www.elsevier.com/locate/jns

Journal of the Neurological Scie

Pseudobulbar affect in multiple sclerosis: Toward the development

of innovative therapeutic strategies

Ariel Miller *

Center for Multiple Sclerosis, Department of Neurology, Carmel Medical Center, Rappaport Faculty of

Medicine and Research Institute, Technion, Haifa, Israel

Received 1 April 2005; received in revised form 9 September 2005; accepted 19 September 2005

Available online 3 May 2006

Abstract

Pseudobulbar affect (PBA), a condition involving involuntary and uncontrollable episodes of crying and/or laughing, occurs frequently in

patients with a variety of neurological disorders, including amyotrophic lateral sclerosis (ALS), stroke, traumatic brain injury, dementia

including Alzheimer’s disease, and multiple sclerosis (MS). Although PBA results in considerable distress for patients and caretakers, it is

underrecognized and undertreated. Agents used to treat psychiatric disorders–particularly tricyclic antidepressants and selective serotonin

reuptake inhibitors–are useful in alleviating PBA, but act on diffuse neural networks rather than targeting those involved in emotional motor

expression. As a result of their nonspecific activity, these agents are associated with a range of unwanted effects that preclude many patients

from using them. Dextromethorphan, a common cough suppressant, specifically targets sigma1 receptors concentrated in the brainstem and

cerebellum, thus providing the possibility of targeting regions implicated in emotional expression. When administered in a fixed combination

with quinidine, dextromethorphan is effective in treating PBA in patients with ALS, and preliminary results suggest that this therapy also is

effective in treating MS-related PBA.

D 2006 Elsevier B.V. All rights reserved.

Keywords: Pseudobulbar affect; Multiple sclerosis; Affect; Emotion; Crying; Laughing

1. Introduction

Pseudobulbar affect (PBA), alongwith depression, bipolar

affective disorder, and euphoria, is one of four major affective

disturbances that occur with multiple sclerosis (MS). Defined

as involuntary and uncontrollable periods of crying and/or

laughing, PBA causes considerable distress to both patients

and their caregivers, resulting in embarrassment and social

isolation [1]. Drugs used to treat psychological disorders have

been used with some success in treating PBA; however, these

agents are not effective in all patients and are associated with

limiting side effects, indicating the need for new therapeutic

options. This article will provide general background on the

most recent research in the pathophysiology and treatment of

PBA, provide some background on MS, and then examine

further the prevalence of PBA in MS.

0022-510X/$ - see front matter D 2006 Elsevier B.V. All rights reserved.

doi:10.1016/j.jns.2005.09.018

* Tel.: +972 4 8250 851; fax: +972 4 8250 909.

E-mail addresses: millera@tx.technion.ac.il, milleras@netvision.net.il.

2. Pseudobulbar affect

2.1. Background

Scientists and physicians have been aware of unusual

and inappropriate emotional output in patients with various

neurological disorders since the late 1800s [2]. Tradition-

ally, these outbursts have been defined as being incongru-

ent with the patient’s subjective feelings of depression and/

or euphoria [3,4]. However, many clinicians have included

in this phenomenon the more common occurrence of

episodes that are congruent with the patient’s mood, but are

grossly out of proportion to the patient’s actual feelings

[1,5,6]. Varying definitions of this condition have led to the

use of numerous terms in the literature, including:

pathological laughing and crying (PLC), emotional lability,

affective lability, pathological emotionality, forced or

involuntary crying, emotional dyscontrol, emotionalism,

emotional incontinence, and PBA [3,7]. Although some

nces 245 (2006) 153 – 159

Table 1

Literature review of therapeutic options for PBA

Study Drug Population Results

Treatment of pseudobulbar affect with tricyclic antidepressants

Schiffer et al., 19851 Amitriptyline, mean dose

58 mg/day, vs placebo for

30 days; crossover design

12 MS patients with PBA Significant improvement in

8 patients with amitriptyline,

with no effect on depression

Robinson et al., 19932 Nortriptyline titrated over 6

weeks up to 100 mg vs

placebo; double-blind

28 patients with post-stroke

PBA; 14 in each group

Significantly greater

improvement on PLACS in

patients given nortriptyline,

independent of depression

Treatment of pseudobulbar affect with SSRI antidepressants

Seliger et al., 19923 Fluoxetine 20 mg daily;

open label

13 patients with PBA: 8

post-stroke, 5 with MS

Decrease in number of episodes

in all 13 patients within 3 to 14 days

Andersen et al., 19934 Citalopram 10–20 mg/day

vs placebo for 3 weeks;

crossover design

16 consecutive patients with

post-stroke PBA

Daily crying episodes decreased by

50% in all 13 evaluable patients on

citalopram vs 2 on placebo

Burns et al., 19995 Sertraline 50 mg daily for

8 weeks; double-blind,

placebo-controlled

28 nondepressed patients

with post-stroke mood lability

Improvement in 13/14 sertraline

patients (93%) vs 9/14 placebo

patients (64%) ( P=0.041)

Muller et al., 19996 13 patients each, treated

with citalopram or paroxetine;

single daily doses of 10 mg to

40 mg; open-label study

26 patients with PBA after

brain injury

Significant improvement in 24/26

(92%) patients with rapid onset of

improvement (within 1 to 3 days)

PLACS=Pathological Laughter and Crying Scale.

References:

1. Schiffer RB, et al. N Engl J Med. 1985; 312:1480–1482.

2. Robinson RG, et al. Am J Psychiatry. 1993; 150:286–293.

3. Seliger GM, et al. Brain Inj. 1992; 6:267–270.

4. Andersen G, et al. Lancet. 1993; 342:837–839.

5. Burns A, et al. Int J Geriatr Psychiatry. 1999; 14:681–685.

6. Muller U, et al. Brain Inj. 1999; 13:805–811.

A. Miller / Journal of the Neurological Sciences 245 (2006) 153–159154

authors have used these terms interchangeably, others have

used different terms to refer to different degrees of

congruity between emotional expression and subjective

mood [8]. Adding to the confusion, there has also been

disagreement as to how involuntary the laughing/crying

must be, with some authors claiming there must be total

lack of control [4] and others defining the condition more

broadly, allowing a limited degree of voluntary control

[6,7,9]. For the purpose of this review, the term PBA will

be used, defined explicitly as the inappropriate and

uncontrollable display of emotional output that may or

may not be congruent with mood.

2.2. Pathophysiology

A complex web of networks involving paralimbic,

subcortical, and cortical areas interact to produce the

visceral, somatic, cognitive, and subjective components of

emotion. Networks involving the prefrontal cortices of both

right and left hemispheres inhibit the automatic visceral and

motor expression of emotion mediated by diencephalic and

brainstem structures [8]. As proposed by Kinnier Wilson, it

is traditionally thought that PBA is caused by a loss of

descending cortical control of brainstem motor nuclei, thus

disrupting these inhibitory mechanisms and resulting in

inappropriate, involuntary laughing and crying [10].

PBA is most frequent in diseases of bilateral pathology

that interfere with the corticohypothalamic and corticobulbar

tracts that control voluntary and involuntary faciorespiratory

mechanisms [11–13]. Dysregulation of these mechanisms

can result from any significant disruption of the frontal–

subcortical, limbic–subcortical, or brainstem emotional

circuits, especially when the disruption affects the interaction

of these circuits with each other. Such disruptions may be the

direct result of lesions to these areas or secondary to alteration

in neurotransmitter control of normal function [8].

Although PBA is more common in conditions causing

bilateral disruption of the descending pathways that inhibit

and regulate the activity of the brainstem and diencephalic

areas, unilateral lesions may also produce this disorder

[4,7,11]. Several studies have demonstrated the involvement

of subcortical areas, particularly the anterior limb of the

internal capsule, as well as the involvement of the bulbar

area [4,7,11–14]. It is important to note, however, that PBA

can be produced by lesions at various neurological levels

and, in fact, these lesions can be widely distributed [11].

A recently proposed extension of this mechanism

suggests that PBA is caused by a partial disconnection of

the neural networks involved in experienced emotion from

those involved in displayed emotion. Parvizi and colleagues

[15] suggest that pathways from higher cortical association

areas to the cerebellum are involved in the coordination of

A. Miller / Journal of the Neurological Sciences 245 (2006) 153–159 155

laughing and crying responses to appropriate environmental

cues [15]. Furthermore, these authors propose that lesions

that interrupt corticopontocerebellar communication disrupt

cerebellar modulation of affective displays, leading to PBA

[15]. In addition to proposing a new potential mechanism

underlying PBA, these findings further reveal the diversity

of lesions for which the final result is involuntary affective

output.

2.3. Assessment

Two easily administered, valid, and reliable scales are

available for the assessment of PBA. The first of these

instruments is the Pathological Laughing and Crying Scale

(PLACS), which consists of 16 items measuring the relation

of laughing and/or crying episodes to external events,

duration, degree of voluntary control, inappropriateness in

relation to emotions, and degree of resultant distress. Eight

of the items relate to pathological laughter and eight to

pathological crying. The PLACS is administered by an

interviewer who rates the severity of each symptom on a

scale of 0–3 points. Scores on all items are then totaled to

determine an overall score. A score of >13 is indicative of

PBA [16]. Validation of this scale was performed in stroke

patients, though this scale has been validated in traumatic

brain injury as well [17].

More recently, a second instrument, the Center for

Neurologic Study-Lability Scale (CNS-LS), has become

available. Validated in patients with amyotrophic lateral

sclerosis (ALS), the CNS-LS consists of 7 items, 4 relating

to laughter and 3 to tearfulness, that measure the frequency,

intensity, lability, degree of voluntary control, and inappropri-

ateness to context of the episodes (Appendix A). Unlike the

PLACS, however, the CNS-LS is self-administered. Respond-

ents indicate how often they experience each of the items on a

scale of 1 (never) to 5 (most of the time). A total score of >13

provides the greatest validity in ALS patients. Importantly,

administration of the CNS-LS accurately predicted neurologist

diagnosis for 82% of ALS patients [18]. Recently, this scale

has also been validated in patients with MS [19].

2.4. Therapeutic options

Several classes of agents, including tricyclic antidepres-

sants, selective serotonin reuptake inhibitors (SSRIs), and

dopaminergic agents, have proven useful in treating PBA

(Table 1). The first of these agents to be investigated was

levodopa. In a trial of patients with cerebrovascular disease,

levodopa controlled PBA almost completely in 10 of 25

patients treated while amantadine hydrochloride improved

symptoms in 4 of 8 patients. Benefit was noted within 2 to 5

days [20].

The tricyclic antidepressant, amitriptyline, also has

resulted in rapid and dramatic improvement in PBA in

patients with MS. Concurrent measurements of depression

showed no change, indicating that the medication’s anti-

PBA effect is distinct from its antidepressant effect [21].

Another tricyclic antidepressant, nortriptyline, also has led

to significant improvement in PBA in post-stroke patients

[16]. Although almost one half of the 14 patients treated

with this agent in one trial had major depression, response to

treatment was independent of their depression status [16].

Treatment of PBAwith SSRIs also is effective. In a study

in post-stroke patients, those receiving citalopram experi-

enced rapid and pronounced improvement in PBA. In this

case, however, improvements in PBAwere accompanied by a

significant decrease in depression [22]. The authors specu-

lated that the concomitant effect on depression might be

secondary to alleviation of the social isolation and fear of

crying in public caused by PBA. Alternatively, depression

and PBA may share a common neurologic abnormality

involving the neurotransmission of serotonin. In nonde-

pressed post-stroke patients with a more loosely defined

lability of mood, sertraline significantly reduced symptoms

as measured on both a patient self-rating scale and an

independent measure and seemed to have an especially

beneficial effect on tearfulness [23]. Few head-to-head

comparisons have been conducted between agents used to

treat PBA. However, in one trial comparing paroxetine and

citalopram in patients with PBA resulting from brain injury,

rapid and equivalent improvements in emotionalism were

observed with use of both drugs [24].

Despite evidence of efficacy, treatment of PBA with

these agents is limited by several factors. Although some

patients may experience benefit, treatment is ineffective in

others. In the trial of levodopa discussed above, 11 of 25

patients experienced only slight benefit from treatment, and

an additional 4 patients experienced no benefit at all [20].

Similarly, 3 of the 12 patients treated with amitriptyline

showed no improvement [21].

In addition, the agents most effective against PBA–

tricyclic antidepressants and SSRIs–are associated with

adverse effects, many of which can cause special problems

in the elderly and those with brain injury. Tricyclic

antidepressants in particular are associated with anticholin-

ergic and cardiovascular effects, including dry mouth,

epigastric distress, constipation, tachycardia, dizziness,

urinary retention, hypotension, and the risk of arrhythmias

[25]. In a direct comparison of paroxetine and nortriptyline,

serum anticholinergicity was significantly greater and

related complaints of dry mouth and tachycardia were

significantly more frequent and more severe in the patients

receiving nortriptyline than in those receiving paroxetine

[26]. Although SSRIs do not pose the same risks of

anticholinergic side effects as tricyclic antidepressants, they

are typically associated with a high risk of nausea, vomiting,

headache, and sexual dysfunction [25].

Importantly, none of these agents specifically targets neural

networks involved in emotional motor expression, such as the

brainstem and cerebellum. Rather, all act on neuromodulatory

systems that regulate diffuse neural networks, resulting in

general, nonspecific activity that in turn causes a range of

A. Miller / Journal of the Neurological Sciences 245 (2006) 153–159156

adverse, as well as beneficial, effects. With better-targeted

therapy, many of these adverse effects might be avoided.

2.5. Dextromethorphan/quinidine

Dextromethorphan (DM) is a widely used, nonopioid

cough suppressant found in many over-the-counter formu-

lations. In addition to its suppressant activity, DM has

anticonvulsant and neuroprotective properties, suggesting

that it could be used to treat neuronal disorders [27,28]. DM

offers a particular advantage in the treatment of PBA. A

potent sigma1 receptor agonist [29,30], DM acts to inhibit

glutamatergic signaling. Because sigma1 receptor sites are

concentrated in the brainstem and cerebellum, DM presents

the opportunity to target specific brain regions implicated in

emotional expression, thereby potentially improving PBA

while reducing the risk of side effects.

The extensive first-pass metabolism of DM results in low

systemic drug concentrations and presumably corresponding

limited clinical benefit [28]. Since DM is metabolized by the

polymorphic cytochrome P450 2D6 (CYP2D6), one way of

increasing systemic levels of DM is to administer it in

conjunction with quinidine (Q), a CYP2D6 inhibitor [31].

Studies have shown that a dose of 25–30 mg Q (10–20 times

lower than that used to treat cardiac arrhythmias) is adequate

to maximally suppress DM metabolism [28]. In a phase III

trial, a fixed combination of DM and Q (AVP-923) was

effective in reducing symptoms of PBA in ALS patients [32].

Patients treated with DM/Q reported greater incidence of

nausea, dizziness, and somnolence, relative to patients treated

with DM alone or Q alone. Reports of these adverse events,

however, were drastically reduced in a similar phase III

clinical trial of DM/Q in MS patients (see below).

2.5. Incidence

Attempts to determine the incidence of PBA have been

complicated by the lack and/or underutilization of standard-

ized instruments and by differing definitions of the disorder.

As would be expected, the broader the definition of PBA,

the greater the incidence recorded. Sudden, involuntary, and

easily provoked spells of crying and/or laughing, with or

without congruent changes in mood, have been observed in

43%–49% of patients with ALS [12,13], 10%–18% of

post-stroke patients [5,9], and 39% of patients with

Alzheimer’s disease [14]. When PBA was defined more

rigorously (i.e., as a dissociation between expressed laugh-

ing and/or crying and subjectively experienced mood) and

assessed using the PLACS, an incidence of 10% was found

in patients with MS [3].

3. Multiple sclerosis

MS is a disease of the central nervous system character-

ized by inflammation, demyelination, axonal loss, neuro-

degeneration, and brain and spinal cord atrophy. MS

commonly results in motor dysfunction, sensory deficits,

and neuropsychological impairment [33]. MS patients have

a 25%–50% lifetime risk for major depression [33], and

40% of patients with MS show evidence of intellectual

decline [3]. Neuropsychological dysfunction is associated

with both lesion burden and diffuse disease. Although

attention has traditionally focused on the impact of lesion

burden, the importance of atrophy has become increasingly

apparent, and it is now recognized that measures of brain

atrophy explain more variance in neuropsychological

dysfunction than do measures of lesion burden [33,34].

Neuropsychological outcomes correspond particularly

strongly to linear measures of subcortical atrophy, such as

ventricle enlargement [33]. Central nervous system (CNS)

atrophy begins early in the course of MS, when it progresses

most rapidly, and proceeds at variable rates, both within and

between individuals [34,35].

The relative influence of lesion burden and atrophy

varies in different neuropsychologic impairments associated

with MS. For example, depression and agitation are

correlated with measures of lesion burden, while disinhibi-

tion (the tendency to speak out impulsively, say or do

embarrassing things) is correlated only with atrophy [33].

Measures of tissue atrophy, including whole brain and

central atrophy, also are strongly correlated with and

predictive of cognitive impairment [33].

3.1. PBA in MS

PBA is one of four major affective disturbances that occur

with MS. Although the other three–depression, bipolar

affective disorder, and euphoria–have received considerable

attention from researchers, PBA has been relatively ignored

[3]. Researchers have cited widely varying frequencies of

PBA in patients with MS, depending largely on the definition

of PBA and the means of diagnosis used. Some studies have

reported an incidence of as high as 95% [36], while in other

studies a much lower rate of approximately 10% has been

found [37]. Most recently, researchers using a standardized,

validated instrument (PLACS) and defining PBA as an

involuntary dissociation between the expressed affect and

subjective mood found an incidence of 10% in patients with

MS, although they noted that a greater number of patients

demonstrated displays of emotion that were excessive but

congruent in relation to subjective mood [3].

PBA generally occurs in the chronic progressive phase

of MS [3]. The severity and frequency of PBA tend to

increase with progression of MS and are associated with

more severe intellectual deterioration, physical disability,

and neurological disability [3,37]. Despite the presumed

association between PBA and brainstem involvement, in at

least one study, 1 in 3 MS patients with PBA displayed no

evidence of brainstem lesions upon neurological examina-

tion [3]. As was pointed out, however, the confluent,

periventricular pattern of lesions most commonly seen in

A. Miller / Journal of the Neurological Sciences 245 (2006) 153–159 157

MS may interrupt neural circuits traversing corticobulbar

regions at several points [3].

3.2. Current clinical trial of DM/Q in MS-related PBA

In light of the benefit demonstrated in patients with

ALS, a phase III trial exploring DM/Q as a treatment for

PBA was conducted in 150 patients with MS at 22 sites in

the United States and Israel. The study was a 90-day

placebo-controlled trial with patients randomized to receive

twice daily a fixed combination of DM/Q (AVP-923; 30

mg DM and 30 mg Q) or placebo. Patients were examined

for general health and an electrocardiogram (ECG) was

performed. Patients with a history of cardiovascular

problems, irregular ECGs, or a history of psychiatric

disturbance were excluded. PBA was assessed by CNS-LS,

and only patients with an initial score of 13 were included.

In addition, quality of life and relationships were evaluated

by visual analog scale (VAS), and the incidence of crying

and laughing episodes was monitored throughout the

study. Patients were administered medication or placebo

for 85 days and received diaries to record episode

incidence. CNS-LS evaluation was performed during clinic

visits on days 1, 15, 29, 57, and 85.

The positive results of this phase III clinical trial [38]

confirm that DM/Q is a safe and effective therapy for PBA

in both MS and ALS patients. Furthermore, in the MS

trial, only nausea and fatigue were reported by signifi-

cantly more patients receiving DM/Q than placebo and

headache was reported by significantly less patients on

DM/Q, relative to placebo. These results suggest that DM/

Q is a safe effective therapy for PBA, regardless of the

underlying neurological condition with which the syn-

drome is associated.

4. Conclusions

As a major affective disorder associated with MS, PBA is

the cause of significant distress for many patients and

caregivers alike. Although it is not as common as depression,

PBA affects a substantial number of MS patients, particularly

when defined to include episodes that are congruent with

subjective mood but dramatically exaggerated in expression.

Although currently available agents are often effective in

treating PBA, many patients are unable to tolerate the

associated side effects or simply do not respond to traditional

therapeutic options. Thus, a new therapeutic option with

significant efficacy and limited side effects would be

especially welcome. Dextromethorphan is a potent sigma1receptor agonist and is inhibitory to glutamatergic neuro-

transmission. As these receptors are concentrated in the

brainstem and cerebellum–regions implicated in emotional

expression–DM may offer a unique opportunity to target the

specific areas involved in PBA. A fixed combination of

dextromethorphan and quinidine, a CYP2D6 inhibitor, has

previously shown efficacy in treating PBA in patients with

ALS. Preliminary results from a subset of patients in a large

trial indicate that DM/Q may be equally beneficial in treating

MS-related PBA [38]. The fact that other drugs are effective

in treating PBA, regardless of the underlying neurological

disorder, suggests that episodes of PBA in different patient

populations share a common pathophysiology and that DM/

Q may have wide applicability as a therapy for PBA beyond

patients with ALS or MS.

Acknowledgements

Supported by grant from Avanir Pharmaceuticals (San

Diego, USA).

A. Miller / Journal of the Neurological Sciences 245 (2006) 153–159158

Appendix A. Center for Neurologic Study-Lability Scale

(CNS-LS)

Source—Smith, R.A., Berg, J.E., Pope, L.E. and Thisted,

R.A. Measuring pseudobulbar affect in ALS. Amyotroph.

Lateral. Scler.OtherMotorNeuronDisord 5Suppl 1, 99–102

(2004).

Applies never Applies rarely Applies occasionally

1 2 3

There are times when I feel fine one minute, and then I will become tearful the n

1 2 3

Others have told me that I seem to become amused easily or that I seem to beco

1 2 3

I find myself crying very easily

1 2 3

I find that even when I try to control my laughter I am often unable to do so.

1 2 3

There are times when I will not be thinking of anything happy or funny at all, b

1 2 3

I find that even when I try to control my crying I am often unable to do so.

1 2 3

I find that I am easily overcome by laughter.

1 2 3

Auxiliary subscale

People have told me at times that I seem to get upset very easily or that I get up

1 2 3

I have noticed that I get upset very easily

1 2 3

Others have told me that I seem to get frustrated very easily or that I seem to ge

1 2 3

I can quickly go from feeling calm to feeling very angry over little things or for

1 2 3

At times I can be feeling no more impatient than others but then I will suddenly

1 2 3

People have told me at times that I seem to get impatient very easily or that I se

1 2 3

Others have told me that I seem to get nervous very easily or that I seem to bec

1 2 3

Sometimes I can be feeling fine one minute and then I will yell or raise my voic

1 2 3

This questionnaire is designed to help us understand

people’s moods and how they change. Using the scale

below, circle the number that describes the degree to which

each item applies to you during the past week. Circle only

one number for each item.

Applies frequently Applies most of the time

4 5

ext over something small or for no rreason at all.

4 5

me amused about things that are really are not funny.

4 5

4 5

4 5

ut then I will suddenly be overcome by funny or happy thoughts.

4 5

4 5

4 5

set over little things.

4 5

4 5

t frustrated over little things.

4 5

no reason at all.

4 5

become very impatient over something small or for no reason at all.

4 5

em to get impatient over little things.

4 5

ome nervous over little things

4 5

e in an angry way the next.

4 5

References

[1] Lieberman A, Benson DF. Control of emotional expression in

pseudobulbar palsy A personal experience. Arch Neurol 1977;34

(11):717–9.

[2] Darwin C. The expression of the emotions in man and animals. New

York’ D Appleton and Company; 1872.

[3] Feinstein A, Feinstein K, Gray T, O’Connor P. Prevalence and

neurobehavioral correlates of pathological laughing and crying in

multiple sclerosis. Arch Neurol 1997;54(9):1116–21.

[4] Poeck K. Pathological laughing and weeping in patients with

progressive balbar palsy. Ger Med Mon 1969;14(8):394–7.

[5] Huffman JC, Stern TA. Poststroke neuropsychiatric symptoms and

pseudoseizures: a discussion. Prim Care Companion J Clin Psychiat

2003;5(2):85–8.

[6] House A, Dennis M, Molyneux A, Warlow C, Hawton K. Emotion-

alism after stroke. BMJ 1989;298(6679):991–4.

[7] Dark FL, McGrath JJ, Ron MA. Pathological laughing and crying.

Aust N Z J Psychiatry 1996;30(4):472–9.

[8] Arciniegas DB, Topkoff J. The neuropsychiatry of pathologic affect:

an approach to evaluation and treatment. Semin Clin Neuropsychiatry

2000;5(4):290–306.

[9] Morris PL, Robinson RG, Raphael B. Emotional lability after stroke.

Aust N Z J Psychiatry 1993;27(4):601–5.

[10] Wilson SAK. Some problems in neurology. II: Pathological laughing

and crying. J Neurol Psychopathol 1924;IV:299–333.

[11] Ironside R. Disorders of laughter due to brain lesions. Brain 1956;

79(4):589–609.

[12] Caroscio JT, Mulvihill MN, Sterling R, Abrams B. Amyotrophic

lateral sclerosis. Its natural history. Neurol Clin 1987;5(1):1–8.

[13] Gallagher JP. Pathologic laughter and crying in ALS: a search for their

origin. Acta Neurol Scand 1989;80(2):114–7.

[14] Starkstein SE, Migliorelli R, Teson A, Petracca G, Chemerinsky E,

Manes F, et al. Prevalence and clinical correlates of pathological

affective display in Alzheimer’s disease. J Neurol Neurosurg Psychi-

atry 1995;59(1):55–60.

[15] Parvizi J, Anderson SW, Martin CO, Damasio H, Damasio AR.

Pathological laughter and crying: a link to the cerebellum. Brain

2001;124(Pt 9):1708–19.

A. Miller / Journal of the Neurological Sciences 245 (2006) 153–159 159

[16] 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 1993;150(2):286–93.

[17] Tateno A, Jorge RE, Robinson RG. Pathological laughing and crying

following traumatic brain injury. J Neuropsychiatry Clin Neurosci

2004;16(4):426–34.

[18] Moore SR, Gresham LS, Bromberg MB, Kasarkis EJ, Smith RA. A

self report measure of affective lability. J Neurol Neurosurg Psychiatry

1997;63(1):89–93.

[19] Smith RA, Berg JE, Pope LE, Callahan JD, Wynn D, Thisted RA.

Validation off CNS emotional liability scale for pseudobulbar affect

(pathological laughing and crying) in multiple sclerosis patients. Mult

Scler 2004;10:1–7.

[20] Udaka F, Yamao S, Nagata H, Nakamura S, Kameyama M. Pathologic

laughing and crying treated with levodopa. Arch Neurol 1984;41(10):

1095–6.

[21] Schiffer RB, Herndon RM, Rudick RA. Treatment of pathologic

laughing and weeping with amitriptyline. N Engl J Med 1985;312(23):

1480–2.

[22] Andersen G, Vestergaard K, Riis JO. Citalopram for post-stroke

pathological crying. Lancet 1993;342(8875):837–9.

[23] 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 1999;14(8):681–5.

[24] Muller U, Murai T, Bauer-Wittmund T, von Cramon DY. Paroxetine

versus citalopram treatment of pathological crying after brain injury.

Brain Inj 1999;13(10):805–11.

[25] Baldessarini RJ. Drugs and the treatment of psychiatric disorders:

depression and anxiety disorders. In: Hardman JG, Limbird LE,

Gilman AG, editors. Goodman and Gilman’s the pharmacological

basis of therapeutics. New York’ The McGraw-Hill Companies, Inc.;

2001. p. 447–83.

[26] Pollock BG, Mulsant BH, Nebes R, Kirshner MA, Begley AE,

Mazumdar S, et al. Serum anticholinergicity in elderly depressed

patients treated with paroxetine or nortriptyline. Am J Psychiatry

1998;155(8):1110–2.

[27] Tortella FC, Pellicano M, Bowery NG. Dextromethorphan and

neuromodulation: old drug coughs up new activities. Trends Pharma-

col Sci 1989;10(12):501–7.

[28] 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 2004;44(10):1132–42.

[29] Maurice T, Lockhart BP. Neuroprotective and anti-amnesic potentials

of sigma (sigma) receptor ligands. Prog Neuropsychopharmacol Biol

Psychiatry 1997;21(1):69–102.

[30] Musacchio JM, Klein M, Canoll PD. Dextromethorphan and sigma

ligands: common sites but diverse effects. Life Sci 1989;45(19):

1721–32.

[31] Zhang Y, Britto MR, Valderhaug KL, Wedlund PJ, Smith RA.

Dextromethorphan: enhancing its systemic availability by way of

low-dose quinidine-mediated inhibition of cytochrome P4502D6. Clin

Pharmacol Ther 1992;51(6):647–55.

[32] Brooks BR, Thisted RA, Appel SH, Bradley WG, Olney RK, Berg

JE, et al. Treatment of pseudobulbar affect in ALS with dextro-

methorphan/quinidine: a randomized trial. Neurology 2004;63(8):

1364–70.

[33] Benedict RH, Carone DA, Bakshi R. Correlating brain atrophy with

cognitive dysfunction, mood disturbances, and personality disorder in

multiple sclerosis. J Neuroimaging 2004;14(3 Suppl):36S–45S.

[34] Zivadinov R, Bakshi R. Central nervous system atrophy and

clinical status in multiple sclerosis. J Neuroimaging 2004;14(3

Suppl):27S–35S.

[35] Matthews PM. An update on neuroimaging of multiple sclerosis. Curr

Opin Neurol 2004;17(4):453–8.

[36] Pratt RT. An investigation of the psychiatric aspects of disseminated

sclerosis. J Neurochem 1951;14(4):326–35.

[37] Surridge D. An investigation into some psychiatric aspects of multiple

sclerosis. Br J Psychiatry 1969;115(524):749–64.

[38] Panitch HS, Thisted RA, Smith RA, Wynn DR, Wymer JP, Achiron A,

et al. Randomized trial of dextromethorphan/quinidine for pseudobul-

bar affect in multiple sclerosis. Ann Neurol in press;59(5).