Frontiers in the treatment of dementia

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  • 1. Frontiers in thetreatment of Dementia A.Gunasekaran,P.V.Krishnan ,M.Radha,A.NithyanandamPROF.A.V.SRINIVASAN
  • 2. Senescence – a second childhood !
  • 3. 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 .
  • 4. 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
  • 5. Assessment• Neuropychological instruments are useful in• diagnosing and classifying the type of dementia• Judging the severity of dementia• following progress• Assess efficacy of Rx
  • 6. 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
  • 7. 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
  • 8. 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
  • 9. 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
  • 10. 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
  • 11. 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
  • 12. akin to dementia …• Delirium• Acute onset• Fluctuating course• Autonomic disturbances• Precipitating factors like infection , metabolic disturbances, drugs
  • 13. 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
  • 14. Age associated cognitive decline•• Decline of more than one SD in area of cognitive functioning in comparision with age matched controls
  • 15. 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
  • 16. 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
  • 17. Mx - a team work• Together• Everyone• Achives• More
  • 18. Mx …• Non-Pharmacological measures• Minimise sensory deprivation• Oral hygiene / Nutrition• Maintain daily routines,reminders,diaries• Flooring/clothing• Foot-wears, walking aids
  • 19. 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
  • 20. Is there answer forAlzhiemer’s disease?
  • 21. 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
  • 22. Phar macologicaltr eatment of dementia  Cholinesterase inhibitors ( ChE-I)  NMDA receptors antagonists  Anti-oxidant drugs  Anti-psychotic drugs
  • 23. ChE-I  Inhibits acetyl cholinesterase  Increases synaptic residue time of Ach.  Increased signal in post synaptic cholinergic neuron  Enhances cognition, improves behaviour, improves global function
  • 24. ChE-I  British psychiatrists group recommend in probable AD in NINDS criteria, MMSE >10 (mild to moderate), duration > 6 mths  Long term therapy found beneficial  When the drug is withdrawn, worsening of ADL ,behaviour needs restarting the drugs
  • 25. AChEI -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
  • 26. NMDA 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
  • 27. 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
  • 28. Other drugs Ginkgo biloba : Mixed results in trials.The effect is smaller than AChEI s Oestrogens : Not successful, risk of Venous thrombosis NSAIDs : Observations showed lower risk of AD with NSAIDs but clinical trials disproved efficacy
  • 29. No time to lose• Early diagnosis and intervention results in clinical and finicial benefit by alleviating the patient and care giver burden
  • 30. 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
  • 31. Vascular dementia Very common cause in india due to high prevalence of CVA/risk factors Unlike other dementias,disease modifying treatments(OHA,AHT,lipid lowering drug) can be beneficial Prevention of stroke and its recurrence is useful
  • 32. Two diverging/converging pataways associated with VaDRisk factor CVD Ischemic Brain injury MRI lesion Clinical syndromeHTNArteriosclerosis 1. occlusion complete infarct lacune  lacunnar stateArteriosclerosis 2. Hypoperfusion Experience can be defined as incomplete infarct WHSM  Bingswanger answer to today’s problems yesterday’s syndrome
  • 33. Short comings1. Not interchangeable hence four fold rise in frequency2. DSM IV R most liberal3. NINDS- AIREN criteria conservative4. Gold standard for VaD (pathological definition difficult)5. Most of the criteria failed to distinguish between small and large vessel subtypes “HealthyMind and Healthyexpression of Emotion go hand in Hand”
  • 34. Diagnosis and prognosisRisk factors Modifiable Non-modifiable Hypertension Age Hyperglycemia Gender Race Heredity Discipline Weighs ounces R egret weighs Tons
  • 35. Diagnosis and prognosis contd…. Vascular phenotype : “CVD”  Arteriosclerosis  Amyloid angiopathy  Other small vessel disease “Y have got to be before y can do ou ou and do before y can have” ou
  • 36. Diagnosis and prognosis contd…. Vascular Mechanism of Pathological distribution Brain injury phenotype “Infarct”Single artery Acute ischemia Multiple lacunarSmall arteriole infarctsSingle artery Acute ischemia Single strategically placed lacunar infarctBorder zone Chronic White matterSmall arteriole hypo perfusion demyelination and axonal loss
  • 37. Diagnosis and prognosis contd….Neuro imaging phenotype CT lucency (lacunes and leukoariosis) MRI hyper intensity (lacunes and WMSH) A true com itm is a heart felt prom to m ent ise yourself fromwhich y will not back down - ou D. Mcnally
  • 38. Diagnosis and prognosis contd….Localisation / Clinical phenotype orneural network syndromeCortico-basal ganglia – Lacunar statethalamocortical loops Apathy, depression, abulia Dysexecutive syndrome Normal visual fields parkinsonismCortico-basal ganglia Strategic infarct dementiathalamocortical loops Dysexecutive syndrome Frontal lobe syndromeDeep white matter Binswanger’s syndromeconnections Slowly progressive depression, bradykinesia, dysexecutive syndrome, gait apraxia, urinary incontinence
  • 39. Diagnosis of Dementia after stroke4 sets of criteria are used Sens Spec1. Hachinski ischemic score 89% 89%< 4 AD / 18, > 7 MID / 182. DSM IV 43% 95%Every discovery contains an irrational 50%3. NINDS – AIREN element or 98% 4 creative intuition4. ADDTC criteria 50% Popper Khrl
  • 40. AD Vs VaD AD VaDNeuro transmitter defect Hemodynamic defectFemale predominance Male predominanceGradual onset Abrupt onsetSteady deterioration Stepwise deterioration, fluctuating courseBP normal HypertensionNo history of stroke History of strokeGlobal decline in cognitive Focal neurologicalfunction symptoms and signsUnlikely to respond to May respond to a drugtreatment which modifies microcirculation and enhance cerebral tissue
  • 41. VaD• ChE-I espescially Galantamine is found effective in VaD +/- AD• Pseudobulbar palsy with emotional incontinene responds to SSRI , TCA or levadopa
  • 42. Role of RIVASTIGMINE in VaDNo.of patients : 12Age group : 50 – 80 yearsFemale : 4Male : 8Most of them had diabetes and hypertensionNot based on subtype of VaD30% showed remarkable improvement in cognitive, curative and affective functions of the brainFuture study needed “ He who cannot forgive others destroy the bridge s over which he him m pass” - Annoy self ust
  • 43. Strategies to prevent – STROKE-TO-DEMENTIA TEN-STEP APPROACH1. Treat hypertension optimally2. Treat diabetes3. Control hyperlipidaemia, use dietary control for diabetes, obesity and hyperlipidaemia4. Persuade patients to cease smoking and decrease alcohol intake5. Prescribe anticoagulants for atrial fibrillation6. Provide antiplatelet therapy for high risk patients foe may prove a curse ; but A open a pretended friend is worse
  • 44. Strategies to prevent – STROKE-TO-DEMENTIA contd…7. Perform carotid endarterectomy for severe (>70%) carotid stenosis8. 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 It antagosists, - ? Rivastigmine is a great misfortune not to possess sufficient wit to speak well nor sufficient judgment to keep silent La Broyers character
  • 45. FTLD• Prominent aphasia and neuro-psychiatric complaints• Familial, mutation in Ch. 17• SSRI decreases disinhibition, compulsion• Adrenergic agonists ,Idazoxan improves planning ,attention & episodic memory
  • 46. Care and Cure !
  • 47. Mx of neuropsychiatricproblems An acurate diagnosis for both dementing illness and concomitant psychiatric symptoms Treatment of psychiatric problems reduce the distress of patient as well as caregiver
  • 48. 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
  • 49. Mx …• Apathy - Methylphenidate,dextro-amphetamine Modafenil• Insomnia - Trazadone , Zolpidem• Delusion- atypical antipychotics• Depression - SSRI, comb. RI eg. Venlafaxin,Mirtazepin
  • 50. 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
  • 51. Therapy -- ? Future
  • 52. 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
  • 53. 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
  • 54. 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
  • 55. ThankYou !