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Neuropsychiatry of Stroke

by Vani Rao, M.D.

Introduction

The definition of a Stroke (WHO Stroke, 1989) is as follows:
• Rapidly developing disturbance of cerebral function
• focal (or global)
• with symptoms lasting 24 hours or longer or leading to death,
• with no apparent cause other than that of vascular origin.

Over the last decade there has been a decrease in incidence and mortality probably secondary to improved measures to treat hypertension, less smoking and better management of heart disease factors.  However, it is still the 3rd leading cause of death with an incidence of 500,000/yr, 1/3 of who die each year.  Additional epidemiologic factors include:
• Prevalence: 3-5 million /year
• Mortality rate:150,000/year
• Annual cost: $43 billion in the US
• permanent disability: 66%

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Pathophysiology of a Stroke
Stroke can be either hemorrhagic (15%) or ischemic (85%).  Hemorrhagic stroke usually results from either vascular anomaly or long history of hypertension.  65% of hemorrhages occur in the basal ganglia-thalamus; 15% in pons. Hemorrhagic stroke is usually progressive and deadly and can evolve over hours or days.

Ischemic strokes are caused by interruption of blood supply to the brain.  Atherosclerosis causes narrowing of blood vessels and vascular occlusion can occur by thrombosis or embolism, which lead to infarcts.

Risk factors for stroke include:
• Age
• Hypertension
• Carotid or arterial disease
• Atrial Fibrillation
• Heart Disease
• Race (African Americans are at highest risk and Hispanics and American Indians are at lowest risk)
• Gender (men are at higher risk than women in all age groups)
• Blood disorders (sickle cell disease and blood disorders that increase blood viscosity)
• Illegal Drugs (especially cocaine)

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Prevalence of Post Stroke Neuropsychiatric Disorders

Neuropsychiatric (NS) disorders are common after stroke.  The entire spectrum of psychiatric illness can be seen. Most common are: depression, anxiety, emotional incontinence and catastrophic reactions.

• Depression:  35%
• Mania: rare
• Bipolar disorder: rare
• Anxiety disorder: 25%
• Apathy : 20%
• Psychosis: rare
• Pathologic affect 20%
• Catastrophic reaction: 20%

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Post Stroke Depression

• introduction
• diagnosis
• core symptoms
• etiopathogenesis
• biological treatment
• prevention

Introduction
It is important to study depression because it is very common, it interferes with rehabilitation, recovery and quality of life, and it significant source of care giver burden.  The frequency of PSD has been examined in numerous studies and is found to be 10-40%.  Such a wide range of prevalence is due to variation in three areas.

1) Measurement - different scales ranging from self-administered  scales to structured psych interviews

2) Source – are patients examined in
hospital or in the community surveys? The mean prevalence in hospitalized acute stroke patients was 30-40% compared to 10-20% in a community sample.

3) Duration – are patients studied during the acute post-stroke period or many months after stroke.

The most important message is that there is conflicting evidence regarding risk factors for post stroke depression.  The table below outlines these factors, although those listed as consistent are not 100%.

Consistent

Controversial

Past Psych history
Dysphasia 
Poor Social Support

Age
Gender
SES
Impaired ADLs
Lesion Location
Lesion Volume

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Diagnosis

Diagnosis of PSD is difficult sometimes because of 

  • language disorders - difficulty in expressing or comprehending,
  • cognitive impairment - anosognosia or lack of insight or lack of awareness of depressive symptoms, and 
  • overlap between symptoms of depression & medical condition - several symptoms of depression such as loss of energy, decreased appetite, insomnia are found among non-depressed stroke patients secondary to hospital environment, use of medications, other medical conditions and stroke itself (decreased sleep, appetite, energy, concentration)

DSV IV Minor Depression Criteria requires the presence of more than 2 but less than 5 depressive symptoms including either a depressed mood or loss of interest. However, the DSM IV Major Depression Criteria can be reliably used to diagnose major PSD.

DSM IV Major Depression Criteria

Presence of depressed mood for 2 wks or more plus > 4 of the following:
  1. decreased/increased appetite/weight
  2. insomnia or hypersomnia
  3. decreased interest or pleasure
  3. psychomotor agitation/retardation
  4. loss of energy
  5. feelings of worthlessness/inappropriate guilt
  6. loss of concentration
  7. Suicidal thoughts

The duration of major PSD is about 9 months to 1 year whereas the duration of minor depression is several years. 

In a study done by Robinson et al in the 1990s on comparison of depressed to non-depressed, most depressed folks had these neuro-vegetative and psychological symptoms of depression compared to the non-depressed folds.  In 1991, Fedoroff et al, examined frequency of depressive symptoms among both depressed and non-depressed patients with stroke.  With the exception of early morning awakening, all neuro-vegetative and psychological symptoms of depression were significantly more frequent among patients with depressed mood compared to those without depressed mood.  Even when the frequency of nonspecific symptoms among the non-depressed patients was taken into account, the frequency of major depression decreased by only 2% from 23 to 21.

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Core Symptoms:

  1. Persistent depression
  2. Guilt
  3. Hopelessness
  4. Anhedonia
  5. Suicidal thoughts

Little is known about the course of major depression after stroke.  Prevalence varies over time with an apparent peak at 3-6 months after stroke and a subsequent decline to about 50% of initial rates at 1 year.  Spontaneous remission can occur 1-2 year post-stroke. (Robinson et al, 1987)

A significant number of stroke survivors develop depression hours to days after stroke following the pattern of what is classically called reactive depression.

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Etiopathogenesis of PSD
Researchers are split into 2 groups with opposing views. Some propose purely biological mechanisms and while other propose psychological mechanisms.  The table below provides the evidence for both mechanisms (Whyte & Mulsant, 2002).

Biological Mechanism

Psychological Mechanism

• High depression frequency in stroke vs other medical illness
• Temporal relationship
• Specific lesion locations: Left Frontal;Left Basal Ganglia,
• Seen in anosognosia
• Differential response to Rx: better response to noradrenergic agents
• Plausible biological mechanism
• Disruption of frontal-striatal circuit

• Increased rate in medical illnesses
• Temp relationship to death/life event
• Lesion location not consistently replicated. Not supported by MA
• PSD profile is not specific
• Weak evidence of treatment response
• Plausible psychological mechanism
• Major life event can overwhelm

Instead of debating biological vs psychological, the best way to look at the etiology of PSD is from the biopsychosocial perspective.  PSD is probably due to a combination of biological, psychological and social factors.

  • Biological:  Broken part in brain - disruption of neural circuits & neurochemicals. Genetic cause.
  • Psychological: Presence of poor coping skills -e.g. neurotic personality style, glass is always half empty
  • Social: Disability, limited social support, loss of independence may overwhelm coping skills

Psychological stressors such as loss of independence and poor physical functioning can overwhelm anyone, and in the setting of biological vulnerability, can cause depression
 
STROKE CAUSES BIOLOGICAL VULNERABILITY.  LIFE SITUATION and PERSONALITY PRECIPITATE DEPRESSION.

Because there is so much debate over Lesion location (LL) and PSD, let’s examine a great article by Bhogal et al 2004, who conducted an extensive literature review and looked at different studies that had examined the association between PSD and lesion location.  This is what they found.

  • 26 original articles reviewed
  • 10 showed no significant association between LL & PSD
  • 2 showed Right hemisphere lesion & PSD
  • 4 showed Left hemisphere & PSD
  • 3 showed Left BG lesions
  • 7 showed changes in association between LL & PSD over time
  • Left hemisphere LL found in hospital inpatient studies
  • Right hemisphere LL found in community studies

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Biological Treatment of PSD

  • 18 reports on biologic Rx of PSD
  • 10 antidepressant trials: Only 3 DBPCT
    • Lipsey et al 1984: N=36 18 months post-stroke; DSM III . Nortriptyline (NTP) vs  Placebo 4-6 weeks. NTP efficacious 
    • Robinson et al 2000: N=56.  6 months post-stroke; DSM IV Major & Minor Depression. Prozac vs. NTP vs Placebo. 9% vs. 63% vs. 23%
    • Wiart et al 2000: N=66. 3mths post-stroke. ICD 10 Major Depression. Prozac vs. placebo; 63% vs. 33 %

The Robinson study was controversial.  It began with 3 arms: Prozac, NTP and placebo.  After the first phase, only 2 arms remained.  The majority of the Prozac group had people from the placebo group, i.e. people with more resistant depression.

Seven studies (either no standardized depression criteria or no randomized controls) indicate:

  • antidepressants are well tolerated
  • 60% respond to medications
  • no particular class has an advantage over the other

There is a widespread belief that PSD is psychological reaction.  Severity of side-effects of psychotropics account for the resistance of many physicians to prescribe antidepressants.

Patients with NTP compared to placebo did better on HAM D and Zung self-rating depression scale; 3 of the 14 treated with NTP dropped out, 2 patients developed delirium and 1 died suddenly of unknown cause.

  • Redding et al,1986: 7 pts on Trazadone did better than 9 on placebo on ADLs
  • Anderson et al, 1994: assessed Citalopram in 66 pts with stroke. The HAMD and Melancholia scores were significantly better 3 & 6 weeks in drug pts compared to placebo
  • Stamenkovic et al, 1996: Fluoxetine efficacious

Three reports on use of psychostimulants - 2 retrospective chart reviews & 1 open label study using Ritalin (Johnson et al 1992; Masand et al, 1991Lazarus et al 1994).  They were found to be safe, well tolerated and efficacious.  However, no definitive conclusions can be made given lack of randomization.

ECT was found useful in 2 retrospective chart reviews (Murray et al 1986; Currier et al 1992).  Currier et al, found 19/20 elderly PSD “markedly or moderately” improved.  None of the pts developed exacerbations of stroke or new neuro deficits.

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Prevention of PSD
Antidepressants have been used as prophylaxis to prevent PSD (Palomaki et al, 1999; Narushima et al, 2002; Rasmussen et al 2003), physical impairment (Narushima et al 2003) and mortality (Jorge et al, 2003).

  • PSD  studies: 2/3  ( Narushimo et al: Fluoxetine/NTP; Rasmussen et al: Sertraline) showed significantly lower rates of PSD compared to placebo
  • Physical impairment: Fluoxetine or NTP given within 1 mth was associated with more improved ADL than when given after 1 month (Narushima et al 2002)

Treatment with Fluoxetine or NTP during the first 6 months post-stroke is associated with significant increase in survival in both depressed and non-depressed patients (68% on antidepressant vs. 36% on placebo) (Jorge et al 2003).  Three reasons are:

  1. antidepressants, neurotropic, stabilize the chemical imbalance;
  2. increased compliance with vascular disease preventing regimens;
  3. they may have an effect on serotonin mediated platelet activation.

However, caution is needed when using antidepressants in stroke patients. These studies are intriguing, but have limitations (uncertain how statistically significant results can be translated into real-life outcomes).  Antidepressants have side-effects such as falls, increased bleeding, seizures, and sedation.  There is a pressing need for further research to better define role of antidepressants in stroke prevention.

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Post Stroke Anxiety

The Prevalence of PSA is about 20%, with a majority of PSA patients also having PSD.

  • DSM IV dx of Anxiety d/o secondary to GMC
  • GAD: worrying state present for at least 6 months  + 3 other symptoms (restlessness, irritability, poor energy, poor concentration, muscle tension, poor sleep)
  • 6-month criteria not often followed

Anatomical Correlates:
Study of 98 stroke patients (Stratkstein, Robinson et al 1990) found:

  • Anxious depressed patients  had higher frequency of cortical lesions than the depressed or control group
  • The depressed group showed higher frequency of subcortical lesions than the AD group

Study of 288 patients (Castillo, Robinson et al 1995), found that Anxiety Depression (AD) was associated with left cortical lesions and anxiety alone with right hemisphere lesions
 
In a 3-year study (Astrom 1996) pure anxiety was associated with right hemisphere lesions and AD with left hemisphere lesions.  Three years after stroke, GAD was associated with both cortical & subcortical atrophy.  

PSA Risk Factors:

  • Longitudinal studies indicate GAD negatively influences recovery (Astrom 1996)
  • ADL impairment associated with GAD in the acute and chronic stage
  • Pts with AD more impaired in ADL compared to PSD alone  (Shimoda & Robinson, 1998)

In the Shimoda and Robinson study of 142 pts with GAD and Depression, 18 had more significant impairment in ADL compared to PSD alone at the end of 2 years. The comorbidity of PSD and GAD produced longer duration of PSD than PSD alone and this prolonged depression might lead to poorer physical and social outcomes.

PSA Treatment
No systematic studies of PSA have been done.  The only information available is from the treatment of idiopathic anxiety disorders.  SSRIs as first line treatment and Benzodiazepines should be avoided.  However, if used, should be time limited.  Buspirone (partial serotonin agonist) effect has not been examined in this population. 

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Post-Stroke Catastrophic Reactions

Catastrophic reaction is an outburst of emotion, such as anxiety, agitation, or crying, that occurs when unable to perform simple tasks that were possible before.  This is not uncommon in stroke patients.  19% in a series of 62 consecutive acute stroke patients were found to display CR (Starkstein et al, 1993).

Catastrophic Reaction is associated with PSD & Basal Ganglia lesions and may be a release phenomenon due to subcortical damage.  It is often associated with expressive aphasia. 

Treatment consists of prophylactic and supportive measures.
 
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Pathological Affect

Other names: Emotional Incontinence; post-stroke emotionalism
A pathological affect is seen in about 15% of stroke patients and is characterized by frequent /easily provoked outbursts of laughter/tearfulness not appropriate or disproportionate to the situation.
Scales are available to measure PLAC 

Treatment:  Antidepressants and mood stabilizers  have been used to treat pathological laughter and pathological crying. However, more research in this area is necessary.

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Post Stroke Psychosis

Psychosis is a rare complication post-stroke.  Rabins et al screened all stroke individuals > 60 over a 9-year period (n=1191). Only 5 patients identified with psychosis.  All had right frontoparietal lesions and subcortical atrophy compared to 5 matched controls.  3 of the 5 had post-stroke seizures. None of the 5 non-psychotic controls had seizures. 

Treatment consists of neuroleptics or anticonvulsants.

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Summary
  • Depression & anxiety are the 2 most common post-stroke syndromes.
  • Both depression and anxiety increase morbidity and delay rehabilitation.
  • There are very few treatment studies available.
  • Treatment of neuropsychiatric post-stroke disorders have the greatest potential for improving outcome and quality of life.

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