Stroke is the fifth leading cause of death in the United States and an important cause of disability. Every year, about 795,000 people in the United States have a stroke. About 610,000 of these are first or new strokes; 185,000 are recurrent strokes.1 Stroke is characterized by the sudden occurrence of a neurologic deficit or syndrome. Typically, especially as it pertains to physical symptoms, the resultant neurologic syndrome corresponds to the portion of the brain supplied by the respective cerebral vessels affected by the stroke (see Figures 22-1 and 22-2). Strokes are broadly categorized as ischemic or hemorrhagic.2 The underlying cause of the vascular occlusion in ischemic strokes may be: (i) atherosclerosis with superimposed thrombosis, affecting large cerebral or extracerebral blood vessels (Figure 22-3), (ii) cerebral embolism, and (iii) occlusion of small cerebral vessels within the parenchyma of the brain. Alternative pathologic processes that may result in ischemic brain damage include arterial dissection, inflammatory conditions such as vasculitis, thrombosis of cerebral veins, and dural sinuses, thrombosis of cerebral vessels due to hypercoagulable conditions, vasospasm, and other mechanisms. Hemorrhagic strokes (Figure 22-4) are caused by the rupture of blood vessels and subsequent bleeding into the brain parenchyma (intracerebral hemorrhage) or the subarachnoid space (Figure 22-5). Contributing factors to hemorrhagic strokes are weakened blood vessels, for instance due to aneurysms or arteriovenous malformations, and hypertension. Hemorrhagic strokes typically do not respect vascular territories and thus may result in more complex syndromes.
Diagram of the left cerebral hemisphere, lateral aspect, showing the courses of the middle cerebral artery and its branches and the principal regions of cerebral localization. Below are the lists of the clinical manifestations of infarction in the territory of this artery and the corresponding regions of cerebral damage. (Reproduced with permission from Ropper AH, Samuels MA, Klein JP, Prasad S. Stroke and cerebrovascular diseases. In: Adams and Victor’s Principles of Neurology. 11th ed. https://accessmedicine.mhmedical.com. Copyright © McGraw Hill LLC. All rights reserved.)
Clinical characteristics of stroke dependent on vascular territory affected. ACA, anterior cerebral artery; LE, lower extremity; MCA, middle cerebral artery; PCA, posterior cerebral artery; UE, upper extremity. (Reproduced with permission from Mitra R. Stroke rehabilitation. In: Principles of Rehabilitation Medicine. https://accessmedicine.mhmedical.com. Copyright © McGraw Hill LLC. All rights reserved.)
Large ischemic infarction of the left cerebral hemisphere mainly in the distribution of the superior division of the middle cerebral artery. CT at 24 hours (left) and 72 hours (right) following the onset of stroke symptoms. The second scan (right) demonstrates marked swelling of the infarcted tissue and rightward displacement of central structures. (Reproduced with permission from Ropper AH, Samuels MA, Klein JP, Prasad S. Stroke and cerebrovascular diseases. In: Adams and Victor’s Principles of Neurology. 11th ed. https://accessmedicine.mhmedical.com. Copyright © McGraw Hill LLC. All rights reserved.)
Unenhanced CT showing hypertensive hemorrhages in the putamen (A), thalamus (B), pons (C), and cerebellum (D). The thalamic hemorrhage (B) has extended into the posterior horn of the right lateral ventricle and the cerebellar hemorrhage (D) has extended into the fourth ventricle. (Reproduced with permission from Ropper AH, Samuels MA, Klein JP, Prasad S. Stroke and cerebrovascular diseases. In: Adams and Victor’s Principles of Neurology. 11th ed. https://accessmedicine.mhmedical.com. Copyright © 2019 McGraw Hill LLC. All rights reserved.)
Subarachnoid hemorrhage as a result of rupture of a basilar artery aneurysm. Left: Axial CT at the level of the lateral ventricles showing widespread hyperdense blood in the subarachnoid spaces and layering within the ventricles with resultant hydrocephalus. There is a blood-CSF level in the posterior horns of the lateral ventricles, typical of recent bleeding. Right: At the level of the basal cisterns, blood can be seen surrounding the brainstem, in the anterior sylvian fissures, and the anterior interhemispheric fissure. The temporal horns of the lateral ventricles are enlarged, reflecting acute hydrocephalus. (Reproduced with permission from Ropper AH, Samuels MA, Klein JP, Prasad S. Stroke and cerebrovascular diseases. In: Adams and Victor’s Principles of Neurology. 11th ed. https://accessmedicine.mhmedical.com. Copyright © 2019 McGraw Hill LLC. All rights reserved.)
The focus of this chapter is the neuropsychiatric disorders and symptoms that may occur as a consequence of stroke. This includes the discussion of post-stroke depression (PSD), anxiety, mania, and psychosis, apathy, emotional aprosodia, and pathological laughing and crying. In addition, this chapter reviews the topic of vascular depression, a disorder characterized by depression, executive dysfunction, and subcortical microvascular disease.
PSD is diagnosed based on the temporal relationship between a clinically apparent stroke and the onset of depression. Unlike idiopathic major depressive disorder, PSD primarily has onset late in life. It has modifiable risk factors, which coincide with the risk factors for cerebrovascular disease itself. Anticipation, recognition, and treatment of depression associated with cerebrovascular disease can reduce its morbidity, and improve outcomes related to vascular disease itself.3
It is estimated that 6.8 million Americans over the age of 20 have suffered a stroke, with an annual incidence of approximately 795,000.4 Among the approximately 75% who survive a stroke, one-third will experience PSD, significantly higher than the incidence in the general population, which ranges from 5% to 13%.5 A study of 4022 patients followed for 15 years in the South London Stroke Register estimated a cumulative incidence of PSD of 55%, with greatest risk in the first year after stroke and 33% of cases occurring in the first 3 months.6–8 The most consistent predictors of PSD include physical disability, stroke severity, and cognitive impairment.5 Two large systematic reviews identified lack of family and social support, history of depression, and post-stroke anxiety as additional risk factors for PSD.7–9 Confounding the relationship between post-stroke impairment and PSD, however, is the observation that the presence of PSD worsens outcomes and increases the degree of residual disability after stroke.10
Several factors may mediate the development of depression in neurological illnesses, including both psychosocial and biological etiologies. Psychologically, the experience of stroke as a sudden loss of physical, verbal, or cognitive function, and the immediate onset of significant disability is a traumatic experience, and PSD shares some of its origins in the reactive nature of depression that emerges in the wake of any significant medical diagnosis or illness. The relationship between severity of post-stroke physical and cognitive impairment and development of PSD symptoms supports the theory that PSD may arise in part from challenges of coping with medical sequelae of the injury itself.11,12 However, larger physical and cognitive impairments may imply a larger stroke. In addition, the stroke location can contribute directly, by affecting the neurocircuitry mediating mood, to more severe depression. Although there is ongoing debate about whether lesion location increases the likelihood of developing PSD, evidence suggests that infarcts in the left frontal lobe and basal ganglia are more likely to precipitate depression. Although not consistently observed, PSD seems to correlate with the proximity of the infarct to the anterior pole of the left frontal lobe.13,14 This correlation was not observed among patients with right-hemisphere stroke.13 A prospective study of 68 first-time ischemic stroke patients demonstrated a relationship between lesions disrupting the left limbic-cortical-striatal-palladial-thalamic circuit and PSD onset. PSD was specifically associated with lesions of the ventral ACC, dorsal ACC, subgenual cortex, amygdala, and subiculum.15
Changes in monoamine neurotransmitters may also be involved in the development of PSD, with serotonergic system disruption specifically implicated in PSD.16,17 Rodent models of stroke have shown ipsilateral depletion of serotonin, norepinephrine, and dopamine after stroke, and reduction of monoamine metabolites has been demonstrated in the CSF of human patients with PSD, suggesting alterations of the monoaminergic circuits as a consequence of the stroke. PET imaging of 5-HT2 receptors shows evidence of greater upregulation of serotonin receptors in the right hemisphere compared to the left in patients with depression after a right-hemisphere stroke. This finding supports the hypothesis of monoamine alterations leading to PSD.18 Proinflammatory cytokines resulting from the underlying cerebrovascular injury may play a role in disrupting serotonin synthesis and disrupting the HPA axis, further contributing to depressive symptoms.19 Small studies of the role of genetic factors in PSD risk have indicated that higher serotonin transporter gene (SLC6A4) methylation in the presence of the s/s (short/short alleles) 5-HTTLPR genotype, as well as higher BDNF gene methylation and BDNF polymorphism val66met, were independently associated with incident PSD.20,21
Symptoms of PSD do not significantly differ from those of idiopathic major depressive disorder. Because of overlapping symptoms of stroke and depression (e.g., changes in energy, sleep, appetite, libido, and cognition), several studies have examined the validity of DSM criteria for major depression in the setting of stroke. Adjusting diagnostic criteria, however, to account for the origin of neurovegetative symptoms (i.e., attempts to exclude symptoms judged to be direct sequelae of the stroke) does not improve the sensitivity or specificity of DSM criteria for major depressive disorder in the setting of stroke.22 In sum, DSM criteria for major depressive disorder are sensitive and apply to PSD as well. Several screening measures may aid in the diagnosis of PSD, displaying high sensitivity in the post-stoke setting. These include the Center of Epidemiological Studies-Depression Scale (CES-D), Hamilton Depression Rating Scale (HDRS), and Patient Health Questionnaire (PHQ-9).5 The symptoms of PSD do not differentiate it from other forms of late-life depression. The particular presentation of individual cases likely depends on the lesion location and the extent of disability, combined with the individual’s reaction to the stroke due to the new and potentially traumatic onset of functional impairment.
Course and Natural History
The course of PSD has been examined in several longitudinal studies, but the conclusions have been inconsistent and the degree of treatment in most case series has not been clearly delineated. There is some consensus, however, that depressive symptoms that emerge rapidly, within hours to days of stroke, tend to peak within 3–6 months of onset and approximately 50% experience remission by 1 year. Patients who develop the onset of depression 2 months after stroke or later, however, typically have a more protracted course, and up to 50% remain depressed 2 years after their stroke. One confounding factor is the degree of physical disability, which correlates with risk of depression; patients with greater disability tend to be overrepresented in the hospital and rehabilitation settings where patients have been recruited for many of these studies.23 The early identification and treatment of PSD has important implications for both medical and psychiatric outcomes from stroke. Patients with PSD are more likely to have worse functional outcomes with lower participation in rehabilitation, lower QOL, and higher mortality (especially in patients under 65).5
Assessment and Differential Diagnosis
Lack of awareness of the high prevalence of PSD, misattribution of depressive symptoms to physical consequences of the stroke, and perception that the patient’s distress may be an “appropriate” reaction to stroke all likely lead to the underdiagnosis of PSD. Recognition of this entity, however, is important, because appropriate treatment of depression can alleviate the suffering of the depressed patient as well as improve rehabilitation outcomes. As discussed, DSM criteria for major depressive disorder are sensitive and specific for PSD. The defining characteristic of this entity is onset after a clinically apparent stroke. Other symptoms can emerge after stroke, however, that can complicate or confound the diagnosis of depression. The most common post-stroke symptom that mimics depression is apathy. Apathy is a reduction of motivation not attributable to emotional distress, cognitive impairment, or level of consciousness.24 Apathy is also a common feature of depression and is included on the Hamilton Depression Rating Scale. However, several studies and reviews demonstrate that apathy and depression are not always correlated and can be differentiated.25 A case series26 compared apathy and depression levels across stroke, Alzheimer’s disease, and idiopathic major depression. While the relationship between apathy and depression varied among the groups, patients with major depression or left-hemisphere stroke tended to have higher depression scores and lower apathy scores. Patients with right-hemisphere stroke had high levels of both apathy and depression, although these symptoms did not correlate with each other in this group. A longitudinal study of patients with PSD found that within 3 months of a stroke, levels of apathy and depression did not correlate, but that a correlation emerged over time and was significant at 1 year. Both apathy and depression were predicted by the presence of dementia, but depression was independently predicted by psychosocial factors, such as not living with a family member. Although the correlation increased, there were a significant number of patients at 1 year who demonstrated apathy or depression, but not both.27
Although apathy and depression are likely related to the disruption of frontal-subcortical networks, distinguishing the two phenomena has treatment implications: apathy is less likely to be responsive to antidepressants28 than PSD. When apathy occurs after stroke, careful assessment for other symptoms of depression is required to differentiate the two syndromes. If apathy coexists with depression, the treatment of both syndromes may be indicated.
Treatment of PSD is important, as degree of depressive symptoms negatively correlates with rehabilitation potential3 and post-stroke outcomes.
Numerous studies comparing antidepressants against alternate agents or placebo have demonstrated widely varying efficacy in antidepressant treatment for PSD. The range of study types, enrollment criteria, and means of assessment make it difficult to draw firm conclusions, but several studies have demonstrated efficacy of antidepressant agents in this population. The most commonly studied agents are selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). In general, antidepressants from either class outperform placebo, although placebo response is high, which is typical for antidepressant trials. Nortriptyline has been shown to significantly outperform both fluoxetine and placebo.23 Tricyclic agents may be effective, but their use is limited by their adverse effects. Patients with PSD tend to be elderly and are more likely to have vascular disease. Anticholinergic effects and risk of cardiac arrhythmias may lead most clinicians to reject these agents in favor of SSRI antidepressants. SSRIs, particularly fluoxetine, may have the added benefit of improving motor recovery—in the FLAME trial, a double-blind, placebo-controlled study of 231 ischemic stroke patients showed that 20 mg fluoxetine plus physiotherapy outperformed physiotherapy alone in motor recovery outcomes at 3 months.29
Several case series and chart reviews have demonstrated the safety and tolerability of psychostimulants in PSD, but data on effectiveness are limited. One placebo-controlled trial of 21 patients in the rehabilitation setting showed that methylphenidate (30 mg/day) improved depressive symptoms and motor recovery.30 Stimulants may be used an adjunct therapy with SSRIs, especially with comorbid cognitive impairment or fatigue, but cardiovascular side effects should be carefully considered and monitored.5
Brain Stimulation Therapies
Two retrospective chart reviews have demonstrated the safety and efficacy of ECT for PSD, with some patients receiving treatment within 1 month of stroke.31 Repetitive transcranial magnetic stimulation (rTMS) has growing evidence for use in recovery of motor and cognitive stroke symptoms, as well as management of post-stroke central pain, but evidence for its efficacy in PSD is limited.32,33
Post-stroke patients struggle with issues of loss of function and many times loss of independence. They may depend on caregivers and the inclusion of caregivers in treatment may increase effectiveness of the interventions. The potential for rehabilitation may change the dynamics of the relationship with caregivers over time. Different approaches including cognitive behavioral therapy (CBT), mindfulness-based interventions, and acceptance and commitment therapy have been used. While the evidence of benefit of psychotherapy in this population has been limited,34 small trials of brief psychosocial interventions (6–20 sessions) have shown some benefit in treating PSD.5
Anxiety disorders are among the most prevalent psychiatric disorders, with up to 33.7% lifetime prevalence in the general population. They include general anxiety disorder (GAD), panic disorder, social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD).35 While all anxiety disorders described in the DSM have been reported after stroke, GAD is the most commonly described.36 A meta-analysis of 44 observational studies reported the prevalence of anxiety as 20% in the first month after stroke, 23% in months 2 through 5, and 24% after 6 months.37 Additional studies report post-stroke anxiety prevalence of 3–30%, with over half of patients experiencing anxiety in the 10 years after injury.38–40
Several factors increase risk for post-stroke anxiety, including young age (below 65 years old), female gender, inability to work, premorbid anxiety or depression, and smoking or alcohol abuse, with stroke severity contributing additional risk.40,41 A longitudinal study of 101 acute stroke patients found that anxiety prevalence remained constant over a 3-year period (even as depression prevalence declined) and was most affected by female gender and previous anxiety diagnoses.42 Premorbid cognitive function, particularly cognitive speed, has been associated with the development of anxiety 3 months post-stroke.43
Limited research examines the effect of premorbid anxiety on risk of stroke. A prospective study of 2625 community-dwelling individuals found no association between HADS-A score and stroke, with no differences reported between anxiety disorder subtypes.44 Anxiety post-stroke is associated with decreased quality of life and functional outcomes, including dependence and social network size.45,46 Ample literature supports a relationship between post-stroke anxiety and depression, with co-occurrence rates between 17% and 80% reported.37,47
The relationship between lesion location and neuropsychiatric outcomes is difficult to assess due to small sample sizes and suboptimal imaging data, with studies relying on CT rather than MRI.48 In a cross-sectional study of 693 acute stroke admissions with MRI, right frontal infarcts were associated with an increased rate of post-stroke anxiety.48 This research supports previous findings in TBI patients linking right orbitofrontal lesions to development of anxiety symptoms.49 Neurocircuitry models of anxiety describe the interaction between the amygdala and cortices, implicating the amygdala in the generation of fear responses and the medial and ventromedial prefrontal cortex in fear extinction.50 Research in rodent and primate models suggest that frontal lesions may lead to dysregulated top-down control of negative emotion, which contributes to anxiety disorders.51–53 In human subjects, medial orbitofrontal cortex abnormalities are associated with trait anxiety,54 and functional imaging studies reveal decreased connectivity between the amygdala and medial prefrontal cortex in several anxiety disorders including SAD, PTSD, and GAD.55 However, the effect of lesion location in post-stroke anxiety remains poorly understood. A meta-analysis of 5760 stroke patients found no statistically significant relationship between lesion location and development of post-stroke anxiety.37 Comorbid anxiety and depression seem to be more likely associated with lesions in the left hemisphere; however, anxiety without depression seems to be more likely associated with lesions in the right hemisphere.46 Cerebral atrophy is associated with development of chronic depression and anxiety but is not associated with psychiatric symptoms in the acute stage.46
The development of post-stroke anxiety disorders may be mediated by the trauma of the cerebrovascular event itself and the psychological distress of extended hospitalization and rehabilitation. Iatrogenic PTSD is well-described in acute medical illness, including asthma, myocardial infarction, and physical trauma.56,57 A review of 1138 stroke and TIA survivors found that up to one-fourth of hospitalized patients may develop significant PTSD symptoms related to the cerebrovascular event.58 Negative cognitive appraisal,56 poor coping strategies, and an unfavorable psychosocial environment contribute to the severity of neuropsychiatric outcomes post-stroke.41 In a 2-year longitudinal study of 142 stroke patients, anxiety was associated with greater functional impairment and depression scores in the 2 years after stroke.59 Increased comorbidities, disability, and recurrent stroke or TIA have also been implicated in post-stroke anxiety disorders.60
The relationship between stroke and anxiety also may be influenced by genetics. One study associates tryptophan hydroxylase 2 (TPH2) polymorphisms with development of post-stroke anxiety in a Han Chinese sample.61 This research supports previous reports linking TPH2 variants with anxiety-related disorders.62,63 TPH is the rate-limiting step in serotonin synthesis, and dysregulated TPH2 expression in rodent models is associated with alterations in serotonergic pathways that cause increased anxiety-related behavior.64
The phenomenology of post-stroke anxiety disorders is diverse, and may include GAD, panic disorder, SAD, OCD, and PTSD. The DSM describes GAD as excessive anxiety and worry that is difficult to control and occurs more often than not, for a period of at least 6 months, with a negative impact on daily functioning and well-being.65 Criteria require at least three additional symptoms, including restlessness, decreased energy, poor concentration, irritability nervous tension, or insomnia.65 While GAD is the most commonly described subtype of anxiety in the post-stroke population, phobic disorders, especially agoraphobia, may also be a frequent presentation of post-stroke anxiety.66 In a prospective study of 175 stroke patients 3 months post-injury, 10% displayed phobic disorders, while 7% displayed both phobic disorders and GAD, and 4% displayed GAD only.45 Phobic disorders included agoraphobia, social phobia, and specific injury-related fears such as recurrence, headache, physical exertion, and falls.45 Even in the absence of a formal diagnosis of an anxiety disorder, subthreshold fears specific to functional status or stroke recurrence may significantly impact quality of life.67,68 Anxiety is commonly comorbid with PSD and may worsen the prognosis of depressive disorders.37,69 Given the substantial co-occurrence of depression and anxiety in post-stroke patients, it is important to consider and treat anxiety in patients diagnosed with PSD.47 Patients with comorbid depression are at greater risk of developing chronic or long-standing anxiety.42
Ample research suggests that post-stroke anxiety negatively impacts the course of recovery from stroke. Patients with anxiety had greater functional and social limitations and lower quality of life 3 months post-stroke.40,45,69 However, a study of global cognitive performance (measured by MMSE) showed no relationship between post-stroke anxiety and cognitive impairment in the acute phase or long-term follow-up in 142 patients.69 The limited studies on the time course and natural history of post-stroke anxiety show that patients who develop anxiety in the acute phase tend to remain anxious in medium and long-term follow-up. In a 6-month, prospective study of 532 consecutive stroke survivors, 40% of patients with initial anxiety continued to experience anxiety at 6 months, while 7% of initially non-anxious patients developed new-onset anxiety at 6 months.70 In additional longitudinal studies, rates of post-stroke anxiety remain high at 3 and 10 years after diagnosis, and patients who had not recovered by 1 year were at significant risk for developing chronic anxiety.40,46 A longitudinal study of 220 patients found that prevalence of anxiety 5 years after stroke was 29%, significantly higher than at 6 months after stroke, indicating that new-onset anxiety may develop even after the acute recovery phase.71
Assessment and Differential Diagnosis
Psychiatric needs often go unaddressed in the acute hospitalization post-stroke. In a survey of 1251 post-stroke patients in the United Kingdom, dissatisfaction with the psychological services was widespread.72 Anxiety in the post-stoke population remains less recognized or studied than PSD.37 Several factors contribute to underdiagnosis of anxiety in post-stroke patients. There is substantial overlap between symptoms of anxiety and sequalae of the cerebrovascular event itself, including fatigue and sleep disturbance.37 Characteristics of the patient population represented in acute stroke survivors, such as advanced age and limited verbal ability, are associated with difficultly diagnosing anxiety.73
The hallmark of post-stroke anxiety is onset after an acute stroke. Clinical characteristics include worry, restlessness, decreased energy, poor concentration, irritation, nervous tension, and insomnia.41 The differential diagnosis includes medical conditions that may present with similar symptoms, including endocrine (hyperthyroidism, pheochromocytoma, or hyperparathyroidism), cardiopulmonary (arrhythmia or obstructive pulmonary diseases), sequelae of the stroke itself, or comorbid neurological illnesses.74 Given detailed medication monitoring in the hospital setting, substance use or withdrawal are less likely but should be ruled out.74 Complicating the differential diagnosis is the increased likelihood of comorbidity with another psychiatric condition. Patients with generalized anxiety often meet criteria for major depressive disorder, and anxiety commonly co-occurs with other mood disorders.75 As discussed above, it is important to consider and address anxiety in patients diagnosed with PSD.
Validated, patient-reported scales can be used to supplement clinical interview and patient history. The Hospital Anxiety and Depression Scale (HADS) is a 14-item self-assessment questionnaire that measures depression and anxiety and was developed for use in nonpsychiatric hospital settings.76 In a review of eight screening tools for anxiety, HADS was the only tool with adequate sensitivity and specificity in the post-stroke population.37 The HADS-Anxiety subscale is the most commonly used in post-stroke anxiety research, though several studies using the HADS-A suggest that lower cutoff scores in post-stroke patients versus the general population should be considered for greater clinical validity.77–82 In patients who are unable to self-report symptoms of anxiety, the Behavioral Outcomes of Anxiety (BOA) scale reported by the caregiver has shown adequate sensitivity and specificity in a small sample of post-stroke survivors but has yet to be validated on a large scale.83 The Beck Anxiety Inventory, Hamilton Anxiety and Depression Scale, and General Health Questionnaire-30 have also been used in studies of post-stroke patients.59,84 Given the correlation between early-onset post-stoke anxiety and previous psychiatric disorders, attention should be given to assessing premorbid psychiatric state.59
Studies of optimal treatment for anxiety in the post-stroke patient population are limited. Guidance can be taken from the treatment of idiopathic anxiety, with additional consideration for patient-specific risk factors including age, cardio/cerebrovascular disease, and interactions with other medications. The timely diagnosis and treatment of anxiety post-stroke has important implications for medical and psychological outcomes. Treatment for anxiety is likely to be multimodal and include pharmacotherapy and psychosocial interventions such as patient education and lifestyle modification.41
Pharmacological treatment for anxiety disorders may include SSRI/serotonin and norepinephrine reuptake inhibitors (SNRIs), TCAs, benzodiazepines, buspirone, and pregabalin, among others. SSRIs increase available serotonin in the brain by inhibiting serotonin reuptake by presynaptic nerve terminals and are typically prescribed for a wide variety of anxiety disorders including panic disorders, OCD, and PTSD.85,86 Considering the frequency of comorbid depression in this population, SSRIs47 and SNRIs may be useful in improving psychiatric outcomes by targeting symptoms of both anxiety and depression. Paroxetine with or without psychotherapy reduced symptoms of anxiety compared to standard care in patients with comorbid anxiety and depression post-stroke but is not well-studied in patients with anxiety alone.86 In a post-stroke GAD prevention study, participants treated prophylactically with 5 mg/day or 10 mg/day of escitalopram had significantly reduced risk of developing post-stroke anxiety.87 There is some clinical evidence that SSRIs in post-stroke patients may improve motor recovery and reduce dependence, disability, and neurological impairment, though most studies are small and heterogenous and the mechanism is poorly understood.88–90 One large RCT of physical therapy plus fluoxetine (20 mg/day) or placebo showed enhanced motor recovery at 3 months in the fluoxetine arm.91 SSRIs are generally well-tolerated in elderly populations, with lower anticholinergic effects than TCAs.92 However, the known side effects of SSRIs merit additional caution in post-stroke patients. SSRIs increase bleeding risk, which should be considered in patients with risk factors for hemorrhagic stroke.93 Patients with acute cerebrovascular events are at greater risk for cardiac arrhythmias,94 which may be exacerbated by the risk of QTc prolongation with SSRI use.95 SNRIs may cause hypertension, which is itself an independent risk factor for stroke.96
Nortriptyline has the strongest evidence base of the TCAs for anxiety after stroke. In a study of 104 post-stroke patients, nortriptyline treatment (100 mg/day) over 12 weeks significantly reduced anxiety and depression symptoms versus SSRI fluoxetine (40 mg/day) and placebo.97 In a merged analysis, nortriptyline outperformed placebo in improving anxiety and depression symptoms in patients with comorbid PSD and GAD.98 In elderly patients with or at-risk for cognitive impairment, and/or patients with vascular disease, the anticholinergic effects of TCAs should be avoided where possible.99 Risk of falls due to postural hypotension should also be considered.100 Of the TCAs, nortriptyline and desipramine have the smallest anticholinergic effect.100
Benzodiazepines are GABA-enhancing anxiolytics that reduce somatic symptoms of anxiety disorders including insomnia and muscle tension.86 Benzodiazepines should generally be avoided in the elderly, and usually are not considered the first line of treatment for post-stroke anxiety, as their complications may include increased fall risk and cognitive decline, in addition to rebound insomnia and anxiety with withdrawal.101 There is limited evidence for buspirone, a partial serotonin agonist, with one RCT of 72 subjects reporting reduction in anxiety symptoms in patients with comorbid anxiety and depression.102 However, the quality of evidence in this study was low, with reported doses in the first week (20–30 mg/day) and second week (40–60 mg/day) but no information about weeks 3 and 4 and a high dropout rate of 22.6%.86 Pregabalin, approved for treatment of epilepsy, fibromyalgia, and neuropathic pain, may have some clinical utility in treating both post-stroke anxiety disorders and central post-stroke pain.103
Psychosocial and Behavioral Interventions
There are few large-scale studies of behavioral and psychosocial interventions in post-stroke anxiety. Psychotherapy, particularly CBT with cognitive rehabilitation strategies, may be useful for improving mood and reducing symptoms of anxiety.104–106 Studies of CBT in acquired brain injury provide strong evidence that therapeutic delivery modified for cognitive deficits increases efficacy in treating anxiety and depression.107–109 Relaxation therapy teaches coping strategies for decreasing arousal and has shown promise in the post-stroke population. A 1-month, home-based intervention delivered by CD reduced anxiety symptoms on the HADS at 3 months, and treatment effects remained robust after 1 year.110,111 Multimodal psychosocial interventions focusing on building patient self-efficacy and acceptance, motivational interviewing for mood, at home leisure activity, and vascular risk management have shown promise in small pilot studios and are a topic for continuing research.112–116 Lifestyle education and modification, including efforts to improve sleep hygiene and exercise as tolerated, may help address somatic symptoms of anxiety including fatigue and restlessness.
Secondary mania is a rare but potentially debilitating consequence of stroke. Quality data regarding the incidence of post-stroke mania is sparse, and to date there has been no large prospective study on the sequelae of stroke wherein patients were systemically examined for signs of mania. Retrospective case reviews report a low incidence—Starkstein et al.117 reported only three cases of post-stroke mania in a series of 700 stroke patients (0.4%), and a smaller series reported three cases of mania in 188 stroke patients (1.6%).118,119
The pathophysiology of stroke-induced mania is incompletely understood. Lesions leading to the emergence of secondary mania have been hypothesized to disrupt neuroanatomic networks important in the regulation of mood, emotional modulation, reward processing, and behavior,117,119–121 but lesion locations contributing to onset of secondary mania are anatomically heterogeneous, and it does not appear that direct damage to any single structure can be considered necessary for the emergence of secondary mania.122 Among these heterogeneous lesion locations, stroke locations reported in association with mania have been hypothesized to be part of a ventral limbic circuit, including the right orbitofrontal and basotemporal cortices, caudate, and thalamus.119 A recent systematic review broadens this scope, identifying associations between secondary mania and lesions in the superior frontal gyrus, medial orbitofrontal cortex, hippocampus and parahippocampal gyrus, superior and middle temporal poles, middle and inferior temporal gyrus, fusiform gyrus, anterior cingulate gyrus (ACG), and thalamus.119,122
Some authors, after observing that a family history of affective disorder appeared more common in patients who developed secondary mania, hypothesized that genetic loading may also play a role123; though sample sizes are too limited to be definitive. It has been suggested that right-hemispheric lesions are more likely to lead to secondary mania than left-sided lesions—this was supported by a recent systematic review of lesion imaging associated with secondary mania.117,120–122 However, left-sided lesions have also been reported in association with mania.117,119,124 A study employing network analysis using human connectome data demonstrated that diverse lesions leading to secondary mania shared common patterns of functional connectivity to orbitofrontal and temporal cortices.125
The clinical manifestations of post-stroke mania are similar to those in primary mania, with characteristic symptoms including elevated or irritable mood, pressured speech, flight of ideas, grandiosity, psychomotor agitation, and insomnia/decreased subjective need for sleep.119 The frequency of these symptoms does not appear to differ significantly between primary and secondary mania.121 In addition to the symptoms of mania, patients affected by post-stroke mania may experience periods of depression,126 and may exhibit cognitive dysfunction including memory disturbances for events that occur during the manic period.127 Patients may also exhibit a wide range of additional neurologic symptoms including motor deficits, hemineglect, focal sensory deficits, and others, based on lesion location. Importantly, other neurologic deficits in post-stroke mania may go underreported, either due to a general lack of insight or anosognosia due to stroke or due to an exaggerated sense of well-being associated with the manic episode.127
Assessment and Differential Diagnosis
The differential diagnosis for post-stroke mania includes a primary psychiatric disorder (bipolar affective disorder, or a primary psychotic disorder), other causes of secondary mania (including mania due to a mass lesion, drug toxicity [e.g., antidepressants, corticosteroids], or metabolic effects), substance use, delirium, and mania due to other medical condition (such has hyperthyroidism, hypothyroidism, or Cushing’s disease).128 Clinicians should consider post-stroke mania in a patient with vascular risk factors who presents with mania atypical for classic bipolar disorder (e.g., first manic episode after the age of 40 years, no prior history of depression or affective disorder, no family history of bipolar illness, presence of neurologic deficits).120
Evaluation for post-stroke mania should begin with a thorough history, including the timing and onset of manic symptoms, the concurrence of and temporal relationship to any new neurologic deficits, screening for vascular risk factors, and screening for personal and family history of affective or psychotic disorders. Patients in whom there is ample suspicion for a secondary cause of mania should undergo further workup with neuroimaging. A brain MRI with evidence of stroke in a patient with new-onset mania and no prior history of bipolar affective disorder can be suggestive of secondary mania if there is a temporal relationship between the occurrence of a new lesion and the onset of manic symptoms.
Treatment of patients with post-stroke mania should emphasize both the management of vascular risk factors to prevent development of an additional stroke128 as well as treatment of the manic episode. The range of psychopharmacologic treatments employed in post-stroke mania is wide and reflects those drugs used in primary mania, but the vast majority of treatment data is on a case report level and it is difficult to draw comparisons between the relative effectiveness of different anti-manic therapies at this time.119 Pharmacologic treatments can include lithium or valproate monotherapy,119,127,128 other mood stabilizers (carbamazepine), and first- (haloperidol) or second-generation antipsychotics (olanzapine, risperidone, and others).119 Clinicians should remain mindful of the potential risks and side effects when selecting an agent for treating secondary mania, especially in the stoke population (e.g., metabolic syndrome associated with some second-generation antipsychotics may worsen neurovascular risk, drug-induced parkinsonism may exacerbate gait difficulties in patients with post-stroke paresis).
Post-stroke psychosis is a relatively rare phenomenon, defined by the presence of hallucinations and/or delusions after stroke. In the post-acute phase (0–6 months), a meta-analysis of 2234 post-stroke patients estimated the 12-year incidence of psychosis at 6.7%, with 4.67% of patients experiencing delusions and 5.05% of patients experiencing hallucinations.129 In a comprehensive, retrospective study of 1129 stroke patients in Western Australia, 6.7% developed a psychotic disorder over the 12-year follow-up period, with mean onset at 6 months following stroke.130 In the acute setting, psychosis may be over-diagnosed due to similarities in clinical presentation to delirium, a reversible syndrome presenting with acute confusion and cognitive impairment caused by altered brain function.65
Reported risk factors for post-stroke psychosis include previous psychiatric history, with depression and alcohol use disorder most commonly reported in the literature.129,131–133 Imaging studies comparing patients who developed post-stroke psychosis to lesion-matched controls suggest that preexisting subcortical atrophy and right-hemisphere lesion location may also confer increased risk.134
Studies looking at the neuropathological basis of delusions suggest that disrupted functional connectivity of the right frontal cortex impairs belief evaluation, prediction error signaling, internal monitoring, attentional surveillance, pragmatic communication, and perceptual integration.131,135–137 A case series of 15 patients showing an association between right posterior temporoparietal lesions and development of delusional ideations within 24 hours of stroke onset138 lends support to this right-hemisphere disconnection hypothesis. A small study of eight patients with right caudate strokes and age-matched controls implicates frontal-subcortical circuits connecting the frontal lobe to the basal ganglia in the formation of content-specific delusions.132
Post-stroke psychosis most commonly presents as delusional disorder, including persecutory delusions, Othello syndrome, reduplicative paramnesia, and somatic delusions.129 Schizophrenia-like psychosis with hallucinations (auditory more common than visual) and mood disorder with psychotic features have also been described.131,134 Unlike post-stoke delirium, post-stroke psychosis is more likely to have a delayed onset similar to post-TBI psychosis, appearing several months after the cerebrovascular accident.139 A multicenter study of 145 patients in skilled nursing facilities found that psychosis was significantly higher in patients who were not successfully discharged after 1 year; optimal management of post-stroke psychosis may improve rehabilitation outcomes.140 Post-stroke psychosis has been associated with higher mortality rates at 10-year follow-up.130
Assessment and Differential Diagnosis
The delayed onset and poor prognosis of post-stroke psychosis elucidate the importance of screening, monitoring, and early intervention, including eliciting caregiver-reported symptoms during rehabilitation. The literature estimates that 14–56% of hospitalized patients over the age of 65 experience delirium.141 While post-stroke delirium most typically occurs in the acute phase and post-stroke psychosis has a delayed onset, it is important to consider delirium in the differential diagnosis because patients with history of stroke remain at high risk for developing delirium due to their brain injury.
Psychopharmacological treatment for post-stoke psychosis typically consists of antipsychotics. Typical or atypical antipsychotics may be used, with haloperidol and risperidone reported most frequently in the literature.129 The side effects of antipsychotics in the post-stroke population should be carefully considered. While atypical antipsychotics are less likely to cause extrapyramidal symptoms or tardive dyskinesia, they may confer increased risk of weight gain, diabetes mellitus, and other metabolic side effects that are independent risk factors for stroke.142,143 Antipsychotics should be avoided, if possible, in elderly patients with dementia due to increased risk of stroke and sudden death.144
A systematic review of 19 studies found that apathy was present in 36.6% of stroke survivors, with similar rates in acute (<15 days post-injury) and post-acute phases of recovery, and was associated with greater depression and cognitive impairment.145 One study of 76 stroke patients showed that apathy was present in 17 patients in the acute phase, and 7 of the acute apathetic patients remained apathetic at 1 year. In addition, 11 new cases of post-stroke apathy were detected at 1 year, suggesting that apathy should be assessed in both phases.146 Post-stroke apathy is associated with poorer functional recovery, physical health, and social participation.147–149
The literature lacks consensus on the relationship between lesion location and post-stroke apathy risk. A recent review found an association between subcortical infarcts, specifically those involving the basal ganglia, and post-stroke apathy.150 This finding is supported by the high prevalence of apathy in neurological conditions affecting the basal ganglia such as PSP, Parkinson’s disease (PD), and Huntington’s disease.151,152 Dysfunction in frontal-subcortical circuits may result in reduced motivation mediated by the anterior cingulate.150,153–155 Most large reviews have not found an association between apathy and laterality or anatomical location. One meta-analysis of 149 studies showed that lesion type may play a role, with hemorrhagic lesions presenting higher apathy risk in the acute phase and ischemic strokes presenting with increased apathy risk in the post-acute phase.156
Clinical Presentation and Diagnosis
Post-stroke apathy is marked by low motivation and presents with decreased motor, verbal, and behavioral output, often accompanied by lack of interest in activities and hobbies. While patients with PSD express low mood and sadness regarding decreased activity, patients with isolated symptoms of apathy often deny low mood and may present with emotional indifference.157 Despite these differences, it is important to remember that besides being an independent entity, apathy can also be one of the symptoms of depression. In addition, apathetic and depressive syndromes can coexist. Though post-stroke apathy is a clinical diagnosis, validated scales may be helpful in establishing this diagnosis and differentiating the presentation from depression. For example, the Apathy Evaluation Scale is commonly used in research and validated in elderly populations and patients with neurological injury.158–161
Psychopharmacological treatment of post-stroke apathy may include dopaminergic agents, including amantadine, methylphenidate-levodopa, and rotigotine, as well as stimulants to increase motivation and activation. A review of 227 patients in trials of dopamine agonists has shown promise in reducing symptoms of apathy following stroke.162 There is some evidence for the use of stimulants for apathy, including methylphenidate and modafinil.163,164 However, cardiovascular side effects, including heart rate and blood pressure elevation, should be carefully monitored in a post-stroke population with underlying cardiovascular risk factors.165 Cholinergic agents such as donepezil may also be used to increase activation.166 In a double-blind, randomized, controlled trial of 70 patients with post-stroke apathy, the nootropic nefiracetam (targeting choline, monoamine, and GABA pathways) showed that 900 mg/day significantly reduced apathy scores compared to a lower dose or placebo.167 In the setting of comorbid depression, antidepressants with dopaminergic or noradrenergic activity may be particularly useful, including bupropion157 or SNRIs such as levomilnacepram, milnacipram, duloxetine, and venlafaxine. A study of problem-solving therapy versus escitalopram (5–10 mg/day depending on age) found that both interventions were more effective in preventing apathy 1-year post-stroke than placebo.168
POST-STROKE EMOTIONAL APROSODIA
Post-stroke emotional aprosodia presents with deficits in the expression or comprehension of the emotional and social components of language—the changes in pitch, loudness, rate, or rhythm that convey a speaker’s emotional intent (linguistic prosody).169 Receptive (or sensory) aprosodia is characterized by difficulty interpreting other’s emotions and decreased empathy, while expressive (or motor) aprosodia is characterized by difficulty inserting emotion into speech through prosody.170,171 Patients may present a combination of both expressive and receptive aprosodia. Estimates of prevalence in the literature vary, ranging from 30% to 49% in the acute setting with relatively few well-characterized cohorts.172,173
While expression and interpretation of emotion are governed by a bilaterally distributed network, right prefrontal and temporal regions play a particularly important role in production and perception of emotion through prosody, based on ERP, fMRI, and lesion studies.172,174,175 Affective aprosodia is most commonly associated with lesions in the right hemisphere, and most typically occurs in right cortical versus subcortical lesions.176–178 Emotional aprosodia following acute cerebrovascular injury is a strong indicator of right-hemisphere dysfunction—in a study of 28 hospitalized patients and age-matched controls, impairment in receptive prosody outperformed unilateral spatial neglect as a reliable measure of right-hemisphere injury.179 Lesions in the right posterior-inferior frontal region are typically associated with motor aprosodia, while lesions in the right posterior-superior temporal region are typically associated with sensory aprosodia.172,177,180 Patients with impaired expressive and receptive prosody are more likely to have lesions in the right anterior temporal pole, suggesting that this region may play a role in a presumed common component underlying both motor and sensory aspects of prosody.177
Motor aprosodia may present with flattened speech and affect, often co-occurring with difficulty expressing or interpreting facial expressions, while sensory aprosodia manifests as a lack of empathy or appropriate emotional response to others.171,181 There may be significant variation in deficits, with some patients experiencing motor aprosodia with no sensory aprosodia, or vice versa.171 Formal bedside testing with the Aprosodia Battery may be helpful in distinguishing flat affect due to impaired prosody from depressive or dysarthric symptoms.171,182 The Aprosodia Battery tests spontaneous production, repetition, and comprehension of affective prosody and has been validated in a number of neurologic conditions.176
Early identification and treatment of emotional aprosodia have important implications for rehabilitation. Prosody impairments may significantly affect quality of life in post-stroke patients, including decreased psychological well-being, difficulties in interpersonal relationships, increased burden of care, and marital dissatisfaction.169,183,184 In a survey of 28 caregivers, the most commonly reported sequela of right-hemisphere stroke was loss of emotional empathy.185 A study of 49 post-stroke patients showed that affective motor aprosodia was strongly predictive of subsequent PSD 3 months post-injury.186 Emotional aprosodia may be especially difficult to identify and treat because right-hemisphere lesions are often associated with anosognosia, in which patients fail to identify or acknowledge impairment, and/or executive/attentional deficits that may impair performance on formal testing.169,171
Treatment approaches for emotional aprosodia typically consist of speech therapy and cognitive rehabilitation services.187 A limited body of literature supports the hypothesis that prosody can be improved with behavioral treatment in patients with impaired communication.171,188,189 Cognitive-linguistic and motor-imitative therapies have shown promise in small studies, with one small study reporting that 12 of 14 subjects with acquired brain injury responded to one or both treatments.190
CASE VIGNETTE 22.1
Ms. M was a 56-year-old right-handed woman who presented to the ED with new-onset left facial weakness and numbness, and drooling. On exam, she was found to have left facial weakness sparing the forehead and left V2-V3 sensory loss. Her brain MRI showed small scattered foci of acute infarction in the right insula and right frontal lobe (MCA territory). MR angiogram showed mild atherosclerotic changes of the origin of the right ICA and left ECA without significant stenosis.
Transthoracic echocardiogram showed LVEF of 60% with diastolic dysfunction. There were no regional wall motion abnormalities. Agitated saline bubble study showed no evidence of right-to-left shunting. Left and right atrial sizes were normal. EKGs showed sinus rhythm. After discharge she had a 30-day cardiac monitor study which showed no significant arrhythmia.
Lipid profile showed markedly elevated LDL and triglycerides. HbA1C was 5.8. ESR was normal.
She had a history of obesity, HTN, hyperlipidemia, and a psychiatric history of generalized anxiety disorder (GAD) and major depressive disorder (MDD), recurrent, moderate, both in full remission by the time of the stroke. She did not smoke and had no history of alcohol or drug abuse. Her medications were HCTZ, venlafaxine XR 150 mg QAM, clonazepam 1 mg QHS.
Her father had type II DM and HTN. Her brother died at 56 of an MI and stroke; he was a smoker with DM, HTN, and hyperlipidemia. She was married and had two children.
She worked as a bank teller for 30 years and retired a short time before her stroke.
She was started on aspirin 325 mg daily, atorvastatin 80 mg daily before discharge from the hospital. On follow-up exam 2 weeks post-stroke, there was very subtle residual weakness of the left lower face, with a tendency to drool from the left side of the mouth. The rest of the exam was normal. The summary assessment was that she had a small ischemic stroke in the right MCA territory. The mechanism was likely embolic, and no cardiac source was found. She had multiple vascular risk factors and mild carotid atherosclerosis. Her stroke was likely due to artery-to-artery embolism from her carotid disease. The recommendations from neurology included secondary stroke prevention with low-dose aspirin and optimal control of her multiple risk factors (HTN, hyperlipidemia, and obesity), including a high-intensity statin agent, a low-calorie and low-fat diet, and regular aerobic exercise. She was encouraged to see her psychiatrist for exacerbation of her anxiety and mood difficulties.
At a visit with her psychiatrist 1-month post-stroke, she presented with fears about her health and about stroke recurrence. She had a feeling of impending doom. She was sleeping well at night but felt anxious throughout the day. She denied depression. She had reduced her psychiatric medications on her own because of fear of taking medications that could sedate her—she was afraid of dying during her sleep. She was now taking Clonazepam 0.5 mg QHS, and had fully stopped her venlafaxine. On mental status exam, her mood and affect were anxious. She also appeared as mildly disinhibited and labile—she was more talkative than at her baseline, and teared up easily. Her MMSE was 30/30; she drew an accurate clock and line bisection was within normal limits. She was attentive through the visit, provided a good history of recent events, and her receptive and expressive language appeared within normal limits.
The impression was that her anxiety and affect changes were likely of multifactorial origin, with contributions from her baseline psychiatric illness, psychological adjustment difficulties to stroke, discontinuation syndrome from her stopping venlafaxine, and effects of the stroke on mood and affect regulation.
Eight months after her initial presentation, she had a second stroke. Her left-sided weakness worsened and included weakness of her left arm. Brain MRI showed an acute ischemic stroke in the right basal ganglia, and MR angiogram showed no flow in the right superior division of the MCA. There was a large flow defect consistent with a large atheroma in the right carotid bulb. This did not cause significant ICA stenosis. Evaluation included telemetry showing no significant arrhythmia, transthoracic echocardiogram showing no significant lesion, no embolic source, LVEF 60%, normal RA and LA sizes, lipid profile with total cholesterol 247, triglycerides 135, HDL 57, LDL elevated to 162. An EEG which showed no epileptiform features.
She acknowledged that she was not taking her medications regularly, including the atorvastatin, before this most recent stroke. She was restarted on aspirin, atorvastatin, and venlafaxine XR 37.5 mg/day before discharge.
A 30-day cardiac rhythm monitoring study post-discharge showed no significant arrhythmia.
On neurological exam 1 month after her second stroke, she presented subtle residual weakness of the left lower face, with a trace of drooping of the left corner of the mouth. There was very mild weakness of the left arm, seen as orbiting on examination. The rest of the exam was normal. She was assessed as having a second ischemic stroke in the right MCA territory, likely embolic, due to artery-to-artery embolism.
On psychiatric examination, also 1 month after her second stroke, she again reported concerns about her health, but appeared much less anxious than previously. However, she cried very intensely during the appointment and was described by her daughter as being “very sensitive about nothing.” Her daughter provided numerous examples of emotionally neutral situations (such as watching TV or having a trivial conversation) where Ms. M had crying spells that she could not explain. These crying outbursts were taking place at least once a day, most days of the week. She denied depression. She had normal levels of energy, activity, appetite, and sleep. She was enthusiastic about her participation in physical rehabilitation and was proud about her recovery. She was assessed—in addition to her baseline GAD and MDD—to present with a syndrome of pathological laughter and crying (PLC), in this case without the laughter component. Her venlafaxine XR was increased to 75 mg/day, and at follow-up 1 month later her crying spells were much diminished.
POST-STROKE PATHOLOGICAL LAUGHING AND CRYING
Pathological laughing and crying (PLC) is a syndrome characterized by frequent, brief, and intense bouts of uncontrollable crying and/or laughing, due to a neurological disorder.191 In addition to post-stroke, PLC may be commonly associated with several other neurological conditions: Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, PD, and traumatic brain injury. Other names used for this syndrome include pseudobulbar affect, emotional lability, and emotional incontinence.
The prevalence of post-stroke PLC is estimated to be about 11%. This value may vary widely across studies due to the different groups evaluated (e.g., clinic-based or population-based), the definition of PLC considered, and the sensitivity/specificity of the instruments used for identifying this syndrome.191,192
PLC may result from lesions that disrupt the neurocircuitry involved in emotional regulation and expression.192 Lesions of heterogeneous localization may precipitate PLC (frontal and parietal lobes, descending pathways to the brain stem, subcortical tracts involving the cerebellum),193,194 in line with a model of an extended emotion and affect regulation neural network that can be affected at different points. A traditional view posits that the cerebral cortex is crucial for the appraisal of the contextual information of an emotional stimulus, and the modulation of the intensity, frequency, and duration of the emotional response. This top-down model proposes that emotional modulation is facilitated by cortico-bulbar pathways, and that PLC may occur due to lesions in cortex, or in these descending tracts.
A more specific description of this model proposes a volitional system, involving frontoparietal (primary motor, premotor, supplementary motor, posterior insular, dorsal ACG, primary sensory, and related parietal) corticopontine projections, and an emotional pathway, involving projections from orbitofrontal cortex, ventral ACG, anterior insular, inferior temporal, and parahippocampal areas, that regulate the amygdala. The amygdala and hypothalamus, in turn, activate the periaqueductal gray (PAG)-dorsal tegmentum (dTg) complex, which activates the displays of laughing and crying. The volitional system inhibits the emotional pathway at multiple levels. Lesions of the volitional corticopontine projections (or of their feedback or processing circuits) can produce PLC.195
An alternative model considers that the cerebellum plays a significant role in modulating emotional expression, and thus lesions that impact the cerebro-ponto-cerebellar pathways responsible for adjusting the automatic execution of laughter or crying can provoke PLC.193
Monoaminergic neurotransmitter systems and specific receptors that may be implicated in PLC include glutamatergic NMDA, muscarinic M1-3, GABA-A, dopamine D2, norepinephrine alpha-1,2, serotonin 5HT1a, 5HT1b/d, and sigma-1 receptors. This explains the efficacy of diverse pharmacological agents active in these systems in patients with PLC.191,195,196
The individual with PLC presents uncontrollable episodes of crying and/or laughing that are mood-incongruent, thus not related to feelings of sadness or joy. In some individuals, there may be an underlying emotional state present (e.g., sad mood), but the affect displayed is clearly excessive with respect to the mood. Similarly, the intense affective display is incongruent with the context surrounding the individual, or a clearly exaggerated response. For instance, a sad commercial may trigger profuse, disproportionate tearfulness. PLC may present as comorbid with other neuropsychiatric disorders, including mood and cognitive disorders.197
Assessment and Differential Diagnosis
Obtaining a very detailed history may be sufficient to assess the presence of this syndrome. On the other hand, because of its overlap with other psychiatric disorders, the use of specific rating scales may be helpful with screening and diagnosis. The Center for Neurologic Study—Lability Scale (CNS-LS, range 7–35) is a self-report measure initially developed to assess affective lability in individuals with ALS,198 later validated for other disorders. It includes an auxiliary subscale for episodes of anger/frustration. The presence of a mood disorder such as major depression may result in a confoundedly high score, potentially producing a false positive for PLC.197 Similarly, a proposed cutoff score of 13 is highly sensitive but not specific. A more conservative cutoff score of 21 appears to be more accurate.192 The Pathological Laughter and Crying Scale (PLACS, range 0–54) is a clinician-administered instrument that measures the severity of PLC symptoms. It was developed for PLC in stroke patients.199 A proposed cutoff of >13 renders a similar PLC prevalence as the CNS-LS cutoff of >21.192
In terms of differential diagnoses, it is important to assess the presence of PLC or a mood disorder such as depression or bipolar disorder and its spectrum. In these mood disorders, mood and affect are congruent. However, PLC may coexist with any of these mood disorders—in this clinical situation it is advised to treat the mood disorder first, as many times this also results in resolution of the PLC manifestations. In rare cases where the bouts of laugher or crying are very stereotyped and present with alteration of consciousness, they may represent seizure activity (gelastic or dacrystic, respectively). Regular EEG, and in some cases video-monitoring EEG, may be indicated.191
PLC should be treated when this syndrome is bothersome to the individual or results in social or occupational dysfunction.191 Multiple pharmacological agents have been shown to be effective.191,200 Tricyclic antidepressants (nortriptyline, amitriptyline, imipramine) have demonstrated to be effective for PLC200 and nortriptyline showed efficacy specifically for post-stroke PLC in a double-blind trial.199
Among the SSRIs, fluoxetine, sertraline, and citalopram showed efficacy for post-stroke PLC in double-blind trials.200 Importantly, SSRIs tend to be used at low therapeutic doses, and the therapeutic response may be evident within the first few weeks, typically sooner than in depression. The combination dextromethorphan/quinidine has proven useful for treatment of PLC in stroke.201 Quinidine prolongs the QT interval, although at the dose used in the dextromethorphan/quinidine combination the risk is considered minor.
Lamotrigine showed effectiveness for post-stroke PLC in a case report.202 Agents that have demonstrated effectiveness in addressing PLC in other neurological illnesses, as indicated in case reports include venlafaxine, duloxetine, reboxetine, mirtazapine,191,203 and valproic acid.204 They should be reserved for cases in which more established agents fail, or added therapeutic benefits (dual action on mood and pain; mood stabilizing properties) are important. Levodopa and amantadine also showed some benefit for post-stroke PLC205 but given the limited evidence for their efficacy, these agents should be considered only when other options have failed.
Vascular depression is an evolving concept that arose from the observation of the correlation between depression and subcortical microvascular disease. This condition has become more widely appreciated in the age of increasingly available MRI. Although cases of depressed elderly patients with atherosclerosis have long been described, “vascular depression” was first hypothesized as a distinct syndrome when Alexopoulos et al.206 described an association of late-life depression with impaired executive function and white matter hyperintensities on T2-weighted MRI. This suggested areas for further investigation, including involvement of frontal-subcortical circuits in idiopathic depression, and also evolved into a recognizable subtype of depression. However, there is not yet a consensus for criteria defining vascular depression, and it is not included in the DSM-5, which complicates attempts to investigate the syndrome. Some investigators prefer the term “subcortical ischemic depression,” and others refer to “depression executive dysfunction,” which describes the syndrome symptomatically, while allowing for other causes. Despite terminology differences, most investigators agree that the triad of depression onset after sixth decade, white matter hyperintensities found on MRI, and executive dysfunction comprise the core features of vascular depression. Additional features may include lack of personal or family history, persistent symptoms without discrete episodes, and lack of insight of patients into their affective symptoms.207
Estimating the prevalence of vascular depression is complicated by the general under-recognition of late-life depression and the requirement of imaging and cognitive assessment for diagnosis. In a large cross-sectional study of 16,423 older adults, vascular depression prevalence was estimated at 3.4% of Americans aged 50 and older, approximately 2.64 million people.208 Vascular depression was defined in terms of meeting DSM-4 criteria for major depression within the last year, in a person with cardiovascular or cerebrovascular disease or risk factors. However, the criteria in this study do not include imaging findings or measures of cognitive impairment, and included patients with PSD, which is a separate diagnostic entity. These factors may have led to an overestimate of prevalence. A smaller study of 783 older adults in Korea that used an imaging-based definition of vascular depression estimated the prevalence at 2.4%.209
Studies on the mechanism of vascular depression have centered on the MRI white matter hyperintensities which represent microvascular disease. The amount of white matter hyperintensities correlates with age, regardless of the presence of depression. There is a correlation between the white matter disease burden in the frontal lobes and the incidence of depression. Periventricular hyperintensities appear equally prevalent in depressed and nondepressed subjects. Deep white matter hyperintensities, however, have consistently been found to be more prevalent in depressed subjects, and in those with late-onset depression in particular.210 These deep white matter lesions are thought to be disruptive to frontal-subcortical-limbic networks crucial to mood regulation, and may also disrupt temporal lobe function to a lesser extent.211
The correlation of executive dysfunction with white matter disease and depression suggests disruption of dorsolateral-prefrontal-striatal circuits. Post-mortem tissue analysis demonstrates that subcortical ischemia disproportionately affects the dorsolateral prefrontal cortex in patients with late-life depression,212 and that white matter hyperintensities in vascular depression are ischemic, rather than inflammatory.213
Vascular depression differs from other forms of depression in several ways, although there is significant overlap.214 Emerging criteria for vascular depression include low energy, reduced insight, anhedonia, deficits in initiation, and slowed processing speed.211 Executive dysfunction, commonly seen in dysfunction of the dorsolateral prefrontal cortex or its connections, is a defining characteristic of vascular depression. Vascular depression shares characteristics with frontal lobe syndromes, particularly those arising from dysfunction of medial or dorsolateral prefrontal cortices. On neuropsychological testing, patients with vascular depression may demonstrate difficulty with task completion, decision making, processing speed, concentration, and attention.207 These cognitive deficits are often paired with irritability and social withdrawal, although cognitive symptoms may be more pronounced and troubling to the patient than mood symptoms.207 Anhedonia as a major symptom is more common in vascular depression than subjectively depressed or low mood. Family history of mood disorder is less common in vascular depression than in idiopathic depression.
Course and Natural History
The clinical course of vascular depression is similar to that of refractory major depression in that it generally becomes a chronic condition and tends not to respond to antidepressant treatment. Progression of white matter disease is a risk factor for the onset of vascular depression,215 but it is not known whether progression of subcortical vascular disease in an individual patient correlates with worsened depression. Patients with diagnosed vascular depression are at increased risk for dementia, as microvascular disease causes subcortical vascular depression and also exacerbates dementia from other etiologies, such as Alzheimer’s disease. A meta-analysis of 23 studies found that late-life depression, including vascular depression, increased the risk of Alzheimer’s disease dementia and vascular dementia.216 An MRI-based study of 161 older depressed subjects showed that both white matter hyperintensity volume and subcortical gray matter hyperintensity volume were associated with incident dementia.217 Vascular depression tends to decrease ability to manage medical comorbidities, and is associated with increased impairments in daily functioning, frailty, and shortened life span.218,219 Even if mood symptoms do not meet DSM criteria for major depression, subthreshold depressive disorders are associated with increased mortality, and decreased functional status and quality of life.220
Assessment and Differential Diagnosis
The presence of executive dysfunction in vascular depression may lead to some confusion over whether a given patient’s symptoms represent depression or dementia. The syndrome of “reversible dementia of depression,” also known as “pseudodementia,” has long been described, with deficits not only of memory but also of executive function. Concern over this syndrome has been that clinicians often overlook depressive symptoms in the presence of cognitive impairment in elderly patients. Awareness of the entity of vascular depression, however, introduces a third consideration in addition to the possible diagnoses of idiopathic depression and dementia due to neurodegenerative process. Vascular depression comprises symptoms of both depression and executive dysfunction and shares features with depression and dementia of other etiologies. Diagnosis of vascular depression, however, implies the presence of microvascular disease, demonstrated by subcortical white matter hyperintensities on T2-weighted MRI. Brain imaging in this setting may help distinguish among idiopathic depression and vascular depression in elderly patients or patients with significant vascular risk factors. Given the high prevalence of white matter hyperintensities in older patients, MRI findings may be read as normal or unremarkable for age. However, in the context of clinical depressive and cognitive symptoms, the presence of imaging-defined cerebrovascular disease, indicated by deep white matter and periventricular hyperintensities as well as subcortical gray matter lesions, may be an important diagnostic clue.207
The syndrome of apathy can also present a diagnostic challenge. Apathy and executive dysfunction may present as features of vascular depression, but also can signify the emergence of a neurodegenerative disorder or the sequelae of a stroke or other structural lesion. Differentiation of apathy from depression has been previously covered in the discussion of PSD, and similar considerations apply with vascular depression.
Given its likely distinct psychopathology, it seems intuitive that the treatment profile of vascular depression would differ at least partially from idiopathic depression. Several studies have demonstrated variable response to SSRIs in these patients. Response to these medications seems to correlate with the degree of neuropsychological impairment and inversely correlate with the progression of white matter hyperintensities.215 In a nonrandomized trial, 33% of patients achieved remission over 12 weeks with SSRI treatment. The likelihood of remission, assessed by MADRS score, diminished with increasing deficits in overall executive function, language processing, episodic memory, and processing speed.221 In general, vascular depression confers an increased risk of nonresponse to treatment with antidepressant medications, with a low expected remission rate of 33%.221 A placebo-controlled trial of sertraline in elderly patients with depression (but not specifically with vascular depression) found that sertraline performed worse than placebo in patients with impaired executive function, as measured by response inhibition.222 This suggests that elderly patients with executive dysfunction and depression, including those with vascular depression, may be subject to the side effects of antidepressants but not their therapeutic effects on mood symptoms. Emerging research suggests that SSRIs may improve neural plasticity223,224 and decrease amyloid-beta production225—however, especially in the absence of measurable affective benefits, the clinical value of this information remains uncertain.
Brain Stimulation Therapies
A study comparing rTMS of the left dorsolateral prefrontal cortex to sham rTMS for patients with vascular depression found a response rate of 39% and a remission rate of 27%,226 including in patients previously unresponsive to treatment with antidepressants. Unlike antidepressants, response to treatment did not correlate with degree of cognitive impairment or executive dysfunction. There was a decreasing response to rTMS with increasing age and also with decreased volume of frontal gray matter. There is limited evidence regarding use of electroconvulsive therapy (ECT) in vascular depression, but one small series and several case reports suggest it is effective and generally well-tolerated, although perhaps with increased risk of delirium compared to ECT in idiopathic depression.227 In elderly patients, cognitive side effects tend to be transient, regardless of underlying cognitive impairment.228 In a study of 81 elderly inpatients with major depression, investigators found a 58% remission rate for a subgroup with more than one cardiovascular risk factor, and the response to ECT was independent of cardiovascular risk.229
Given the usual age of onset of vascular depression, psychotherapy with these patients shares characteristics with psychotherapy with other ill, elderly patients. CBT for insomnia may be useful in addressing sleep disturbances contributing to cognitive deficits. Executive dysfunction may be targeted through problem-solving therapy or problem-adaptation therapy, and cognitive rehabilitation therapy may play a role in helping develop behavioral strategies to circumvent cognitive deficits.207 An important role of psychotherapy with this population is to support the work patients need to do in sustaining positive health behaviors, to help decrease their vascular risk factors. Managing sleep, exercise, diet, medication adherence, hypercholesterolemia, hypertension, and other metabolic disorders is an important component of therapy for vascular depression. Several aspects of psychotherapy in the context of cognitive impairment, including supportive therapy and behavioral activation, apply to this population as well; importantly, the inclusion of caregivers in the plan of care may augment treatment results. See Chapter 10 for further discussion about the adaptation of psychosocial approaches when treating individuals with cognitive impairment.
SUMMARY AND KEY POINTS
In addition to significant physical disability, stroke can also have neuropsychiatric sequelae, which can be an independent cause of disability and exacerbate the residual physical symptoms of a stroke.
In general, neuropsychiatric disorders after stroke lead to poorer functional outcomes in rehabilitation. Their treatment may include medication, psychosocial interventions, and brain stimulation with rTMS or ECT.
Pharmacological treatment generally follows the guidelines of the treatment of primary psychiatric disorders, with additional considerations for increased adverse effects due to age, poor balance/fall-risk, cognition (anticholinergic effects), and cardiovascular risk factors in stroke patients.
Depression can emerge after an infarct to many different neuroanatomic locations (especially left frontal lobe), with up to one-third of post-stroke patients experiencing PSD. Patients with personal and family histories of depression are at higher risk. TCAs and SSRIs have demonstrated efficacy, and ECT has been successfully used in severe and refractory depression.
The prevalence of anxiety after stroke has been reported from 3% to 30%, commonly presenting as GAD or phobic disorders, with substantial overlap between anxiety and PSD. Risk factors include young age, premorbid psychiatric history, and substance dependence.
Apathy is reported in 36.6% of stroke survivors and is often associated with subcortical infarcts, especially in the basal ganglia. Apathy may be a symptom of PSD or a distinct clinical diagnosis in the absence of low mood.
Mania and psychosis are rare but debilitating and may lead to underreporting of cognitive and functional limitations. Stroke locations reported in association with mania have included a right ventral limbic circuit, including the right orbitofrontal and basotemporal cortices, caudate, and thalamus.
The estimated prevalence of emotional aprosodia ranges from 30% to 49%. It may present with expressive or receptive deficits in emotional expression through language. Treatment typically consists of speech and cognitive rehabilitation therapy.
Pathological laughing and crying is prevalent in approximately 11% of stroke patients and is associated with disruption of circuits mediating emotional and affect regulation.
Vascular depression often presents with cognitive symptoms characteristic of subcortical dementia and is associated with subcortical microvascular disease. Response to antidepressants appears to be poor in vascular depression; prevention of cerebral microvascular disease through managing CVD risk factors may offer protection.
MULTIPLE CHOICE QUESTIONS
Which of the following is incorrect regarding PSD and vascular depression?
Vascular depression is associated with white matter hyperintensities on MRI.
Vascular depression presents with cognitive deficits including executive dysfunction and slowed processing speed, while the presentation of cognitive deficits in PSD is variable.
Vascular depression is generally more responsive to SSRIs than PSD.
Age is a risk factor for vascular depression, but not clearly so for PSD.
Family history of psychiatric disorders is less common in vascular depression than PSD.
Which of the following pharmacological agents—side effects matches is correct, and an important consideration when treating patients with cerebrovascular injury?
Atypical antipsychotics—weight loss
SNRIs—increased blood pressure
Which of the following statements about post-stroke anxiety is false?
Rates of post-stroke anxiety are high in the weeks following stroke, and a large proportion of patients continue to report symptoms of anxiety 6 months later.
Nortriptyline has the strongest evidence base, among the tricyclic antidepressants, for the treatment of post-stroke anxiety.
Cognitive limitations after a cerebrovascular injury can interfere with the timely diagnosis of anxiety.
Benzodiazepines are the first line of treatment for post-stroke anxiety.
Post-stoke anxiety is likely to present with symptoms of GAD and/or phobic disorders.
Which of the following is not associated with increased risk of post-stroke depression?
Infarcts in the right frontal lobe or basal ganglia
Lack of family and social support
Severity of functional impairment and physical disability
History of premorbid depression
MULTIPLE CHOICE ANSWERS
While SSRIs have been effective in treating post-stroke mood symptoms and enhancing motor recovery, their efficacy is limited in vascular depression. SSRIs are more effective in vascular depression patients with less white matter burden and executive dysfunction. PSD primarily onsets in later life because the risk of stroke is higher; however, age is not a known independent risk factor for the development of depression given a cerebrovascular injury.
The risk of post-stroke depression is increased in the presence of post-stroke anxiety, physical/functional limitations, or lack of social support structures. History of premorbid depression also increases risk. While depression can emerge after an infarct in any location, evidence suggests that post-stroke depression is more likely to be associated with lesions in the left frontal lobe or basal ganglia.
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