This monograph summarizes the proceedings of a roundtable meeting convened to discuss pseudobulbar affect (PBA). Two didactic lectures were presented, followed by a moderated discussion among 11 participants. Post-meeting manuscript development synthesized didactic- and discussion-based content and incorporated additional material from the neuroscience literature. A conceptual framework with which to distinguish between disorders of mood and affect is presented first, and disorders of affect regulation are then reviewed briefly. A detailed description of the most common of these disorders, PBA, is the focus of the remainder of the monograph. The prevalence, putative neuranatomic and neurochemical bases of PBA are reviewed, and current and emerging methods of evaluation and treatment of persons with PBA are discussed. The material presented in this monograph will help clinicians better recognize, diagnose, and treat PBA, and will form a foundation for understanding and interpreting future studies of this condition.
When the ability to regulate emotion is compromised by disease or injury, the impact is substantial for patients, their families, and society.1-3 Most clinicians are familiar with the division of emotion into two major categories, mood and affect, with the former denoting a subjective emotional state and the latter denoting the observable expression of emotion. When an individual’s mood and affect are congruent, as is commonly the case among persons with prototypical major depressive disorder (MDD) episodes, these terms describe that individual’s emotional state reasonably well: he or she reports feeling persistently and excessively sad, downhearted, or “blue” (depressed mood) and his or her appearance is consistent with that subjective report (sad affect). Similarly clear are the presentation by patients with brief, functionally disabling, episodic dysregulation of emotion characterized by paroxysms of crying or laughing in the absence of a congruent subjective emotional state—either during and/or between such paroxysms. In such cases, the excess of expressed emotion (affect) independent of a congruent subjective emotion (mood) is understood as a dysregulation of affect alone, and the patient is not regarded as suffering from a mood disorder.
Exceptions to these typical presentations are common. For example, it is common for older persons in the midst of a depressive episode to deny feeling persistently and excessively sad, but nonetheless appear so to clinicians and family members. If the patient experiences additional symptoms consistent with depression, particularly appetitive, sleep, energy, and psychomotor symptoms, many clinicians are inclined to regard the patient as suffering from a mood disorder (an MDD episode, specifically) even in the absence of his or her subjective report of persistent sadness (ie, even in the absence of depressed mood in the common use of the term mood). Conversely, some persons with depressive episodes report a persistent state of sadness while appearing either “flat” (without clear expressed emotions), or sometimes more cheerful than would be expected based on their subjectively reported mood. When additional symptoms of a mood disorder are present, most clinicians regard the subjective report of such patients as the anchor for the diagnosis of a MDD episode, and often disregard such patients’ mood-incongruent affect as an interesting clinical feature but one of unclear diagnostic value.
Similarly perplexing are the presentations of patients with brief, functionally disabling paroxysms of emotional dysregulation in the absence of a sustained change in baseline emotion. In these episodes, both the subjective and objective components of emotion are involved (ie, crying and feeling sad, laughing and feeling mirth), but between episodes there is no pervasive or persistent disturbance of emotion. Clinicians in neurology and neuropsychiatry are familiar with such presentations among persons with a variety of conditions, including stroke, traumatic brain injury (TBI), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and the neurodegenerative dementias, among others. In these cases, clinicians using the traditional nosology of mood and affect face a difficult diagnostic challenge: if the patient states clearly that he or she feels sadness in the midst of crying episodes, is it reasonable to conclude that the patient is suffering from a mood disorder? If he or she feels sad only during but not between the emotional displays, can his or her condition be accurately regarded as a mood disorder? Is it more reasonable to conclude that the patient is experiencing a dysregulation of affect alone? If so, how do such presentations fit within the current Diagnostic and Statistical Manual of Mental Disorders (DSM)-based classification of disorders of emotional regulation?
With respect to the last of these questions, it appears that such presentations do not fit well within the DSM-based classification system. Nonetheless, the DSM-based classification of disorders of emotion may offer some initial guidance in such diagnostic formulations. In the glossary of terms provided by the DSM-III-R4 and subsequent iterations of this manual, mood is defined as a sustained emotional state (or emotional baseline), whereas affect is an emotional state of relatively short duration superimposed on the prevailing mood. An analogy is offered therein that likens mood to climate, and affect to weather. In that analogy, disorders of mood are likened to a sustained shift in the emotional climate in which the disturbance in baseline emotion (mood) is maintained over a relatively long period of time (at least several days, and generally much longer). For example, the overall climate of a region may be temperate (euthymic) but subject to relatively short-term changes in the weather. If those relatively short-term changes are within the range of expected variability given the climate (ie, normal range of affect), little notice is given to them. However, if those short-term changes are excessively intense (ie, dysregulated affect), they tend to capture the attention of either or both those living in that climate and those observing it. In less temperate climates, a sustained shift to a relatively “cold” (ie, depressed) or “hot” (ie, euthymic, irritable, or expansive) climate may occur, and the variability of weather in that climate tends to shift in a manner that is congruent with the prevailing climate. However, even in those less temperate climates, the weather may be unpredictable (ie, dysregulated affect may still occur).
Recognizing that the primary disturbances of emotion occurring during depressive, hypomanic, and/or manic episodes are ones of mood, the DSM-III-R4 and subsequent versions of this manual reclassified affective disorders as mood disorders. While the shift to mood disorders terminology provides a useful conceptual and linguistic framework within which to diagnose and study the disorders of emotion considered in the DSM-based system, that shift left unaccounted those disorders in which a disturbance of moment-to-moment emotion, or affect, is the primary feature.3,5 The lack of inclusion of disorders of affect in the DSM-based diagnostic system has had the unintended consequence of limiting the psychiatrist’s usual repertoire of diagnostic considerations to mood disorders alone. As discussed later in this monograph, there are several disorders in which the primary disturbance of emotion is one of affect rather than mood, and in those disorders the dysregulation of affect is not limited to the expression of emotion alone. Accordingly, a heuristic that affords a broader consideration of emotion and emotional disorders is needed in order to guide the assessment and study of persons with these conditions.
A Framework for Conceptualizing Disorders of Emotion
Guided by both historical and current nosological considerations, Arciniegas and Topkoff5 suggested a heuristic in which emotion is regarded as superordinate category, and mood and affect are ordinate categories. Mood and affect are defined first on the basis of duration, with mood denoting the sustained emotional baseline and affect the moment-to-moment emotional variability. Next, mood and affect are characterized by their subordinate elements: subjective (experienced) and objective (expressed). The subjective element includes visceral sensation and emotion-related cognitions that contribute to the conscious “feeling” or experience of emotion. The objective element includes emotion-related vocalizations, visceral/autonomic activity, and/or motor behaviors. Each of these subordinate elements is defined further by their variability, intensity, contextual appropriateness, and amenability to voluntary control (Figure).
The evaluation of persons with disorder of emotion is usefully guided by this conceptual framework (Table). Patients with a sustained change in emotion are best regarded as experiencing a disorder of mood, whereas patients with dysregulation of moment-to-moment affect are best regarded as experiencing a disorder of affect. Among persons with mood disorders, the experience and expression of mood may be disturbed. In typical major depressive episodes, the patient reports and is observed to be persistently and excessively sad even in contexts where that emotion appears (to the patient or others) to be unwarranted, and to have little volitional control of their emotional baseline. In the examples of less prototypical depressive episodes, such as the geriatric patient that appears depressed nearly every day for ≥2 weeks but denies feeling so, this framework captures that patient within the mood disorder category by permitting dissociation between the experienced and expressed elements of mood disturbance in that disorder.
Conversely, we propose that patients with paroxysms of crying or laughing in the context of a euthymic emotional baseline are most accurately understood as suffering from a disorder of affect. The disorders of affect are numerous, including those characterized by excesses of affect, such as pathological laughing and crying, affective lability, essential crying, witzelsucht, and also those in which a deficit of affect is the primary feature, such as the placidity of Klüver-Bucy-like syndromes. These conditions are reviewed briefly in the next section in the service of providing the background needed by clinicians to develop a broader differential diagnosis of disorders of emotion than that afforded by the DSM-based diagnostic system alone.
Common Disorders of Affect
Pathological Laughing and Crying
In his seminal paper on dysregulation of affect, Wilson6 presented a series of clinicopathological case examples of pathological laughing and crying (PLC). In these cases, patients presented with paroxysms of crying or laughing in the setting of neurological disorders that interrupted corticobulbar pathways. Wilson believed that interruption of these pathways disrupted volitional control of a brainstem “faciorespiratory center” involved in emotional displays (discussed in more detail in the Neuroanatomy section of this monograph). Poeck3,7 subsequently offered criteria for such pathological displays of laughing or crying, according to which a PLC episode is an affective display that occurs without voluntary control or modulation and is not meaningfully related to the stimulus that provokes it. The PLC patient cries without feeling sad and laughs without feeling mirth or amusement. This dissociation between the expression and experience of affect is the essential feature of the emotional disturbance in PLC. Poeck’s criteria also suggest that the affective display is stereotyped from one presentation to the next, regardless of the stimulus that incites it. Additionally, these expressions do not influence the patient’s subjective emotional state. When the episode is over, it is over completely, with respect to both the primary affective display and also any concomitant cognitive, behavioral, and physical components. In fact, patients with PLC are frequently euthymic with respect to mood between these episodic displays of affect, although such displays may also occur among patients with mood disorders due to their underlying neurological condition as well.
Consistent with Wilson’s early description of this condition, PLC is recognized as a relatively common consequence of a host of neurologic conditions, including stroke, ALS, Parkinson’s disease with right-sided hemiparkinsonism, MS, frontotemporal dementia (FTD), TBI, Alzheimer’s disease (AD), epilepsy, normal pressure hydrocephalus, progressive supranuclear palsy, Wilson’s disease (hepatolenticular degeneration), and neurosyphilis, among others.1,5,8
Although PLC is not itself a life-threatening consequence of neurological disorders, it is a source of substantial morbidity and suffering for persons with this condition and their families. These displays may be so frequent as to impair the patient’s ability to participate effectively in rehabilitative therapies for the other consequences of his or her underlying neurological condition, may interfere with feeding or other basic care needs, and may be a source of considerable embarrassment and social disability for both patients and their families.3,5,7,8 The early development of PLC after stroke, particularly among younger and more severely disabled stroke survivors, may predict subsequent development of post-stroke depression.9 Accordingly, clinicians should be aware of PLC as a disorder of affect with significant personal, functional, and prognostic implications, and as a condition requiring therapeutic intervention.
Although similar in many respects to PLC, affective lability denotes paroxysms of dysregulated experience and expression of affect.5,10,11 Although these episodes are somewhat more variable, less discretely paroxysmal, and may be more understandably related to the stimulus that incites them, they are excessively intense and not fully amenable to voluntary control. As with PLC, patients with affective lability are often euthymic with respect to mood between their episodes, although the frequency and intensity of these episodes may increase in the context of a mood disorder. Similarly, affective lability does not produce changes in cognition, behavior, or physical function sustained beyond the episode of dysregulated affect itself.
Affective lability occurs most commonly in the setting of the same neurological conditions that produce PLC, and particularly in the context of relatively milder severities of those conditions, and carries a similar set of functional consequences as those entailed by PLC.5,9-11 Accordingly, it may be useful to regard affective lability as a disorder of affect that exists at a point on a continuum between normal affective variability and the more severe end of the continuum characterized by PLC.
The terminology used to describe PLC and affective lability is used inconsistently in the scientific literature, with these and related terms at times used in the manner above (denoting distinct conditions), and at other times as synonyms for a disturbance in which dysregulated affect is the primary clinical feature.12 In some reports, the distinction between mood and affect is abandoned altogether in favor of terms that connote a disturbance in emotion more generally, such as emotional lability, emotional incontinence, emotional dyscontrol, and excessive emotionalism.1,12 Feinstein and colleagues12 liken the language used to describe these conditions to a “semantic minefield” in which any attempt to describe these conditions almost inevitably involves a misstep that engenders conflict and criticism. It is likely that in clinical practice the distinction between PLC and affective lability is relatively more subtle than the definitions provided above would suggest, particularly as it regards the nature of the subjective experience of affect that occurs during an abnormal affective display. However, less arguable is the distinction between mood and affect during these episodes: in both PLC and affective lability, the primary dysregulation of emotion occurs on a moment-to-moment basis, and neither requires nor produces a disturbance of the subject’s emotional baseline. Accordingly, any term used to denote these conditions should capture the primary disturbance of the condition, namely dysregulation of affect occurring independent of dysregulation of mood.
Among the available terms, the relatively older term pseudobulbar affect (PBA) is reemerging as a preferred term for the clinical diagnosis of the two major disorders of affect, PLC and affective lability. Although adoption of the term PBA is unlikely to end the semantic debate entailed by the use of any such term, its present appeal stems from its reasonably high recognition among most clinicians in the neurosciences, its greater acceptability to patients and their families given the lack of the qualifier “pathological” in the description of the clinical syndrome, and its ability to capture both PLC and affective lability under a single diagnostic term. While recognizing the potential disadvantages of this term (and especially its relatively close association with another historical term denoting a separate problem, pseudobulbar palsy), we will in this monograph use PBA to denote functionally disabling episodes of involuntary crying and/or laughing that are excessively intense, lacking contextual appropriateness, and that occur independent of the prevailing mood.
Uncommon Disorders of Affect
Green, McAllister, and Bernat13 coined the term essential crying in their report describing 46 medically and surgically hospitalized persons referred for evaluation of depression due to episodes of crying noted by the referring physician. Among these subjects, their evaluations identified a psychiatric disorder (most often MDD) in 20%, a primary neurological disorder in 33%, both psychiatric and neurological disorders in 43%, and the previously undescribed entity, essential crying, in 4%. This latter group of patients had experienced a lifelong propensity of crying easily that appeared to have a familial tendency toward excessive emotionality. Unlike PBA, the disturbance of affect regulation experienced by persons with essential crying is not predicated on the presence of an underlying neurological disorder, and does not entail a marked disruption in personal, social, or occupational function. Accordingly, essential crying is probably not usefully understood as a pathological condition, and is more likely the reflection of the normal variability in the emotionality domain of temperament.
A German word that translates roughly to “a peculiar addiction to trivial joking,” witzelsucht denotes a condition in which patients frequently and inappropriately experience most things as genuinely funny, often laugh, and have a childish, facetious, sarcastic, and latently hostile, sense of humor. More often than not, the patient him- or herself is the only one who finds a particular situation funny.5,14,15 Unlike patients with pathological laughing, witzelsucht involves a pathologic experience and expression of mirth; unlike patients with affective lability, in which similar dysregulation of the experiences (mirth) and expression (laughter) of affect may occur, witzelsucht involves an admixture of irritability and mirth.
Witzelsucht is a relatively uncommon disorder of affect, tending to occur among persons with relatively severe involvement of frontal-subcortical circuits, particularly in the right hemisphere.5,14,15 Although classically described in the context of right frontal tumors, this condition also occurs following severe TBI, stroke and related cerebrovascular disorders, and neurodegenerative conditions such as FTD.5
Placidity in Klüver-Bucy-like Syndromes
In contrast to the disorders of excessive and contextually inappropriate affect discussed thus far, there are conditions in which the primary disturbance of emotion is a relative deficit in the generation of contextually appropriate affect. The classic example of this deficit in affect generation is the placidity of the Klüver-Bucy-like syndromes. In this condition, bilateral amygdalar lesions produce impairment in the ability to generate appropriate affective responses.16 The classic experiment of Bucy and Klüver17 demonstrated loss of the normal affective response (panic) upon introduction of a rubber snake into the cage of macaque monkeys that had been bilaterally amygdalectomized. Rather than demonstrating the normal escape behavior and distress vocalizations expected by presentation of this stimulus, the monkeys remained placid and initiated approach behaviors to it.
Among humans, the causes of Klüver-Bucy-like syndromes are numerous, and include herpes simplex encephalitis, TBI, FTD, ischemia or anoxia (including carbon monoxide poisoning), temporal lobectomy (eg, epilepsy surgery), progressive subcortical gliosis, adrenoleukodystrophy, systemic lupus erythematosus, Rett syndrome, porphyria, and limbic encephalitis (paraneoplastic syndrome).16 As with lower primates, lack of normal affect generation is only one of several features of this condition, the others including hyperorality, hypermetamorphosis, altered sexual behavior, associative visual agnosia, aphasia, amnesia, echopraxia, and seizures. Nonetheless, the affective placidity observed in the context of lesions to lateral limbic structures is informative regarding the neural bases of normal affect generation.
The Clinical Problem of Pseudobulbar Affect
Prevalence of PBA
PBA is most accurately understood as a syndrome of affect dysregulation produced by an underlying neurological condition. As described in the preceding section of this monograph, PBA is a relatively common sequela of MS, ALS, stroke, TBI, and neurodegenerative dementias such as AD, among other conditions. If only these underlying causes are considered in the development of a conservative estimate of PBA, it suggests that PBA affects nearly 1.5 million persons in the United States. Given that PBA also develops in the context of many other relatively common neurologic conditions, including Parkinson’s disease, the frontotemporal dementias, vascular dementia, cerebral neoplasms, epilepsy, normal pressure hydrocephalus, progressive supranuclear palsy, Wilson’s disease (hepatolenticular degeneration), and neurosyphilis,1,5,8 among others, the actual prevalence of PBA is likely to be considerably higher than this estimate suggests.
Despite the high prevalence of PBA among persons with neurological conditions, it is underrecognized and undertreated in psychiatric, neurological, and general medical settings. The lack of familiarity with PBA among clinicians in the clinical neurosciences and other branches of medicine is a multifactorial problem. As noted in the first section of this monograph, the language used by most clinicians to describe emotion and its disorders presents a barrier to accurate conceptualization of and distinction between disorders of affect and disorders of mood. The lack of inclusion of disorders of affect, including PBA, in either DSM-based or the International Classification of Diseases coding systems reflects this same problem, and adds to it by establishing a documentation and reimbursement barrier even for clinicians that identify PBA as a problem among their patients. Additionally, PBA has not been the subject of the same types of industry-driven diagnosis and treatment discussions commonly afforded to other neuropsychiatric conditions. Although industry-driven physician education is a subject of considerable criticism and debate, the attention afforded to a clinical problem by industry helps familiarize clinicians to that problem. While coding and industry-driven considerations are debatable justifications for affording attention to this issue, it is useful to understand their role in the problem of clinician unfamiliarity with PBA.
In the service of providing clinicians with an understanding of the neural bases of PBA that may guide the evaluation, diagnosis, and treatment of persons with this condition, the putative neural bases of PBA are reviewed in the next section of this monograph. Thereafter, we return to the clinical evaluation and differential diagnosis of PBA, and offer a brief review of treatments for this condition.
Neurobiology of Pseudobulbar Affect
Classically, PBA is conceptualized as a disruption of descending cortical inhibition of brainstem centers that regulate emotional motor output.6 In 1924, Wilson introduced his classic theory of frontotemporal inhibition of affect regulation predicated on both his own observations and those of Nothnagel (1889) and Brissaud (1895). Wilson proposed a model involving two neuroanatomic pathways, the first of which is a voluntary emotional-motor pathway that extends from motor areas through the internal capsule to a rostral pontine faciorespiratory center (FRC) including cranial nerves VII and X, and the phrenic nerve. In this formulation, the FRC regulates facial expression, respiration, and other effector organs involved in emotional expression (and particularly laughing and crying). The second pathway, a so-called involuntary emotional-motor pathway, involves the posterolateral ventral frontal cortex and medial temporal lobe projecting to the thalamus, alongside the hypothalamus and subthalamic nucleus, to the tegmentum and medulla. This pathway is regarded as one that drives involuntary emotional displays to provocative stimuli (whether internal or external), and may be subject to at least a degree of modulation by the voluntary emotional-motor pathway. More recent findings confirm voluntary (dorsolateral prefrontal, anterior cingulate, supplementary motor area, primary motor cortex) and involuntary (medial temporal lobe, insula, operculum) projections through the internal capsule to the pons, periaqueductal gray (PAG), and tegmentum, and subsidiary circuits to these primary pathways. Subsidiary circuits include ponto-cerebello-frontal, ponto-cerebello-thalamo-frontotemporal, hypothalamo-temporal, and hypothalamo-frontotemporal connections.
To better understand these systems, the distinction between volitional facial paresis (VFP) versus emotional facial paresis (EFP) may be instructive. VFP results from a lesion to corticobulbar pathways that innervate the nucleus of cranial nerve VII, resulting in impairments in voluntary facial expression without weakness of emotionally driven facial expression.18-21 These patients will respond to a joke with both laughter and mirth, yet they are unable to smile voluntarily. Conversely, EFP is a weakness of emotionally driven facial expression without weakness of voluntary facial expression. In these patients, there is damage to the involuntary emotional-motor pathway involving the frontal operculum, the temporal insular cortex, and the medial temporal lobe, which results in deficits in emotion-driven facial expression despite preservation of volitional facial expression.21 A similar phenomenon is the dissociation between volitional and emotional respiratory paresis. Munschauer and colleagues22 describe a patient in whom a discrete ventral basis pontis infarction produced a complete loss of voluntary modulation of automatic respiratory motor function, but preservation of emotion-driven modulation of automatic respiration. They suggest that pathways subserving limbic modulation of automatic respiration descend in the pontine tegmentum and/or lateral portion of the basis pontis unaffected by the lesion, and posit that the anatomic and functional bases of voluntary and emotion-related modulation of automatic respiration are distinct.
Of note, these emotional-motor pathways also appear to differ with respect to their role in the subjective experience of emotion. Neurosurgical stimulation of the anterior cingulate gyrus can produce the motor behavior of laughter without the emotion of mirth in VFP patients, whereas stimulation of the fusiform gyrus or the parahippocampal gyrus generates laughter with mirth.23 Importantly, this observation suggests that moment-to-moment emotion (affect) is not inextricably linked to baseline emotional state (mood), and that displays and experiences of affect may be produced when the neural systems serving these functions are activated inappropriately—whether by disease or by direct stimulation. These observations lend support to the heuristic for emotion presented earlier in this monograph.
Subsequent models of affect regulation have in large part built upon the work of Wilson,6 and generally have been additive rather than alternative to his prescient formulation. In the 1930s, Foerster and Gagel24 and Bard25 suggested that stimulation of the caudal hypothalamus produces laughter. Hermann and Brown,26 in 1967, introduced the theory that the cerebellum inhibits the FRC. In light of more recently available data, Garg and colleagues18 suggested that the dorsolateral prefrontal cortex might afford inhibition of the anterior cingulate and the temporal cortex as related to their role in the production of laughing and crying.
More recently, dysregulation of affect, such as occurs in PBA, has been reconceptualized as a condition produced by impairments of a complex cortico-limbic-subcortico-thalamo-ponto-cerebellar network.5,6,27 Thoracic spinal cord lesions are also associated with PBA but are thought to involve secondary corticospinal tract degeneration.28 That network is regarded as a large-scale set of parallel-distributed circuits involved in the integration of personal and social context data, and the fine-tuning of both the experience and expression of affects such that they remain appropriate and amenable to voluntary control with respect to duration, intensity, and context. Given the widespread areas involved in these networks, the location of lesions involved in the genesis of PBA are many and varied. For example, lesions in the corona radiata,18,29-31 internal capsule,29,32 PAG,31 midbrain tegmentum,31,33-35 as well as bulbar and cerebellar areas,29,32,36,37 have been associated with PBA.
Although persons with PBA often have injury in many of these areas, a single strategically located lesion may also produce this condition. For example, Kim and Choi-Kwon38 studied 148 subjects, 34% of whom had “excessive or inappropriate” laughing, crying, or both after single unilateral strokes. When compared to persons with single unilateral stroke without PBA, persons with PBA were more likely to have lesions in lenticulocapsular, basal pontine, medial medullary, and cerebellar infarcts. Among these sites of lesion, lenticulocapsular strokes were most strongly associated with the development of PBA.
Okun and colleagues39 observed the development of PBA (crying) in response to monopolar stimulation of the subthalamic nucleus. Although an uncommon mechanism by which to develop PBA, clinicians should remain mindful of the possibility of PBA as an adverse response to single-site deep brain stimulation. Isolated lesions to the pons and medulla,26,32,40-42 cerebellum,27,43 thalamus,44 as well as stimulation of the hypothalamus,45 may result in PBA. In addition, lesion laterality may play a role in the type of PBA manifested,46 though additional studies are needed to confirm this.38
The studies reviewed in the preceding section of this monograph suggest that a large-scale distributed cortico-limbic-subcortico-thalamo-ponto-cerebellar network is involved in the regulation of affect, and that almost any condition disrupting the structure and/or function of that network may produce PBA. Given that the presently available treatments for PBA are neurochemical in nature, integrating structural and neurochemical anatomy is necessary to understand the rationale for the prescription of such treatments. Although the neurochemistry of PBA is not completely understood, dysfunction of serotonergic,5 dopaminergic,47 and glutamatergic48 systems are most often suggested as the neurochemical foundations of this condition.
The serotonergic hypothesis suggests that PBA results from impairment of the normal modulatory tone afforded by serotonergic afferents into widespread portions of the networks serving affect regulation. Similarly, the dopaminergic hypothesis suggests that PBA arises in the context of impaired dopaminergic tone in those affect-regulating networks—most likely their dorsal components. Accordingly, augmentation of either serotonergic or dopaminergic function in the cortico-limbic-subcortico-thalamo-ponto-cerebellar network serving affect regulation would effect improved descending inhibition in that network, and thereby reduce the frequency and severity of PBA.
Until recently, the serotonergic hypothesis of PBA has been the primary focus of most clinico-radiologic and pharmacologic studies of PBA. For example, in the study by Andersen and colleagues32 noted earlier, 12 subjects with post-stroke PBA (crying) were studied for the purpose of correlating the severity of PBA with lesion size and location. They report that subjects with the most clinically severe PBA had large bilateral pontine lesions without hemispheric lesions; subjects with PBA of intermediate severity had bilateral central hemispheric lesions; and subjects with the least severe PBA had predominantly unilateral large subcortical lesions. On the basis of these observations, they conclude that post-stroke PBA (crying) may be attributable to at least partial destruction of the serotonergic raphe nuclei in the brain stem or their ascending projections to the hemispheres. Similarly, Derex and colleagues49 observed persistent PBA in a patient with a left choroidal artery infarct in the retrolenticular part of the posterior limb of the left internal capsule extending upward into the posterior paraventricular corona radiata region, and posited that this patient’s PBA resulted from unilateral disruption of the capsular ascending projections of the brainstem raphe (serotonergic) nuclei. They report that treatment of this patient with paroxetine resulted in remission of PBA within the first 24 hours following initiation of this agent. They interpreted their observations as supporting the serotonergic hypothesis of PBA on the basis of clinico-radiologic correlation and by inference on the basis of treatment response. Additionally, Murai and colleagues50 used [123I]β-CIT single photon emission computed tomography (SPECT) to estimate central (midbrain/pons and thalamus/hypothalamus) serotonin transporter (SERT) densities among 15 stroke survivors with and without PBA (crying). They observed significantly lower SERT binding ratios in midbrain/pons areas among the subjects with post-stroke PBA than among those without this condition. Additionally, the severity of PBA correlated with lower midbrain and pontine 5-HT transporter concentration, and was independent of the presence of other depressive symptoms.
However, it is also possible that lesions to the cortico-limbic-subcortico-thalamo-ponto-cerebellar network serving affect regulation may result in excessive excitatory tone in the portions of that system involved in the generation and expression of affect; this formulation is the foundation of the glutamatergic hypothesis of PBA. Since glutamate is the primary excitatory neurotransmitter in the central nervous system, including the networks serving affect regulation, reducing or stabilizing glutamate activity might also improve PBA. A strategy to afford such reduction or stabilization of glutamate function might include the use of sigma-1 receptor agonists and/or uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists. Sigma-1 receptors are concentrated in the brain stem and cerebellum,51 and limbic and motor central nervous system regions.52 Sigma-1 receptor agonists demonstrate a fast onset of action with respect to modulation of glutamatergic transmission in the hippocampus and elsewhere, and also demonstrate a fast onset of action with respect to increasing serotonergic function in the dorsal raphe nucleus.53,54 By these mechanisms, sigma-1 receptor agonists such as dextromethorphan (DM) may effect improved regulation of affect. Uncompetitive NMDA receptor antagonists, such as DM, memantine, and amantadine, appear to stabilize glutamatergic neurotransmission by virtue of their low-affinity, voltage-dependent effects.55 Agents with these properties enter the NMDA receptor-associated ion channel preferentially when it is open, and dissociate quickly enough to avoid interference with normal synaptic transmission. These agents may prevent excessive glutamate-mediated excitatory activity but permit relatively normal glutamate-mediated excitatory neurotransmission. Although the glutamate hypothesis of PBA requires further investigation, inferential evidence from pharmacologic studies using DM (a sigma-1 agonist and uncompetitive NMDA receptor antagonist48) suggest that glutamatergic modulation may be a useful approach to the treatment of PBA.
Evaluation of Pseudobulbar Affect
As noted above, PBA is a secondary manifestation of an underlying neurological condition affecting the cortico-limbic-subcortico-thalamo-ponto-cerebellar network involved in affect regulation. Identification of the underlying neurological condition is a prerequisite to the diagnosis of PBA. In most cases, the neurological diagnosis underlying a patient’s presentation with PBA will already be known to the evaluating clinician. In the relatively uncommon circumstance in which a neurological diagnosis is not clearly established (eg, previously unidentified lenticulostriate lacunar infarction, MS, mild TBI, etc), a thorough neurological evaluation should be undertaken in order to identify and, where possible, treat that condition so as to reduce progression and worsening of its sequelae, including PBA. As a part of such evaluations, magnetic resonance imaging is preferred for both ascertaining the neurological diagnosis and also identifying lesions associated with PBA.
Although it is uncommon for PBA to exist as the sole secondary manifestation of these conditions, it may go unrecognized or misunderstood as a disorder of mood if clinicians do not include a specific assessment for PBA as a part of standard clinical evaluation of persons with these conditions. Absent a model for considering disorders of affect separately from disorders of mood, many patients with PBA almost certainly receive mood disorder diagnoses (eg, depressive, hypomanic, manic, or mixed mood episodes; MDD; and bipolar disorder diagnoses, including “ultra-rapid cycling” bipolar disorder), when a diagnosis of PBA would be more appropriate. The heuristic presented in the Figure and the organization of emotional disorders presented in the Table may be useful in this regard.
Accordingly, the next step in the evaluation of paroxysms of crying or laughing is the generation of a differential diagnosis inclusive of both disorders of mood and disorders of affect. The former includes major and minor depressive episodes; bipolar disorder types I and II, especially with rapid cycling; mixed mood episodes; and cyclothymia. In these conditions, the essential feature is a sustained and pervasive change in mood, with similarly sustained and pervasive alterations in mood-related cognition, behavior, and physical (neurovegetative) functions. The latter includes PBA, essential crying, and witzelsucht. In these conditions, cognitive, behavioral, and physical (eg, sleep, appetitive) disturbances are commonly comorbid with disorders of affect. However, the disorder of affect itself does not produce changes in cognition, behavior, or physical function (neurovegetative features) between episodes of dysregulated affect. It is therefore important to consider other conditions that produce paroxysms of affect, including anxiety disorders; disorders of personality (eg, borderline and histrionic personality disorders); personality change due to a general medical condition resulting in episodic disinhibition and/or irritability; organic aggressive syndrome; and intermittent explosive disorder. Finally, PBA may be comorbid with disorders of mood and/or anxiety in patients with neurological conditions as well as in patients with primary and psychiatric disorders. However, when PBA arises in the setting of a primary psychiatric disorder, the development of a new neurological condition should be suspected.
Epilepsy is another important consideration in the differential diagnosis of PBA, specifically dacrystic (quiritarian) and gelastic seizures. Dacrystic seizures involve unprovoked crying as the ictal manifestation, whereas gelastic seizures involve unprovoked laughing as the ictal manifestation. These episodes of uncontrollable crying or laughing can be difficult to distinguish from PBA. However, dacrystic and gelastic seizures are typically associated with ictal electroencephalogram (EEG) changes and are generally followed by at least a brief period of postictal confusion. Clinicians should also be mindful that PBA can occur among patients with epilepsy, underscoring the need to distinguish between ictal and interictal displays of pathological affect. While a careful history and observation of these events facilitates distinction between these seizure types and PBA, consideration of these types of seizures is particularly important in light of the relatively frequent occurrence of seizures in many of the conditions associated with PBA (ie, stroke, traumatic brain injury, etc). When history and observation leave uncertainty regarding the distinction between PBA and epileptic affective displays, video-EEG monitoring may be required to clarify the diagnosis.
Several scales may be of use in the identification and assessment of PBA. The Pathological Laughter and Crying Scale (PLACS) is an assessment scale for PLC symptoms and has been validated in stroke.56 The Emotional Lability Questionnaire is an adaptation of the PLACS that has been applied to the study of emotional dysregulation in patients with ALS.57 The Affective Lability Scale58 evaluates lability and intensity of affect, although its use to-date in the study of PBA is limited to persons with TBI.59 The Center for Neurologic Study-Lability Scale (CNS-LS) screens for pathologic laughing and crying symptoms, and has been validated in patients with ALS and MS.11,60 These scales may be particularly useful in the study of PBA, and the items used to screen for symptoms may assist clinicians in developing a repertoire of questions to use in the identification and evaluation of PBA. These scales may also be valuable for the purpose of establishing a baseline severity of PBA against which to assess the effects of treatment.
In addition to identification and quantification of PBA symptoms, clinicians are encouraged to assess the functional consequences and effects on quality of life, both among persons with this condition and their families/caregivers. Although there are at present no formal functional assessment measures validated specifically for use among persons with PBA, clinicians are encouraged to undertake at least an informal assessment of the personal and social consequences in the daily life of persons with this condition. For example, patients and their families/caregivers may limit their social activities or participation in instrumental activities of daily living (eg, recreation, shopping, transportation, etc.) due to the embarrassment associated with their episodes. In rehabilitation settings, crying and/or laughing may limit the patient’s ability to participate in therapies required to improve or compensate for other sequelae of the neurological condition. Ascertaining the effects of and treatments for PBA on these types of functional activities and quality of life is an essential component of the evaluation of persons with this condition.
Treatment of Pseudobulbar Affect
Ideally, medications used to treat PBA would effect improvements across the several neurotransmitter systems (ie, serotonin, dopamine, and glutamate) implicated in its development in such a way that the function of the cortico-limbic-subcortico-thalamo-ponto-cerebellar network serving affect regulation is improved, with little or no adverse effect on other cognitive, emotional, behavioral, or motor systems. However, most of the literature regarding the treatment of PBA has focused only on the serotonergic hypothesis of PBA, and has emphasized the use of low-dose selective serotonin reuptake inhibitors (SSRIs) or tricyclic/heterocyclic antidepressants (TCAs) with relatively high serotonergic reuptake inhibition properties.5,56,61-65
Among the SSRIs, fluoxetine, sertraline, paroxetine, citalopram, and fluvoxamine may be effective for the treatment of PBA.5,66 Available evidence offers little to suggest a differential benefit of one of these agents over the others. Among the TCAs, low-dose amitriptyline, imipramine, and nortriptyline may afford similar benefits with respect to PBA symptoms. As with the SSRIs, there are at present no studies that offer convincing evidence of a differential benefit between these agents. The selection of such agents is therefore guided less by their potential effects on PBA but rather by their potential to effect (either adversely or beneficially) the underlying neurological condition responsible for the production of PBA. For example, in a report by Muller and colleagues,67 both citalopram and paroxetine were effective for the treatment of PBA following stroke or TBI, but citalopram was better tolerated—presumably as a result of its relative lack of systemically significant antimuscarinic effects. Such considerations may be useful in the selection of these agents among persons with neurological conditions (eg, AD, Parkinson’s disease, TBI, etc) in which the non-serotonergic properties of these agents may limit their tolerability with respect to cognitive or motor function. Given the relatively greater tolerability and more limited drug-drug interactions of the SSRIs when compared to the TCAs, particularly among older patients, cognitively impaired patients, and patients with significant cardiac disease, the SSRIs are generally regarded as the favored class when antidepressants are used for the treatment of PBA.
More recently, the combination of DM 30 mg plus quinidine sulphate (Q) 30 mg given twice daily (DM/Q) was investigated as a treatment for PBA among persons with ALS. Brooks and colleagues48 compared 65 ALS patients treated with combination DM/Q, versus 30 patients with DM alone, and 34 patients with Q alone. They found significant differences (P=.001) in score on the CNS-LS, a measure of PBA severity, among groups, with the group receiving the combination showing significantly greater improvement than either the DM- or Q-alone groups. There was no significant difference between the DM- and Q-alone groups.
Although the mechanism of action for DM/Q in the treatment of PBA remains unknown, the neurochemical properties of DM suggest several possibilities. First, DM acts as a sigma-1 receptor agonist.68 As discussed in the neurochemistry section of this monograph, sigma-1 receptors are concentrated in the brain stem and cerebellum,51 and limbic and motor central nervous system regions.52 Agents that act as agonists on these receptors demonstrate a rapid onset of action with respect to modulation of glutamatergic transmission in many of the structural elements of the affect regulation network, and also increase serotonergic function at the level of the dorsal raphe nucleus.53,54 DM also demonstrates evidence of uncompetitive NMDA antagonism,69,70 which allows it to decrease excitatory glutamatergic signaling. To the extent that excess excitatory glutamatergic signaling is involved in the production of PBA, this antagonism might attenuate the frequency and severity of PBA symptoms. Uncompetitive NMDA antagonism may also increase dopaminergic function in the frontal-subcortical elements of the affect regulation network either by activation of ascending dopamine neurotransmission,71,72 treatment-induced increases in the expression striatal dopamine receptors,73 or other similar mechanisms. Finally, there is evidence that DM modulates serotonergic neurotransmission, particularly at 5-HT2 receptors74,75 and may also bind to the serotonin reuptake transporter.76 The effects of DM on serotonergic neurotransmission suggest that this may also be an important mechanism of action for this agent with respect to reducing the frequency and severity of PBA. In light of all of these mechanisms, DM fits well with the model proposed above for the properties of an optimal agent for the treatment of PBA.
The combination of DM and Q is important in that the latter agent inhibits cytochrome P450 2D6 and produces a 20-fold increase in circulating DM levels. This elevation in DM levels is required to achieve central nervous system concentrations sufficient to produce the clinical benefits observed by Brooks and colleagues,48 given that neither DM nor Q alone afforded similar symptomatic improvements. Although additional studies of DM/Q on PBA are required to more fully evaluate the consistency of its therapeutic benefits and tolerability, this agent appears promising as a novel addition to the pharmacotherapy of PBA.
Finally, it is noteworthy that many, although not all, reports regarding the treatment of PBA suggest that the response to treatment often occurs more quickly (ie, within 1–7 days of treatment initiation), and with relatively lower doses of medications, than is generally observed in the treatment of depressive episodes. Although the reasons for differences in dose- and temporal-responses to treatment between PBA and depressive episodes are uncertain, it is possible that the types of neurochemical disturbances in these conditions may not be identical. The lesion studies described above suggest that PBA may reflect either losses of ascending afferents that effect modulation or inhibition of the cortico-limbic-subcortico-thalamo-ponto-cerebellar network involved in affect regulation, excessive excitatory signaling in the ventral portions of that network, or both. Compensating for lesion-related serotonergic deafferentation, dopaminergic deafferentation, or excess glutamatergic activity might be accomplished readily by receptor-level treatments, such as are afforded by all of the medications currently prescribed for PBA. The neurochemistry of depression is rather more complex than that of PBA, and involves a cascade of neurochemical, neurogenetic, and neurohormonal disturbances.77,78 Accordingly, depression is probably better understood as a post-receptor (eg, second messenger-mediated, genomic, proteomic) or multi-receptor disturbance that is less easily or quickly, even if eventually, remediated by antidepressant agents whose effects are primarily at the receptor level. Although speculative, further investigation of this hypothesis may inform the differences in dose- and temporal-response to treatment between PBA and depressive disorders.
Disorders of affect such as PBA are relatively common consequences of many neurological conditions, but are underrecognized and undertreated in psychiatric, neurological, and primary care settings. The status quo of PBA is explained in terms of nosological and diagnostic-systems issues that have confounded efforts to describe, study, and investigate these conditions. A heuristic was presented that describes mood and affect, first on temporal grounds, and then with respect to their subjective and objective elements, in order to provide clinicians with a conceptual framework for distinguishing between disorders of mood and affect. After reviewing both common and uncommon disorders of affect regulation, a detailed description of the most common of these conditions, PBA, was presented, including its prevalence, putative neuroanatomic and neurochemical bases, evaluation, and treatment. Based on the material presented in this monograph, clinicians should be able to better recognize, diagnose, and treat PBA, and should be better able to understand and interpret studies of this condition presented in the medical literature.
Q: Does pseudobulbar affect (PBA) exist as a primary disorder, or is it always secondary to a medical or neurologic condition?
The consensus among panel members was that PBA is a secondary manifestation of a primary neurological condition. Although the conditions that PBA may accompany are numerous, including at least myotropic lateral sclerosis, multiple sclerosis, stroke, Huntington’s disease, mental retardation, traumatic brain injury, dementia or intellectual disabilities, the panel opined that the development of PBA in all cases suggests the development of a condition affecting the neural networks serving affect regulation. At times it may be difficult to determine the underlying etiology of the condition producing PBA. Although unusual, it is possible that in some cases, PBA may be the only clinically identifiable manifestation of the neurological condition. In light of the overlap between the neurology of affect regulation and the neurology of some conditions traditionally viewed as “psychiatric,” and particularly schizophrenia, PBA may sometimes occur in the latter context as well.
Q: How commonly do you see patients with PBA in your clinical practice?
The panel members noted considerable variability in their experience with respect to how frequently they identify PBA as a problem in the patients served in their clinical practices. Further discussion suggested that these differences may, at least in part, arise as a result of differences in the patient populations they serve. First, the number of PBA cases identified differed depending on the stage and severity of the underlying neurological conditions. Panel members serving persons with early and/or less severe neurological conditions reported a lower frequency of PBA than those serving persons with more advanced and/or severe neurological conditions. Second, differences in referral patterns appeared to influence the observed frequency of PBA. Some of the panel members practicing in tertiary centers reported higher frequencies of PBA, and suggested that lack of recognition and/or misdiagnosis of PBA on the part of referring physicians may increase the frequency with which patients present with this condition. Alternatively, at least one panel member suggested that the referring physicians in that panel member’s area are relatively savvy with respect to the identification and treatment of PBA, and only send patients on when initial treatment attempts fail. In this context, the number of patients with this condition was lower than that reported by other panel members.
One panel member reported that among the 20 stroke patients admitted to his acute rehabilitation unit monthly, ~10% present with PBA. In this same panel member’s experience, ~5% of patients admitted to acute rehabilitation following severe TBI demonstrate PBA. Another panel member serving patients with Parkinson’s plus syndromes reported a relatively higher frequency of PBA than among patients with Parkinson’s disease alone, and attributed the higher frequency of PBA to misdiagnosis of the condition as a disorder of mood among the Parkinson’s plus patients. In general, however, panel members with primarily outpatient-based clinical practices reported relatively low rates of PBA.
Q: Among patients with PBA, what is the relative frequency of crying versus laughing versus both?
The consensus among panel members was that crying is a much more common symptom of PBA than is laughing. One panel member with >20 years of clinical experience reported that he had in the week prior to the roundtable meeting seen only his second patient (one with a traumatic brain injury) with pathological laughing. Another panel member reported seeing only one patient every 1–2 years with pathological laughing. Panel members caring for persons with neurodegenerative dementias reported more experience with laughter as a symptom of PBA, but reiterated that this symptom is seen only occasionally. One panel member reported that in the preceding 5 years, only three patients with dementias had presented with pathological laughter. This experience was echoed by another panel member whose clinic focuses on the care of persons with frontotemporal dementia, and it was reported that episodic irritability, anxiety, and tearfulness were much more common than paroxysms of laughing. Another panel member with a comparable clinical population reported a similar experience, and added that when pathological laughter develops, it is a very problematic and functionally disruptive symptom for both patients and their families.
Q: Is it common for PBA symptoms to be apparent during the clinical interview?
Most of the panel members reported that PBA symptoms are usually evident during the clinical interview and examination when such symptoms are significant enough to merit treatment. However, several panel members presented examples of situations in which the diagnosis of PBA may be missed, despite being a problem of clinical concern. One panel member suggested that missed diagnoses of PBA may occur when another clinician (eg, referring physician, resident physician, or allied health-care provider) interviews, examines, and then reports findings to a consulting or supervising physician. If the consulting or supervising physician neither examines the patient directly, nor questions the reporting clinician about PBA, this diagnosis may be easily misunderstood or missed altogether. Another panel member described a case in which initial interview and examination of a patient with post-stroke PBA did not reveal PBA. After that clinician discussed the case further with the physical and occupational therapists treating the patient, it was learned that the patient was experiencing PBA that interfered with those therapies. The panel member reported that only upon asking the patient about the crying behavior did the symptom itself become evident. The panel member reiterated the importance of asking patients rather specifically about PBA symptoms, both for the purpose of identifying the symptom in the clinical history and also for the purpose of evoking it.
Q: Do you use formal assessment scales in evaluation of persons with PBA?
The panel members unanimously agreed that the use of formal symptom assessment scales, while essential for research purposes, is not common in the day-to-day evaluation of persons with PBA. Some panel members felt that familiarity with these scales may help clinicians develop a repertoire of questions used to identify PBA. However, the panel agreed that use of some measure of function, whether informal or formal, should be included in the assessment of persons with PBA. It was suggested that an interview of the patient and, when applicable, his or her caregiver, regarding the effect of PBA symptoms on instrumental activities of daily living is an important element of the clinical assessment of these patients.
Q: How often do you prescribe pharmacologic treatments for PBA?
Panel members differed considerably with respect to their prescription of treatments for PBA, but these rates were on average relatively low: most of the panel members reported treating less than one third of patients presenting with PBA. Among patients treated for this condition, most of the panel members described that such treatments (usually selective serotonin reuptake inhibitors or tricyclic antidepressants) were reasonably effective. The panel member that identified the co-occurrence of episodic tearfulness and irritability noted that the treatment of this symptom complex may entail the use of other agents (ie, anticonvulsants, β-adrenergic antagonists, buspirone, and/or lithium carbonate), but indicated that such treatments are usually offered and are reasonably effective.
After noting the low rates of pharmacologic treatment of PBA reported by the panel members, one panel member indicated that if an agent became available that was well-suited to the treatment of PBA and had a wide margin of effectiveness and tolerability across the spectrum of the disorder, that he would be more likely to offer pharmacologic treatment to patients with PBA.
Q: In summary, what are the most important points clinicians in general psychiatry or neurology practice should know about PBA?
The panel stressed the importance of making physicians aware of the distinctions between disorders of mood and disorders of affect, and the need for consideration of the latter in the differential diagnosis of emotional disturbances. Recognition of PBA as a secondary manifestation of a neurological disorder was also emphasized, particularly when recognition of PBA prompts evaluation of a previously unrecognized neurological disorder. The panel agreed that clinicians should be aware of the distress and disability among patients with PBA and their families/caregivers. The panel concluded that the diagnosis of PBA requires a specific fund of knowledge and clinical interviewing skill set, and that additional education of clinicians on these issues is needed. Finally, the panel emphasized the potential benefits of treating PBA for both affected patients and their families, as well as the need for additional multicenter, randomized, placebo-controlled studies of the treatment of PBA.
- Pseudobulbar affect (PBA) is underrecognized and undertreated in neurological, psychiatric, and general medical settings.
- PBA is distinguishable from other disorders of affect and from disorders of mood.
- PBA is a syndrome that develops due to an underlying neurological condition that impairs the function of large-scale neural networks serving affect regulation.
- When PBA occurs, crying is a more common symptom than is laughing.
- PBA produces substantial distress and disability among affected patients and their families/caregivers.
- PBA is a treatment-responsive condition, and intervention with an appropriate neuropharmacologic agent is strongly encouraged.
- Physician education regarding the differences between disorders of affect and disorders of mood is needed to increase PBA recognition, and to facilitate the provision of treatment to persons with this condition.
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