Download Neuropsychiatric Sequelae of Stroke 113010

Neuropsychiatric Sequelae of Stroke
David B. Arciniegas, M.D.
Michael K. Cooper Professor of Neurocognitive Disease
Director, Neurobehavioral Disorders Program
Associate Professor of Psychiatry and Neurology
University of Colorado Health Sciences Center
Post-Stroke Neuropsychiatric Problems
•  Depression
–  Major
–  Minor
•  Mania and Bipolar
Disorder
•  Anxiety Disorders
•  Pathological
Laughing and
Crying (PLC)
•  Witzelsucht
•  Apathy
•  Aggression
•  Psychosis
Selective Distributed Networks Subserving Executive Function,
Comportment, Motivation, and Emotion
Dorsolateral
Prefrontal
Cortex
Anterior Cingulate
Posterior Cingulate
Infracallosal
Cingulate
(Lateral)
Orbitofrontal
Cortex
(Medial)
Multimodal
Sensory
Information
Striatum
GPi
GPe
Nuc.
Acc.
Hypothalamus
Thalamus
STn
Amygdala
Hippocampus
(Mega and Cummings 1994; Mega et al. 1997; Mayberg 1997; Arciniegas and Topkoff 2000)
Post-Stroke Depression
•  Most common non-cognitive
neuropsychiatric consequence of stroke
•  Affects 30-50% of all stroke patients within
the first two years post-stroke
–  about 50% of these patients meet criteria for
major depression
–  about 50% of these patients meet criteria for
minor depression (~ dysthymic disorder)
Robinson et al. 1997; Robinson 2003; Desmond et al. 2003; Lincoln et al. 2003; Aben et al. 2002
Post-Stroke Depression
•  Bimodal (or multimodal) distribution
–  May develop in the immediate post-stroke period
•  ~ 20% of stroke survivors during the acute and
rehabilitation hospitalization periods
–  Onset may be delayed by several months
•  ~25% of outpatient stroke survivors
–  When depression develops in the late (>12 month)
period after stroke, causal relationship to stroke is at
best uncertain
Robinson 2003; Narushima et al. 2003; Bhogal et al. 2004; Tateno et al. 2002; Williams et al. 1986
Post-Stroke Depression
•  Laterality may affect severity of post-stroke
depression
–  Major depression:
•  50% in left hemisphere stroke
•  16% in right hemisphere stroke
–  Minor depression was equally common (25%) in
both groups
Spalletta et al. 2003
Post-Stroke Depression
•  Lateralized relationship between post-stroke
depression and cognitive impairment
–  Major depression occurring after a left-hemisphere stroke is
associated with significant cognitive impairments
•  Importantly, treatment of post-stroke depression may improve
cognitive functioning as well as depression
–  Major depression occurring after a right-hemisphere stoke
is not strongly associated with cognitive impairment
•  However, this may be an artifact of assessment methods and not a
true difference
Vataja et al. 2001; Narushima et al. 2003; Spalletta et al. 2002; Kimura et al. 2000; Vataja et al. 2004
Post-Stroke Depression
•  Mild pre-existing subcortical atrophy appears to
predispose to development of post-stroke depression
•  Among all demographic variables, personal or
family history of depression may influence poststroke depression risk
•  Premorbid “neuroticism” (based on the Five Factor
Model of personality) may increase post-stroke
depression risk
•  Five Factor Model: neuroticism, extraversion, openness,
agreeableness, and conscientiousness
Starkstein et al. 1987; Aben et al. 2002; Morris and Robinson 1995
Post-Stroke Depression
•  Early and late post-stroke depression may not be the
same
–  Early post-stroke major depression:
•  more strongly related to interruption of networks (especially in the
left hemisphere in proximity to the frontal pole) regulating emotion
•  associated with larger lesion volumes
•  more severe (ie, vegetative and psychological symptoms)
•  more functionally impairing than late post-stroke depression
–  Late post-stroke depression appears to be more reactive to
stroke-related disability
Robinson 2003; Narushima et al. 2003; Bhogal et al. 2004; Tateno et al. 2002; Robinson et al. 1996; Williams et al. 1986
Post-Stroke Depression
•  Early post-stroke depression is not necessarily a
transient disorder
–  Average duration of about 9-10 months
•  In Berg et al. (2003):
–  54% of 100 subjects reported at least minor depressive
symptoms during the first 18 months post-stroke
–  46% of those with depressive symptoms in the first 2 months
post-stroke were also depressed at 12 and 18 months poststroke
Robinson 2003; Berg et al. 2003
Post-Stroke Depression
•  Recovery from early post-stroke depression after one
year may be quite limited without treatment
–  a subset of patients with both major and minor poststroke
depression will develop a chronic depression
•  Resolution of early post-stroke depression may be
influenced by lesion location
–  Limited recovery with cortical lesions and large subcortical
lesions
–  Better recovery with small subcortical lesions and cerebellarbrainstem lesions
Moon et al. 2004; Whyte et al. 2004; Williams et al. 2004
Post-Stroke Depression
•  Recovery from early post-stroke depression is
influenced by:
–  lower levels of total support (negative)
–  ability to develop a sense of meaning in one’s life poststroke (positive)
–  avoidance coping (negative)
•  Recovery from late post-stroke depression is
negatively influenced by:
–  lower levels of family functioning
–  absence of support
King et al. 2002
Post-Stroke Depression
•  Early post-stroke depression decreases the
effectiveness of acute rehabilitation
•  Early post-stroke depression is associated with
low quality of life (QOL) at 2 months following
stroke
•  The availability of emotional support, the presence
of depression, and severity of functional disability
account for 38% of the variance in QOL at 6
months post-stroke
Gillen et al. 2001; Moon et al. 2004; Jaraca and Kozubski 2003
Post-Stroke Depression
•  Early post-stroke depression predicts the
persistence of post-stroke depressive symptoms at
2 years, independent of functional disability,
cerebrovascular risk factors, and previous
depressive symptoms
•  Early post-stroke depression and anxiety are
independent predictors of handicap at 2 years
post-stroke
•  Post-stroke depression (at any point after stroke)
increases 3-year mortality risk among persons
with ischemic stroke
Moon et al. 2004; Sturm et al. 2004; Whyte et al. 2004; Williams et al. 2004
Stroke and Suicide
•  Teasdale et al. (2001) studied the relationship between stroke
and suicide in Demark from 1979-1993
–  Database of 114,098 patients with stroke discharged from the hospital
during the study period with a registry of causes of death over the
same time period
–  Identified 359 suicides in this population
–  The annual rate of suicide among persons with stoke was nearly twice
that of the general population
•  Suicide risk was greatest among stroke patients 50 years or younger
•  Duration of hospitalization was inversely associated with suicide risk,
being lowest among those hospitalized longer than three months poststroke and highest among those hospitalized less than two weeks poststroke
Stroke and Suicide
•  The time of suicide does not bear a clear
relationship to the time of stroke, although the risk
for suicide appeared to be greatest in the first five
years following stroke
•  In both studies, annual suicide rates following stroke
were lowest among persons age 80 years or older,
although the risk in this group remained elevated in
comparison to the general population
Teasdale et al. 2001; Stenager et al. 1998
Post-Stroke Depression
•  Possible neurobiological mechanisms of early poststroke depression are uncertain
•  Often cited hypothesis is interruption of ascending
noradrenergic and serotonergic projections
–  Lesions in basal and frontal areas result in greater
interference with these projections than do posterior
lesions
–  Offered as an explanation for the association between
frontal strokes and early-onset depression
Post-Stroke Depression
•  Lateralized findings in the response of biogenic amine
(DA, NE, 5-HT) regulation following stroke
–  Right hemisphere stroke results in large compensatory
upregulation of biogenic amine receptor densities
bilaterally
–  Left hemisphere stroke result in modest upregulation of
biogenic amine receptor densities
•  Less robust compensatory response may result in
functional deficiencies in biogenic amine systems
•  These deficiencies (especially of NE and/or 5-HT) may
result in depression
Post-Stroke Depression
Evaluation
•  DSM-IV criteria appear adequate for the diagnosis of
poststroke depression, with 97% sensitivity and 95%
specificity
–  Reliance on non-somatic factors rather than somatic factors may
improve diagnostic accuracy in this population
•  There is a lack of consensus on the utility of self-report
measures of post-stroke depression
–  Lincoln et al. suggest these are not sufficiently reliable to obviate
clinical interview for these symptoms
–  Aben et al. suggest that the sensitivity of these measures is
superior to observer-rated scales, but their specificity is lower
Robinson 2003; Desmond et al. 2003; Lincoln et al. 2003; Aben et al. 2002
Post-Stroke Depression
Treatment
•  Treatment of early post-stroke depression with either
fluoxetine or nortriptyline decreases mortality for up to 9
years post-stroke
–  Interestingly, treatment of non-depressed stroke survivors with
these agents also decreased mortality over this period of study
•  Prophylactic treatment with sertraline, citalopram,
fluoxetine, and nortriptyline has been demonstrated to
decrease the incidence of post-stroke depression in the first
3 months after stroke
–  However, prophylactic treatment of stroke survivors with
antidepressants for either depression or long-term post-stroke
mortality is not presently supported by large RCTs or metaanalyses of smaller studies
Jorge et al. 2003; Rasmussen et al. 2003; Anderson et al. 2004
Post-Stroke Depression
Treatment
•  Double-blind placebo controlled studies:
–  Nortriptyline: effective as assessed by Ham-D scores, but 20% incidence
of delirium and agitation
–  Nortriptyline: improvement in depression, and associated improvements in
ADLs in treatment responders
–  Nortriptyline vs. fluoxetine vs. placebo: nortriptyline wins
–  Fluoxetine: improved outcome at 18 months post-stroke
–  Fluoxetine: improves MADRS scores at 6 weeks post-stroke
–  Trazodone: improves Zung Depression Scale and ADL scores
–  Sertraline: decreased Ham-D scores
–  Citalopram: effective as assessed by Ham-D scores, no significant adverse
events
–  Methylphenidate: improved MDRS scores over 3 weeks in acute rehab
•  Open-label studies
–  Sertaline improved depressive symptoms at 4 and 12 weeks, with a low
rate (3%) of side-effect mediated treatment discontinuations
Rasmussen et al. 2003; Chemerinski et al. 2001; Robinson et al. 2000; Fruehwald et al. 2003; Wiart et al. 2000; Reding et al. 1986; Van
de Meent et al. 2003; Rampello et al. 2004; Lazarus et al. 1992; Spalletta and Caltagirone 2003; Zifko et al. 2002;
Post-Stroke Depression
Treatment
•  At present, there is a lack of consensus on
the optimal pharmacotherapy of post-stroke
depression
•  Based on presently available data,
citalopram, sertraline, fluoxetine, and
nortriptyline are favored by most stroke
neuropsychiatrists as first-line agents when
a pharmacotherapeutic approach is used
Post-Stroke Depression
Treatment
–  ECT is safe and effective
–  rTMS may also be effective
–  Group and family therapy
•  Widely recommended, but no data to support it
–  Psychotherapy
•  Widely recommended, but no data to support it
•  In fact, there is at least one negative trial of CBT for
post-stroke depression, and no positive studies of
this psychotherapy for this condition
Weintraub and Lippman 2000; Currier et al. 1992; DeQuardo and Tandon 1988; Murray et al. 1986; Jorge et al.
2004; Lincoln and Flannaghan 2003
Brief Considerations of Other Non-Cognitive
Post-Stroke Neuropsychiatric Conditions
Post-Stroke Mania
•  A relatively rare complication of stroke (! 1%)
•  Typically, pre-stroke mania is absent
•  DSM-IV criteria appear adequate for the diagnosis
of secondary mania
•  Right hemisphere (most often right basotemporal,
subcortical, and midline) lesions are more often
associated with secondary mania than are left
hemisphere lesions
Post-Stroke Mania
•  Risk factors for poststroke mania
–  Premorbid subcortical atrophy
–  Family history of affective illness
•  Mechanism of secondary mania is not known, but
may include:
–  Disruption of biogenic amines systems producing
strong compensatory upregulation of relevant receptor
densities in limbic cortex
–  Release of tonic inhibitory input to the basotemporal
cortex and limbic system
Post-stroke Mania
Treatment
–  Largely unknown
•  Case reports and expert opinion suggest that
valproate, carbamazepine, lithium, typical and
atypical antipsychotics, and clonidine may be useful
in some cases
–  Use caution when prescribing any of these
agents in a person with stroke
•  May impair cognition and motor function
•  Other problems?
Post-Stroke Bipolar Disorder
•  A even more rare complication of stroke (! 1%)
•  DSM-IV criteria adequate for the diagnosis
•  Subcortical right hemisphere lesions more
common than right cortical or left hemisphere
lesions
•  Prior depressive episode occurs in about 1/3 of
patients with poststroke bipolar disorder
•  Mechanism of poststroke bipolar disorder is not
known
•  Optimal treatment unknown
Post-stroke Anxiety Disorder
•  Relatively common consequence of stroke (about
25%), especially when considered in the context
of post-stroke depression
•  About half of poststroke depression patients will
also have significant anxiety symptoms
–  Anxiety here is defined as the Generalized
Anxiety Disorder (GAD) criteria without the 6month duration requirement
•  However, a minority (~ 6%) of patients of stroke
patients will meet GAD criteria in the absence of
other mood symptoms
Post-Stroke Anxiety Disorder
•  DSM-IV criteria for Generalized Anxiety Disorder
appear to best characterize poststroke anxiety
•  Cortical right hemisphere lesions are most
common associated with anxiety-only
•  Depression-anxiety is more commonly associated
with cortical left hemisphere lesions
Post-Stroke Anxiety Disorder
•  Past history of alcohol dependence appears to be a
risk factor for the development of post-stroke
anxiety
•  Poststroke anxiety disorder may be either early- or
late-onset
–  Early-onset is of shorter duration (1.5 months vs. 3
months)
–  Early-onset is more strongly related to premorbid
psychiatric (including alcohol) history
Post-Stroke Anxiety Disorder
•  In meta-analysis (Kimura et al. 2003),
nortriptyline appears to improve comorbid poststroke anxiety disorder and depression
•  SSRI’s are used commonly for post-stroke anxiety
symptoms, but data support this practice are
limited at present
•  Most experts suggest avoiding benzodiazepines
given their adverse effects on cognition and motor
function
Post-Stroke Pathological
Laughing and Crying (PLC)
A.  Frequent brief episodes of involuntary and uncontrollable crying and/or
laughing
B.  Episodes of crying and laughing may involve an episode-congruent
feeling, but do not necessarily reflect and do not produce a persistent
change in the prevailing mood
C.  Episodes are excessively intense with respect to the stimulus that incites
them, and may be inappropriate to the context in which they develop (i.e.,
laughing when crying would be expected or vice versa)
D.  Episodes reflect a change from usual affect regulation
E.  There is evidence of an underlying neurological condition
F.  The episodes are subjectively distressing and/or produce clinically
significant impairments in social, occupational, or other important aspects
of function
(Wortzel, Anderson, and Arciniegas 2007)
PLC
•  Other terms have been used to describe such episodes of
involuntary, uncontrollable crying and/or laughing:
– 
– 
– 
– 
– 
– 
– 
emotionalism
emotional dyscontrol
emotional incontinence
emotional lability
excessive emotionality
forced laughter or crying
inappropriate hilarity
– 
– 
– 
– 
– 
– 
– 
pathological affect
pathologic emotionality
pathological emotionalism
pathological weeping
pseudobulbar affect (PBA)
pseudobulbar crying
“Involuntary emotional expression disorder”
•  Distinctions between these conditions are at best arbitrary
•  We will use PLC as a synonym and abbreviation for these
terms
(Schiffer and Pope 2005; Arciniegas et al. 2005; Wortzel et al. 2008)
Is PLC a disturbance of emotion and feeling?
•  “It is important, at the same time, to be assured of the fact
that the emotional display [PLC] is a genuine
manifestation of feeling. No one who has seen these
attacks of involuntary laughing or weeping can doubt the
reality of their emotional content…”
•  “[The laughing and weeping] is too definite to be mistaken
for the mere ‘shell’ of a mental state empty or devoid of
emotional tone. I cannot, therefore, agree with Bianchi
[1922] when he declares that the ‘weeping and laughter of
such sufferers are only simulacra of the real emotions’…”
S. A. Kinnier Wilson: Some Problems in Neurology. No. II - Pathological Laughing and Crying. Journal of Neurology and
Psychopathology. 1924;16:299-333.
Is PLC a disturbance of emotion and feeling?
•  “In a word, it [PLC] differs from legitimate
emotional performances solely in its
inevitability, its frequency, its uncontrollable
character, the occasional contradictory relation
of ‘cause’ and ‘effect,’ and the extreme facility
with which it is induced; in expression and
accompaniments [i.e., feeling] it is identical.”
•  In short, yes…or at least sometimes yes.
S. A. Kinnier Wilson: Some Problems in Neurology. No. II - Pathological Laughing and Crying. Journal of Neurology and
Psychopathology. 1924;16:299-333.
Post-Stroke PLC
•  Common, but exact frequency is not well
established, but is in the range of 10-20%
•  Tends to develop in the immediate post-stroke
period
•  Appears to involve disruption of serotonergic and
possible dopaminergic afferents from midbrain
and through frontal poles
–  Recent evidence suggests that disruption of frontalsubcortical-cerebellar circuits may also produce PLC
Post-Stroke PLC
•  Although PLC may occur with depression, scores on
measures of PLC (e.g., PLACS) are not correlated
with scores on depression measures (HAM-D)
•  Improvement of PLC occurs independently of
improvement in depression
–  suggests that PLC and depression are distinct disturbances
of emotional regulation
(Schiffer et al. 1985; Robinson et al. 1993)
Post-Stroke PLC
•  Responds rapidly (often within several days days)
of initiating treatment with serotonergically active
antidepressants
–  Fluoxetine, sertraline, citalopram, paroxetine,
nortriptyline
–  Case reports also suggest that venlafaxine and
lamotrigine may be of use for this problem
–  Expect to hear about [dextromethorphan + quinidine]
(Neudexta) for this problem in the near future
–  “Mood-stabilizers” generally not helpful
Essential Crying
•  A lifelong and hereditary propensity to easy
crying
•  Congruent affective expression and
experience
•  May be embarrassing but not functionally
impairing
•  May lie on the continuum between PLC and
normal affective variability
(Green and Bernat 1999; Green, McAllister, and Bernat 1987)
Witzelsucht
•  Literally translated from German as ‘seeking
wit,’ its functional translation is “a peculiar
addiction to trivial joking”
•  Patient has a frequently and inappropriately
elevated, ‘giddy,’ and irritable/hostile affect in
which the patient experiences most everything as
genuinely funny and frequently laughs and
makes childish, facetious, or sarcastic remarks
(Berkovic and Andermann 1999; Duchowny 1983)
Witzelsucht
•  Distinguished from pathologic laughing by
virtue of:
–  admixture of irritability and mirth
–  generally less discretely paroxysmal and
affectively stereotyped
•  Most commonly seen in patients with frontal
lobe disease or injury
–  particularly right frontal lobe tumors or trauma
(Berkovic and Andermann 1999; Duchowny 1983)
Post-Stroke Apathy
Anterior Cingulate Circuit (ACC)
Figure 4.9 The anterior cingulate
circuit. This axial MRI depicts the
approximate pathway of this circuit.
The starting and ending arrows in this
figure arise out of the right anterior
cingulate gyrus. The pathway follows
the same general course as that
described for the DLPFC and
orbitofrontal circuits.
Anterior
Cingulate
Gyrus
Post-Stroke Apathy
•  Uncommon as a consequence of unilateral stroke
•  More common in the setting of acute ACA stroke
superimposed on prior cerebrovascular disease
affecting the contralateral ACA territory
–  ie, usually need both anterior-cingulate subcortical
circuits involved to produce apathy
•  Treatment generally involves dopaminergic
augmentation
–  Stimulants, other pro-dopaminergic agents
–  Cholinesterase inhibition may also be useful in some
cases
Post-Stroke Aggression
and Psychosis
•  Rare as isolated post-stroke problems
•  More common in vascular dementia
•  May be more common in the setting of post-stroke
depression, anxiety, and/or mania
•  Treatments are not established
–  usually involves addressing the other major post-stroke
neuropsychiatric condition (ie, depression, anxiety,
mania, and/or dementia)
Post-Stroke Neuropsychiatric Problems
•  Vascular Cognitive
Impairments
•  Depression
–  Major
–  Minor
•  Mania and Bipolar
Disorder
•  Anxiety Disorders
•  Pathological
Laughing and
Crying (PLC)
•  Witzelsucht
•  Apathy
•  Aggression
•  Psychosis