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Praha & EU: Investujeme do vaší budoucnosti Evropský sociální fond

Dementia

1861-1915

Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277


Problem: medical, social, economic, ethical

10 -15% inhabitants of developed countries over 65 years suffer from detectable intelect deterioration and more than 5% are affected so

severely they gradually lose their ability to take care of themselves

(Wang 1977).



Problém: medical, social, economic, ethical

Estimation of dementia incidence 35

%

30 25 20

Line 1 Line

15 10

2

5 0 60-65

65-70

70-75

A

75-80

80-85 Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277


Definition of dementia (DSM IV., ICD 10)‫‏‬

• slowly progressing brain disease • always with memory disturbance • + at least one disruption of cognitive-executive functions (spatial orientation, recognition, learning, thinking, speech, calculation etc) without quantitative disruption of consciousness • disease leads to loss of social functions (work, family, self-reliance...)



disorders that most frequently mimic dementia

• Age-dependent memory disturbances, benign senile forgetfulness, MCI • transient cognitive disorders accompanying systemic diseases • side effects of pharmacotherapy

• MAJOR DEPRESSION • delirium Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277


Basic clinical classification of cognitive disorders: ORGANIC

EPISODIC DISTURBANCES

delirium brain trauma epilepsy intoxication brain hypoperfusion brain inflammation TGA

PERSISTENT DISORDERS

normotensive hydrocephalus dementia syndromes SDH isolated cognit. impairment tumors -sensory metabolic encephalopathy - symbolic CPM - cognitive intracranial hypertension - mnestic pseudotumor cerebri - dysexecutive

PSYCHOGENIC – disorders specific by situation Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277

Differential diagnosis between dementia and delirium Praha & EU: Investujeme do vaší budoucnosti Evropský sociální fond

dementia • SLOW, STEALTHY ONSET • CHRONIC COURSE • PROGRESSION WITHIN MONTHS, YEARS • WITHOUT OR WITH MILD FLUCTUATION OF SYMPTOMS • VIGILANCE IS NOT AFFECTED • WITHOUT DRAMATIC PSYCHOMOTORIC SYMPTOMS, WITHOUT AGITATION, ACUTE DISORIENTATION

delirium • SUDDEN ONSET • ACUTE DISEASE • PROGRESSION WITHIN DAYS - WEEKS • SUBSTANTIAL FLUCTUATION OF SYMPTOMS • FLUCTATION OF VIGILANCE • PSYCHOMOTORIC AGITATION • FREQUENT HALLUCINATIONS



basic examination in a patient with cognitive disorder:

• MMSE, Clock test, (Addenbrook test ?)

• biochemical screening including blood levels of glucose, B12, T3/4 (TSH) • morphological brain imaging techniques (CT, MRI) • neurological examination • neuropsychological examination



MMSE

• MMSE sensitivity 82% • MMSE specificity 64% In contrast to ACE -R doesn´t examine: • verbal functions • delayed memory • retrograde memory • memory storage (registration)-recall •executive functions • neglect Insufficiently: • visuospatial functions



Addenbrook cognitive test (Mathuranerth et al 2000)

score 0 - 100 points (norm)‫‏‬

+ substantial increase in sensitivity and specificity

< 88 points: sensitivity 94%,

specificity 89 %

+ detection of FTLD

< 84 points: specificity 100 %

+ outpatient applicability

MMSE + clock test are included in the test - longer administration - recognition of VD - recognition of LBD


Geriatric Depresive Scale

Barthel scale



Hachinski Ischaemia Score Praha & EU: Investujeme do vaší budoucnosti Evropský sociální fond

Hachinski V. C., Iliff L., Du Boulay G. H., McAllister V. L., Marshall J., Ross Russel R. W., Symon L.

• • • • • • • • • • • • •

1. Abrupt onset 2. Stepwise cognitive deterioration 3.Fluctuating course 4.Nocturnal confusion 5.Relative preservation of personality 6.Depression 7.Somatic complaints 8.Emotional incontinence 9.History of hypertension or actual hypertension 10.History of strokes 11.Evidence of associated (extracerebral) atherosclerosis 12.Focal neurological symptoms (phatic, motor) 13.Focal neurological signs (pathological reflexes, hemianopsia)

• • • •

Assessment 0 - 4 points: putative Alzheimer´s disease 5 - 6 points: can not differentiate 7 and more points: putative vascular dementia

2 1 2 1 1 1 1 1 1 2 1 2 2


Primary Dementia Praha & EU: Investujeme do vaší budoucnosti Evropský sociální fond

- the most common diseases with dementia as an inital or predominant syndrome

• Alzheimer´s disease • Vascular dementia

transitional forms

• Lewy body disease • Frontotemporal lobar degeneration • Dementia with rapid progression (heterogenous group)‫‏‬



Estimated prevalence of particular types of dementia

AD-LBD 12%

FTD LBD 5% 3%

others 5%

2 - 5% < 65 let VD 5% AD-VD 10%

AD 60%



TAU PROTEIN

Frontotemporal dementia (Pick)‫‏‬

Parkinson ALFA SYNUKLEIN Lewy body (Lewy body)‫‏‬

BETA AMYLOID

Alzheimer´s disease

Vascular dementia

F

brainste m,BG, cortex P,O T, P

Executive dysfunction disinhibition, apathy

Visuoconstruction PM retardation, depression, REM, hallucinations Episodic memory aphasia, psychosis

Multiple defects cortex F,T,P,O Common executive subcortical dysfunctions Reforma pregraduální výuky neurologie na 1.LF UK v Praze

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Brain distribution of atrophy in the most common types of dementia


Progression of cognitive deterioration Praha & EU: Investujeme do vaší budoucnosti Evropský sociální fond

LBD VD AN


Secondary dementia Praha & EU: Investujeme do vaší budoucnosti Evropský sociální fond

•Tumors (up to 52%) •Brain trauma and its complications •Infection (AIDS complex) •Poisoning •Disorders of CNS metabolic supply •Nutritional deficit •Genetic-enzymatic defects •Phakomatoses and dysontogenetic disorders •Demyelinating diseases •Paget´s disease •Central pontine myelinolysis Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277


Alzheimer´s disease

1861-1915



Epidemiology of AD

• the

most common cause of dementia • prevalence 48 - 73 % • rare presenile form, (40 - 65 years) with incidence 0,04 %. • described rare (0,005 %) early-onset AD form

In Czech Republic by estimation 120 000 affected people, while less then 20% with appropriate treatment. Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277




Beta-amyloid formation

82 AK

beta secretasis presenilin

gama secretasis

APO E 4 Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277

Loss of neuronal connectivity Praha & EU: Investujeme do vaší budoucnosti Evropský sociální fond

inflammation

inflammation

inflammation Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277

Clinical picture and progression of disease Praha & EU: Investujeme do vaší budoucnosti Evropský sociální fond

Mild stage (MMSE 16-25/30) • disruption of episodic and short-term memory • depression may be present • amnestic aphasia (+ other cognitive symptoms) Moderate stage (MMSE 8-16/30)‫‏‬ • complete loss of orientation • deterioration of ability to take care of oneself • behavioral disorders • aimless behavior or apathy

Advanced (severe) stage (MMSE <8/30)‫‏‬ • complete loss of ability to take care of oneself • substantially limited communication • cognitive medication without effect Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277


Diagnostics and therapy of AD

Patient affected by cognitive decline? – Complaints? Enivronment? Physician?

• Detailed medical history + objectivizing • Screening for cognitive deterioration (MMSE, ACE-R..)

• Exclusion of depression and other influences (GDS, Zung Scale, NPI ..) • Exclusion of somatic influences (biochemistry, CBC,T3,4, B12, blood pressure, fever, dyspnoe … )

• Syndrome: - Isolated cognitive impairment (ICI) ? - Mild cognitive impairment (MCI) ? - Dementia?



LIKELY ALZHEIMER´S DISEASE (NINCDS/ADRDA) (National Institute of Neurological and Comunicative Disorders Alzheimer Disease and Related Disorders Association)

• dementia proven by clinical examination (ACE-R, ADAS, Wechsler-R . . . )‫‏‬ • disruption of two or more cognitive modalities

• progressive deterioration of memory and other cognitive functions • absent disturbance of consciousness • onset between 40 - 90 years of life, most frequently > 65 years • Absence of systemic diseases and other brain diseases that may lead to memory and cognitive decline



Diagnostics and therapy of AD

In case of suspected Alzheimer´s disease • Objective neurological examination • Brain CT (MRI) A: activity of daily living: (Barthel index, PSMS …) B: behavioral changes (neuropsychiatric inventory..) • A-B-C scaling C: cognition (WMS-R, ADAS Cog …) • Biomarkers (?) In case of suspected ICI: • Objective neurological examination • Brain CT (MRI) • Targeted psychological examination Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277


2007 – revision,‫‏‬biomarkers‫?…‏‬ In the proposal of the NINCDS-ADRDA criteria: (Dubois et al.; 2007)

• disruption of episodic memory +: - positive findings in CSF (tau, phosphotau, APP, presenilin..)

- reduced hippocampal volume(voxel b. MRI) - altered perfusion, SPECT or PET - APO

E4

(- other genetic markers?) Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277


Dementia confirmed?

• Hachinski: score < 4 ? • ACE – R: score > 3,2 ? • Meets the criteria of NINCDS-ADRDA ? PUTATIVE AD (ultimate diagnosis can be confirmed only by autopsy – if quantitative criteria according to CERAD consensus are met)

Does not meet the criteria?

Differential diagnosis Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277


Therapy of AD

• Inhibitors of AChE are standard medication for mild and moderate AD (MMSE 12 – 24)‫‏‬

• Results of pharmacological studies demonstrate efficacy of early and longterm treatment by AChEI


Centrally acting Treatment of AD- inhibitors of acetylcholinesterase Praha & EU: Investujeme do vaší budoucnosti Evropský sociální fond

Donepezil (Aricept): Initial dose 5 mg, after 4 weeks raised up to 10 mg very good tolerance, few side effects Rivastigmine (Exelon): Initial dose 2x1,5 mg, may be doubled every 14 weeks up to 2x6 mg. Should be taken with food. Nausea 4x and vomiting 6x more common then in donepezil Galantamine (Reminyl): Initial dose 8 mg, raised to 16 mg after 4 weeks, with good tolerance up to 24 mg after other 4 weeks. Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277


Memantine akatinol (Ebixa)‫‏‬

• Competitive antagonist of glutamate NMDA receptors • Inhibits neuronal apoptosis • Modulates information processing in establishing of memory trace • Indicated in moderate AD (MMSE 8 – 16/30)‫‏‬ • In MMSE 12-16 often favourably combined with IChE • Initial dose 5 mg, raised by 5 mg after weeks up to total dose 2x10 mg • Minimal side effects Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277

Clinical picture and progression of disease Praha & EU: Investujeme do vaší budoucnosti Evropský sociální fond

Mild stage (MMSE 16-25/30) disruption of episodic and short-term memory depression may be present amnestic aphasia (+ other cognitive symptoms) Moderate stage (MMSE 8-16/30)‫‏‬ complete loss of orientation deterioration of ability to take care of oneself behavioral disorders aimless behavior or apathy

Advanced (severe) stage (MMSE <8/30)‫‏‬ complete loss of ability to take care of oneself substantially limited communication cognitive medication without effect

AChEI

memantine

atyp. neuroleptics

(tiapride, olanzapine, quetiapine …) Reforma pregraduální výuky neurologie na 1.LF UK v Praze

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AN‫‏‬vede‫‏‬ke‫‏‬snížení‫‏‬regionálního‫‏‬ krevního‫‏‬průtoku‫‏‬mozkem INCREASED INCIDENCE OF Praha & EU: Investujeme do vaší budoucnosti Evropský sociální fond

CVA zejména: TEMPORÁLNÍ a PARIETÁLNÍ kortex

Anti-inflammatory medication: • anti-inflammatory effect Výsledky SPECT vyšetření u zdravé ženy (nahoře) a u pacientky s AN (dole): • antiplatelet effect Acetylsalicylic acid 100mg/1-2x/per day



Progressive worsening of symptoms is typical for AD

Major symptoms COGNITION

Disease stages MILD

FUNCTION. STATE BEHAVIOR

MMSE

26 MILD TO MODERATE MODERATE

12

moving patient to long-term care facility TAKING CARE OF A CAREGIVER IS A PART OF THE THERAPY !!! Reforma pregraduální výuky neurologie na 1.LF UK v Praze

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scale ADFACS

Functional capacity of patients (Alzheimer Disease Functional Assessment and Change

Scale)

basic ADL using toilet feeding clothing personal hygiene bathing walking

instrumental ADL Ability to:

use a PHONE take care of HOUSEHOLD use DEVICES in own household take care of own FINANCES do SHOPPING make FOOD ORIENTATE oneself at home, outdoors engage in HOBBIES, leisure activites take care of own CORRESPONDENCE UNDERSTAND situation and na 1.LF UK v Praze EXPLANATIONS Reforma pregraduální výuky neurologieCZ.2.17/3.1.00/33277


Non–alzheimer dementias


Vascular dementia: Praha & EU: Investujeme do vaší budoucnosti Evropský sociální fond

NINCDS – AIREN kriteria

•Dementia according to ICD 10 •Evidence for cerebrovascular disease •Temporal relation of these disorders (tolerance 2 months) •Falls + gait disturbances •Urinary incontinence •Pseudobulbar syndrome •Personality changes •Focal neurological signs



• • • • •

Nonhomogenous group

Multiple infarcts of territorial vessels Multi-infarct lesion Infarct in strategically important region Hypoxia-hypoperfusion Combined lesion (most frequently)

Critical volume of white matter lesion for dementia – 35%


Characteristic features of vascular dementia Praha & EU: Investujeme do vaší budoucnosti Evropský sociální fond

• Hachinski score >6: likely vascular dementia • Low sensitivity for mixed (combined) forms (HS 4-6)! Does it meet NINCDS - AIREN criteria? • Frequently pronounced disruption of symbolic functions in one domain – depending on localization • If severe disruption – especially in case of global aphasia, dementia not accessible to examination - thus, not diagnosed • In case of uncertainty, therapeutic test with acetylcholinesterase inhibitors, objectified by psychological examination in 2-month interval, may be recommended



Frontal lobe • speech fluency • executive dysfunction • personality – emotional regulation – discrimination • working memory + recall Temporal + parietal lobe • memory tests – disruptions of STM, learning, registration • sensory-phonemic phatic disorders • visuospatial perception • disruptions of symbolic functions • attention – neglect Occipital lobe • visual agnosia • visuo-constructional abilites • Balint´s syndrome


dysfunction Praha & EU: Investujeme do vaší budoucnosti Evropský sociální fond

Promising effect of AChEIs – especially in multi-infarct dementia

Cognitive rehabilitation – speech + other functions depending on individual disablement – early initiation!

- knowledge of focal symptoms in symbolic and cognitive domain + their correlations with morphologic findings



Lewy body disease

• incidence 12-15% (?) of dementia (common misdiagnosed, as AD) • onset: continual or sudden, often misinterpreted as delirium • course: shorter than AD • CAVE neuroleptic medication! Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277

Diagnostic criteria for LBD Praha & EU: Investujeme do vaší budoucnosti Evropský sociální fond

Major symptoms: •Chronic progressive course •Short-term fluctuation of attention, cognitive functions, consciousness •Hypertonic hypokinetic extrapyramidal syndrome •Visual hallucinations •Paranoid signs •Marked negative effect of neuroleptic medication •High incidence of delirium

Symptoms that support diagnosis: •Frequent falls •Vasovagal syncope •Common depression

Mc Keith et al Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277


Lewy body disease (LBD)‫‏‬

•Synucleopathy (cortex + subcortical regions) •Beta-amyloid + tubular tangles •Continuum LBD - AD •Cholinergic and dopamineregic system affected in both cases

1) Diffuse LBD: absence of senile plaques; and Lewy bodies (LB) are distributed in limbic system, brainstem and cortex 2) Senile LBD: numerous senile plaques, except from CERAD LB distributed in a diffuse manner 3) Form of AD with LBD: meets CERAD criteria Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277

Treatment of Lewy body disease: Praha & EU: Investujeme do vaší budoucnosti Evropský sociální fond

!!!CONTRAINDICATION!!! TYPICAL INCISIVE D2 RECEPTOR-BLOCKING NEUROLEPTIC DRUGS

Particularly: •Haloperidol •Chlorpromazine, Chlorprotixen, Levopromazine, Thioridazine

•Melperone (Buronil) •Prochlorperazine, Perfenazine SOME PROKINETIC DRUGS •Cerucal


Therapy of Lewy body disease: Praha & EU: Investujeme do vaší budoucnosti Evropský sociální fond

Acetylcholinesterase inhibitors – more cautious titration •DONEPEZIL RIVASTIGMIN Antipsychotics – only if necessary, in minimal dosage: -QUETIAPINE -RISPERIDONE -OLANZAPINE -ARIPIPRAZOLE -CLOZAPINE Dopaminergic therapy mostly ineffective, some authors recommend: •Carbidopa/Levodopa (Sinemet)



Frontotemporal lobar degeneration

Group of rare diseases affecting frontal lobes • Incidence 3-5%, up to 10% in the 7th decennium • onset: slow, most frequently 50-60 years of age • progression: slow • clinical picture: early personality changes, disturbances in social and emotional regulation, aphasia, mutism, amimia, stereotypy, delirogenic effects of cognitive drugs • OFTEN MISDIAGNOSED AS DEPRESSION! Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277


Frontotemporal lobar degeneration (FTLD) Pick bodies

Tauopathy: Pick´s disease, multiple system atrophy, tauopathy with tau mutation (FTDP-17), corticobasal degeneration progressive supranuclear palsy Non-tauopathies: FTLD in motor neuron disease FTLD with neuronal filamentous inclusions FTLD with ubiquitin inclusions (tauopathy?) FTLD without histological findings (tauopathy?)

Microvacuolar degeneration


Typical frontal symptomatology Praha & EU: Investujeme do vaší budoucnosti Evropský sociální fond

• • • •

NONFLUENT, SEMANTIC APHASIA ECHOPRAXIA – repeating of observed movements ECHOLALIA – repeating of heard vocalizations loss of DISCRIMINATION, e.g. between pleasant and unpleasant stimuli • DELIBERATION of feeding and sexual instincts • PUERILISM - „childish“ behavior with inserting objects into mouth • loss of SOCIAL SELF-CONTROL – emotional incontinence • incapability of abstract THINKING – incapability of REASONING (interpreting proverbs, understanding relations) • EXECUTIVE dysfunction – incapability of PLANNING, anticipation • deterioration of ATTENTION, short-term and working memory


Secondary dementia Praha & EU: Investujeme do vaší budoucnosti Evropský sociální fond

(from neurological point of view)

rare neurodegeneration: • parkinson + • chorea + • heredoataxia

toxic–metabolic diseases: • Wilson´s disease • Wernicke – Korsakov (doesn´t fulfill definition of dementia) • Disorders of lipid, protein or carbohydrate metabolism inflammatory, immune and systemic diseases • AIDS complex • SLE • spongiform encefalopathy • limbic encephalitis



Parkinsonism +

A group of diseases with common features: • • • • •

parkinsonism without tremor „subcortical“ dementia other characteristic neurological abnormalities overlapping of syndromes insufficient effect of L-dopa

• Parkinson´s disease with dementia (cca 20%PD)‫‏‬ • progressive supranuclear palsy • multiple system atrophy


Chorea + Praha & EU: Investujeme do vaší budoucnosti Evropský sociální fond

Huntington´s chorea • 4-7/ 100.000, 30- 45 years (but juvenile forms exist as well) • clinical picture: personality changes – often as the first symptom. Dementia is preceded by motor dysfunction – choreoatethoid dyskinesias; depression, psychotic symptoms. •

conflicting therapy (neuroleptic medication)

•

AD (mutation - p.4 - CAG triplets)

•

Dif.dg: m. Wilson, SLE, neuroakanthocytosis, HallervordenSpatz... Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277


Concept of subcortical dementia

• bradyphrenia • perseverations • rather deterioration of recall than disruption of memory registration

• executive dysfunction • verbal, visuospatial, functions and personality are relatively preserved • motor symptoms of primary disease • frequent concomitant depression



Fast progressing dementias and subacute confusional states – the most common causes

Reversible

With paroxysms of cephalea

Fatal irreversible

With gait disorder and incontinence



Fast progressing dementias and subacute confusional states

reversible: • Intoxication: CO, heavy metals, industrial poisons, organophosphates, volatile substances, drugs, ethanol • Side effects of medication: sedative drugs, analgesic therapy, cardial medication, onkologic therapy, anticholinergic agents, antiepileptic drugs, antiparkinsonic medication, corticosteroids, cimetidine • Ethanol: intoxication, withdrawal syndrome, Wernicke – Korsakov • Metabolic causes: thyroid dysfunction, deficiency of vit. B12, dysbalance of metabolism of electrolytes, calcium; liver and kidney dysfunctions • Cerebral infarct • Autoimmune: nonvaskulitic autoimmune inflammatory ME Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277



With paroxysmal headache: •

neoplasm: primary or metastatic affliction

•

chronic subdural hematoma

•

craniocerebral trauma

•

chronic meningitis

With gait disturbance and incontinence •

normotensive hydrocephalus

•

multi-infarct dementia Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277



Fatal irreversible conditions: •

Creutzfeldt-Jakob spongiform encefalopathy • myoclonus • extraocular or cerebellar affliction • pyramidal/extrapyramidal symptoms • akinetic mutism • typical elektroencephalogram throughout the course of disease

•

Paraneoplastic limbic encephalitis Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277

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