visual hallucinations in DLB are associated with greater deficits in cortical acetylcholine and predict better response 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.
TREATMENT DILEMMA
EPS
PSYCHOSIS
TREAT HALLUCIANTIONS.......
EPS
Chen A.W.
TREAT ESP.............
HALLUCINATIONS & PSYCHOSIS
EPS
Chen A.W.
NEUROLEPTIC SENSITIVITY
LEWY BODY DEMENTIA
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)
Aarsland et at. J Clin Psychiatry 2005 May;66(5):633-7 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).
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).
initial sedation Sudden onset of rigidity Postural instability, Falls. Rapid general deterioration, Increased confusion, Immobility, rigidity, Fixed flexion posture, Decreased food intake
F Fever A Autonomic instability L Leukocytosis T Tremor E Elevated enzymes (elevated CPK) R Rigidity of muscles
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
AUTONOMIC DYSFUNCTION
LEWY BODY DEMENTIA
Autonomic Dysfunction
62% of patients with DLB experience significant autonomic failure, and dysautonomia is observed in up to 80% of patients with PD
Approximately
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 swallowingwhich may lead to aspiration pneumonia. Sexual disturbances/impotence,
OH
Primary Autonomic Failure/dysf unction of CVS in LBD Supine or nocturnal hypertensi on Postprandi al hypotensio n, (PPH) Carotid 60% Sinus Syndrome 40%
QTc
Chen A.W.
Bradyarrhythm ias
Diuretics, alpha-blockers, Oral nitrates, Tricyclic antidepressants, beta-blockers, alpha-1 adrenergic receptor antagonists, Calcium channel blockers, monoamine oxidase inhibitors, ethyl alcohol abuse.
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 .
Treating OH
Compression
stockings Frequent, small meals, High-salt diet, Increased fluid intake Fludrocortisone, Midodrine, Ephedrine. SSRIs
Anatomy of Sleep
N-REM SLEEP
Stage 11 Stage II Stage III Stage IV
Dreaming Irregular Breathing Muscular Atonia Elevated Blood Pressure Rapid Movement of Eyes
REM SLEEP
Che n A. W (2012)
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.
DEPRESSIVE PHENOTYPE
LEWY BODY DEMENTIA
NEUROIMAGING
LEWY BODY DEMENTIA
LBD
Generalized atrophy. Sparing MTL Moderate increase relative to normal
Peri-venricular WM on Comparable to normal Comparable to normal MRI SPEC (blood flow) SPEC (dopamine transporter) Global reduction. > posterior P-T, MTL ~ Normal for age Global reduction. > occipital. MTL normal Reduced in putamen, similar to PD
18F-Dopa
Normal control
PET image provided by, and used with the kind permission of, Dr Pablo Martnez-Lage
90
DLB
LBD
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.
Age: Date: ..
YES / NO
2. Is there shuffled gait or rigidity? YES / NO 4 3. Is there evidence/history of vivid visual hallucinations? YES / NO 4 4. Is there fluctuation of cognition or attention? YES / NO 5. Is there a history of sensitivity to neuroleptics? YES / NO 6. Is there complains of sleeping disorder, acting out dreams? YES / NO 7. Is there a history of frequent falls or black-outs? YES / NO 8. Is memory relatively intact? YES / NO 9. Is there hypotension, constipation or excessive sweating? YES / NO 10. Is there an evident tremor? YES / NO 2 11. Did motor signs and cognitive impairment occur within 18 months of each other? YES / NO 12. Are there false ideas about other persons or situations? YES / NO 2 TOTAL SCORE: /34 Interpretation: 20 or more Lewy Body Dementia
4 4 2 2 2 2 2
Proposed Treatment
DONEPEZIL RIVASTIGMINE GALANTAMINE HCL
INCREASE DOPAMINE LEVEL INHIBIT REUPTAKE OF 5HT ?? SYNUCLEOPATHIES BENIGN NEGLECT CAREGIVER TRAINING
NMDA- RECEPTOR INHIBITION
Sinemet ?? ?? Benign neglect, PT SSRIS NOT NEEDED?? AChEI may help MELATONIN CLONAZEPAM SEROQUEL MEMANTINE HCL Salt & fluid intake, SSRI, Elevate bed head, laxatives
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.
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 John ofsize. Salisbury, their giant "
THANK YOU!
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.
You have dementia, none of the drugs work so theres 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 Frustrate need to live in a d doctor
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
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 crosslinked protein aggregates from the brain?
LBD Prevalence
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.
Prevalence of LBD
to 30% of all dementias at autopsy. Possibly more common than vascular dementia. Most common incorrect diagnosis in brain bank programs.
Neuropathology In DLB A. Substantial nigra hematoxylin-eosin stain, arrows -- Lewy bodies. C. Cerebral cortex hematoxylin-eosin stain, arrows -- Cortical Lewy body. E. Basal forebrain synuclein stain, arrow -- Lewy body, arrowhead -- Lewy neurite G. Cerebral cortex synuclein stain, arrow -- Cortical Lewy body, arrowhead -- Lewy neurite