Differential diagnosis of dementia

of DementiaEmeritus Prof of Neurology and Former Professor of Neurology Head Institute of Neurology

PROF.A.V.SRINIVASAN, MD, DM, Ph.D,DSc(HON), F.A.A.N, F.I.A.N,

Differential diagnosis

Senescence – a second childhood !

Whatever the Mind can conceive and Believe, the mind can Achieve Napoleon Hill

MemoryMemory

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

Every discovery contains an irrational element or 4 creative intuition Khrl Popper

DementiaDementia – as a concept – as a concept

Mental disorder – accompaniment of Mental disorder – accompaniment of senescence ?senescence ?

Alzheimer-1906- Amyloid plaques,Alzheimer-1906- Amyloid plaques,

neurofibrillary tanglesneurofibrillary tangles Dementia : concept / a symptom/ a Dementia : concept / a symptom/ a

sign ,not a disease - sign ,not a disease - decline in cognitive and intellectual decline in cognitive and intellectual functions compared to previous status functions compared to previous status

One is the most independent, unconventional and individualistic of all numbers

Case burden of Dementia

Incidence: Vas et al . 2001 – 0.2& in males 0.3 & in females Chandra et al - 4.7 per 1000 person years in age

65 or above

Reputation is made in a moment; character is built in a life time

Reversible dementiasReversible dementias

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

Improves with treatment Improves with treatment

Experience can be defined as yesterday’s answer to today’s problems

Features suggesting reversibilityFeatures suggesting reversibility

Shorter duration of illnessShorter duration of illness Subcortical type of dementiaSubcortical type of dementia Moderately severe disturbanceModerately severe disturbance Younger age of onsetYounger age of onset Prominent gait disturbanceProminent gait disturbance Urinary dysfunctionUrinary dysfunction Focal neurological signsFocal neurological signs

“Anger Begins In Folly And Ends In Repentance”

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

Two is the most gentle of all numbers and represents, diplomacy and tact

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

“Social Isolation is in itself a pathogenicFactor for disease production”

Akin To Dementia …Akin To Dementia …

DeliriumDelirium– Acute onset Acute onset – Fluctuating courseFluctuating course– Autonomic disturbances Autonomic disturbances – Precipitating factors like infection, Precipitating factors like infection,

metabolic and drugsmetabolic and drugs

The Truth is Fear & Immorality are two of the greatest inhibitors of Performance to progress

Benign syndrome of MIBenign syndrome of MI

Emil Kraeplin – OBSEmil Kraeplin – OBS Consider when Consider when

symptoms not progresssymptoms not progress Normal ageing >> Border Normal ageing >> Border

zone << ADzone << AD related to systemic related to systemic

neurological diseases, neurological diseases, alcoholism, CCF, COPDalcoholism, CCF, COPD

Science is below the mind;

Spirituality is beyond the mind

AGE ASSOCIATED AGE ASSOCIATED COGNITIVE DECLINECOGNITIVE DECLINE

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

When they tell you to grow up, they mean stop When they tell you to grow up, they mean stop growinggrowing

AssessmentAssessment

Neuropychological instruments are useful inNeuropychological instruments are useful in

diagnosing and classifying the type of diagnosing and classifying the type of dementia dementia

Judging the severity of dementiaJudging the severity of dementia following progressfollowing progress Assess efficacy of RxAssess efficacy of Rx

In any field, find the strangest thing and explore it

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

Of a burning and unremitting character - F.W.PAVY

Rx of dementia …Rx of dementia …

• Treat potentially reversible primary Treat potentially reversible primary and concomitant conditionsand concomitant conditions

• Multidisciplinary activity consists of Multidisciplinary activity consists of neurologist, psychiatrist neurologist, psychiatrist neurophysiologist and social workerneurophysiologist and social worker

• A concerned general practitioner A concerned general practitioner knowing the patient & familyknowing the patient & family

Three is the most playful of all numbers and also creative, inspirational and motivating

Dementia with lewy bodyDementia with lewy body

Prominent attention deficit, fluctuating Prominent attention deficit, fluctuating cognition, visualcognition, visual hallucins, parkinsonism hallucins, parkinsonism

Dopaminergic drugs useful Dopaminergic drugs useful Aypical antipsychotic drugs are used Aypical antipsychotic drugs are used

because marked sensitivity to neuroleptics because marked sensitivity to neuroleptics Rivastigmine improves cognition and Rivastigmine improves cognition and

some behavioural disturbances some behavioural disturbances

Nine is the most humanitarian of all numbers. It is effort and sacrifice without the need for reward.

Rx …Rx …____________________________________________________________________________________________

Non-Pharmacological measuresNon-Pharmacological measures Minimise sensory deprivationMinimise sensory deprivation Oral hygiene / NutritionOral hygiene / Nutrition Maintain daily routines, reminders, diaries Maintain daily routines, reminders, diaries Flooring/clothingFlooring/clothing Foot-wears, walking aidsFoot-wears, walking aids

NATURE, TIME AND PATIENCE are the 3 great physicians

Care giver supportsCare giver supports Acceptance , measures to counter physical, Acceptance , measures to counter physical,

psychological, financial burdenpsychological, financial burden No denial or guiltNo denial or guilt Forming groups Forming groups Education or providing recent treatment optionsEducation or providing recent treatment options Instituionalisation if necessaryInstituionalisation if necessary

Number four is the most practical of all numbers, with attention and a sharp eye for details

RxRx - a team work - a team work

TTogetherogetherEEveryoneveryoneAAchiveschivesMMoreore

It is a great misfortune not to possess sufficient wit to speak well nor sufficient judgment to keep silent

-La Broyers character

Is there an answer for Dementia

Discipline Weighs ounces Regret weighs Tons

General principles inGeneral principles in PharmacotherapyPharmacotherapy

One agent at a timeOne agent at a time Increase dose at 5-7 days intervalIncrease dose at 5-7 days interval Sedative side effects used to Sedative side effects used to

advantageadvantage Improving cognition not the only goalImproving cognition not the only goal Treat ass. behavioural disordersTreat ass. behavioural disorders High CNS side effects can occur in very High CNS side effects can occur in very

old patients old patientsFive is the most dynamic of all numbers. It is persuasive, versatile and adaptable

Pharmacological Treatment Pharmacological Treatment of Dementiaof Dementia

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

“Men of Genius Admired: Men of Wealth envied women of power feared but only women of character are trusted”

A- Friedman

ChE-IChE-I Inhibits acetyl cholinesterase Inhibits acetyl cholinesterase Increases Increases

synaptic residue time of Ach.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

Knowledge without action is useless;Action without knowledge is foolish

ChE-IBritish psychiatrists group recommend in

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

Long term therapy found beneficialWhen the drug is withdrawn, worsening of

ADL, behaviour needs restarting the drugs

Number sixth is the most loving of all numbers and is harmonious with all other number

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

Number seven is the most spiritual of all numbers. It is the seeker of truth.

NMDA Receptor NMDA Receptor AntagonistAntagonist

Glutamine – learning , memoryGlutamine – learning , memory AD- increased glutamate activity at AD- increased glutamate activity at

NMDA receptor NMDA receptor excitotoxic cell excitotoxic cell deathdeath

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

Improves cognitive and global function Improves cognitive and global function We learn by thinking and the quality of the learning outcome is

determined by the quality of our thoughtsR.B. Schmeck

MEMANTINEMEMANTINE Started in the dose of 5mg per day in first week Started in the dose of 5mg per day in first week

and increased to 10mg per day and increased to 10mg per day Memantine can be combined with ChE-I Memantine can be combined with ChE-I

(Donapezil) for synergistic action (Donapezil) for synergistic action Antioxidant drugs like vitamin E Selegeline Antioxidant drugs like vitamin E Selegeline

found to delay the occurance of milestones in found to delay the occurance of milestones in the progression of dementia the progression of dementia

Eight is the most result-oriented of all numbers and represents a balanced world

Other drugsOther drugs Ginkgo biloba:Ginkgo biloba:

Mixed results in trials. The effect is smaller Mixed results in trials. The effect is smaller than AChEI sthan AChEI s

Oestrogens:Oestrogens:Not successful, risk of Venous thrombosisNot successful, risk of Venous thrombosis

NSAIDs:NSAIDs:Observations showed lower risk of AD with Observations showed lower risk of AD with NSAIDs but clinical trials disproved efficacy NSAIDs but clinical trials disproved efficacy

The True Art of Memory is The Art of Attention - S.Johnson

No time to lose No time to lose

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

Take time to think; it is the source of powerTake time to read; it is the foundation of wisdomTake time to work; it is the price of success

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

“By Nature All Men/ Women are alike butby Education widely different” - Chinese

Two Diverging / Converging Two Diverging / Converging

Pataways associated with Pataways associated with VaDVaDRisk factor Risk factor CVD CVD Ischemic Ischemic Brain injury Brain injury MRI lesion MRI lesion

Clinical syndromeClinical syndromeHTNHTN

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

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

Experience can be defined as

yesterday’s answer to today’s problems

Short comingsShort comings1.1. Not interchangeable hence four fold rise in Not interchangeable hence four fold rise in

frequencyfrequency2.2. DSM IV R most liberalDSM IV R most liberal3.3. NINDS- AIREN criteria conservativeNINDS- AIREN criteria conservative4.4. Gold standard for VaD (pathological definition Gold standard for VaD (pathological definition

difficult)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 prognosis

Risk factors Modifiable Non-modifiable

Hypertension Age

Hyperglycemia Gender

Race

Heredity

Discipline Weighs ounces Regret weighs Tons

Diagnosis and prognosis contd….

Vascular phenotype : “CVD” Arteriosclerosis Amyloid angiopathy Other small vessel disease

“You have got to be before you can do

and do before you can have”

Diagnosis and prognosisDiagnosis and prognosis contd….contd….

Vascular Vascular distributiondistribution

Mechanism Mechanism of Brain of Brain injuryinjury

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 prognosisDiagnosis and prognosis contd….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 prognosisDiagnosis and prognosis contd…. contd….

Localisation / Localisation / neural networkneural network

Clinical phenotype or Clinical phenotype or syndromesyndrome

Cortico-basal ganglia Cortico-basal ganglia – thalamocortical – thalamocortical loopsloops

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 strokeDiagnosis of Dementia after stroke

Four sets of criteria are used Four sets of criteria are used SensSens SpecSpec

1.1. Hachinski ischemic score 89% 89%Hachinski ischemic score 89% 89% < 4 AD / 18, > 7 MID / 18< 4 AD / 18, > 7 MID / 18

2.2. DSM IV DSM IV 43% 95% 43% 95%

33. NINDS – AIREN. NINDS – AIREN 50% 98% 50% 98%

4.4. ADDTC criteria ADDTC criteria 50% 90% 50% 90%

Every discovery contains an irrational element or

4 creative intuition - Khrl Popper

AD Vs VaDAD Vs VaD

ADAD 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 symptoms Focal neurological symptoms and signsand signs

Unlikely to respond to Unlikely to respond to treatment treatment

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

A good teacher is a perpetual learner

VaD ChE-I especially Galantamine is

found effective in VaD +/- AD Pseudo bulbar palsy with emotional

incontinene responds to SSRI , TCA or levadopa

“Serious, sincere, systematic study surely secures supreme success”

Role of RIVASTIGMINE in VaDRole of RIVASTIGMINE in VaD

No.of patients : 12No.of patients : 12Age group Age group : 50 – 80 years : 50 – 80 yearsFemaleFemale : 4 : 4MaleMale : 8 : 8Most of them had diabetes and hypertension Most of them had diabetes and hypertension Not based on subtype of VaD Not based on subtype of VaD 30% showed remarkable improvement in cognitive,30% showed remarkable improvement in cognitive,curative and affective functions of the braincurative and affective functions of the brainFuture study neededFuture study needed

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

pass” - Annoy

Strategies to preventStrategies to prevent – – STROKE – TO - DEMENTIASTROKE – TO - DEMENTIA

TEN-STEP APPROACHTEN-STEP APPROACH1.1. Treat hypertension optimallyTreat hypertension optimally2.2. Treat diabetesTreat diabetes3.3. Control hyperlipidaemia, uControl hyperlipidaemia, use dietary control for se dietary control for

diabetes, obesity and hyperlipidaemiadiabetes, obesity and hyperlipidaemia

4.4. Persuade patients to cease smoking and Persuade patients to cease smoking and decrease alcohol intakedecrease alcohol intake

5.5. Prescribe anticoagulants for atrial fibrillationPrescribe anticoagulants for atrial fibrillation6.6. Provide antiplatelet therapy for high risk Provide antiplatelet therapy for high risk

patientspatients

A open foe may prove a curse ; but

a pretended friend is worse

Strategies to prevent – Strategies to prevent – STROKE-TO-DEMENTIASTROKE-TO-DEMENTIA contd…contd…

7.7. Perform carotid endarterectomy for severe (>70%) carotid Perform carotid endarterectomy for severe (>70%) carotid stenosisstenosis

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

stress, decrease salt intake)stress, decrease salt intake)

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

10.10. Intervene early for stroke and transient ischemic attacks with Intervene early for stroke and transient ischemic attacks with

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

antagosists, -? Rivastigmineantagosists, -? Rivastigmine

It is a great misfortune not to possess sufficient wit to speak well

nor sufficient judgment to keep silent - La Broyers character

FTLDFTLD Prominent aphasia and neuro-Prominent aphasia and neuro-

psychiatric complaints psychiatric complaints Familial, mutation in Ch. 17Familial, mutation in Ch. 17 SSRI decreases disinhibition, SSRI decreases disinhibition,

compulsioncompulsion Adrenergic agonists ,Idazoxan Adrenergic agonists ,Idazoxan

improves planning ,attention & improves planning ,attention & episodic memoryepisodic memory

“The Truth is fear and immorality are two of the greatest inhibitors of Performance to progress”

HIV associated DementiaHIV associated Dementia

Symptoms- Change in personality- mild to Symptoms- Change in personality- mild to psychotic psychotic

Loss of concentration, confusionLoss of concentration, confusion Cognitive impairementCognitive impairement Progressive subcortical dementiaProgressive subcortical dementia Signs –FND, seizures, meningeal signs, Signs –FND, seizures, meningeal signs,

increased ICP signsincreased ICP signs

“Healthy Mind and Healthy expression of Emotion go hand in Hand”

Care and Cure !

It is not your position that makes you happy or unhappy It is your disposition

Rx of

Neuropsychiatric Problems

An accurate diagnosis for both dementing illness and concomitant psychiatric symptoms

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

As one is common to all numbers, it is often seen as the origin of all things

Rx 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

Two symbolizes partnership implying that accomplishments are best through coordination.

Rx … Apathy -

Methylphenidate, dextro-amphetamine Modafenil

Insomnia - Trazadone, Zolpidem

Delusion- atypical antipychotics Depression –

SSRI, Comb. RI eg. Venlafaxin,Mirtazepin

Hate screeches, fear squeals; conceits trumpetsbut love sings lullabies

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

Three can be seen in the divisions of a human in mind, body and spirit

Therapy--? Future

“Knowledge can be communicated but not Wisdom” - Hermann Hesse

Future Future therapiestherapies

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

Gene therapy using nerve growth factor Gene therapy using nerve growth factor administered by implanting genetically administered by implanting genetically engineered autologous fibroblasts engineered autologous fibroblasts

“Motivation is the Spark that lights the Fire of Knowledge and

fuels the engine of Accomplishment

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

Learn to adapt, adjust and accommodate Learn to give, not to take and learn to serve not to rule

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

In all of us, even in good men, there is a wild - beast nature which peers out in sleep

Dedicated to my family for making everything worthwhile

Thank youThank youMy sincere thanks to

Mr.K.THUDHIMUGAN for his meticulous computer work

My sincere thanks to Mr.K.THUDHIMUGAN for his meticulous

computer work

READ not to contradict or confute

Nor to Believe and Take for Granted

but TO WEIGH AND CONSIDER