Neuropsychiatric manifestations of Alzheimer and other dementias

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Neuropsychiatric manifestations of Alzheimer and other dementias Powered By Docstoc
					Dory G. Hachem, M.D.
 In 1901 , German psychiatrist Alois Alzheimer
  identified Auguste D.(paranoia,delusion of sexual
  abuse,hallucinations, screaming)
 During the next five years, 11 similar cases were

 The disease was first described as a distinctive disease
  by Emil Kraepelin (German psychiatrist), as a
  subtype of senile dementia in the eighth edition of his
  Textbook of Psychiatry, published in 1910
 There are 3 expressions of the clinical syndrome of
 dementia :

    1- Cognitive deficits –amnesia, aphasia, apraxia,
   2- Psychiatric features BPSD
   3- Activities of daily living
 1996,The Consensus group, consisting of some 60
 experts in the field, from 16 countries, produced a
 statement on the definition of the BPSD: “The term
 behavioral disturbances should be replaced by the
 term behavioral and psychological symptoms of
 dementia (BPSD), defined as:

 Symptoms of disturbed perception, thought content,
 mood or behavior that frequently occur in patients
 with dementia.

                                           (Finkel & Burns, 1999)
                     Prevalence of BPSD
Sign or symptom                    Reported frequency (% of
        Delusions                      20–73
        Misidentifications             23–50
        Hallucinations                 15–49
        Depression                     up to 80
        Mania                          3–15

       Personality change              up to 90
       Behavioral symptoms             up to 50
       Aggression/hostility            up to 20

                                                         Finkel, 1998
BPSD- behavioural symptoms
most common        common        less common

•Apathy         •Agitation       •Crying
•Aggression     •Disinhibition   •Mannerisms
•Wandering      •Pacing
(aka walking)   •Screaming
•Restlessness   •Sundowning
BPSD- psychological symptoms
most common      common         less common

•Depression   •Delusions      •Misidentification
•Anxiety      •Hallucinations
 Psychiatric symptoms are not required for the diagnosis of dementia,
  90% of elderly dementia patients will experience at least one symptom
  of any severity over their illness course

 is an umbrella term ,is a descriptive one and does not reflect a
  diagnostic entity but rather highlights an important clinical dimension
  of dementia.

 BPSD are treatable and generally respond better to therapy than other
  symptoms or syndromes of dementia

                           (Aalten et al. 2005; Steinberg et al. 2003; Tariot et al. 1995)
 BPSD related to functional decline.

 Are important in determining the QOL of both the
  patient and the caregiver (safety and welfare…)

 Are one of the most important factors when assessing
  the need for institutionalization of dementia patients

 May help in the Differential Dx of the causes of dementia

 Can be managed by both pharmacological and
  environmental interventions respond to therapy

 Lead to a substantial increase in the financial costs

                                                      Finkel et al., 1996.
   Methods of Assessment
 The gold standard that has been used so far in most
 studies is the :
 -*NPI (neuropsychiatric inventory)
 -The Cohen-Mansfield Agitation Inventory (CMAI),
 -The Behavioral Pathologic Rating Scale for
     Alzheimer’s disease (BEHAVE-AD),
 -The Consortium to Establish a Registry in AD

 The most prevalent symptoms were apathy (27%),
 depression (24%), and agitation (24%)
                                           (Lyketsos et al. 2000)
       NeuroPsychiatric Inventory
Motor aberrant dysfunction
Nighttime Disturbances
Appetite/Eating Disturbances
                 MMSE( 30 pts)
-Orientation to Place (state, county, town, hospital, and
-Orientation to Time (year, season, month, day, and
-Registration (immediately repeating three words),
-Attention and concentration (serially subtracting 7,
  beginning with 100, or, alternatively, spelling the word
  world backward)
-Recall (recalling the previously repeated three words),
-Language (naming two items, repeating a phrase,
  reading aloud and understanding a sentence, writing a
  sentence, and following a three-step command),
-Visual construction (copying a design)
In the Cache County Study on Memory, Health and Aging,
the largest community-based longitudinal cohort study of
dementia, the most prevalent symptoms were
       -Apathy (27%)
       -Depression (24%)
       -Agitation (24%)

Despite the high occurrence of and morbidity caused by
the psychiatric symptoms of dementia, well-studied
and consistently effective treatments currently are lacking.

                                                  (Lyketsos et al. 2000)
                                Cache County Study
The authors report findings from a study of 5,092 community residents who constituted
  90% of the elderly resident population of Cache County, Utah. METHOD: The 5,092
  participants, who were 65 years old or older, were screened for dementia. Based on
  the results of this screen, 1,002 participants (329 with dementia and 673 without
  dementia) underwent comprehensive neuropsychiatric examinations and were rated
  on the Neuropsychiatric Inventory, a widely used method for ascertainment and
  classification of dementia-associated mental and behavioral disturbances. RESULTS:
  Of the 329 participants with dementia, 214 (65%) had Alzheimer’s disease, 62 (19%)
  had vascular dementia, and 53 (16%) had another DSM-IV dementia diagnosis; 201
  (61%) had exhibited one or more mental or behavioral disturbances in the past
  month. Apathy (27%), depression (24%), and agitation/aggression (24%) were the
  most common in participants with dementia. These disturbances were almost four
  times more common in participants with dementia than in those without. Only
  modest differences were observed in the prevalence of mental or behavioral
  disturbances in different types of dementia or at different stages of illness:
  participants with Alzheimer’s disease were more likely to have delusions and less
  likely to have depression. Agitation/aggression and aberrant motor behavior were
  more common in participants with advanced dementia. CONCLUSIONS: On the
  basis of their findings in this large community population of elderly people, the
  authors conclude that a wide range of dementia-associated mental and behavioral
  disturbances afflict the majority of individuals with dementia. Because of their
  frequency and their adverse effects on patients and their caregivers, these
  disturbances should be ascertained and treated in all cases of dementia

          Constantine G. Lyketsos, M.D., M.H.S., Martin Steinberg, M.D., JoAnn T. Tschanz, Ph.D., Maria C. Norton, M.S.,
    Inadequate Knowledge of Effective Therapies

No pharmacotherapeutic agent has a U.S. Food and
Drug Administration (FDA) indication to treat any
neuropsychiatric symptom in dementia..

Although multiple clinical trials suggest benefit of atypical
neuroleptics for psychosis and agitated behaviors in
dementia, these agents now carry an FDA warning because of
increased mortality risk in elderlys with dementia

A recent study demonstrated that when treatment benefits were
balanced against side effects, atypical neuroleptics in
dementia offered little benefit over placebo
                                                (Schneider et al. 2006)
              Symptoms Versus Syndrome:
                What Is Being Treated?
 Few of the phenomena observed fit neatly into any DSM-IV-TR

 In case of depression; more severely demented persons often
  cannot report symptoms such as guilt and suicidal ideation, which
  would support a DSM-IV-TR diagnosis of major depressive

 In addition, there are significant differences in the frequency of
  many symptoms reported by elderly patients with and without
  dementia: For example, delusions are more common in
  depression of Alzheimer disease than in late-life depression

                                                      (Zubenko et al. 2003).
               Symptoms Versus Syndrome:
                 What Is Being Treated?
 Apathy can be an isolated symptom or a syndrome including, but
  not limited to, decreased motivation and impaired ability to persist
  in activities.

 Furthermore, apathy can also occur as an individual symptom in
  another syndrome, such as executive dysfunction syndrome

                                                            (Marin 1991)
BPSD Symptom Complexes
            1. Depression

             2. Psychosis

              3. Apathy

  4. Executive Dysfunction Syndrome

       5. Agitation/Aggression
1. Depression
 Depression is a major co-morbidity in dementia

 It can be the 1st sign of dementia :
 - around 20% of patients who are initially
   diagnosed with depressive pseudodementia
  (“reversible dementia”) may remit from the
  depression without regaining their cognitive
      i.e. their dementia becomes irreversible
     to dx it as irreversible dementia must be
  maintained for 2 yrs after recovery from depression
             Depression in AD :
 Depressive sx in dementia patients often fluctuate.

 Depressed pts with AD exhibit more self-pity, rejection
  sensitivity, anhedonia, and psychomotor disturbances
  than depressed older pts without dementia

 Major Depression in AD is correlated with an increased
  mortality rate , but not with an acceleration in cognitive

 The most common confounds are apathy, psychosis, and
  medical comorbidity.
             Depression in AD :
 a 2000National Institute of Mental Health workgroup
 empirically developed provisional criteria for
 “Depression of Alzheimer Disease” (dAD)

 Modeled on DSM-IV criteria for MDD, these criteria
 differ by requiring presence of only three symptoms
 (vs. five in DSM-IV), allowing for symptoms to be
 present intermittently instead of nearly every day,
 adding the criterion of irritability, and specifying the
 criteria of decreased positive affect or pleasure as “in
 response to social contact and usual activities

                                                  (Olin et al. 2002).
                Depression of Alzheimer Disease
 Clinically significant depressed mood (e.g., depressed, sad,
    hopeless, discouraged, tearful)
   Decreased positive affect or pleasure in response to social contacts
    and usual activities (either 1 or 2 are required)
   Disruption in appetite
   Disruption in sleep
   Psychomotor changes (e.g., agitation or retardation)
   Fatigue or loss of energy
   Feelings of worthlessness, hopelessness, or excessive or
    inappropriate guilt
   Diminished ability to think or concentrate
   Recurrent thoughts of death, suicidal ideation, plan, or attempt
   Social isolation or withdrawal
   Irritability
    Depression Scales in Dementia :
 The most widely used instrument is the Cornell
  Scale for Depression in Dementia.
  This 19-item scale is designed to distinguish between symptoms of
  depression and confounding symptoms that may reflect either the
  primary dementia process or medical comorbidity.

 Some clinicians may prefer to use the Hamilton Rating Scale for
  Depression (Ham-D; Hamilton 1960). Although not specific to
  depression in dementia, the Ham-D is widely used and familiar to
  more clinicians than the Cornell Scale is. The Ham-D may be less
  reliable than the Cornell Scale, however, in detecting depression,
  detecting treatment response in clinical trials, and in assessing changes
  in depression severity (Lee and Lyketsos 2003; Lyketsos et al. 2000).

                                                           (Alexopoulos et al. 1988)
2. Psychosis
 Diagnostic criteria for psychosis of AD
  1. Presence of one or more of:
                 –visual/auditory hallucinations
                 - delusions
   2. All the criteria for dementia of Alz. Type are met
   3. Chronology :Hx shows that psychotic sx were not
       continuous before the onset of dementia
   4. Duration of at least 1 month (even intermittently)
   5. Cause significant impairment of fxn
   6. R/0 psychotic d/o, general medical condtition,
      substance abuse
 Delusions and hallucinations often occur in the context of
  a delirium. Features suggesting delirium include:
       clouded sensorium, attentional deficits, marked
       symptom fluctuation, and disruption of sleep-wake
       cycle, and these should always be assessed in
       psychotic dementia patients.

 Common causes of delirium in the elderly include:
  infections (e.g., urinary tract infection, pneumonia),
  dehydration, and medication side effects (e.g.,
  anticholinergic side effects, sequelae of polypharmacy).
Psychosis of AD vs of Schizophrenia
             in Elderly
                            Psychosis in AD   Psychosis in

Bizarre or complex          rare              frequent

Misidentification of        frequent          rare
Common form of              Visual            Auditory
Schneiderian first-rank     rare              frequent
Active suicidal ideation    rare              frequent

Past history of psychosis   rare              frequent
                    3. Apathy
 Recent studies have stressed on the distinction between
  depression and apathy

 Both are manifested by reduced interests, energy and
  motivation levels, but in apathy these occur without dysphoria
  (vs. in depression)

 Apathy is the most common BPSD, not depression. It
  includes a decrease in motivation and initiative,emotional
  blunting and indifference, and impaired ability to persist in
  activities. The most commonly used measure of apathy in the
  elderly is the Apathy Evaluation Scale (AES).

                                                      (Marin et al. 1991)
    Apathy may be the earliest occurring feature in dementias in
     the elderly, preceding even early cognitive impairment

     It is important to ensure that decreased activity caused by
    pain or discomfort is not mistaken for apathy. The standard
    evaluation of a patient with recent onset of apathy should
    include a laboratory study:
                        metabolic abnormalities
4-Executive Dysfunction Syndrome
 With limited evidence for effective therapies, treating this syndrome has been
  described as “very challenging and mostly unsuccessful”

 Symptoms include: sexually inappropriate behavior, pacing, silly comments, eating
  nonfood objects, and perseverative repetition of phrases. Apathy may also be

 Although executive dysfunction syndrome can occur in all dementias, it is
  especially common in dementias with prominent frontal-subcortical involvement,
  such as the frontotemporal dementias and Huntington disease. Because these
  dementias often affect younger persons, the behaviors are sometimes interpreted as
  volitional and reflecting character traits or moral flaws

 The disinhibited and hypersexual behaviors characteristic of executive dysfunction
  syndrome can resemble mania or hypomania.

                                                                   (Drayton et al. 2004).
5. Agitation & Aggression:
        Agitation & Aggression
 Agitation can be defined as inappropriate verbal,
 vocal or motor activity that is not judged by an
 outside observer to result directly from the
 confusion of the patient (i.e. not directly due to the
 dementia itself)

 Physically non-aggressive: restlessness, repetitive
  mannerisms, hiding objects, pacing
 Physically aggressive: hitting, pushing…
 Verbally non-aggressive: negativism, chanting…
 Verbally aggressive : temper outbursts, cursing…
Dementia type-specific BPSD
      4 main types of dementia :

       -Dementia with Lewy Bodies

         -Frontotemporal dementia

            - Vascular dementia

             - Alzheimer’s d/s
                   1. DLB
 The most frequent BPSD here are visual
  hallucinations and paranoid delusions (“people are
  stealing things”)
 One of the core features for the dx of DLB is the
  description of a recurrent visual hallucination which
  is typically well-formed
 The BPSD in this dementia type have the highest
  burden on caregivers
 May have ethnic differences in the prevalence of
  these BPSD
                   2. FTD
 Much younger mean age of onset than other
  dementia (~50 yo)
 Most notable BPSD here is activity disturbance
  (includes purposeless activity, wandering and
  inappropriate activities)
 But these people also have impairment of language
  function early on , so other BPSD could be masked
  (e.g. hallucinations/affective disturbances…)
                    3. VaD
 Nearly half of these pts exhibit affective disturbances
  (depressed mood, tearful episodes…)
 May also exhibit
      - aggressive behavior (verbal outbursts >
  physical violence)
      - diurnal rhythm disturbances : sleep
  disturbances, sundowning more common here
  than in AD
      - paranoid/delusional ideations
                    4. AD
 Different studies found that the BPSD for AD had
 ethnic and cultural dependencies

 More apathy and depression in Western
 More activity disturbances and aggressiveness in
  the Oriental societies
Alzheimer’s Vascular         Lewy body     Fronto-

Apathy          Apathy       Hallucinations Apathy
Agitation       Depression Delusions       Disinhibition
Depression      Delusions    Depression    Elation
Anxiety         Sleep.Dist   Sleep         Obsessions
Irritab,Aggr.                              Lang.Dysfx
Managing BPSD in
Treatment options
 Identify cause
 Wait and see?
 Education and counselling
 Prophylaxis
 Environmental modification
 Direct behavioural approaches
 Medication
 Sleep-wake cycle
    Sleep hygiene
 Exposure to daylight
    Melatonin
 Exercise
 Stimulation
BPSD- management
 Environmental modification
    Stimulation/noise levels
    Exercise
    Food/hydration
    Lighting

 Relate problem to individual’s life story
Education and support

 Important
 May help carers understand and tolerate symptoms
 Facilitates development of creative distractions
BPSD management
 aromatherapy
 multisensory stimulation
 therapeutic use of music and/or dancing
 animal-assisted therapy
 massage

   NICE 2006
BPSD management
 Behavioural approaches
    Individually tailored
    Driven by analysis
    Delivered by trained staff
    Sustained effort
BPSD management
 Drug treatment
   Last resort
   Should target specific symptoms
   Specialist initiation
   Regular review
BPSD management
 Depression / Anxiety
   Antidepressants?
 Agitation/aggression
    Antipsychotics- ?
    Anticholinesterases?
    Benzodiazepines?
    Mood stabilisers?
 Delusions/hallucinations
    Antipsychotics?
  Manage BPSD accordingly

 -DLB patient with hallucination  controlling
 environmental stimuli

 -FTD patient who’s wandering designing a pacing

 -VaD patient with a depression emotional support
            Pharmacological Treatment

 Depression in dementia:
  -little placebo-controlled evidence but clinical
 experience indicates that SSRIs are safe and effective.
   - avoid TCAs because the antimuscarinic s/e may
 impair the cognition even more.
    -depression in dementia is Rx-responsive, but it tends
 to recur.

 Apathy:
     -Case reports : dopamine-agonist drugs or direct
 stimulants such as methylphenidate (Ritalin) but no
 clinical trials so far.
     -best-established Rx now is the discontinuation of
 drugs known to cause or aggravate lethargy or apathy.
                SSRIs in Dementia
 Because SSRIs are most widely studied in dementia, with several
    demonstrations of efficacy, they are reasonable first-line
    antidepressants for most dementia patients
   They are typically begun at the lowest dose and increased as
    needed. Thus the importance of reaching a therapeutic dose
    before concluding that an SSRI is not effective cannot be
   SSRIs are generally well tolerated, with gastrointestinal side effects
    most common. Other side effects that require monitoring include
    insomnia and increased confusion.
   The potential for SSRIs to cause the syndrome of inappropriate
    antidiuretic hormone (SIADH) is a concern in the elderly, and
    intermittent monitoring of electrolytes is advisable.
   Dementia patients are less likely to report or be distressed by
    sexual side effects of SSRIs.
                 Sertraline       25      150      Gastrointestinal (GI) upset
                 Citalopram       10      60       Insomnia
                 Escitalopram     5       20       Confusion
reuptake                          10      40       Akathisia
   inhibitor                      10      40       Syndrome of
                                                   inappropriate antidiuretic

Serotonin        Venlafaxine    37.5      300       GI upset
norepinephrine                            30 bid
                 Duloxetine     20 bid              Confusion
inhibitor                                           Hypertension with venlafaxine

α1 Antagonist    Mirtazapine    7.5       45        Sedation

                 Bupropion      100       450        GI upset
inhibitor                       d
                                release              Seizure risk
                             Apathy Treatment
Pharmacotherapeutic interventions are difficult to recommend with confidence at present
  given the paucity of available data, but empirical treatment trials may be indicated when
  behavioral interventions are unsuccessful or the apathy is so severe that the patient
  refuses to get out of bed.

 The most consistent evidence for benefit, and the only evidence based on placebo-
  controlled studies, is for cholinesterase inhibitors (Cummings et al. 2005; Mizrahi and
  Starkstein 2007; Wynn and Cummings 2004).

 Cholinesterase inhibitors are standard care for many dementia patients, and some
  apathetic patients may have the extra benefit of improvement in this behavior. Several
  other agents have been investigated for treatment of apathy at the case study level,
  although not specifically in dementia patients.

 Most enhance dopamine transmission, putatively associated with apathy, and include
  amantadine(Marin at el. 1995; van Reekum et al. 1995), bupropion (Corcoran et al. 2004;
  Marin et al. 1995), and methylphenidate (Marin et al. 1995; Padala 2005, 2007; van
  Reekum et al. 1995)
                   Rx Apathy
Donepezil            5         10
Galantamine          8         16–24
Rivastigmine         3         12

  Amantadine       50           300

  Bupropion        37.5–75       300

 Methylphenidate   2.5–5          20
 Psychotic sx:
     - Neuroleptic agents more effective than placebo .
 Caution because patients with dementia are more
 sensitive to extrapyramidal, anti-cholinergic side
 effects than the general population.
      - Atypical antipsychotics have better tolerability
 and side-effect profile

 Agitation :
       - when frequent mood fluctuations or sudden
 spontaneous attacks of agitation are the problems 
 antiepileptics (eg, valproic acid, carbamazepine)
       - when irritability is the prominent sx 
 serotonergic drugs (eg, trazodone, nefazodone,
 sertraline, buspirone)
        Rx Executive Dysfunction Syndrome
Selective serotonin
reuptake inhibitors
 Sertraline           25
 Citalopram           10
 Escitalopram         5
 Fluoxetine           10
 Paroxetine           10
Mood stabilizers
 Valproic acid        125
 Carbamazepine        100

Amantadine            50-100
Bupropion             100 slow

Methylphenidate       2.5–5
                        KEY POINTS

 Although consistently effective treatments for neuropsychiatric symptoms are
  currently lacking, clinical experience suggests most symptoms are treatable.

 Treatment strategies need to be comprehensive, employing
  nonpharmacological strategies in addition to Rx.

 Agitation and aggression are nonspecific symptoms, and treatment strategies
  should be guided by the presumed cause of the behavior.

 Although minimal evidence exists for effective treatments, Treatment is
  required very often
Thank you
 There’s emerging evidence that regional differences
 in brain atrophy correlate with the variant disease

 One study suggested that the type of BPSD is
 determined by regional GM loss , whereas the
 severity of the overall BPSD seems to correlate with
 the extent of WM injury.

 Depression:
       - left frontal lobe lesion, especially anteriorly.
 Paranoid Delusions:
   - reduced GM density in left frontal lobe/right
 frontoparietal cortex/left claustrum

 Apathy :
    - reduced GM density in anterior cingulate/
 bilateral frontal cortex/ bilateral putamen

 Agitation/Aggression :
     - reduced GM density in left insula/ bilateral
 anterior cingulate
    - functional imaging (PET) showed decreased
 frontal and temporal cortical metabolic rates
290.0    Dementia of the Alzheimer’s Type, With Late Onset, Uncomplicated

290.10   Dementia due to Pick's Disease
290.10   Dementia due to Creutzfeld-Jacob disease
290.10   Dementia of the Alzheimer’s Type, With Early Onset, Uncomplicated

290.11   Dementia of the Alzheimer’s Type With Early Onset, With Delirium

290.12   Dementia of the Alzheimer’s Type, With Early Onset, With Delusions

290.13   Dementia of the Alzheimer’s Type,With Early Onset, With Depressed Mood

290.20   Dementia of the Alzheimer’s Type, With Late Onset, With Delusions

290.21   Dementia of the Alzheimer’s Type, With Late Onset, With Depressed Mood

290.3    Dementia of the Alzheimer’s Type, With Late Onset, With Delirium

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