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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 !
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