Prof.Dr.dr. H. Rusdi Lamsudin, M.Med.Sc Neurologist Medical Doctor, Faculty of Medicine, UGM, 1971 Neurologist, Unair-UGM, 1978 Master of Medical Sciences, New Castle Univ, Australia, 1986 Head of Executive Board Muhammadiyah Hospital, Yogyakarta, 1993-1999 Vice Dean, Faculty of Medicine Muhammadiyah Yogyaakarta University, 1993-1999 PhD, UGM, 1996 Short-course, Unit Stroke & Neuro-Intensive, Insburck, Austria,1997 Head of Stroke Unit, Sardjito Hospital, Yogyakarta, 2001-2005 Head of Neurology Department Faculty of Medicine, UGM, 2001-2005 Dean of Faculty Medicine, Indonesia Islamic University, Yogyakarta, 2001-2006, 2006-2010 Head of Neurology Department YARSIS Hospital, Surakarta President IIMA, 2006-2012

DEMENTIA Epidemiology, Economic-Impact and Clinical’s Aspect Prof Dr. dr. Rusdi Lamsudin MMedSc Neurologist Department of Neurology YARSIS HOSPITAL Faculty of Medicine Indonesian Islamic University

Overview Epidemiology Economic Impacts Definition Clinical presentation Diagnosis Differential Diagnosis Etiology Workup Non-pharmacologic Treatments Drug Treatments Terminal Care

EPIDEMIOLOGY

Epidemiology Dementia affects 17–25 million people worldwide Estimated 4 million in the US and an estimated 800,000 people in the UK [Ritchie, 1995; Keefover, 1996]. It affects predominantly elderly people, The prevalence of dementia in people over the age of 65 is 5% and in people over 80, it is 20%. It has been estimated that 26% of women and 21% of men over the age of 85 have some form of dementia, of whom approximately 50% have Alzheimer’s disease (AD) [Melzer, 1997].

Epidemiology In case of AD: Age specific prevalence rates almost double with every additional 5 years of age from 1% of 65, rising to about 8-10% at age 80 and 30- 40%at age 90 African-Americans and Hispanics may have a higher risk than Caucasians-Americans. It also occurs less frequently in Asians than Americans

Growth of numbers of people with dementia The World Alzheimer Report (2009) estimated: 35.6 million people living with dementia worldwide in 2010 Increasing to 65.7 million by 2030 115.4 million by 2050

Economic Impact

Worldwide cost of dementia The societal cost of dementia is already enormous. Dementia is already significantly affecting every health and social care system in the world. The economic impact on families is insufficiently appreciated. The total estimated worldwide costs of dementia are US$604 billion in 2010. These costs are around 1% of the world’s GDP 0.24% in low income 1.24% in high income

Worldwide costs of dementia The World Alzheimer Report (2010) estimated that: If dementia care were a country, it would be the world’s 18th largest economy

Definition

Definition a syndrome characterized by progressive decline of intellectual ability from a previously attained level the decline in mental inability usually involves variable deterioration in  speech  memory  judgment  mood without alteration of consciousness medslides.com 6/00

Definition Multiple Cognitive Deficits: Cognitive Disturbances: Memory dysfunction especially new learning, a prominent early symptom At least one additional cognitive deficit aphasia, apraxia, agnosia, or executive dysfunction Cognitive Disturbances: Sufficiently severe to cause impairment of occupational or social functioning and Must represent a decline from a previous level of functioning

Clinical Presentation

Clinical Presentation onset of dementia it is usually insidious dementia is often progressive (degenerative disease) but may be static (post-traumatic brain injury) initial presentation may include slight forgetfulness, attention and concentration deficits, and increasing repetitiousness or inconsistencies in usual behavior later presentation may display impaired judgment, inability to abstract or generalized, and personality change with rigidity, perseveration, irritability, and confusion; affective disturbances may be prominent with loss of personality and self-care medslides.com 6/00

Impairment of 2 or more cognitive domain 1 Memory loss 2 Language 3 Abstract thinking & Judgment 4 Praxis (learned motor behavior) 5 Spatial processing 6 Personality 7 Social conduct

Risk Factors for Dementia Gender: male Age: 60-70 years Prior stroke Hardening of the arteries Heart disease High blood pressure Diabetes Cholesterol problems Atrial fibrillation Smoking Education Race Family history (CADASIL-cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy )

Most common causes of dementia Alzheimer’s disease Vascular dementia Lewy body dementia Frontotemporal dementia

Established risk factors for dementia Age Female sex Head trauma Low level of education

Risk factors for dementia Coronary artery disease High dietary saturated fat and cholesterol Serum cholesterol Hyperhomocysteinemia Smoking Diabetes mellitus Hypertension Apolipoprotein E status All these are vascular risk factors!

Diagnosis and Diffeerential Diagnosis

Differential Diagnosis:TopTen (commonly used mnemonic device: AVDEMENTIA) 1. Alzheimer Disease (pure ~40%, + mixed~70%) 2. Vascular Disease, MID (5-20%) 3. Drugs, Depression, Delirium 4. Ethanol (5-15%) 5. Medical / Metabolic Systems 6. Endocrine (thyroid, diabetes), Ears, Eyes, Environ. 7. Neurologic (other primary degenerations, etc.) 8. Tumor, Toxin, Trauma 9. Infection, Idiopathic, Immunologic 10. Amnesia, Autoimmune, Apnea, AAMI

Comparison of the Clinical Features Dementia Depression Delirium Insidious/slow and often unrecognized; depends on cause Coincides with major life changes; often abrupt, but can be gradual Sudden/abrupt; depends on cause; often at twilight or in darkness Clinical Features: ONSET COURSE, PROGRESSION, ATTENTION, MEMORY, THINKING

Neurologic Diseases Associated with Intellectual Dysfunction DISEASE PHYSICAL SIGNS CLINICAL FEATURES Creutzfeldt-Jakob Myoclonus , cerebellar signs, Subacute course; EEG has specific abnormalities, eye movement abnormalities brain biopsy diagnostic Huntington's disease Choreiform movements, Often positive family history; caudate atrophy corticospinal signs by CT or MRI Multiple sclerosis Brainstem signs, optic atrophy, Usually long-standing disease; episodic illness corticospinal signs with remissions; often extensive white matter abnormalities by MRI Wilson's disease Extrapyramidal signs , hepatic Onset in adolescence or young adult life, dysfunction, Kayser-Fleischer psychiatric disorders rings Progressive Failure of vertical downgaze, Eye movement abnormalities; differentiate from supranuclear extrapyramidal signs Parkinson's disease; unresponsive or only palsy transiently responsive to levodopa * = invariably present; all other physical signs are neither invariably present nor pathognomonic. medslides.com 6/00

Etiologic Diagnosis of Progressive Dementias in Adults Neurodegenerative Diseases Alzheimer’s disease Parkinson’s disease Diffuse Lewy body disease Progressive supranuclear palsy Multisystem atrophy Huntington’s disease Frontotemporal dementias – e.g. Pick’s disease

Etiology contd. Structural Disease or Trauma Vascular Disease Normal pressure hydrocephalus Neoplasms Dementia pugilistica Vascular Disease Vascular dementia Vasculitis Heredometabolic Disease Wilson’s disease Other late-onset lysosomal storage diseases

Etiology contd. Demyelinating or Dysmyelinating Disease Multiple sclerosis Infectious Disease Human immunodeficiency virus, type 1 Tertiary syphilis Creutzfeldt-Jakob disease Progressive multifocal leukoencephalopathy Whipple’s disease Chronic meningitis – e.g. Cryptococcal

DELIRIUM Acute brain dysfunction characterized by: Global symptoms (affecting both cerebral hemispheres) including impairment of consciousness and attention Primary physiological changes with potential for reversibility ‘waxing and waning’ symptoms – usually worse in evening Life-threatening conditions underlying the syndrome

Symptoms of Delirium Common symptoms of a delirium include: Waxing and waning levels of consciousness Poor attention and disorientation Disturbed memory (long and short term) Psychosis Sleep dysregulation Fearfulness with agitation and aggression Seriously impaired insight and judgment

Epidemiology of Delirium Very Common - 10-15% med/surg inpatients (30%+ if elderly) 30% of Adult Burn Patients 80%of delirious patients have pre-existing dementia Predisposing Factors: old age, postcardiotomy, s/p burns prexisting brain damage drug withdrawal states AIDS

Causes of Delirium Often multifactorial Infections, trauma, brain diseases Cardiac diseases, lung disease, hypoxia, hypoglycemia Toxins, or intoxications Medication effects Substance withdrawals (e.g. DTs) Endocrinopathies In elderly dementia patients: UTI, dehydration and pneumonia are the most common causes

DELIRIUM - TREATMENT Must look for medical cause(s) and treat Symptoms can be helped by antipsychotic drugs such as haldoperidol or risperidone (especially psychosis, agitation) Consider anticholinesterases for anticholinergic delirium Comfort measures include reorientation strategies, reducing stimulation, frequent reassurance

Delirium vs Dementia (summary) General rules of thumb: Delirium Dementia acute chronic reversible irreversible physiological structural primary attention primary memory deficits deficits Delirium and dementia can coexist; in fact delirium is very common in demented patients CAUSES OF DELIRIUM: Infectious - encephalitis, meningitis, UTI - also systemic infections with sepsis, fever Withdrawal Acute Metabolic - electrolyte changes, dehydration, blood sugsr changes, acidosis, hepatic or renal failure Trauma CNS pathology - seizures, tumors, strokes, etc. Hypoxia Deficiencies - b12, thiamine Endocrine Acute Vascular Toxins,Drugs Heavy Metals I WATCH DEATH

Work-up

Workup History Physical Examination Laboratory studies medslides.com 6/00

History - etiology the most important component of the initial evaluation adequate history with help of a family member is critical description of cognitive, memory, and behavior problems effect on daily life - difficulty with driving, work, or family relationships details on temporal course of illness chronic progressive (Alzheimer or other neurodegenerative disease) stepwise (multi-infarct) static (traumatic injury, episode of severe hypotension) medslides.com 6/00

History - treatable causes Vascular dementia - presence of cardiovascular risk factors (smoking, HTN, chol, diabetes) Normal pressures hydrocephalus - triad of dementia, gait, incontinence with a prior history of meningitis or subarachnoid hemorrhage Mass lesion - history of head trauma, unexplained focal neurologic deficit, unilateral headache worsening over time Parkinson’s disease - resting tremor and rigidity Wilson’s disease - hepatocellular disease and dementia HIV and neurosyphilis - high-risk sexual behavior hereditary - family history dementia, Down’s syndrome, psychiatric disorders medslides.com 6/00

History - treatable causes B12 deficiency - previous gastric surgery B12, thiamin, niacin deficiency - inadequate nutrition, alcohol abuse medications - opiates, sedative-hypnotics, analgesics, anticholinergics, anticonvulsants, corticosteroids, centrally acting anti-hypertensives, psychotropics symptoms of hypothyroidism, pituitary insufficiency occupational history - exposure to toxic substances (aniline dyes, heavy metals) medslides.com 6/00

Diagnostic Criteria For Dementia Of The Alzheimer Type (DSM-IV, APA, 1994) Multiple Cognitive Deficits 1. Memory Impairment 2. Other Cognitive Impairment Deficits Impair Social/Occupational Course Shows Gradual Onset And Decline Deficits Are Not Due to: 1. Other CNS Conditions 2. Substance Induced Conditions Do Not Occur Exclusively during Delirium F. Not Due to Another Psychiatric Disorder

Mental Status Examination Examination should be geared to both the detection of focal lesions and to signs of general brain dysfunction immediate memory testing (three object recall, recite digits forward and backward, recall a short story) remote memory testing (recall of historical events, family milestones, or recent local or international news) reproducible drawings discern similarities among objects decision-requiring tasks (finding a stamped letter or seeing a fire in a theater) medslides.com 6/00

Mini-Mental Status Tests Score Recall: 3 Ask for 3 objects repeated above. Give one point for each. Language: 2 Name a pencil and watch (2 points). 1 Repeat the following: "No ifs ands or buts." 3 Follow a 3-stage command: "Take a paper in your right hand: fold it in half, and put it on the floor." (3 points). 1 Read and obey the following: "Close your eyes." 1 Write a sentence. 1 Copy design. Total Score: [ ] Maximum Score: 30 medslides.com 6/00

Physical and Neurologic Examinations Check for focal evidence of neovascular risk factors - carotid bruits, signs of alcoholism, hepatocellular injury, renal insufficiency, other systemic illnesses specific neurologic abnormalities frontal lobe release signs (grasp, suck, snout, root) visual field cut and extraocular movement limitations abnormal pupillary reactions extrapyramidal features (carditis dyskinesis, tumors, asterixis, Korea, monoclonal disc, it) sensory deficit and gait disorder medslides.com 6/00

Screening Laboratory Studies 1. Complete blood count and sedimentation rate 2. Chemistry panel (electrolytes, calcium, albumin, BUN, creatinine, transaminase) 3. Thyroid-stimulating hormone (TSH) 4. VDRL test for syphilis 5. Urinalysis 6. Serum B12 and folate levels 7. Chest x-ray 8. Electrocardiogram 9. Head computed tomography (CT) medslides.com 6/00

Neuroimaging Head CT or MRI is appropriate in the presence of 1) history suggestive of a mass lesion 2) focal neurologic signs or symptoms 3) dementia of abrupt onset 4) history of seizures 5) history of stroke MRI with gadolinium contrast enhancement is superior to CT for the diagnosis of multi-infarct dementia and problems referrable to the posterior fossa medslides.com 6/00

Other Ancillary Studies Lumbar puncture routine LP for initial evaluation of dementia is not justified may be indicated when other clinical findings suggest an active infection or vasculitis and as part of the evaluation of normal pressure hydrocephalus sugar, protein, cell count, cultures, gamma globulins, the serology for stiffness should be obtained medslides.com 6/00

Other Ancillary Studies Electroencephalogram (EEG) usually normal or with nonspecific rhythm slowing indicated in patients with episodic altered consciousness and in whom seizures may be suspected may occasionally raise suspicion of a particular etiology: focal, delta slowing is seen with tumor unilateral attenuation of voltage may suggest an extracranial mass such as subdural hematoma excessive beta activity may be consistent with drug ingestion Creutzfeldt-Jakob disease has a highly specific EEG pattern medslides.com 6/00

Other Ancillary Studies Formal neuropsychologic evaluation appropriate for more specific information when the diagnosis is in doubt also helpful in providing additional information about the nature of impairment following focal brain injury Speech analysis may improve patient and family communication with therapy Formal psychiatric assessment may be desirable if depression in addition to dementia is suspected medslides.com 6/00

Studies of Limited or Uncertain Utility Cerebral blood flow and metabolism measurements PET and SPECT scans have no routine use at present Brain biopsy rarely justified for non-neoplastic or noninfectious diseases Progressive multifocal leukoencephalopathy or Creutzfeldt-Jakob disease is diagnosed by biopsy Noninvasive neurovascular studies (carotid ultrasound, Doppler flow studies) if MRI or CT demonstrates infarction, or clinical course or physical examinations is suggestive of cerebralvascular disease medslides.com 6/00

Treatment

General Treatment Principles For Dementia Treatment Of Underlying Disease Process (Primary Treatment) Management Of Behaviors and Symptoms (Secondary Treatment) Caregiver Support and Education

Primary Treatment Strategies (for progressive dementias) 1. Prevention Identify risks and mitigate Develop neuroprotective strategies for those at risk 2. Slow or halt progression of illness Understanding pathophysiology leads to treatment ideas 5 year delay in onset ---> 1/3 decrease in prevalence Delaying institutionalization by 1 month saves $1.2 billion/yr 3. Reverse symptoms Compensate through augmentation of remaining neurons or other systems Reversal of destructive processes & regeneration of tissue

Symptomatic Management and Counseling Improving mental functioning Management of confusion and agitation Maintaining the patient at home Risk factor reduction and attention to underlying etiologies medslides.com 6/00

Improving Mental Functioning no established treatment for Alzheimer’s disease or for patients with multi-infarct dementia findings of degeneration of cholinergic neurons and depletion of choline-acetyl transferase in Alzheimer's disease have led to attempts at improving cholinergic transmission lecithin supplements (dietary choline repletion) tacrine (a centrally active, reversible cholinesterase inhibitor) There is no evidence to support the use of: restorative therapy with nerve growth factor, protective therapy with antioxidants, preventive therapy with drugs that inhibit beta amyloid formation, and “cerebral vasodilators” (papaverine, dihydroergotoxine) to improve memory medslides.com 6/00

Management of Confusion and Agitation The chronic use of sedatives and psychoactive agents in the confused patient should be avoided unless persistent extreme agitation hampers care The lowest possible doses should be used and for the shortest time possible thioridazine (10 to 25 mg qhs) haloperidol (0.5 to 1 mg bid or tid ) often a first choice in the setting of delusions and hallucinations; must be careful to avoid long-term use because of the risk of inducing tardive dyskinesia medslides.com 6/00

Management of Confusion and Agitation Avoid regular use of sedative/hypnotic agents for sleep Beta-blocking agents and anticholinergics may exacerbate confusion Patients with depression may improve with a tricyclic compound with low anticholinergic side effects  desipramine (25 to 50 mg qhs) A recent study of nursing home patients demonstrated substantial improvement in many patients when chronically prescribed psychotropic drugs were discontinued or reduced in dose medslides.com 6/00

Maintaining the Patient at Home An important task is helping the family maintain and care for the patient at home The goal is to sustain the highest level of function possible: facilitate and promote an orderly home situation regular routine use of calendars, television, newspapers, and other means of orientation limit the use of potentially dangerous appliances provide convenient toilet facilities advice against driving when early impairment of judgment and spatial concepts is present medslides.com 6/00

Maintaining the Patient at Home Families can often find help in local support groups, day care and group therapy services, and social service agencies When care at home begins to exhaust and strain the family, sensitive counseling can do much to help a family cope with the difficult decision regarding institutionalization some dementing diseases are infectious (eg, HIV infection) and that the bodily fluids and tissues of such patients require special handling to avoid transmission. It is particularly important to emphasize when home care is rendered by lay persons medslides.com 6/00

Risk factor reduction and attention to underlying etiologies Central to an effective outcome : control of cerebrovascular risk factors as hypertension, diabetes mellitus, smoking , hyperlipidemia , and coronary artery disease endarterectory deserves consideration when a vascular etiology is strongly suspected and a significant stenosis is found Avoidance of toxins, correction of vitamin deficiencies, discontinuation of causative drugs, initiation of hormonal replacement therapy in cases of deficiency, and treatment of underlying infectious etiologies medslides.com 6/00

Improving Support for Families and Other Caregivers Who are the AD Caregivers? (slide 37) Demands of Caregiving (slide 38) Technology and Caregiving (slide 39) National Support for Caregivers (slide 40) How to Contact the ADEAR Center (slide 41) Slide 36

Support for Caregivers Demands of Caregiving AD takes a huge physical and emotional toll. Caregivers must deal with changes in a loved one’s personality and provide constant attention for years. Thus, caregivers are especially vulnerable to physical and emotional stress. Peer support programs can help link caregivers with trained volunteers. Other support programs can offer services geared to caregivers dealing with different stages of AD. Slide 38

Treatment of AD…

Tacrine Cholinesterase inhibitor 1 systematic review with 5 RCTs, 1434 people, 1-39 weeks No difference in overall clinical improvement Some clinically insignificant improvement in cognition Significant risk of LFT abnormalities: NOT USED

Donepezil Aricept Cholinesterse inhibitor Easy titration (start 5/day, then 10) Side effects: GI (nausea, diarrhea) Can be associated with bradycardia… Main effect seems to be lessening of rate of decline, delayed time to needing nursing home/more intensive care

Other agents… Rivastigmine Galantamine Cholinesterase inhibitors ?more side effects, more titration required Future directions: Prevention of delirium in at risk patients (cholinergic theory of delirium) Behavioral effects in those with severe dementia? Treatment of Lewy Body dementia Treatment of mixed Vascular/AD dementia

Comments about cholinesterase inhibitor studies… Highly selected patients (mild-moderate dementia) ?QOL improvements… Not known: severe dementia and mild CI

Memantine NEJM april 2003 Moderate to severe AD (MMSE 3-14) N-methyl D aspartate (NMDA) receptor antagonist; theory that overstimulation of NMDA receptor by glutamate leads to progressive neurodegenerative damage 28 week, double blinded, placebo controlled study; 126 in each group; 67% female, mean age 76, mean MMSE 7.9

Memantine… Found less decline in ADL scores, less decline in MMSE (-.5 instead of –1.2) Problem: significant drop outs (overall 28% dropout rate) in both groups; data analyzed did not account for drop outs, followed those “at risk”

Selegiline Unclear benefit Less than 10mg day, selective MAO B inhibitor Small studies, not very conclusive

Vitamin E (alpha tocopherol) NEJM 1997: selegiline, vit E, both , placebo for tx of AD Double blind, placebo controlled, RCT with mod AD; 341 patients Primary outcome: time to death, institutionalization, loss of ADLS, severe dementia Baseline MMSE higher in placebo group No difference in Primary outcomes; adjusted for MMSE differences at baseline and found delay in time to NH from 670 days with vit E to 440 days with placebo

Ginkgo Biloba 1 systematic review of 9 double blind RCTs with AD, vascular, or mixed dementia Heterogeneity, short durations High withdrawal rates; best studies have shown no sig change in clinician’s global impression scores

Other treatments NO good evidence to support estrogens or NSAIDS

Other treatments… Behavioral/agitation: Nonpharmacologic strategies Reasons for NH placement: Agitation Incontinence Falls Caregiver stress

?Antipsychotics NO data to support any significant benefit for treating behavioral symptoms of dementia with antipsychotic agents Small group of patients with active psychoses, disturbing hallucinations, or aggressive behaviors who may have some benefit

Antipsychotics: Side Effects: Warnings: Sedation Anticholinergic effects Prolonged QT Edema Orthostasis Weight gain Confusion Warnings: FDA black box warning for increased mortality (OR 1.5- 1.7), and increased ?increased stroke risk

Prevention? HTN and DM linked to future development of ALL types of dementia (not just vascular)… Large initial studies of treating systolic hypertension in the elderly (SHEPS and others) demonstrated decreased risk of development of cognitive impairment over time in those patients in the original treatment group! Decreased risk included vascular AND alzheimer type dementias… Cholinesterase inhibitors seem to work as well (or as poorly) for both vascular and alzheimer type of dementias… What is the link? Both common in elderly, may be that one “unmasks” the other…

Conclusion International studies make it clear that dementia occurs in every country of the world. Dementia affects 1 in 20 people over the age of 65 and 1 in 5 over age of 80 Worldwide there are an estimated 35.6 million people with dementia. By 2050 the number will rise to over 115 million. For at least the last 15 years, the majority of people with dementia worldwide have been living in developing regions of the world. They account already for over 60% of all cases. By 2040 this portion will have risen to 71%.

Conclusion cont’ The worldwide cost of dementia will exceed 1 per cent of global GDP in 2010, at US$604 billion. If dementia care a country, it would be the world’s 18th largest economy The costs of caring for people with dementia are likely to rise even faster than the prevalence- especially in the developing world, as more formal social care systems emerge, and rising incomes lead to higher opportunity costs.

Conclusion cont’ Dementia is a progressive, degenerative brain syndrome that affects memory, thinking, behavior and emotion The progressive syndrome of dementia is define as loss of memory plus impairment in at least one other cognitive function, such as aphasia, apraxia, agnosia and disturbance in executive function, which is severe enough to interfere with activities of daily living and represent decline (DSM-IV, 1994

Conclusion cont’ Dementia presents with variety of clinical manifestations regardless of aetiology, and in most cases it caused by organic barain disease. It characterized by three main symptomatic domains as; 1) activities- inability to perform activities of daily life, 2) behaviours-psychiatric symtoms/behavioural disturbances and 3) cognition- neuropsychological impairment

Conclusion cont’ There are four main types of dementia: 1) Alzheimer’s disease (60% of cases), 2) Vascular dementia (30-40%; including about 20% where dual pathology exists), 3) Dementia with Lewy bodies (15% of cases), and 4) Fronto-temporal dementia (5% of cases).

Conclusion cont’ The treatments options for dementia include both pharmacological and nonpharmacological therapeutic approaches. These can be further subdivided into therapies for cognitive impairment and neuropsychiatric disturbances (psychiatric symptoms and behavioural disturbances).

Conclusion cont’ The quality of life patients with dementia is paramount and long-term care of the patient requires continued education and communication with clinicians, primary carers, care staff and family members.