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Areal reason for patients with pseudobulbar affect to smile.

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CLINICAL NEUROSCIENCE
A Real Reason for Patients with
Pseudobulbar Affect to Smile
Howard J. Rosen, MD,1,2 and Jeffrey Cummings, MD3
Pseudobulbar affect (PBA) is a dramatic disorder of emotional expression and regulation characterized by uncontrollable
episodes of laughing and crying that often cause embarrassment, curtailment of social activities, and reduction in quality of
life. The disorder occurs in patients with brain injury caused by many types of neurological disease, including stroke, tumors,
and neurodegenerative gray and white matter disorders. Although the pathophysiology is unknown, PBA may relate to release
of brainstem emotional control centers from regulation by the frontal lobes. Diagnosis of PBA can be difficult and relies on
careful characterization of episodes and differentiation from depression. Although there are no US Food and Drug Administration–approved treatments for PBA, several agents have been shown to be effective, including tricyclic antidepressants,
selective serotonin reuptake inhibitors, and a new agent containing dextromethorphan and quinidine. The growing number
of treatment options, some of great benefit to patients, highlights the importance of accurate diagnosis of this disorder.
Ann Neurol 2007;61:92–96
Pseudobulbar affect (PBA) is a disorder of emotional
expression and regulation characterized by uncontrollable outbursts of laughing, crying, or both that are
inconsistent with, or disproportionate to, the emotions felt by the patient. It has been recognized as a
distinctive disorder for more than 100 years, but interest has increased recently with the publication of
two trials demonstrating the efficacy of the combination of dextromethorphan and quinidine (DM/Q).1,2
Episodes of PBA can have a significant adverse impact
on quality of life by disrupting communication, causing embarrassment and frustration, and forcing patients to curtail their social activities.3 Thus, treatment can have a dramatic impact on quality of
life, highlighting the importance of identifying the
disorder.
Clinical Features
PBA can sometimes be difficult to diagnose. A key to
the diagnosis of PBA is recognizing that episodes are
incongruent with or are greatly exaggerated compared
with what the patient is feeling, such as laughing at a
funeral. Phenomenologically, PBA episodes have a paroxysmal quality at onset, and often occur in an inappropriate context. Before they can return to their
preepisode activities, patients must often “wait out” an
episode, which typically resolves after a few seconds or
minutes.
From the 1Department of Neurology and 2Memory and Aging Center, University of California, San Francisco; and 3Departments of
Neurology, Psychiatry, and Behavioral Neuroscience, The David
Geffen School of Medicine at University of California Los Angeles,
University of California, Los Angeles, CA.
Received Sep 29, 2006. Accepted for publication Oct 13, 2006.
92
In 1969, Poeck4 crystallized the features of PBA into
four criteria. First, the episodes are inappropriate to the
situation and can be precipitated by nonspecific stimuli, such as contraction of facial muscles, removal of
bedcovers, or the approach of someone toward the patient. Second, there is not a close relation between the
emotional expression and how the patient is feeling.
Third, the episodes are relatively stereotyped, and it is
difficult for patients to control the extent and duration
of the episodes. Last, there are no episodic mood
changes corresponding to the episodes, and there is no
sense of relief as the emotions are expressed. This last
criterion tries to capture the fact that the episodes appear to come unprovoked and out of context. Although Poeck’s criteria and the literature in general
give the impression that there are no specific precipitants, this is often not the case.5–7 Crying episodes can
be induced by stimuli that may normally induce crying, such as touching or poignant scenes, and patients
may be able to identify specific thoughts that reliably
induce the phenomenon. This can be useful in the
clinic, because discussing the episodes and their precipitants can be enough to precipitate the phenomenon,
and thus allow a clinician the opportunity to observe
them.
All these features serve to differentiate PBA from
depression, where crying usually is context appropriate.8 Although patients with depression may deny
Published online Jan 9, 2007 in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.21056
Address correspondence to Dr Rosen, UCSF Department of Neurology, Memory and Aging Center, 350 Parnassus Avenue, Box
1207, Suite 706, San Francisco, CA 94143.
E-mail: hrosen@memory.ucsf.edu
© 2007 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
that they are depressed because of the associated
stigma, they will usually admit that the things that
make them cry are sad or disturbing in some way.
Statements such as “I’m a happy person; there’s no
reason I should be crying” (possible depression) must
be differentiated from “I know my face looks sad, but
I’m not really feeling sad at all” (PBA). As discussed
later, PBA occurs exclusively in the setting of
neurological disease. The same conditions that induce
PBA are also frequently associated with depression,
and thus the two may cooccur, increasing the
difficulty of diagnosis. Only by characterization of
the episodes of laughing and crying themselves, including their precipitants and the associated emotions, if any, can PBA be differentiated from crying
caused by depression. PBA can be the first symptom
of neurological illness; thus, episodes of PBA
occurring in the absence of known central nervous
system pathology should prompt a neurological evaluation.
Lesion-behavior studies have also been of limited
use for advancing our understanding the pathophysiology of PBA. Focal lesions causing PBA have been
described in nearly every part of the brain, including
frontal cortical and subcortical structures, 4,14 –16
brainstem regions,14,16 –21 and anterior temporal regions.6 It has been observed in both unilateral and
bilateral injury.4,6 PBA from isolated parietal or occipital lesions is rarely reported.15 Although the caveats regarding diagnostic criteria apply to the lesion behavior studies and the prevalence data, it is reasonable
to infer from the bulk of these studies that PBA is
more closely associated with anterior cerebral lesions,
most of which could plausibly affect the descending
motor systems that Wilson10 highlighted, either in
the cerebral cortex, basal ganglia/internal capsule region, or the brainstem. More evidence for a frontally
based mechanism comes from studies demonstrating
that PBA in ALS22 and MS23 is associated with cognitive evidence of frontal lobe dysfunction.
Cause of Pseudobulbar Affect
PBA has been recognized for well more than a century.
In fact, Darwin9 noted the disorder in his studies of
human emotion. However, Wilson10 published the
first systematic study of the disorder in 1924; Wilson
observed that it is frequently associated with damage to
descending motor systems. Wilson linked the phenomenon to normal-appearing, involuntarily expressed
emotions that occur in the context of upper motor
neuron lesions, even with facial paresis. He theorized
that PBA represents the release of a fasciorespiratory
control center for emotional expression in the brainstem from voluntary control by higher cortical brain
centers.
Unfortunately, since the writings of Wilson, little
progress in understanding the pathophysiology of
PBA has been made. Although the disorder has been
described exclusively in the context of neurological
disease, the types of pathophysiology involved are numerous. 7,11,12 PBA is probably most common in
amyotrophic lateral sclerosis (ALS), where prevalence
has been estimated as high as 50%,13 followed by
multiple sclerosis (MS). Atypical Parkinsonian disorders (especially progressive supranuclear palsy) are another common clinical context. PBA also occurs after traumatic brain injury and with focal injury
from brain tumors and strokes. The prevalence of
PBA within and across these disorders is difficult to
assess, because the difficulty in recognizing the disorder has led to differences in diagnostic approaches,
with some authors accepting behaviors that are
congruent with mood, 6 or not differentiating
mood-congruent from mood-incongruent laughing
and crying.14
Nomenclature
Several terms are used interchangeably with PBA.
PBA is frequently used because the phenomenon often occurs in the setting of pseudobulbar palsy caused
by documented or putative frontal lobe injury.24
Some have argued that the link between PBA and pseudobulbar palsy is imperfect, and that other terms should
be preferred; however, the term is common and familiar to most physicians.
In contrast, more descriptive terms such as pathological laughing and crying,7,10 affective lability,25
emotional incontinence,26 and emotionalism27 may
have some advantages over PBA in that they do not
imply a specific pathophysiology or clinical context,
but they may be overly general. For example, pathological laughing and crying is also used to refer to
inappropriate laughter caused by gelastic epilepsy.28
The terms emotionalism and affective lability25 are
probably the least specific, and they are applicable to
crying from depression. The term emotional incontinence is clinically attractive because it evokes the characteristic paroxysmal quality to the episodes without
implying a specific cause; however, it has probably
been avoided because it is distasteful to patients.
Recently, the term involuntary emotional expression
disorder was coined.29 Although this term is somewhat counterintuitive in that most, if not all, true
emotional expression is involuntary, the term has
merit in that it does not imply a specific cause or a
specific clinical context, and it taps into the hypothesized pathophysiology emanating from failure of voluntary mechanisms for controlling emotional expression. Ultimately, the best term for this disorder will
likely emerge together with a better understanding of
its pathophysiology.
Rosen and Cummings: Pseudobulbar Affect
93
Table. Controlled Trials of Treatments for Pseudobulbar Affect
Author
Diagnosis
N
Design
Andersen and
colleagues32
Stroke
16
Double-blind, placebocontrolled, crossover
Citalopram
10–30mg/day
Brooks and
colleagues1
ALS
Randomized, doubleblind, controlled
DM 30mg/Q
30mg (n ⫽
70); DM
alone (n ⫽
33), Q alone
(n ⫽ 37)
1 tablet twice
daily
Lawson and
MacLeod5
Stroke
Double-blind, placebocontrolled crossover
Imipramine
10–20 mg
Panitch and
colleagues2
MS
Pentobarbitone
DM/Q
30mg/Q
30mg
30 mg
1 tablet twice
daily
Robinson
and colleagues33
Schiffer and
colleagues30
Stroke
28
Nortriptyline
MS
12
Escalating dose
to max of
100mg
Max: 75mg/
day (mean:
58mg)
a
140
7
150
Randomized, doubleblind, placebocontrolled
Randomized, doubleblind, placebocontrolled
Double-blind, placebocontrolled crossover
Agent(s)
Amitriptyline
Dose
Outcome
50% decrease in crying
episodes in 13/13 on
treatment vs 2/13 on
placebo
Greater improvement
in CNS-LS score in
DM/Q vs DM alone
and vs Q alone.
52% symptom-free
in DM/Qa vs 23%
receiving DM alone
and 12% Q alone
More improvement in
imipramine than
placebo or pentobarbitone
Greater improvement
in CNS-LS score in
DM/Q vs placebo.
25% with ⬎1 episode/weekb in
DM/Q vs 64% on
placebo
Greater improvement
in PLACS score in
treated group
8/12 with significant
improvement on
drug
In final 2 weeks of study.
b
In final 4 weeks of study.
ALS ⫽ amyotrophic lateral sclerosis; DM ⫽ dextromethorphan; Q ⫽ quinidine; CNS-LS ⫽ Center for Neurologic Study Lability Scale25;
MS ⫽ multiple sclerosis; PLACS ⫽ Pathological Laughing and Crying Scale.
Treatment
Treatment can be effective for PBA; however, the US
Food and Drug Administration has not yet approved
any agents for its treatment. Several small trials of
tricyclic antidepressants and selective serotonin reuptake inhibitors, some placebo controlled (reviewed
in the Table), have shown efficacy in PBA.5,30 –34
Support for the role of serotonin in PBA can be
found in studies showing reduced brainstem serotonin
transporter activity in patients with PBA from cortical
lesions.35 Case reports and case series have used other
antidepressants,36 dopaminergic agents37,38 and other
agents39 as well, with some success.
DM/Q has been shown to be effective in ameliorating PBA in both ALS and MS,1,2 and it has been
assessed in a larger number of patients than any previous drug used to treat PBA; however, it has not
been compared with the other agents that have previously shown efficacy. The utility of DM/Q for PBA
was discovered serendipitously during trials assessing
its use for altering disease progression in ALS.2 Pa-
94
Annals of Neurology
Vol 61
No 2
February 2007
tients spontaneously reported that it helped them
control their involuntary emotional outbursts.
The mechanism by which DM/Q helps PBA is unknown. DM, the active ingredient (Q is used to slow
metabolism of DM), is an N-methyl-D-aspartate
(NMDA) receptor antagonist,40 a property that originally prompted its study in ALS. An NMDA receptor–mediated mechanism for its effects in PBA appears unlikely because other NMDA antagonists, such
as riluzole, have not been reported to affect PBA in
ALS (although the specific site or type of NMDA antagonism could be important). DM is also a ␴-1 receptor agonist. The functions of these receptors and
their endogenous ligands are not known (endogenous
ligands may include sex steroids), but they are most
heavily expressed in limbic and motor regions in the
central nervous system and in the periphery,41 suggesting that they may play a role in emotional functions. Indeed, DM and other ␴-1 agonists have been
shown to reverse conditioned stress responses in
rats.42 Should DM/Q be approved and become avail-
able for clinical use, it will provide an important
treatment for PBA; however, the utility of this compound to treat other disinhibition and dysmodulation
syndromes will require exploration.
The choice of whether to prescribe DM/Q must
include cost considerations, side effects, and other
clinical factors. If depression is also evident, treatment
with an antidepressant should be considered first.
However, if the episodes are consistent with PBA and
antidepressants are not effective, DM/Q will represent
an important therapeutic choice. In the absence of a
head-to-head comparison between DM/Q and antidepressants, whether antidepressants should always be
tried first will depend on the cost and side effects of
DM/Q. Regardless, if approved by the US Food
and Drug Administration, DM/Q will become the
first agent approved for the management of a neuropsychiatric disorder in a neurological illness, and this
may be the initial step in a promising armamentarium
of agents for the treatment of neuropsychiatric
symptoms in neurologically compromised patients.
Disclosure
H.J.R. and J.C. have received consulting fees from
Avanir Pharmaceuticals.
This study was supported by the NIH (National Institute on Aging, K08 AG20760-02, H.J.R.; Alzheimer’s Disease Research Center (ADRC), 1 P50 AG-03-006-01, H.J.R.; P50 AG16570, J.C.),
California Department of Health Services/Alzheimer’s Disease
Program (DHS/ADP; 03-75271 and 04-35521, H.J.R.), Alzheimer’s Research Center of California (ARCC; J.C.), the Sidell Kagan Foundation (J.C.), and the Deane F. Johnson Alzheimer’s Research Foundation (J.C.).
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