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Pseudobulbar affect:
the spectrum of clinical
presentations, etiologies
and treatments
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Expert Rev. Neurother. 11(7), 1077–1088 (2011)

Ariel Miller†1,
Hillel Pratt2 and
Randolph B Schiffer3
1
Technion-Israel Institute of
Technology, Carmel Medical Center,
Department of Neurology,
7 Michal St., Haifa 34362, Israel
2
Technion-Israel Institute of
Technology, Evoked Potentials
For personal use only.
Pseudobulbar affect (PBA) consists of uncontrollable outbursts of laughter or crying inappropriate
to the patient’s external circumstances and incongruent with the patient’s internal emotional
state. Recent data suggest disruption of cortico–pontine–cerebellar circuits, reducing the threshold
for motor expression of emotion. Disruption of the microcircuitry of the cerebellum itself may
likewise impair its ability to act as a gate-control for emotional expression. Current evidence also
suggests that serotonergic and glutamatergic neurotransmission play key roles. Although
antidepressants have shown benefit, the supportive clinical data have often derived from small
numbers of patients and unvalidated measures of PBA severity. Dextromethorphan/quinidine,
the first FDA-approved PBA medication, is a novel therapy with antiglutamatergic actions. As life

Laboratory, Haifa, Israel

3
PO Box 1566, Santa Fe, NM 87504, expectancy lengthens and the neurologic settings of PBA become more common, the need for
USA treatment can be expected to increase.
†
Author for correspondence:
Tel.: +972 4 8250 851
Fax: +972 4 8250 909
Keywords : cerebellum • cortico–pontine–cerebellar circuit • dextromethorphan/quinidine • event-related
millera@tx.technion.ac.il potentials • involuntary emotional expression disorder • pseudobulbar affect • selective serotonin reuptake
inhibitors • tricyclic antidepressants

Pseudobulbar affect (PBA) is a disorder of emo-
tional expression characterized by uncontrol-
lable outbursts of laughter or crying that lack
an appropriate environmental trigger and may be
exaggerated or incongruent with the underlying
emotional state. It is a distinct neurologic condi-
tion associated with various neurologic diseases
or brain injuries [1,2] . Although reported preva-
lence rates vary greatly, it may be most common
in patients with amyotrophic lateral sclerosis
(ALS) [3] and stroke [4] , where rates as high as
50% or more have been estimated. PBA is also
reported in patients with multiple sclerosis (MS;
10–29%) [5,6] , Parkinson’s disease (5–17%) [7–9] ,
Alzheimer’s disease (39%) [10] and traumatic
brain injury (5–11%) [11,12] .
Pseudobulbar affect is an added burden to
patients who may already be disabled or expe-
riencing a reduced quality of life due to their
underlying neurologic disorder. Because of the
embarrassment associated with an inappropri-
ate outburst of emotion, patients’ social interac-
tion may be impaired [12] . The risk of depression
and anxiety symptoms may be increased, and
quality of life is often decreased [9,12] . PBA can
also interfere with rehabilitation [13] . Although
PBA continues to be underdiagnosed and under-
treated [14] , understanding of the condition has
been advancing in recent years. This review will
summarize the established knowledge in PBA,
as well as recent findings related to its presen-
tation, etiology, underlying mechanisms and
emerging treatments.
Taxonomy of emotional
expression disorders
The terminology associated with the naming
and description of disorders of emotion has been
unclear and confusing, and may contribute to
the under- and mis-diagnosis of these disorders.
The problem is twofold, in that the same or simi-
lar disorders have been given multiple names,
and the language used to describe the disorders
has been inconsistent or misleading. In addition
to PBA, symptomatology has been described as
affective instability, compulsive laughing or
weeping, emotional or affective lability, emo-
tional incontinence, emotionalism, excessive

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 Review Miller, Pratt & Schiffer

emotionality, inappropriate hilarity, involuntary emotional
expression disorder, pathological laughter and crying, pathologic
emotionality and under other names [1,2] . Some of these terms
have been used interchangeably, while others have been used to
make distinctions between similar disorders.
When describing disorders of emotion or emotional expres-
sion, it is important to differentiate between affect and mood.
According to Diagnostic and Statistical Manual of Mental
Disorders – Fourth Edition – Text Revision (DSM-IV-TR),
affect reflects moment-to-moment changes in emotional state
that are superimposed on mood, which is a sustained emotional
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The spectrum of PBA & its diagnosis
The confusion attached to the terminology for disorders of emo-
tion affects the question of whether some terms are ‘umbrella
terms’ spanning multiple conditions. Conceivably, PBA may be
a spectrum ranging from affective lability at one end to severe
pathological laughing and crying (with uncontrollable, mood-
incongruent displays of emotion, including outbreaks of uncon-
trollable anger) at the other end. Nevertheless, the boundaries
of such a spectrum have not been clearly defined, nor have the
diagnostic criteria for PBA been well established. Moreover, PBA
and other disorders of affect are not included in DSM-based diag-

state. Understanding this difference helps in diagnosis. PBA is
a disorder of affect. Depressive and bipolar disorders are mood
disorders because of the persistent nature of the emotional state.
Mood disorders may sometimes coexist with disorders of affect,
but can and should be distinguished from them.
Disorders of affect may be differentiated among themselves by
considering whether they involve objective (expression) versus sub-
jective (experience) or voluntary versus involuntary displays of emo-
tion. Affective lability and pathological laughing and crying are the
two major disorders of affect [15] . For patients with affective lability,
the emotion expressed is exaggerated relative to the stimulus, but
is congruent with the subjective (internally experienced) emotional
state [14] . In pathological laughter and crying, the emotion expressed
For personal use only.
nostic criteria or International Classification of Diseases coding
systems [14] . The most recently proposed diagnostic criteria for
PBA (termed involuntary emotional expression disorder) are listed
in Box 1 [16] . The episodes of laughing or crying in PBA are stereo-
typed in that the frequency, severity, duration and type of episode
are similar in a given patient, but may differ among patients. A
patient may, however, have both laughing and crying episodes [16] .
Pseudobulbar affect must be distinguished from other disorders
of affect and from mood and personality disorders. Depression
is probably the most common misdiagnosis for PBA. However,
many clinical features distinguish PBA episodes from depres-
sion symptoms. The most prominent difference is duration.
Depression symptoms, including depressed mood, typically last

is exaggerated relative to both the stimulus and the experienced weeks to months, while an episode of PBA lasts seconds to min-
emotional state. It may also be incongruent with the experienced utes [16] . In addition, crying, as a symptom of PBA, may be unre-
emotional state as far as valence. The expression of emotion in lated or exaggerated relative to subjective mood, while crying is
pathological laughter and crying is involuntary and uncontrollable. congruent with subjective mood in depression. Other symptoms
In affective lability, the expression may be partially controllable [14] . of depression, such as fatigue, anorexia, insomnia, anhedonia and
Pseudobulbar affect is a broader term defined to encompass feelings of hopelessness and guilt, are not associated with PBA [16] .
pathological laughter and crying and affective lability [14] . As such, PBA can also be differentiated from bipolar disorders with rapid
PBA is a disorder of involuntary emotional expression (typically cycling or mixed mood episodes because of the relatively brief
laughing and crying) that is uncontrollable, inappropriate to the duration of laughing or crying episodes (with no mood distur-
circumstance, and may be exaggerated or incongruent with the bance between episodes), compared with the sustained changes in
underlying subjective emotional state [14] . The disorder is called mood, cognition and behavior recognized in bipolar disorders [14] .
‘pseudobulbar’ because it can be a symptom of pseudo­bulbar Other disorders in the differential diagnosis are relatively rare.
syndrome, a disorder associated with damage to corticobulbar Essential crying is a lifelong propensity for crying not accompanied
tracts that also has features such as dysphagia, impaired facial and by an underlying psychiatric or neurologic disorder. It does not
tongue movements, dysphonia, and slow, slurred speech. Use of interfere with function and may be a variant of normal emotion
the term ‘pseudobulbar’ should not be interpreted to suggest that in which the threshold for sadness and crying are lowered [15] . In
PBA is an unreal (e.g., a factitious) disorder. Witzelsucht, patients frequently and inappropriately experience
Box 1. Proposed diagnostic criteria for pseudobulbar affect.
Essential criteria
• Patient experiences episodes of involuntary or exaggerated emotional expression that result from a brain disorder, including episodes of
laughing, crying or related emotional displays
– Episodes represent a change in the patient’s usual emotional reactivity, are exaggerated or incongruent with the patient’s subjective
emotional state, and are independent or in excess of the eliciting stimulus.
– Episodes cause clinically significant distress or impairment in social or occupational functioning.
– The symptoms cannot be attributed to another neurologic or psychiatric disorder or to the effects of a substance.
Supportive criteria
• Patient may experience accompanying autonomic changes (e.g., flushing of face) and pseudobulbar signs (e.g., increased jaw jerk,
exaggerated gag reflex, tongue weakness, dysarthria and dysphagia).
• Patients may exhibit a proneness to anger.
Adapted from [16].

1078 Expert Rev. Neurother. 11(7), (2011)

 Pseudobulbar affect: the spectrum of clinical presentations, etiologies & treatments
situations as being funny, and laugh in response. Facetiousness,
sarcasm and irritability can also be facets of this condition.
Witzelsucht has been associated with brain insult affecting the
function of frontal cortex [15] . Crying and laughing that occur in
epilepsy, as dacrystic and gelastic episodes, respectively, may be con-
fused with PBA, but these disorders may be accompanied by other
epilepsy symptoms, such as impaired consciousness [16] . Gelastic
epilepsy has been associated most frequently with hypothalamic
tumors (hamartoma).
Pathophysiology of PBA
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The pathophysiology of PBA is not fully understood. Along with
neuroanatomical forms of evidence (as described below), now
augmented by direct neurophysiological studies (also described
below), the available evidence derives from studies of PBA treat-
ment, for example, with antidepressants. On the latter basis, the
pathophysiology of PBA appears to be at least partly distinct
from that of depression, despite similarities in symptomatology.
One study in patients with stroke and PBA found no difference
in response to nortriptyline among patients with and with-
out coexisting depression; this study also found no correlation
between scores on an assessment of PBA symptoms (Pathological
Laughter and Crying Scale) and on the Hamilton Rating Scale for
Depression (HRSD) [17] . Similarly, in a study of patients with MS
For personal use only.
and PBA, most patients’ PBA showed a response to amitriptyline,
but there was no significant change from baseline in mean HRSD
or Beck Depression Inventory (BDI) scores, which were low at
baseline [18] . Several studies have found little or no association
between depression symptoms or diagnoses and PBA symptoms
or diagnoses [6,7,19] . Still other studies have found some associa-
tion  [12,20] . However, the response of PBA to an antidepressant
has often been observed within a few days after initiation of treat-
ment  [21–23] , much sooner than would be expected for an anti­
depressant effect [24] . Moreover, response to an antidepressant has
been reported for laughing as well as crying episodes [25] .
Whether or not PBA symptoms correlate with depression
symptoms may relate to the differences in location of the specific
neuro­pathology. In some patients, neuropathology may be limited
to substrates involved primarily in the motor expression of emo-
tion, whereas in other patients, damage may extend to areas and
neuronal systems involved in sustained emotional state (mood).
The neural pathways believed to be involved in depression are
widespread, complex and involve multiple neurotransmitter sys-
tems [26] , while those proposed to be involved in emotional expres-
sion are more limited [27] . Understanding such differences may be
important because of the implications for PBA-specific treatment.
Neuroanatomical clues to pathophysiologic mechanisms
Because PBA occurs in a wide variety of neurologic disorders,
commonalities in the location of brain lesions appear to be
more important to the pathophysiology of PBA than the specific
pathological mechanism(s) of the underlying disorder. Studies of
brain lesion location have suggested specific neural substrates and
circuits that are disrupted in PBA. In one such study, compar-
ing 14 MS patients with PBA and 14 MS patients without PBA,
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MRI findings for parcellated brain regions identified significantly
greater lesion volume in the PBA group for six regions: brainstem
hypointense lesions, bilateral inferior parietal and medial inferior
frontal hyperintense lesions, and right medial superior frontal
hyperintense lesions [28] . The data were interpreted as implicating
“a widely-dispersed neural network involving frontal, parietal and
brainstem regions in the pathophysiology of PBA.”
The accepted theory of PBA pathophysiology was based on
post-mortem studies. Wilson hypothesized that lesions to the
motor cortex resulted in a loss of voluntary inhibition of brain-
stem nuclei that control emotional expression [29] . In this way,
involuntary laughing and crying were believed to be disinhib-
ited. This theory has been revised and extended, based on more
recent data from neuroimaging studies, which allow for more
precise localization of brain lesions than post-mortem ana­lysis
permits. In particular, Parvizi et al. proposed that dysfunction
in a cortico–pontine–cerebellar circuit is responsible for PBA
symptoms  [27,30] . This circuit includes motor, limbic and asso-
ciation cortices with descending pathways to the brainstem,
basis pontis and cerebellum. Within this proposed circuit, the
cerebellum automatically (unconsciously) modulates emotional
expression, scaling it appropriately and producing an emotion-
ally congruent response, according to the contextual information
received from the cortex. In PBA, disruption of the cortico–pon-
tine–cerebellar connection would therefore produce a lowered
threshold for emotional response or a response incongruent to
the patient’s circumstances.
Recent data from an electrophysiologic study of event-related
potentials (ERPs) support the concept of cortico–pontine–cer-
ebellar circuit disruption in PBA [31] . ERPs are transient voltage
waveforms in brain tissue, as recorded, in this case by scalp elec-
trodes, after experimental stimuli, in this case a spoken list of
bisyllabic first names chosen for being subjectively significant or
neutral to a given subject. In 11 patients with PBA in the setting of
MS, as compared with 11 controls without MS or PBA, ERP cur-
rent densities were greater in the MS plus PBA group, suggesting
that stimulus processing differs between these groups. In response
to subjectively significant stimuli, the differences were seen at
later stages of processing (in pre-motor and supplementary motor
cortical areas), consistent with a difference in the processing of
meaning and context. In response to both neutral and subjectively
significant stimuli, the differences were seen at early processing
stages (in sensory areas), during stimulus discrimination. The
sensory processing differences between the groups preceded the
motor processing differences, and for both subjectively significant
and neutral stimuli, activation of motor areas was significantly
greater in MS patients with PBA than in controls.
These data are the first to show evidence of sensory in addi-
tion to motor involvement in PBA. Based on these findings, the
authors proposed a ‘gate-control’ theory of emotional expres-
sion [31] . According to this theory, in patients with PBA, inhibi-
tory transmission from sensory cortices to motor and limbic
cortex is reduced. This results in ‘disinhibition’ of a gate-control
mechanism in the cerebellum, and therefore a lowered emotional
expression threshold (Figure 1) .
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Normal PBA

Somatosensory Somatosensory
Motor cortex Motor cortex
cortex cortex

Frontal and Frontal and

temporal cortex temporal cortex
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Cerebellum Cerebellum

Brainstem Brainstem

Voluntary Involuntary
laughing/crying laughing/crying

Emotional motor expression network The network’s excitatory input The network’s inhibitory input
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Figure 1. Proposed brain circuitry involved in emotional expression, and its hypothesized dysfunction in pseudobulbar
affect (PBA). Normally (A), an emotional motor expression network including cortico–ponto–cerebellar afferentation (upper blue
arrows) enables the cerebellum to act as a ‘gate-control’ for the motor expression of emotion (lower blue arrows). Inputs to this network
(green and red arrows) include an inhibitory influence from sensory cortices. In PBA (B), reduced inhibitory influence at the cortical level
(broken red cortical arrows) results in increased aberrant activation within the network (broken blue arrows), giving rise to the motor
manifestations of pathological laughing/crying.

Neurochemistry disorders [33] . Serotonin may be involved in the pathophysiology

The neurotransmitters and neuromodulators involved in PBA
pathophysiology could potentially include any that play a role
in emotion and its expression, including serotonin, norepine-
phrine, glutamate, dopamine, acetylcholine, GABA, adenosine,
corticotropin-releasing hormone and corticosteroids [2] . However,
serotonin and glutamate appear to be particularly relevant, based
not only on their participation in circuits thought to underlie PBA
pathophysiology, but also on the types of therapies (serotonergic
or antiglutamatergic) used to treat PBA.
Serotonergic projections and serotonin receptors are wide-
spread in the CNS, with potential to modulate most neural
functions. In particular, serotonergic neuronal cell bodies are
situated predominantly in the brainstem raphé nuclei, with axon
terminals diffusely distributed throughout the brain. The termi-
nals are most densely localized in cortico-limbic areas, including
cerebral cortex, hippocampus and amygdala; density is relatively
low in cerebellum and ventral pons [32] . The role of serotonin
in memory, learning, sleep, sex and appetite is well known, and
disturbance of these functions is characteristic of mood and
anxiety disorders [32] . Serotonin has been viewed as a nonspecific
neuropsychiatric stabilizer because of its potential to modu-
late numerous psychobiological functions and the pervasive
usefulness of serotonergic drugs across a variety of psychiatric
of PBA through the diffuse cortico-limbic networks involved
in emotion or via serotonergic neurotransmission in the cer-
ebellum. Selective serotonin reuptake inhibitors (SSRIs) and
tricyclic antidepressants increase the synaptic availability of
serotonin and are believed to improve PBA symptoms through
their serotonergic actions.
Glutamate is the major excitatory neurotransmitter in the
CNS. Unlike serotonin and other monoamines, glutamate cell
bodies are not limited to brainstem areas but are disseminated
throughout the brain, particularly in the cortex. They are also
present in the thalamus, hippocampus and cerebellum [34] .
Glutamate terminals are also widespread and have been iden-
tified in cortex, hippocampus, striatum, amygdala, substantia
nigra, pons, cerebellum, and other areas [34] . Drugs modulating
glutamatergic transmission could potentially affect diverse neural
circuits, depending on the types and location of the glutamate
receptors modulated. The efficacy of dextromethorphan/quini-
dine (DMQ), recently US FDA-approved as therapy for PBA, is
believed to be related to antiglutamatergic effects at NMDA and
s-1 receptors [35] . An ERP study in patients with MS and PBA,
as compared with healthy controls, found that waveforms elicited
by subjectively significant verbal stimuli tended to normalize
after treatment with DMQ [36] . The authors speculate that the

1080 Expert Rev. Neurother. 11(7), (2011)

 Pseudobulbar affect: the spectrum of clinical presentations, etiologies & treatments
normalization may have resulted from agonism of pre­synaptic
s-1 receptors or uncompetitive antagonism of postsynaptic
NMDA receptors, leading to reduced glutamatergic activity in
the cortex. Such reduction may contribute to improvements in
PBA symptoms by reducing transmission to the brainstem, thus
compensating for the proposed gate-control disinhibition deemed
responsible for PBA [31] .
Cerebellar mechanisms
As the CNS structure proposed to monitor context and modu-
late emotional expression accordingly, the cerebellum may be a
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key substrate in PBA pathophysiology [27] . Lesions confined to
the cerebellum [37–39] , to the basis pontis, a relay center to the
cerebellum [40–42] , or to the thalamus, an output node from the
cerebellum [43] , have been sufficient to produce PBA symptoms
without any other known brain pathology. Indeed, in a recent
detailed review of the available neuroanatomical evidence for
localization of PBA [30] , the basis pontis, a convergence point for
descending pathways carrying cerebellar input, “stands out as
the only identified site where a discrete lesion can cause [PBA].”
Understanding the functional anatomy and neurochemistry of
the cerebellum might therefore be particularly relevant for PBA
diagnosis and treatment.
The functions attributed to the cerebellum now extend beyond
For personal use only.
sensorimotor control to include cognitive function and affective
processing [44,45] . Based on data from anatomical, functional-
imaging and clinical studies in patients with cerebellar damage,
distinct cortico–pontine–cerebellar loops have been proposed to
underlie motor, cognitive and affective function [45] . Motor func-
tion is believed to be subserved by a circuit from sensori­motor
cortex to pontine nuclei to anterior parts of the cerebellum, while
cognitive and affective function may involve association cortex
and limbic areas with connections through pontine nuclei to pos-
terior regions of the cerebellum. Each loop is completed through
output connections to thalamus that then return to the originat-
ing cortical or limbic area [45] . It has been suggested that affec-
tive processing may be further subdivided, in that connections
between association cortex and cerebellar hemispheric lobules VI
and VII may relate especially to cognitive aspects of emotional
processing, such as empathy, while connections between lim-
bic structures and the posterior cerebellar vermis may be most
relevant to processes such as emotion-related autonomic func-
tion  [45] . Potential vermis involvement in autonomic responses
was demonstrated in a patient with a tumor in the vermis who
had pathological laughter followed by syncope [38] .
In consonance with the hypothesized cerebellar involvement in
PBA, the disproportionate laughter and crying characteristic of
PBA have been viewed as an ‘affective dysmetria’ related to pos-
terior cerebellar lesions, much as overreaching a target is defined
as a limb dysmetria related to anterior cerebellar lesions [46] . The
cytoarchitectonic structure of the cerebellar cortex supports this
concept, in that its uniformity across cerebellar regions [44] would
allow for uniform processing of information, with the connec-
tions to specific areas of the cerebrum determining whether limb
dysmetria, PBA (affective dysmetria), or dysregulation of some
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Review
other function results from cerebellar damage. PBA may be more
common in patients with cerebellar damage than has been rec-
ognized. Affective dysregulation, emotional lability and behav-
ioral disinhibition are common features of cerebellar cognitive
affective syndrome, a disorder characterized by abnormalities
in executive, visuospatial, linguistic and emotional function in
patients with infection, degeneration or lesions confined to the
cerebellum [47] . In a case-series study of patients with multiple
system atrophy–cerebellar type (MSA-C), a chart review (trig-
gered by the discovery of PBA in a single patient with MSA-C)
determined that 36% met PBA criteria [48] . This is the highest
prevalence rate reported for PBA outside the ALS population.
All patients in this series had cerebellar and brainstem atrophy
and, in addition to PBA, they demonstrated symptoms of auto-
nomic dysfunction (orthostatic hypotension), dysarthria and
other dysmetrias.
The cell types and their functional interactions within the
microcircuitry of the cerebellum suggest that it could perform
a gate-control function. The structure of the cerebellar cortex
consists of three organized cell layers (granular, Purkinje cell
and molecular), with Purkinje cells serving as the main proces-
sor of information. Granule cells receive information, via mossy
fibers, from the pontine nuclei. From granule cells, as many as
200,000 parallel fibers then transmit information to each Purkinje
cell [44] . Axons from Purkinje cells project to the deep cerebellar
nuclei, from which projections return through the thalamus to the
cerebral cortex [44] . Within the cerebellar microcircuitry, it has
been proposed that Golgi cells may perform a gating function on
cerebellar output. In a study in rats, Holtzman et al. noted that
activation of Golgi cells inhibits the firing of weakly activated
granule cells and leads to decreased firing in Purkinje cells [49] ;
however, when afferents from many parts of the periphery are
activated (by tactile stimulation in their study), most Golgi-cell
firing is depressed, allowing for an increase in granule-cell fir-
ing and consequent Purkinje-cell firing (Figure 2) . The researchers
proposed that the convergence of signals from spatially distinct
areas and possibly even from different sensory modalities that
occurs in Golgi cells and Purkinje cells sets up this circuit as a con-
text-specific gate for cerebellar output. Disruptions of inhibitory
pathways and related regulatory circuits would interfere with this
gate-control, lower the threshold for emotional expression, and
lead to uncontrolled cerebellar output and associated pathological
laughter and crying in patients with PBA.
Holtzman et al. also hypothesized that the mechanism under­
lying depression of Golgi-cell firing in their study may have
involved an increase in serotonergic activation of inhibitory cer-
ebellar Lugaro cells synapsing with Golgi cells, or possibly gluta-
matergic activation of inhibitory metabotropic glutamate recep-
tors on Golgi cells [49] . Although these speculations are intriguing
because of the use of serotonergic and antiglutamatergic drugs in
PBA, the function of various cells and neurotransmitters within
the cerebellar microcircuitry, or their specific role in PBA, has
not been clearly defined, and researchers continue their efforts
to elucidate potential mechanisms within this circuitry and their
potential role in cerebro–cerebellar loops [50–53] .
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Molecular
layer
Stellate
cell

Parallel
fiber
Basket
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cell

Granular Purkinje Lugaro

layer cell cell
Golgi
cell Granule
cell

Cerebellar
Mossy
white matter
fiber
Deep cerebellar
Climbing nuclei
fiber
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Cerebellar Cerebellar
input output

Figure 2. Circuitry of the cerebellum, including interactions that may be involved in a gating function relevant to emotional
expression. In brief, mossy fibers (from, for instance, the pontine nuclei) synapse with granule cells, which in turn distribute signals, via
parallel fibers, to several cells types. Of these, only Purkinje cells generate cerebellar cortical efflux (to the deep cerebellar nuclei). Among
cerebellar interneurons, stellate cells, basket cells and Lugaro cells are all inhibitory, while climbing fibers (from the inferior olivary
nucleus) are strongly disinhibitory. For their part, Golgi cells are remarkable for inhibiting granule cells.

Treatment of PBA
As mentioned above, treatment of PBA has primarily involved use
of medications that modulate serotonergic or glutamatergic neuro­
transmission. Serotonergic therapies such as amitriptyline and
fluoxetine may exert effects by increasing serotonin in the synapse,
and dextromethorphan may act via antiglutamatergic effects at
NMDA receptors and s-1 receptors. However, it is important to
note that SSRIs and tricyclic antidepressants have affinities to a
wide variety of receptor types, including s-1 receptors, although
binding affinities at the s-1 receptor are lower for fluoxetine and
amitriptyline than for dextromethorphan [54] . Similarly, the bind-
ing profile of dextromethorphan is not limited to s-1 or NMDA
receptors, but also includes affinities for the 5-HT transporter and
a-2 noradrenergic receptors (although lower than those reported
for fluoxetine or amitriptyline) [54] .
Serotonergic agents
Selective serotonin reuptake inhibitors, serotonin/norepinephrine
reuptake inhibitors (SNRIs) and tricyclic antidepressants are used
off-label to treat PBA, with evidence of efficacy based on findings
from case studies [4,27,39,55,56] , open-label trials [21,57] and placebo-
controlled trials [17,18,22,23,58,59] , most of which have been small.
The data from the placebo-controlled trials may be most helpful
for assessing efficacy, although these studies have been criticized
for not clearly defining PBA symptoms or requiring standard
diagnostic criteria and for using ill-defined or inconsistent efficacy
measures [1,30,60,61] . We identified six placebo-controlled trials
that evaluated PBA symptoms treated with fluoxetine, sertraline,
citalopram, nortriptyline or amitriptyline (Table 1) . Five of the six
studies enrolled post-stroke patients only [17,22,23,58,59] , and one
enrolled patients with MS [18] .
The largest of the trials had a double-blind, parallel-group
design [59] ; it assessed fluoxetine 20 mg/day versus placebo in
91 patients with post-stroke ‘emotional incontinence’, defined as
excessive or inappropriate laughing or crying or both (compared
with pre-stroke status) that had occurred on at least two occa-
sions, as judged by the patients and their relatives without use of
assessment tools. Some of these patients also had depression or
‘anger proneness’. The intensity of emotional incontinence was
measured on a visual analogue scale (VAS) at baseline and after

1082 Expert Rev. Neurother. 11(7), (2011)

 Pseudobulbar affect: the spectrum of clinical presentations, etiologies & treatments Review

Table 1. Placebo-controlled trials of pharmacotherapeutic options in pseudobulbar affect.

Drug class Study (year) Active drug vs Study design PBA N Main findings Ref.
placebo setting
Tricyclic Schiffer et al. Amitriptyline Crossover; 1 month per MS 12 Reduced episode rate [18]
antidepressants (1985) treatment
Robinson et al. Nortriptyline Parallel-group; 6 weeks Stroke 28 Reduced severity on [17]
(1993) validated scale (PLACS)
Selective serotonin Andersen et al. Citalopram Crossover; 3 weeks per Stroke 16 Reduced episode rate [22]
reuptake inhibitors (1993) treatment
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Brown et al. Fluoxetine Parallel-group; 10 days Stroke 20 Reduced severity on [23]

(1998) unvalidated scale
Burns et al. (1999) Sertraline Parallel-group; 8 weeks Stroke 28 Reduced lability on [58]
unvalidated scale
Choi-Kwon et al. Fluoxetine Parallel-group; 6 months Stroke 91 Reduced crying on [59]
(2006) unvalidated scale
Antiglutamatergics Panitch et al. DMQ Parallel-group; 12 weeks MS 150 Reduced severity on [63]
(2006) validated scale (CNS-LS);
reduced episode rate
Pioro et al. (2010) DMQ Parallel-group; 12 weeks ALS or MS 326 Reduced severity on [68]
validated scale (CNS-LS);
reduced episode rate
ALS: Amyotrophic lateral sclerosis; CNS-LS: Center for Neurologic Study–Lability Scale; DMQ: Dextromethorphan/quinidine; MS: Multiple sclerosis;
For personal use only.

PBA: Pseudobulbar affect; PLACS: Pathological Laughter and Crying Scale.

1, 3 and 6 months of treatment. Compared with the placebo
group, the fluoxetine-treated patients had significant mean per-
cent decreases from baseline at all follow-up visits for VAS crying
scores, but there were no significant differences in VAS laughing
scores at any follow-up. The percent of fluoxetine-treated patients
with self-reported improvement in emotional incontinence was
significantly greater than in the placebo group at all follow-up
visits in both the group with crying and the group with laughing
as a symptom. Adverse events were reported only for the study
group as a whole, which included patients with other disorders
of emotion.
Another, smaller parallel-group study of fluoxetine 20 mg/day
recruited 20 patients with a 4-week history of ‘emotionalism’
(undefined) [23] . After 3 and 10 days of treatment with fluoxetine,
scores on the modified Lawson and MacLeod scale (a measure of
severity of laughing or crying episodes) were significantly reduced
and the proportion of patients with >50% reduction in emotional
outbursts were significantly increased compared with placebo.
Adverse event rates were not reported. One sertraline-treated
patient withdrew because of skin rash.
Two small studies evaluated other SSRIs for PBA symp-
toms in post-stroke patients. In a double-blind, parallel-group
trial, 28 nondepressed patients with ‘lability of mood’ (unde-
fined) were treated with sertraline 50 mg or placebo daily for
8  weeks  [58] . A significantly higher proportion of the sertra-
line group had improvement on a lability scale that measured
frequency and other characteristics of tearfulness, and also on
a clinician’s impression of global change. Laughing episodes
were not reported. It was also not specified whether patients’
tearfulness was exaggerated or incongruent with experienced
emotion. Skin rash, hip fracture and death (due to stroke) were
reported as causes of study withdrawal in three patients from
the sertraline group.
The other study of an SSRI in post-stroke patients was a
double-blind crossover trial comparing citalopram 10–20 mg/
day with placebo, each administered for 3  weeks to patients
with ‘involuntary outbursts of crying’ [22] . Six of 16 enrolled
patients reported that crying was evoked by nonemotional stim-
uli, and three of 16 reported laughing in addition to crying.
Among 13 patients whose crying frequency could be assessed,
the proportion of patients with ≥50% decrease in crying epi-
sodes was significantly greater during citalopram treatment
compared with placebo. HRSD scores were also significantly
decreased (vs baseline). Changes in laughing episodes were not
described. Although adverse events were not comprehensively
described, a trend for increased incidence of orthostatic dizzi-
ness and insomnia and increased spasticity was reported during
citalopram treatment.
A single study evaluated a tricyclic antidepressant (nortrip-
tyline) in post-stroke patients with “pathological emotions or
depression with excessive crying”, as defined by the patient
or a referring physician [17] . During 6 weeks of double-blind
treatment, patients received nortriptyline (titrated up to
100 mg/day) or placebo. Two patients (one in each group of
14) had pathological laughter; the remainder had pathological
crying. Mean scores on the Pathological Laughter and Crying
Scale (PLACS) decreased significantly in the nortriptyline
group after 4 and 6  weeks of treatment compared with the
placebo group. A subset ana­lysis of patients with comorbid
major depression (n = 19) compared with nondepressed patients

www.expert-reviews.com 1083
 Review Miller, Pratt & Schiffer
(n = 9) found that response on PLACS did not differ based on
depression status. One patient discontinued because of sedation
on nortriptyline.
Only one double-blind study evaluated serotonergic medi-
cations in a population other than post-stroke patients. This
crossover trial evaluated 12 patients with MS and ‘involuntary
laughing or weeping’ who completed a month of amitriptyline
treatment (75 mg/day maximum dose) and a month of placebo
separated by a 1-week wash-out [18] . At baseline, two of these
patients had laughing and weeping episodes, two had laugh-
ing only, and eight had weeping only. Reduction in weekly epi-
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Florida State University on 10/31/14
sode rate was significantly greater after amitriptyline treatment
compared with placebo, as was the number of patients with a
clinical judgment of improvement in pathologic emotionality.
All patients with laughing episodes were considered respond-
ers to amitriptyline. Overall, BDI scores and HRSD scores did
not change significantly; ana­lysis by treatment group or in the
group of responders was not reported. Four patients required
amitriptyline dose reduction because of side effects including
dry mouth and drowsiness.
A recent Cochrane review analyzed studies of antidepressants
(SSRIs and tricyclic antidepressants) used for ‘emotionalism’ after
stroke [61] . Four of the studies reviewed above met the criteria for
inclusion [17,23,58,59] ; in addition, the review included a study that
For personal use only.
enrolled patients with depression without a requirement of emo-
tionalism [62] . The ana­lysis found that the frequency and intensity
of emotionalism were reduced by use of antidepressants; however,
the 95% confidence intervals were wide, indicating that benefit
may be small, or possibly in the wrong direction. The authors
concluded that recommendations on treatment of post-stroke
emotionalism could not be made until better-designed trials
were performed. Recommended methodological improvements
included standardization of methods for diagnosing emotionalism
and measuring changes, use of a standard assessment of depres-
sion (to be treated as a confounder), increase in the numbers
of patients enrolled, and systematic collection and reporting of
adverse event data.
Dextromethorphan/quinidine
Dextromethorphan/quinidine has antiglutamatergic properties
and is an emerging therapy in PBA [35,63] . Of its constituent
agents, dextromethorphan has shown neuroprotective effects in
animal models and, for this reason, it was studied as a poten-
tial treatment for ALS. Although neuroprotective effects were
not seen, it was serendipitously noted that PBA symptoms
decreased [63] . Because of the rapid metabolism of dextrometh-
orphan via CYP2D6 enzymes in the liver, it has been combined
with a low dose of quinidine (a CYP2D6 inhibitor) in order to
increase dextromethorphan plasma concentrations [64] .
Although dextromethorphan may affect serotonergic neuro-
transmission through binding at 5-HT transporters and receptors
involved in serotonergic function [54,65] , its effects on glutamater-
gic transmission via s-1 agonism could be particularly important
for PBA treatment. Dextromethorphan binding is most promi-
nent in the brainstem and cerebellum [66] , brain areas known
1084
to be rich in s-1 receptors [67] and key sites implicated in the
pathophysiology of PBA [37–42] . Evidence from an ERP study
also suggests glutamatergic modulation at the cortical level [36] .
Although the precise mechanisms of DMQ in ameliorating PBA
are not known, modulation of excessive glutamatergic transmis-
sion within cortico–pontine–cerebellar circuits may contribute
to its benefits.
Three large, parallel-group, double-blind, multicenter, indus-
try-sponsored trials have demonstrated efficacy of DMQ in
patients with PBA [35,63,68] . The first of these trials evaluated
twice-daily dosing with a combination of dextromethorphan
30 mg plus quinidine 30 mg (DMQ 30/30, n = 65) compared
with each drug taken individually at the same dose (dextro-
methorphan [DM] 30, n = 30, or quinidine [Q] 30, n = 34) for
28 days [35] . Enrolled patients had ALS and PBA, as indicated
by history and a score ≥13 on the Center for Neurologic Study
Lability Scale (CNS-LS)  [69,70] . Improvement in CNS-LS score
(average of day 15 and 29) was significantly greater in the DMQ
30/30 group than in either the DM 30 or Q 30 groups. Weekly
laughing and crying episode rates, as recorded on patient diaries,
were reduced significantly, by approximately twice as much in
the DMQ 30/30 group as in the DM 30 or Q 30 groups. Scores
on HRSD were low at baseline (<6 in each treatment group) and
did not correlate with CNS-LS scores, indicating that patients
were not depressed and suggesting that PBA improvements were
not mediated by improvements in depression. Nausea, diarrhea,
dizziness and headache were the most frequently reported adverse
events for DMQ. Withdrawals due to adverse events were reported
in 24% of the DMQ group versus 6% of the DM group and 5%
of the Q group.
A second double-blind trial of DMQ 30/30 enrolled patients
with MS and clinically diagnosed PBA with baseline CNS-LS
scores ≥13 [63] . Screening for depression symptoms was not
reported; however, antidepressant use was not permitted. Patients
received DMQ 30/30 (n = 76) or placebo (n = 74) twice daily
for 12 weeks. Adjusted mean scores on CNS-LS (averaged across
weeks 2, 4, 8 and 12) were significantly reduced in the DMQ
30/30 group versus placebo. The mean number of episodes of
laughing and crying per week (from diaries) was also significantly
lower for DMQ 30/30 than for placebo. Dizziness, nausea and
headache were the most common adverse events in the DMQ
group, although headache was reported by a greater percentage
of placebo-treated patients than DMQ-treated patients. Adverse
events led to treatment discontinuation in 14.5% of the DMQ
group and 10.8% of the placebo group.
A recent placebo-controlled trial for new-drug submission to
the FDA evaluated lower quinidine doses in DMQ for PBA [68] .
Nondepressed patients with MS or ALS and clinically significant
PBA, as defined by a CNS-LS score ≥13, received DM 30 mg
plus Q 10 mg (DMQ 30/10; n = 110), DM 20 mg plus Q 10 mg
(DMQ 20/10; n = 107) or placebo (n = 109) twice daily for
12  weeks. Episodes of laughing and crying were reported on
patient diaries throughout the study, and CNS-LS scores were
obtained on weeks 2, 4, 8 and 12. The reduction in daily epi-
sode rate was significantly greater in both DMQ groups than for
Expert Rev. Neurother. 11(7), (2011)
 Pseudobulbar affect: the spectrum of clinical presentations, etiologies & treatments Review

placebo, with reduction exceeding that for placebo by 46.9% in
the DMQ 30/10 group and by 49.0% in the DMQ 20/10 group.
Moreover, in both DMQ groups the proportion of patients report-
ing remission (no episodes throughout the study’s final 14 days)
was significantly greater than for placebo. Mean reduction in
CNS-LS score was also significantly greater than for placebo.
Mental Summary mean score on the Medical Outcomes Study
36-Item Short-Form Health Survey (and its subdomains for social
functioning and mental health) were significantly improved in the
DMQ 30/10 group versus placebo. A significant improvement in
the mean BDI II score was also demonstrated in the DMQ 30/10
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Florida State University on 10/31/14
Expert commentary
Pseudobulbar affect is a common and burdensome disorder in
patients with neurologic insult. From a patient- and family-cen-
tered perspective, the impact on daily life is not ‘pseudo’ but very
real and very debilitating. Accordingly, it is important to recognize
PBA and distinguish this condition from depression and other
mood disorders. Although the mechanisms that underlie PBA are
not fully known, recent data suggest involvement of cortico–pon-
tine–cerebellar circuits, including potential inputs from sensory
cortical areas. Disruption of frontal and cortical motor inputs into
these circuits, or of the cerebellum itself, may impair its ability to

group as compared with the placebo group, although patients
were not clinically depressed at baseline. The authors suggested
that these improvements may have resulted from quality of life
improvements related to a reduction in PBA episodes, but analge-
sic and antidepressant effects of DMQ, as part of its more general
psychotropic actions, are also possible [71,72] .
The overall adverse-event rate was similar regardless of treat-
ment group. Falls, dizziness, headache, diarrhea and nausea were
the most commonly reported event types; falls and headache were
slightly more frequent for placebo than in either DMQ group,
dizziness and diarrhea were more frequent in both DMQ groups
than for placebo, and nausea rates were highest in the DMQ
30/10 group and lowest in the DMQ 20/10 group. Adverse-event-
For personal use only.
act as a gate-control for emotional expression. Therapeutically, the
circuits involved in PBA may be affected by drugs that modulate
any number of neurotransmitters; however, current evidence sug-
gests that serotonergic and glutamatergic transmission play key
roles. As a therapeutic target, the former has been addressed by
antidepressants, including SSRIs and tricyclic agents. The latter
is now addressed by DMQ, a novel PBA therapy with distinctive
antiglutamatergic mechanisms of action. In large, well-controlled
trials, DMQ has demonstrated efficacy versus either of its com-
ponents (DM or Q) and versus placebo. The recent approval of
DMQ for PBA makes it the first medication with this indication
and offers a needed treatment option.

related withdrawals were most common in the DMQ 20/10 group
(9.3%), followed by the DMQ 30/10 group (5.5%) and the pla-
cebo group (1.8%). Seven deaths were reported (three for DMQ
30/10, three for DMQ 20/10, and one for placebo), all of which
were considered related to respiratory causes likely resulting from
progression of ALS.
Although long-term DMQ usage in PBA has not been exten-
sively studied, a 12-week open-label extension (OLE) of the above
trial reported continuing efficacy of DMQ 30/10 (the only dose
used). CNS-LS scores decreased further from OLE baseline, with
statistical significance regardless of treatment received during
the double-blind phase; however, this reduction was numerically
greatest in the group that had previously received placebo [72] .
Five-year view
The terminology used to describe PBA has been confusing and mis-
leading, and despite the condition’s impact on patient quality of life,
the diagnosis of PBA is often missed. Recently proposed diagnostic
criteria and the availability of an FDA-approved pharmaco­therapy,
DMQ, may help to increase the recognition and treatment of PBA.
Although SSRIs and tricyclic antidepressants have shown benefit,
larger trials with better control are needed to evaluate those off-label
therapies more fully. Meanwhile, elucidation of the mechanisms
underlying PBA can be expected to advance. Neuroimaging studies
have already refined our understanding of the condition’s neuroana-
tomical substrates. Electrophysiological studies may now assume
a prominent role, aiding efforts not only to understand PBA, but

Key issues
• Pseudobulbar affect (PBA) is a common comorbidity and source of psychosocial disability in patients with neurologic insult. However,
the terminology utilized to describe it has been unclear and confusing, perhaps contributing to both under- and mis-diagnosis.
• Although the pathophysiologic mechanisms responsible for PBA are not yet well understood, recent data suggest dysfunction of
cortico–pontine–cerebellar circuits, potentially affecting cerebellar input from sensory as well as frontal and motor cortical areas.
• Disruption of the microcircuitry of the cerebellum itself may likewise impair its ability to act as a gate-control for motor expression
of emotion.
• Disruption of cerebellar capacity to modulate its output based on context may constitute a disinhibition reducing the threshold for
emotional expression, conceivably producing an ‘affective dysmetria’ analogous to limb dysmetria.
• Neurochemically, the circuits involved in PBA may be affected by drugs that modulate any of a variety of neurotransmitters. However,
current evidence suggests that serotonergic and glutamatergic transmission play key roles.
• Although antidepressants have shown benefit in PBA, interpretation of the clinical data is limited by the small numbers of patients
studied and by the previous lack of standardization of PBA diagnostic criteria and measures of PBA severity.
• Dextromethorphan/quinidine is a novel PBA therapy with antiglutamatergic actions. Its recent FDA approval for treating PBA makes it
the first medication with this indication.
• As life expectancy lengthens, the broad variety of neurologic disorders underlying PBA – for example, stroke, Alzheimer’s disease and
Parkinson’s disease – will only become more common, creating a heightened need for PBA recognition and treatment.

www.expert-reviews.com 1085
 Review Miller, Pratt & Schiffer

also to differentiate it from mood disorders not simply phenomeno­
logically but also neurophysiologically and neuro­chemically. As a
facet of the overall research efforts, intensified study of the hypoth-
esis that cerebellar microcircuitry performs a context-specific ‘gate-
control’ function may support the conceptualization of PBA as
essentially a dysmetria. As another facet of the overall research,
preclinical studies of glutamatergic neurotransmission and clinical
studies of its therapeutic modulation may identify potential benefits
such as analgesia.
Financial & competing interests disclosure
Ariel Miller has indicated that he receives travel expenses for speaking engage-
ments from Avanir Pharmaceuticals. The authors have no other relevant
affiliations or financial involvement with any organization or entity with a
financial interest in or financial conflict with the subject matter or materials
discussed in the manuscript apart from those disclosed.
Editorial assistance in the preparation of this manuscript was provided
by the Curry Rockefeller Group, LLC. Support for this assistance was funded
by Avanir Pharmaceuticals.

References 10 Starkstein SE, Migliorelli R, Teson A et al. difficulties that researchers encounter in
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Florida State University on 10/31/14

Papers of special note have been highlighted as:
• of interest
•• of considerable interest
1 Schiffer R, Pope LE. Review of
pseudobulbar affect including a novel and
potential therapy. J. Neuropsychiatry Clin.
Neurosci. 17(4), 447–454 (2005).
• Useful survey of pseudobulbar affect
(PBA), including the difficulties arising
from its confusing terminology.
2 Wortzel HS, Oster TJ, Anderson CA,
Arciniegas DB. Pathological laughing and
crying: epidemiology, pathophysiology and
treatment. CNS Drugs 22(7), 531–545
For personal use only.
Prevalence and clinical correlates of
pathological affective display in Alzheimer’s
disease. J. Neurol. Neurosurg. Psychiatry
59(1), 55–60 (1995).
11 Zeilig G, Drubach DA, Katz-Zeilig M,
Karatinos J. Pathological laughter and crying
in patients with closed traumatic brain
injury. Brain Inj. 10(8), 591–597 (1996).
12 Tateno A, Jorge RE, Robinson RG.
Pathological laughing and crying following
traumatic brain injury. J. Neuropsychiatry
Clin. Neurosci. 16(4), 426–434 (2004).
13 Sacco S, Sarà M, Pistoia F, Conson M,
Albertini G, Carolei A. Management of
attempting to obtain meaningful clinical
data, in this case for the tricyclic
agent nortriptyline.
18 Schiffer R, Herndon RM, Rudick RA.
Treatment of pathological laughing and
weeping with amitriptyline. N. Engl. J.
Med. 312(23), 1480–1482 (1985).
19 Phuong L, Garg S, Duda JE, Stern MB,
Weintraub D. Involuntary emotional
expression disorder (IEED) in Parkinson’s
disease. Parkinsonism Relat. Disord. 15(7),
511–515 (2009).
20 Calvert T, Knapp P, House A. Psychological
associations with emotionalism after stroke.

(2008).
3 Gallagher JP. Pathologic laughter and crying
in ALS: a search for their origin. Acta
Neurol. Scand. 80(2), 114–117 (1989).
4 Kim SW, Shin IS, Kim JM, Lim SY,
Yang SJ, Yoon JS. Mirtazapine treatment for
pathological laughing and crying after
stroke. Clin. Neuropharmacol. 28(5),
249–251 (2005).
5 Pratt RT. An investigation of the psychiatric
aspects of disseminated sclerosis. J. Neurol.
Neurosurg. Psychiatry 14(4), 326–335
(1951).
6 Feinstein A, Feinstein K, Gray T, O’Connor
P. Prevalence of neurobehavioral correlates
of pathological laughing and crying in
multiple sclerosis. Arch. Neurol. 54(9),
1116–1121 (1997).
7 Petracca GM, Jorge RE, Ación L, Weintraub
D, Robinson RG. Frequency and correlates
of involuntary emotional expression disorder
in Parkinson’s disease. J. Neuropsychiatry
Clin. Neurosci. 21(4), 406–412 (2009).
8 Siddiqui MS, Fernandez HH, Garvan CW
et al. Inappropriate crying and laughing in
Parkinson disease and movement disorders.
World J. Biol. Psychiatry 10(3), 234–240
(2009).
9 Strowd RE, Cartwright MS, Okun MS,
Haq I, Siddiqui MS. Pseudobulbar affect:
prevalence and quality of life impact in
movement disorders. J. Neurol. 257(8),
1382–1387 (2010).
pathologic laughter and crying in patients
with locked-in syndrome: a report of 4
cases. Arch. Phys. Med. Rehabil. 89(4),
775–778 (2008).
14 Arciniegas DB, Lauterbach EC,
Anderson KE et al. The differential
diagnosis of pseudobulbar affect (PBA).
Distinguishing PBA among disorders of
mood and affect. Proceedings of a
roundtable meeting. CNS Spectr. 10(5),
1–14 (2005).
15 Arciniegas DB, Topkoff J. The
neuropsychiatry of pathologic affect:
an approach to evaluation and treatment.
Semin. Clin. Neuropsychiatry 5(4),
290–306 (2000).
16 Cummings JL, Arciniegas DB, Brooks BR
et al. Defining and diagnosing involuntary
emotional expression disorder. CNS Spectr.
11(Suppl. 6), 1–7 (2006).
• Survey incorporating the most recent
efforts to resolve the terminological
difficulties and standardize the
diagnostic criteria.
17 Robinson RG, Parikh RM, Lipsey JR,
Starkstein SE, Price TR. Pathological
laughing and crying following stroke:
validation of a measurement scale and a
double-blind treatment study. Am. J.
Psychiatry 150(2), 286–293 (1993).
• Early double-blind, placebo-controlled
antidepressant trial that also validated a
syndrome-severity scale, illustrating the
J. Neurol. Neurosurg. Psychiatry 65(6),
928–929 (1998).
21 Seliger GM, Hornstein A, Flax J, Herbert J,
Schroeder K. Fluoxetine improves
emotional incontinence. Brain Inj. 6(3),
267–270 (1992).
22 Andersen G, Vestergaard K, Riis JO.
Citalopram for post-stroke pathological
crying. Lancet 342(8875), 837–839
(1993).
23 Brown KW, Sloan RL, Pentland B.
Fluoxetine as a treatment for post-stroke
emotionalism. Acta Psychiatr. Scand. 98(6),
455–458 (1998).
24 Iannaccone S, Ferini-Strambi L.
Pharmacologic treatment of emotional
lability. Clin. Neuropharmacol. 19(6),
532–551 (1996).
25 Panzer MJ, Mellow AM. Antidepressant
treatment of pathologic laughing or crying
in elderly stroke patients. J. Geriatr.
Psychiatry Neurol. 5(4), 195–199 (1992).
26 Mayberg HS. Modulating dysfunctional
limbic-cortical circuits in depression:
towards development of brain-based
algorithms for diagnosis and optimised
treatment. Br. Med. Bull. 65, 193–207
(2003).
27 Parvizi J, Anderson SW, Martin CO,
Damasio H, Damasio AR. Pathological
laughter and crying: a link to the
cerebellum. Brain 124(Pt 9), 1708–1719
(2001).

1086 Expert Rev. Neurother. 11(7), (2011)

 Pseudobulbar affect: the spectrum of clinical presentations, etiologies & treatments
• Early advocacy of the hypothesis
that the cerebellum regulates the
context-dependent expression of crying
and laughter.
28 Ghaffar O, Chamelian L, Feinstein A.
Neuroanatomy of pseudobulbar affect:
a quantitative MRI study in multiple
sclerosis. J. Neurol. 255(3), 406–412
(2008).
29 Wilson SAK. Some problems in neurology.
J. Neurol. Psychopathol. 4, 299–333 (1924).
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Florida State University on 10/31/14
30 Parvizi J, Coburn KL, Shillcutt SD et al.
Neuroanatomy of pathological laughing
and crying: a report of the American
Neuropsychiatric Association Committee
on Research. J. Neuropsychiatry Clin.
Neurosci. 21(1), 75–87 (2009).
•• Detailed examination of the
neuroanatomical evidence guiding efforts
to uncover the mechanisms of PBA.
31 Haiman G, Pratt H, Miller A. Brain
responses to verbal stimuli among multiple
sclerosis patients with pseudobulbar affect.
J. Neurol. Sci. 271(1–2), 137–147 (2008).
•• Initial application of electrophysiological
For personal use only.
methods to uncovering the mechanisms
of PBA.
32 von Bohlen und Halbach O, Dermietzel R.
Serotonin (5-hydroxytryptamine). In:
Neurotransmitters and Neuromodulators:
Handbook of Receptors and Biological Effects
(Second Edition). von Bohlen und Halbach
O, Dermietzel R (Eds). Wiley-VCH Verlag
GmbH & Co. KGaA, Weinheim,
Germany, 132–143 (2006).
33 Petty F, Davis LL, Kabel D, Kramer GL.
Serotonin dysfunction disorders:
a behavioral neurochemistry perspective.
J. Clin. Psychiatry 57(Suppl. 8), 11–16
(1996).
34 von Bohlen und Halbach O, Dermietzel R.
Glutamate and aspartate. In:
Neurotransmitters and Neuromodulators:
Handbook of Receptors and Biological Effects
(Second Edition). von Bohlen und Halbach
O, Dermietzel R (Eds). Wiley-VCH Verlag
GmbH & Co. KGaA, Weinheim,
Germany, 90–107 (2006).
35 Brooks BR, Thisted RA, Appel SH et al.
Treatment of pseudobulbar affect in ALS
with dextromethorphan/quinidine:
a randomized trial. Neurology 63(8),
1364–1370 (2004).
36 Haiman G, Pratt H, Miller A. Effects of
dextromethorphan/quinidine on auditory
event-related potentials in multiple sclerosis
patients with pseudobulbar affect. J. Clin.
Psychopharmacol. 29(5), 444–452 (2009).
www.expert-reviews.com
•• Initial application of electrophysiological
methods to elucidate treatment effects
in PBA.
37 Andersen G, Ingeman-Nielsen M,
Vestergaard K, Riis JO. Pathoanatomic
correlation between poststroke
pathological crying and damage to brain
areas involved in serotonergic
neurotransmission. Stroke 25(5),
1050–1052 (1994).
Famularo G, Corsi FM, Minisola G,
38
De Simone C, Nicotra GC. Cerebellar
tumour presenting with pathological
laughter and gelastic syncope. Eur. J.
Neurol. 14(8), 940–943 (2007).
39 Parvizi J, Schiffer R. Exaggerated crying
and tremor with a cerebellar cyst.
J. Neuropsychiatry Clin. Neurosci. 19(2),
187–190 (2007).
40 Tei H, Sakamoto Y. Pontine infarction due
to basilar artery stenosis presenting as
pathological laughter. Neuroradiology
39(3), 190–191 (1997).
41 Arif H, Mohr JP, Elkind MS. Stimulus-
induced pathologic laughter due to basilar
artery dissection. Neurology 64(12),
2154–2155 (2005).
42 Oh K, Kim HJ, Kim BJ, Park KW,
Lee DH. Pathological laughter as an
unusual manifestation of acute stroke. Eur.
Neurol. 59(1–2), 83–84 (2008).
43 Lauterbach EC, Price ST, Spears TE,
Jackson JG, Kirsh AD. Serotonin
responsive and nonresponsive diurnal
depressive mood disorders and pathological
affect in thalamic infarct associated with
myoclonus and blepharospasm. Biol.
Psychiatry 35(7), 488–490 (1994).
44 Ramnani N. The primate cortico-
cerebellar system: anatomy and function.
Nature Rev. 7(7), 511–522 (2006).
45 Stoodley CJ, Schmahmann JD. Evidence
for topographic organization in the
cerebellum of motor control versus
cognitive and affective processing. Cortex
46(7), 831–844 (2010).
• Recent survey of the remarkable breadth
of cerebellar function.
46 Schmahmann JD, Weilburg JB,
Sherman JC. The neuropsychiatry of the
cerebellum – insights from the clinic.
Cerebellum 6(3), 254–267 (2007).
•• Intriguing conceptualization of
cerebellar dysfunction as a variety
of dysmetrias.
47 Schmahmann JD, Sherman JC. The
cerebellar cognitive affective syndrome.
Brain 121(Pt 4), 561–579 (1998).
Review
48 Parvizi J, Joseph J, Press DZ,
Schmahmann JD. Pathological laughter
and crying in patients with multiple
system atrophy-cerebellar type. Mov.
Disord. 22(6), 798–803 (2007).
49 Holtzman T, Rajapaksa T, Mostofi A,
Edgley SA. Different responses of rat
cerebellar Purkinje cells and Golgi cells
evoked by widespread convergent sensory
inputs. J. Physiol. 574(Pt 2), 491–507
(2006).
50 Barmack NH, Yakhnitsa V. Functions of
interneurons in mouse cerebellum.
J. Neurosci. 28(5), 1140–1152 (2008).
51 Crowley JJ, Fioravante D, Regehr WG.
Dynamics of fast and slow inhibition from
cerebellar Golgi cells allow flexible control
of synaptic integration. Neuron 63(6),
843–853 (2009).
52 Prsa M, Dash S, Catz N, Dicke PW,
Thier P. Characteristics of responses of
Golgi cells and mossy fibers to eye saccades
and saccadic adaptation recorded from the
posterior vermis of the cerebellum.
J. Neurosci. 29(1), 250–262 (2009).
Dean P, Porrill J, Ekerot CF, Jörntell H. The
53
cerebellar microcircuit as an adaptive filter:
experimental and computational evidence.
Nat. Rev. Neurosci. 11(1), 30–43 (2010).
54 Werling LL, Keller A, Frank JG,
Nuwayhid SJ. A comparison of the binding
profiles of dextromethorphan, memantine,
fluoxetine and amitriptyline: treatment of
involuntary emotional expression disorder.
Exp. Neurol. 207(2), 248–257 (2007).
55 Kim JS. Pathologic laughter after unilateral
stroke. J. Neurol. Sci. 148(1), 121–125
(1997).
56 Ferentinos P, Paparrigopoulos T,
Rentzos M, Evdokimidis I. Duloxetine for
pathological laughing and crying. Int. J.
Neuropsychopharmacol. 12(10), 1429–1430
(2009).
57 Müller U, Murai T, Bauer-Wittmund T,
von Cramon DY. Paroxetine versus
citalopram treatment of pathological crying
after brain injury. Brain Inj. 13(10),
805–811 (1999).
58 Burns A, Russell E, Stratton-Powell H,
Tyrell P, O’Neill P, Baldwin R. Sertraline
in stroke-associated lability of mood. Int. J.
Geriatr. Psychiatry 14(8), 681–685 (1999).
59 Choi-Kwon S, Han SW, Kwon SU,
Kang DW, Choi JM, Kim JS. Fluoxetine
treatment in poststroke depression,
emotional incontinence, and anger
proneness: a double-blind, placebo-
controlled study. Stroke 37(1), 156–161
(2006).
1087
 Review Miller, Pratt & Schiffer
60 Miller A, Panitch H. Therapeutic use of
dextromethorphan: key learnings from
treatment of pseudobulbar affect. J. Neurol.
Sci. 259(1–2), 67–73 (2007).
61 Hackett ML, Yang M, Anderson CS,
Horrocks JA, House A. Pharmaceutical
interventions for emotionalism after stroke.
Cochrane Database Syst. Rev. (2),
CD003690 (2010).
62 Murray V, von Arbin M, Bartfai A et al.
Double-blind comparison of sertraline and
placebo in stroke patients with minor
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Florida State University on 10/31/14
depression and less severe major depression.
J. Clin. Psychiatry 66(6), 708–716 (2005).
63 Panitch HS, Thisted RA, Smith RA et al.
Randomized, controlled trial of
dextromethorphan/quinidine for
pseudobulbar affect in multiple sclerosis.
Ann. Neurol. 59(5), 780–787 (2006).
64 Pope LE, Khalil MH, Berg JE, Stiles M,
Yakatan GJ, Sellers EM. Pharmacokinetics
of dextromethorphan after single or
multiple dosing in combination with
quinidine in extensive and poor
metabolizers. J. Clin. Pharmacol. 44(10),
1132–1142 (2004).
For personal use only.
1088
65 Bermack JE, Debonnel G. Distinct
modulatory roles of s receptor subtypes on
glutamatergic responses in the dorsal
hippocampus. Synapse 55(1), 37–44 (2005).
66 Craviso GL, Musacchio JM. High-affinity
dextromethorphan binding sites in guinea
pig brain. I. Initial characterization. Mol.
Pharmacol. 23(3), 619–628 (1983).
67 Maurice T, Urani A, Phan VL, Romieu P.
The interaction between neuroactive steroids
and s-1 receptor function: behavioral
consequences and therapeutic opportunities.
Brain Res. Rev. 37(1–3), 116–132 (2001).
68 Pioro EP, Brooks BR, Cummings J et al.
Dextromethorphan plus ultra low-dose
quinidine reduces pseudobulbar affect.
Ann. Neurol. 68(5), 693–702 (2010).
•• Large double-blind, placebo-controlled
dextromethorphan/quinidine trial, pivotal
in the treatment’s approval as first-in-class
PBA therapy.
69 Moore SR, Gresham LS, Bromberg MB,
Kasarkis EJ, Smith RA. A self report
measure of affective lability. J. Neurol.
Neurosurg. Psychiatry 63(1), 89–93 (1997).
70 Smith RA, Berg JE, Pope LE, Callahan JD,
Wynn D, Thisted RA. Validation of the
CNS emotional lability scale for
pseudobulbar affect (pathological laughing
and crying) in multiple sclerosis patients.
Mult. Scler. 10(6), 679–685 (2004).
71 Thisted RA, Klaff L, Schwartz SL et al.
Dextromethorphan and quinidine in adult
patients with uncontrolled painful diabetic
peripheral neuropathy: a 29-day,
multicenter, open-label, dose-escalation
study. Clin. Ther. 28(10), 1607–1618
(2006).
72 Pioro EP, Brooks BR, Cummings J et al.
Persistent efficacy of dextromethorphan
(DM)/quinidine (Q) for pseudobulbar
affect (PBA): results from a 12-Week,
Open-Label Extension (OLE) Study.
Presented at: 62nd American Academy of
Neurology Annual Meeting. Toronto,
Ontario, Canada, 10–17 April 2010.
Expert Rev. Neurother. 11(7), (2011)