Stroke and Emotional Effects

R1 ณัฐพล เจริญมรรคผล/R2 ณภัทร์ ศิรินิ่มนวลกุล

19 June 2020
 Introduction
O
U Post-stroke depression

T Post-stroke anxiety

L Post-stroke emotional incontinence

I Post-stroke aggression and anger proneness

N Post-stroke fatigue

E Post-stroke mania
 Introduction
Mood and emotional
Distressing for both the patients Negatively influences patients’
disturbances are frequent
and their caregivers quality of life
symptoms in stroke survivors.

Include post-stroke
Negative impacts on patients’
Negatively influences later depression/mania/anxiety/
clinical outcomes and
functional outcomes/occupations emotional incontinence/
increases mortality
anger proneness/fatigue
Post-stroke depression
(PSD)
 • Epidemiology
• Factor associated
with PSD
• Symptom
Post-stroke depression characteristics
• Screening tools
(PSD) • Pathophysiology
• Treatment
• Prevention
• Vascular depression
 PSD is the most frequent psychiatric
problem.

Post-stroke PSD is strongly associated with further

worsening of physical and cognitive recovery,

depression functional outcome, quality of life and ability

to engage in rehabilitation therapies.

PSD is commonly used to define any

depression state present after stroke.
 The prevalence of PSD varied across studies
(ranged from 5 to 67%).

Epidemiology Longitudinal studies provided conflicting results

as to the time course of PSD.

Outcomes of PSD are severe disability, anxiety,

lower QoL, speech and language dysfunction,
anhedonia, feeling of despair, functional and
cognitive impairment, greater dependency on
ADL and poor medication compliance.
ที่มา : Aniwattanapong, Daruj. "ภาวะ ซึม เศร้า หลัง โรค หลอดเลือด สมอง." Journal of the Psychiatric Association of Thailand 63.4 (2018): 383-418.
 The most consistent factors associated
with PSD are severe stroke, and early or
late physical disability.

A history of depression before stroke and

cognitive impairment were associated
Factor with.
Associated
with PSD Age and sex were not consistently
associated with PSD.

No consistent association between

hemisphere of stroke, lesion location, or
pathological subtype and depression
 Symptom
Characteristics

• Depressed mood
• Anhedonia
• Loss of energy
• Decreased concentration
• Somatic symptoms : common
(loss of energy, agitation,
insomnia, loss of appetite)
• Guilty feelings : not common
• Suicidal ideations : not common
 Issues In Use of Self-Report Screening Tools for PSD
Screening • Anosognosia – lack of awareness may affect
sensitivity and specificity of instruments.
Tools for PSD • Physical and cognitive deficits may make use of
these tools prohibitive.
 Designed for screening for
depression in older individuals
Geriatric
Depression
Scale (GRS) Good sensitivity and specificity
in stroke patients, but not well
tolerated in hospitalized medical
patients in part due to 30 items.
 Well validated and reliable

Beck
Depression Easy to administer
Inventory
(BDI-2)
Some difficulty with scale
completion reported
 Comprising the first 2 items of the PHQ-9,
the PHQ-2 inquires about the degree to
which an individual has experienced
depressed mood in over the past two weeks.

Patient Health
Questionnaire Its purpose is to screen for depression.
Patients who screen positive should be
(PHQ-2 & further evaluated with the PHQ-9.

PHQ-9)
The PHQ-2 and PHQ-9 have been validated in
3 studies.
 Eight cartoon face and verbal descriptions

Visual For stroke patients with communication

disorders
Analogue
Mood Scale
(VAMS) Not affected by neglect

However, not validated yet in stroke

population
 Designed to diagnose and
monitor depression in patients
with aphasia

Aphasic
Depression Training required to use
Rating Scale instrument

(ADRS)
Provides good sensitivity and
specificity for depression in
patients with Aphasia.
 • Pathophysiology of PSD is complex and
multifactorial, resulting from the combination
Pathophysiology of ischemia-induced neurobiological
dysfunctions and psychosocial distress.

A primary biological mechanism with stroke affects neural circuits involved

in mood regulation which in turn causes post-stroke depression.
VS
Post stroke depression is caused by social and psychological stressors that
emerge as a result of stroke.
 Brain lesions
• Anterior proximity → increased risk
• Left anterior frontal and basal ganglia lesions →
increased risk
• Lateralization → no association

Neurotransmitters
Biological
• The possible role of anterior frontal lobe damage
Pathophysiology and the involvement of the frontal-basal ganglia
brainstem pathway → alterations in 5-HT, NE, DA
system.
Immune system and inflammation
• Neuroinflammatory response → activation of
microglia and astrocytes and upregulation of pro-
inflammatory cytokines (IL-1, IL-6, IL-18 and TNF-α).
 Stressful life event
• Level of disability

Social factors
Psychosocial
Pathophysiology • Poor social activity → Social withdrawal
→ Inadequate social support

Behavioral factors
• Low Barthel Index score (scale assessing
functional independence on basic ADL)
 Pharmacological treatment

• Anti-depressants are more effective than

placebo in reducing the symptoms in
PSD patients, disability, neurological
deficit, depression and death.
Treatment
Non-pharmacological treatment

• There was no evidence for effectiveness

of psychological therapies alone for the
treatment of PSD.
 European and American guidelines
recommend pharmacological treatment,
such as SSRI or TCA drugs for patients
with PSD, along with monitoring for
effectiveness and side effects.
Pharmacological
treatment
It is recommended that treatment be
continued for at least 6-12 months after
initial recovery and considered
maintenance treatment in high risk
patients.
 SSRI : sertraline, fluoxetine, paroxetine,
citalopram, escitalopram
• Drug-drug interaction should be concerned e.g.
fluoxetine and warfarin.
• From studies, risk for intracranial hemorrhage was not
statistically significant.

TCA : nortriptyline
Antidepressants
• Caution for side effects e.g. arrhythmia, anticholinergic
effects

SNRI : duloxetine, venlafaxine

• Drug efficacy was not inferior to SSRI.

• Higher risk for intracranial hemorrhage than SSRI, but
statistical insignificant.
 SARI : trazodone (dosage 300 mg/day)

NaSSA : mirtazapine
Antidepressants • May be useful for patients with sleep problems
or poor appetite.
- Further study is
Melatonin receptor agonist : agomelatine
needed!!
• May improve cognitive function and movement.

DNRI : bupropion
• Useful in patients with tobacco smoking
Others • Psychostimulants : MPH
• Further study is needed.
pharmacological • Efficacy was not inferior to nortriptyline
treatment and can improve dependency on ADL.
 Brain stimulation therapy

• Electroconvulsive therapy (ECT) : for high

risk suicide, poor response to anti-
depressants or refractory PSD
Non- • Repetitive transcranial magnetic
pharmacological stimulation (rTMS) : for refractory PSD
treatment
Psychotherapy

• Cognitive behavioral therapy (CBT)

• Problem solving therapy (PST)
 • Pharmacological prevention
• SSRI : sertraline, fluoxetine, escitalopram
Prevention • TCA : nortryptyline
• SNRI : duloxetine
• NaSSA : mirtazapine
 “Post-stroke depression” :
Post-stroke Depression that develop after an
acute cerebrovascular event
depression
&
Vascular “Vascular depression" :
Depression that develop in
depression association with chronic
ischemic changes in the brain
 • Associated with older age at onset of depression,
vascular comorbidity, greater psychomotor slowing,
anhedonia, increased functional impairment, and
lower incidence of psychosis
• The diagnosis of vascular depression requires MRI
Vascular brain, expressed by hyperintensity (in T2 or FLAIR) of
the periventricular, deep white matter and
depression subcortical gray matter or confluent white matter
lesions.
• Higher risk of developing vascular dementia
• Vascular depression showed worse outcome and a
poorer response to antidepressant drugs, compared
with PSD.
Post-stroke
Anxiety
(PSA)
 Prevalence
According to a recent meta-analysis revealed that anxiety disorders were present in 28.1% of stroke patients
during the first year after stroke.

Anxiety disorders was defined as the Hospital Anxiety and Depression Scale-anxiety part (HADS-A) > 6 points.

Individuals recovering from stroke usually worry about recurrence of stroke, their ability to return to work and
occurrence of fall accidents.
Hospital Anxiety and Depression Scale
 Factor Associated
PSA tends to last longer
PSA is closely associated with PSD.
when it is associated with PSD.

Early-onset PSA is more often associated with Other factors associated of PSA without PSD
previous psychiatric disorder than late-onset. remain unknown.

PSA results in worse social functioning and lower quality of life. (Not functional/cognitive recocery)
 Lesion Locations
▪ Earlier studies proposed that,

Left hemispheric stroke, PSA Right hemispheric stroke, PSA

with PSD is associated with without PSD is associated
cortical infarcts. with posterior infarcts.

▪ However, a more recent meta-analysis showed that there is no association between PSA and lesion location.
Treatment

No randomized, placebo-controlled trial.

Not enough evidence regarding the management of PSA.

Suggestion: Antidepressant/antianxiety drugs alone

or with behavioral therapy may reduce PSA symptoms.
 Post-stroke
Emotional
Incontinence
(PSEI)
 Prevalence
%
100
90
80
70
60
50
40
30
20
10
0
1 month 6 months 12 months

The prevalence of PSEI is 15%, 21% and 11% at 1, 6 and 12 months, respectively.
 Symptom Characteristics
Uncontrollable outbursts of involuntary laughing and crying.

Typically, without apparent motivating stimuli or in response to stimuli that would not
normally evoke such responses.

Sudden, episodic and uncontrollable/unheralded.

Variety of terminologies: Pseudobulbar affect, pathologic laughing and crying,

emotionalism, lability of mood, involuntary emotional expression disorder.
Diagnostic Criteria
Diagnostic Criteria
The Pathological Laughter and Crying Scale
(PLACS)
interviewer-rated instrument that
validated in stroke patients
measures the severity of PBA symptoms

PLACS

8-item scale. Each item is scored for Cut-off total score of ≥13, sensitivity of
severity (0=rarely or not at all, 88%, specificity of 96% and a positive
3=frequently) predictive value of 83%
The Pathological Laughter and Crying Scale
(PLACS)
The Pathological Laughter and Crying Scale
(PLACS)
 Factor Associated
Acute stroke/at the time of admission

Lesion at subcortical area

3 months post-stroke
Functional status Post-stroke depression
Low social support
Neurological deficit Serotonin polymorphism
 Lesion Locations
- Lenticulocapsular and brainstem lesions
- Anterior cortex-internal capsule/basal ganglia-ventral
brainstem circuitry

Thalamus
Cerebellum

Although the lesion locations are similar to that producing PSD, PSEI seems to be more closely related to subcortical
(basal ganglia and pontine) lesions.
Pathophysiology
Pathophysiology
 Pathophysiology
PSEI is caused by the release (or disinhibition) of a brainstem fasciorespiratory control center for emotional expression secondary to
lesions of descending regulatory pathways.

A complex cortico-limbic subcorcito-thalamic-ponto-cerebellar system deficit may lead to PSEI.

From neuroanatomical lesion studies suggest the involvement of serotonergic fibers, that ascends from the brainstem raphe nuclei to
limbic forebrain structures and then project though the basal ganglia to the frontal cortex.
Serotonin gene
polymorphisms
Serotonin transporter binding ratios in the midbrain and pons regions are lower in patients with PSEI.

Dopamine and glutamate may have role in regulating the influence of the motor cortex on the brainstem laughing/crying centers. The
balance of glutamatergic system is modulated by other neurotransmitter systems, such as dopamine, serotonin and sigma receptor systems.
 Treatment
Pharmacological Treatment

5 RCTs showed that SSRIs are effective in reducing the frequency and severity of PSEI.

While 2 RCTs have shown that TCAs are effective in treating PSEI.

SSRIs should be the first option due to better tolerated and more promply reduce symptoms.
Treatment
 Treatment
▪ Dextromethorphan/quinidine is another potentially useful drug (found to be effective in ALS and MS).

quinidine for increases the bioavailability

▪ A sigma-1 receptor agonist: increases the
serotonergic function of the dorsal raphe nucleus.
▪ Non-competitive glutamate receptor antagonists:
stabilize glutamatergic neurotransmission.
Treatment

SNRIs and dopaminergic drugs (Levodopa and amantadine) are currently reserved for patients who fail to respond to SSRIs.
 Treatment
Non-pharmacological
Treatment
▪ No controlled investigations of cognitive
behavioral therapy (CBT) for PSE have
been carried out, even though CBT has
been shown to be effective in the
treatment of other emotional difficulties
following stroke.)
Case ▪ Contingency management
Report
▪ Self-control
Post-stroke aggression
and anger proneness
(PSAP)
Post-stroke • Epidemiology
aggression • Symptom characteristics
• Screening tools
and anger • Factor associated with PSAP
proneness • Pathophysiology
(PSAP) • Treatment
 15-35% of patients during the acute stage
(during admission)

Epidemiology
32% of patients in the subacute stage
(after discharge)
 Physical aggression

• Hitting or hurting others, kicking, biting, grabbing,

pushing, throwing objects

Symptom Verbal aggression

characteristics • Cursing, screaming, making noises, hostile muttering

Anger-proneness or inability to control anger

and aggression is a much more common.
• More irritable, impulsive, hostile, and less tolerable
• Some of the patients’ anger may be a manifestation of
depression or frustration.
 The State Anger scale assesses the
intensity of anger as an emotional
state at a time.

Screening tools : The Trait Anger scale measures

Spielberger Trait how often angry feelings are
experienced over time.
Anger Scale

The Anger Expression and Anger

Control scales assess four relatively
independent anger-related traits
 A semi-structured interview, intended to
provide an objective evaluation of symptoms
associated with mental disorders.

Screening tools :
Present State It contains 140 items, each scored on a 3-
point or 4-point scale
Examination
Screening examines a person's Big Five
tools : personality traits

NEO
Personality
openness to experience,
Inventory conscientiousness, extraversion,
Revised agreeableness, and neuroticism
Screening
tools : • evaluate behavioral aspects of sadness,
Emotional aggressiveness, disinhibition, adaptation,
passivity, indifference, and denial
Behavior
Index
Factor Biological factors Psychological factors
associated - Motor dysfunction
- Dysarthria
- Premorbid neuroticism
personality trait

with PSAP - High National Institute of Health

Stroke Scale (NIHSS) scores
- History of depression

- Previous history of stroke

- Low monoamine oxidase A
activity
 PSAP is more closely associated with PSEI
than PSD and that the distribution of lesion
locations associated with PSAP is similar to
that of lesions associated with PSEI (fronto-
lenticulo-capsular-pontine base area).

Serotonergic dysfunction due to brain

Pathophysiology damage seems to play a role in the
development of PSAP.

Genetic polymorphisms involving

monoamine oxidase A are associated with
the development of PSAP.
 SSRIs such as fluoxetine and citalopram
are of benefit in the treatment of
aggressive behavior in patients with
personality disorder or dementia.

Treatment
Beta adrenergic antagonists and lithium
may reduce aggressiveness in patients
with brain injury.
Post-stroke
Fatigue
(PSF)
 Prevalence
The prevalence of PSF range from 23% to 75%.

This wide range is attributable to differences in the definition of PSF.

7 longitudinal cohort studies – the prevalence of PSF decreased with time after stroke.
 Symptom Characteristics
▪ “A feeling of early exhaustion developing during mental activity with weariness, lack of energy, aversion to effort”
▪ “Subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with
usual and desired activities.”
▪ “Sense of exhaustion, lack of perceived energy or tiredness, distinct from sadness or weakness.”

(There is no consensus among clinicians or researchers on one best definition of PSF.)

 Factor Associated
▪ PSF may attributed to post-stroke
depression.
▪ such as hypertension, etc.
▪ Some studies have show that the
association between disability and ▪ Medication such as sedative
PSF in the subacute state is lost drugs or antidepressants.
after controlling depression
during the chronic state.
Neurological Medical
deficit co-morbidities

Post-stroke Pre-stroke
pain fatigue
 Lesion Locations and Pathophysiology
▪ Chronic inflammation of the brain and altered immune responses
after stroke may also be involved in PSF.
Inflammation/
Immune process

Neurotrans
mitters

▪ According to lesion locations, the Lesion

alterations in neurotransmitter that lead
to PSF are dopamine and adrenaline.
▪ PSF is related to damage to the medial prefrontal cortex,
basal ganglia and the brainstem/thalamic reticular formation.
▪ However, more recent MRI-based studies have found no
association between PSF and lesion location.
 Treatment
▪ Several double-blinded placebo-controlled trials show that Fluoxetine, Duloxetine, Citalopram and Sertraline
was not effective.
▪ Thus, SSRIs may not be effective for PSF.
▪ Modafinil (400 mg) shows improvement in PSF, as measured by the Fatigue Severity scale in a recent RCT.
(FSS: A 10-Item self-rating scale for how a person has felt in the past week using a 7-point Likert scale)

(But the neurobiochemical effect remain unclear.)

Fatigue Severity Scale
Post-stroke mania
Post-stroke mania

• Epidemiology
• Symptom characteristics
• Lesion locations
• Treatment
Epidemiology

• Mania is reported as an unusual

manifestation after
cerebrovascular accidents; its
frequency is ,1% in comparison
with depression and other mood
disorders.
Symptom
characteristics

• The clinical profile of post-stroke

mania is similar to primary mania
• Elevated mood
• Pressured speech
• Flight of ideas
• Grandiosity
• Insomnia
 Symptom
characteristics

• The temporal relationship between

stroke and mania ranged from
immediately preceding stroke till 2
years.
• The majority of mania cases appeared
in the first days after stroke, with 53%
immediately after stroke, 23% during
the first month after stroke and 23%
after this first month [*].

[*] Santos, Catarina O., et al. "Mania and stroke: a systematic review." Cerebrovascular Diseases 32.1 (2011): 11-21.
Lesion locations

• Lesions responsible for post-stroke

mania can be located in the thalamus,
caudate nucleus, and temporal,
parietal, and frontal lobes.
• Mania seems to be more associated
with right-sided lesions.
• However, there are also reports of
mania following left-sided lesions.
Treatment

• Lithium was frequently used with favorable

results, but its use is controversial in cases
with cerebral lesions.
• Antipsychotics were used in cases of severe
mania with psychotic symptoms, and
atypical antipsychotics have been preferred
because of less side effects.
• Benzodiazepines were also used as
adjunctive treatment for hyperactivity and
insomnia.
 References
• Kim JS. Post-stroke Mood and Emotional Disturbances: Pharmacological Therapy Based on Mechanisms. J Stroke.
2016;18(3):244-55.
• Villa, Roberto Federico, Federica Ferrari, and Antonio Moretti. "Post-stroke depression: Mechanisms and
pharmacological treatment." Pharmacology & therapeutics 184 (2018): 131-144.
• Speakers’Bureau, Jean Luciano–Genentech. "Post Stroke Depression: Screening and Assessment Tools.“
• Aniwattanapong, Daruj. "ภาวะ ซึม เศร้า หลัง โรค หลอดเลือด สมอง." Journal of the Psychiatric Association of Thailand 63.4 (2018):
383-418.
• Taylor WD, Aizenstein HJ, Alexopoulos GS. The vascular depression hypothesis: mechanisms linking vascular disease
with depression. Mol Psychiatry. 2013;18(9):963–974. doi:10.1038/mp.2013.20
• Choi-Kwon, Smi, et al. "Fluoxetine treatment in poststroke depression, emotional incontinence, and anger proneness:
a double-blind, placebo-controlled study." Stroke 37.1 (2006): 156-161.
• Shoaib, Maria, and Muhammad Aadil. "Assessment of poststroke mania and diagnosis." Neuropsychiatric disease and
treatment 13 (2017): 557.
• Santos, Catarina O., et al. "Mania and stroke: a systematic review." Cerebrovascular Diseases 32.1 (2011): 11-21.
• Chun HY, Whiteley WN, Dennis MS, Mead GE, Carson AJ. Anxiety After Stroke: The Importance of Subtyping. Stroke.
2018;49(3):556-64.
 References
• Rafsten L, Danielsson A, Sunnerhagen KS. Anxiety after stroke: A systematic review and meta-analysis. J Rehabil
Med. 2018;50(9):769-78.
• Miller A, Pratt H, Schiffer RB. Pseudobulbar affect: the spectrum of clinical presentations, etiologies and
treatments. Expert Rev Neurother. 2011;11(7):1077-88.
• Girotra T, Lowe F, Feng W. Pseudobulbar affect after stroke: a narrative review. Top Stroke Rehabil. 2018:1-7.
• House A, Dennis M, Molyneux A, Warlow C, Hawton K. Emotionalism after stroke. BMJ. 1989;298(6679):991-4.
• House AO, Hackett ML, Anderson CS, Horrocks JA. Pharmaceutical interventions for emotionalism after stroke.
Cochrane Database Syst Rev. 2004(2):CD003690.
• Acciarresi M, Bogousslavsky J, Paciaroni M. Post-stroke fatigue: epidemiology, clinical characteristics and
treatment. Eur Neurol. 2014;72(5-6):255-61.
• Robinson RG, Parikh RM, Lipsey JR, Starkstein SE, Price TR. Pathological laughing and crying following stroke:
validation of a measurement scale and a double-blind treatment study. Am J Psychiatry. 1993;150(2):286-93.
• Gillespie DC, Cadden AP, West RM, Broomfield NM. Non-pharmacological interventions for post-stroke
emotionalism (PSE) within inpatient stroke settings: a theory of planned behavior survey. Top Stroke Rehabil.
2020;27(1):15-24.