Frontiers in the Frontiers in the treatment of treatment of

Dementia Dementia

Frontiers in the Frontiers in the treatment of treatment of

Dementia Dementia A.Gunasekaran,P.V.KrishnanA.Gunasekaran,P.V.Krishnan,M.Radha,A.Nithyanandam,M.Radha,A.NithyanandamPROF.A.V.SRINIVASANPROF.A.V.SRINIVASAN

Senescence – a second childhood !

Memory

• Memory holds together past and present , gives continuity and dignity to human life …. The companion…the tutor , the poet, the library with which you travel .

Dementia – as a concept

• Mental disorder – accompaniment of senescence ?

• Alzheimer-1906- Amyloid plaques,

• neurofibrillary tangles

• Dementia : concept/ a symptom/ a sign ,not a disease - decline in cognitive and intellectual functions compared to previous status

Assessment

• Neuropychological instruments are useful in

• diagnosing and classifying the type of dementia

• Judging the severity of dementia

• following progress

• Assess efficacy of Rx

Case burden of Dementia

• Incidence :

• Vas et al . 2001 – 0.2& in males 0.3 & in females

• Chandra et al - 4.7 per 1000 personyears in age 65 or above

Reversible dementias

• Common causes ; Alcohol , Medication related Metabolic – Hypothyroidism/ parathyr. B 12 def. CNS infections – HIV ,syphilis Surgical causes – NPH,chronic SDH tumour

• Improves with treatment

Features suggesting reversibility

• Shorter duration of illness

• Subcortical type of dementia

• Moderately severe disturbance

• Younger age of onset

• Prominent gait disturbance

• Urinary dysfunction

• Focal neurological signs

Reversible dementias …

• Lab – CBC , PS,ESR, blood glucose LFT , RFT, Thyroid function tests Serum electrolytes incl. Calcium Serum B 12, VDRL, HIV

• Neuropsychological evaluation

• MRI ,CT

• CSF examination incl. VDRL

• EEG

HIV associated Dementia

• Symptoms- Change in personality- mild to psychotic

• Loss of concentration,confusion

• Cognitive impairement

• Progressive subcortical dementia

• Signs –FND , seizures , meningeal signs , increased ICP signs

Conditions akin to dementia

–Depression –• onset precisely dated , rapid

progression , pervasive affective changes , unwilling to attempt cognitive testing

• No risk factors for dementia• Can be a co-morbid condition

akin to dementia …

• Delirium

• Acute onset

• Fluctuating course

• Autonomic disturbances

• Precipitating factors like infection , metabolic disturbances, drugs

Benign syndrome of MI

• Emil Kraeplin – OBS• Consider when

symptoms not progress

• Normal ageing >> Border zone << AD

• related to systemic neurological diseases , alcoholism, CCF , COPD

Age associated cognitive decline

•

• Decline of more than one SD in area of cognitive functioning in comparision with age matched controls

Assessment of dementia• Criterias used for identification• NINCDS-ADRDA ( AD)• VaD diagnostic criteria• FTD diag. criteria• DSM IV • Diagnosis of presence and extent

assessed with MMSE , CDR

Mx of dementia …

• Treat potentially reversible primary and concomitant conditions

• Multidisciplinary activity consists of neurologist, psychiatrist neuropsychologist and social worker

• A concerned general practioner knowing the patient & family

Mx - a team work

• Together

• Everyone

• Achives

• More

Mx …

• Non-Pharmacological measures• Minimise sensory deprivation• Oral hygiene / Nutrition• Maintain daily

routines,reminders,diaries • Flooring/clothing• Foot-wears, walking aids

Care giver supports

• Acceptance , measures to counter physical, psychological, financial burden

• No denial or guilt• Forming groups • Education or providing recent treatment

options

• Instituionalisation if necessary

Is there answer for Alzhiemer’s disease?

General principles in pharmacotherapy

• One agent at a time

• Increase dose at 5-7 days interval

• Sedative side effects used to advantage

• Improving cognition not the only goal

• Treat ass. behavioural disorders

• High CNS side effects can occur in very old patients

Pharmacological Pharmacological treatment of dementiatreatment of dementia

Cholinesterase inhibitors ( ChE-I)Cholinesterase inhibitors ( ChE-I) NMDA receptors antagonistsNMDA receptors antagonists Anti-oxidant drugsAnti-oxidant drugs Anti-psychotic drugsAnti-psychotic drugs

ChE-IChE-I

Inhibits acetyl cholinesterase Inhibits acetyl cholinesterase Increases synaptic residue time of Ach.Increases synaptic residue time of Ach.

Increased signal in post synaptic Increased signal in post synaptic cholinergic neuroncholinergic neuron

Enhances cognition, improves behaviour, Enhances cognition, improves behaviour, improves global function improves global function

ChE-IChE-I

British psychiatrists group recommend in British psychiatrists group recommend in probable AD in NINDS criteria, MMSE probable AD in NINDS criteria, MMSE >10 (mild to moderate), duration > 6 mths>10 (mild to moderate), duration > 6 mths

Long term therapy found beneficialLong term therapy found beneficial When the drug is withdrawn, worsening When the drug is withdrawn, worsening

of ADL ,behaviour needs restarting the of ADL ,behaviour needs restarting the drugs drugs

AChEI -DosagesAChEI -Dosages

• Donapezil : Start on 5 mg OD , if tolerated increase to 10 mg OD , max. dose – 10 mg a day

• Galantamine : Start on 4 mg BD and after 4 wks- 8mg BD may increase to max. dose 12 mg BD

• Rivastigmine : Start on 1.5 mg BD –after 2 wks 3mg BD may increase to max. dose 6 mg BD

NMDA receptor antagonistNMDA receptor antagonist

• Glutamine – learning , memory

• AD- increased glutamate activity at NMDA receptor excitotoxic cell death

• Memantine – non competitive voltage dependant NMDA receptor antagonist low to moderate affinity

• Improves cognitive and global function

memantine

Started in the dose of 5mg per day in first week and increased to 10mg per day

Memantine can be combined with ChE-I (Donapezil) for synergistic action

Antioxidant drugs like vitamin E Selegeline found to delay the occurance of milestones in the progression of dementia

Other drugs

Ginkgo biloba : Mixed results in trials.The effect is smaller than AChEI sOestrogens : Not successful, risk of Venous thrombosisNSAIDs : Observations showed lower risk of AD with NSAIDs but clinical trials disproved efficacy

No time to lose

• Early diagnosis and intervention results in clinical and finicial benefit by alleviating the patient and care giver burden

Dementia with lewy body

Prominent attention deficit,fluctuating cognition,visual hallucins,parkinsonism

Dopaminergic drugs useful

Aypical antipsychotic drugs are used because marked sensitivity to neuroleptics

Rivastigmine improves cognition and some behavioural disturbances

Vascular dementiaVascular dementia

Very common cause in india due to Very common cause in india due to high prevalence of CVA/risk factors high prevalence of CVA/risk factors

Unlike other dementias,disease Unlike other dementias,disease modifying treatments(OHA,AHT,lipid modifying treatments(OHA,AHT,lipid lowering drug) can be beneficiallowering drug) can be beneficial

Prevention of stroke and its Prevention of stroke and its recurrence is usefulrecurrence is useful

Two diverging/converging pataways Two diverging/converging pataways associated with VaDassociated with VaD

Risk factor Risk factor CVD CVD Ischemic Ischemic Brain injury Brain injury MRI lesion MRI lesion Clinical syndromeClinical syndrome

HTNHTN

Arteriosclerosis Arteriosclerosis 1. occlusion 1. occlusion complete complete infarct infarct lacune lacune lacunnar state lacunnar state

Arteriosclerosis Arteriosclerosis 2. Hypoperfusion 2. Hypoperfusion incomplete infarct incomplete infarct WHSM WHSM Bingswanger syndromeBingswanger syndrome

Experience can be defined as

yesterday’s answer to today’s problems

Short comingsShort comings

1.1. Not interchangeable hence four fold rise Not interchangeable hence four fold rise in frequencyin frequency

2.2. DSM IV R most liberalDSM IV R most liberal3.3. NINDS- AIREN criteria conservativeNINDS- AIREN criteria conservative4.4. Gold standard for VaD (pathological Gold standard for VaD (pathological

definition difficult)definition difficult)5.5. Most of the criteria failed to distinguish Most of the criteria failed to distinguish

between small and large vessel subtypesbetween small and large vessel subtypes

“Healthy Mind and Healthy expression of Emotion go hand in

Hand”

Diagnosis and prognosisDiagnosis and prognosis

Risk factorsRisk factorsModifiableModifiable Non-modifiableNon-modifiable

HypertensionHypertension Age Age

HyperglycemiaHyperglycemia Gender Gender

RaceRace

HeredityHeredity

Discipline Weighs ounces Regret weighs Tons

Diagnosis and prognosis contd….Diagnosis and prognosis contd….Vascular phenotype : “CVD”Vascular phenotype : “CVD” Arteriosclerosis Arteriosclerosis Amyloid angiopathyAmyloid angiopathy Other small vessel diseaseOther small vessel disease

“You have got to be before you can do

and do before you can have”

Diagnosis and prognosis contd….Diagnosis and prognosis contd….Vascular Vascular

distributiondistributionMechanism of Mechanism of Brain injuryBrain injury

Pathological Pathological phenotype phenotype “Infarct”“Infarct”

Single arterySingle artery

Small arterioleSmall arterioleAcute ischemiaAcute ischemia Multiple lacunar Multiple lacunar

infarctsinfarcts

Single arterySingle artery Acute ischemiaAcute ischemia Single Single strategically strategically placed lacunar placed lacunar infarctinfarct

Border zoneBorder zone

Small arterioleSmall arterioleChronic Chronic

hypo perfusionhypo perfusionWhite matter White matter demyelination demyelination and axonal lossand axonal loss

Diagnosis and prognosis contd….Diagnosis and prognosis contd….

Neuro imaging phenotypeNeuro imaging phenotype

CT lucency (lacunes and leukoariosis)CT lucency (lacunes and leukoariosis)

MRI hyper intensity (lacunes and WMSH)MRI hyper intensity (lacunes and WMSH)

A true commitment is a heart felt promise to yourself from which you

will not back down -

D. Mcnally

Diagnosis and prognosis contd….Diagnosis and prognosis contd….

Localisation / Localisation / neural networkneural network

Clinical phenotype or Clinical phenotype or syndromesyndrome

Cortico-basal ganglia – Cortico-basal ganglia – thalamocortical loopsthalamocortical loops

Lacunar stateLacunar state

Apathy, depression, abulia Apathy, depression, abulia

Dysexecutive syndromeDysexecutive syndrome

Normal visual fieldsNormal visual fields

parkinsonismparkinsonism

Cortico-basal ganglia Cortico-basal ganglia thalamocortical loopsthalamocortical loops

Strategic infarct dementiaStrategic infarct dementia

Dysexecutive syndromeDysexecutive syndrome

Frontal lobe syndromeFrontal lobe syndrome

Deep white matter Deep white matter connectionsconnections

Binswanger’s syndromeBinswanger’s syndrome

Slowly progressive depression, Slowly progressive depression, bradykinesia, dysexecutive bradykinesia, dysexecutive syndrome, gait apraxia, urinary syndrome, gait apraxia, urinary incontinenceincontinence

Diagnosis of Dementia after Diagnosis of Dementia after strokestroke

4 sets of criteria are used  4 sets of criteria are used  SensSens Spec Spec

1.1. Hachinski ischemic score 89% 89%Hachinski ischemic score 89% 89%

< 4 AD / 18, > 7 MID / 18< 4 AD / 18, > 7 MID / 18

2. DSM IV2. DSM IV 43% 43% 95% 95%

3. NINDS – AIREN3. NINDS – AIREN 50% 98% 50% 98%

4. ADDTC criteria4. ADDTC criteria 50% 90% 50% 90%

Every discovery contains an irrational element or

4 creative intuition Khrl Popper

AD Vs VaDAD Vs VaDADAD VaDVaD

Neuro transmitter defect Neuro transmitter defect Hemodynamic defectHemodynamic defect

Female predominance Female predominance Male predominanceMale predominance

Gradual onsetGradual onset Abrupt onsetAbrupt onset

Steady deterioration Steady deterioration Stepwise deterioration, Stepwise deterioration,

fluctuating coursefluctuating course

BP normal BP normal HypertensionHypertension

No history of stroke No history of stroke History of strokeHistory of stroke

Global decline in cognitive Global decline in cognitive function function

Focal neurological Focal neurological symptoms and signssymptoms and signs

Unlikely to respond to Unlikely to respond to treatment treatment

May respond to a drug May respond to a drug which modifies which modifies microcirculation and microcirculation and enhance cerebral tissue enhance cerebral tissue perfusionperfusion

VaD

• ChE-I espescially Galantamine is found effective in VaD +/- AD

• Pseudobulbar palsy with emotional incontinene responds to SSRI , TCA or levadopa

Role of RIVASTIGMINE in VaD

No.of patients : 12Age group : 50 – 80 yearsFemale : 4Male : 8Most of them had diabetes and hypertension Not based on subtype of VaD 30% showed remarkable improvement in cognitive,

curative and affective functions of the brainFuture study needed

“ He who cannot forgive others destroys the bridge over which he

himself must pass” - Annoy

Strategies to prevent – STROKE-TO-DEMENTIATEN-STEP APPROACH

1. Treat hypertension optimally2. Treat diabetes3. Control hyperlipidaemia, use dietary control for

diabetes, obesity and hyperlipidaemia

4. Persuade patients to cease smoking and decrease alcohol intake

5. Prescribe anticoagulants for atrial fibrillation6. Provide antiplatelet therapy for high risk

patientsA open foe may prove a curse ; but

a pretended friend is worse

Strategies to prevent – STROKE-TO-DEMENTIA contd…

7. Perform carotid endarterectomy for severe (>70%) carotid stenosis

8. Recommend lifestyle changes (e.g., weight loss, exercise, reduce

stress, decrease salt intake)

9. N-methyl-D-aspartate receptor antagonists, antioxidants)

10. Intervene early for stroke and transient ischemic attacks with

neuroprotective agents (e.g., propentofylline, calcium channel

antagosists, - ? RivastigmineIt is a great misfortune not to possess sufficient wit to speak well

nor sufficient judgment to keep silent

La Broyers character

FTLD

• Prominent aphasia and neuro-psychiatric complaints

• Familial, mutation in Ch. 17

• SSRI decreases disinhibition, compulsion

• Adrenergic agonists ,Idazoxan improves planning ,attention & episodic memory

Care and Cure !

Mx of neuropsychiatric problems

An acurate diagnosis for both dementing illness and concomitant psychiatric symptoms

Treatment of psychiatric problems reduce the distress of patient as well as caregiver

Mx of psychiatric sympt. Agitation – Mood stabilisers like CBZ , divalproax ,

Trazadone for night time aggression Buspirone for anxiety related aggression Medroxyprogesterone for sex aggression

Anxiety - Oxazepam , Lorazepam ,Buspirone

Mx …

• Apathy - Methylphenidate,dextro-amphetamine Modafenil

• Insomnia - Trazadone , Zolpidem

• Delusion- atypical antipychotics

• Depression - SSRI, comb. RI eg. Venlafaxin,Mirtazepin

Antipsychotic drugs

• when behavioural changes are severe and urgent treatment is needed , a Psychotropic drug can be used prior to use of a ChE-I drug

Therapy -- ? Future

Future therapies

• Recently,intranasal insulin – improves cognitive function in AD who lack Apo E

• Gene therapy using nerve growth factor administered by implantinggenetically engineered autologous fibroplasts

Future therapies• Regenerating neurons show

trophic response reduction in rate of cognitive decline by 50 % for about 2 years

• Beta secretase inhibitors are found to interrupt amyloid cascade

Future therapies• Drugs to counter Glycogen synthase

kinase,which is involved in phosphorylation of tau,is under study

• Plaque busters inserts themselves in polymerizing amyloid and so slows accumulation of Neuritic plaques

ThankThankThankThank

You !You !