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

(Mega and Cummings 1994; Mega et al. 1997; Mayberg 1997; Arciniegas and Topkoff 2000)

Dorsolateral Prefrontal

Cortex

Hippocampus

Anterior Cingulate Posterior Cingulate

Amygdala

(Lateral)

Orbitofrontal Cortex

(Medial)

Infracallosal Cingulate

Hypothalamus

Striatum

GPe GPi

STn

Thalamus

Multimodal Sensory

Information

Nuc. Acc.

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

•  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

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 post-stroke 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 post-stroke

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 cerebellar-brainstem 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 post-stroke (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

•  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 post-stroke and highest among those hospitalized less than two weeks post-stroke

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

Stroke and Suicide

Teasdale et al. 2001; Stenager et al. 1998

Post-Stroke Depression •  Possible neurobiological mechanisms of early post-

stroke 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 meta-analyses 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

•  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 Mania

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 6-month 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 post-stroke 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

•  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)

–  pathological affect –  pathologic emotionality –  pathological emotionalism –  pathological weeping –  pseudobulbar affect (PBA) –  pseudobulbar crying –  “Involuntary emotional expression disorder”

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.

•  “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.

Is PLC a disturbance of emotion and feeling?

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 frontal-subcortical-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

•  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

Essential Crying

(Green and Bernat 1999; Green, McAllister, and Bernat 1987)

•  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

Witzelsucht

(Berkovic and Andermann 1999; Duchowny 1983)

•  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

Witzelsucht

(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