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: firstname.lastname@example.org © 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.). References 1. Brooks BR, Thisted RA, Appel SH, et al. Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial. Neurology 2004;63:1364 –1370. 2. Panitch HS, Thisted RA, Smith RA, et al. Randomized, controlled trial of dextromethorphan/quinidine for pseudobulbar affect in multiple sclerosis. Ann Neurol 2006;59: 780 –787. 3. Lieberman A, Benson DF. Control of emotional expression in pseudobulbar palsy. A personal experience. Arch Neurol 1977; 34:717–719. 4. Poeck K. Pathophysiology of emotional disorders associated with brain damage. Handbook of clinical neurology. 1969;3: 343–367. 5. Lawson IR, MacLeod RD. The use of imipramine (“Tofranil”) and other psychotropic drugs in organic emotionalism. Br J Psychiatry 1969;115:281–285. 6. House A, Dennis M, Molyneux A, et al. Emotionalism after stroke. BMJ 1989;298:991–994. 7. Dark FL, McGrath JJ, Ron MA. Pathological laughing and crying. Aust N Z J Psychiatry 1996;30:472– 479. 8. 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 2005;10:1–16. 9. Darwin C. The expression of emotions in man and animals. New York: Appleton and Company, 1872. 10. Wilson SAK. Some problems in neurology: no. 2 pathological laughing and crying. J Neurol Psychopathol 1924;4:299 –333. 11. Zeilig G, Drubach DA, Katz-Zeilig M, Karatinos J. Pathological laughter and crying in patients with closed traumatic brain injury. Brain Inj 1996;10:591–597. 12. Schiffer R, Pope LE. Review of pseudobulbar affect including a novel and potential therapy. J Neuropsychiatry Clin Neurosci 2005;17:447– 454. 13. Gallagher JP. Pathologic laughter and crying in ALS: a search for their origin. Acta Neurol Scand 1989;80:114 –117. 14. Kim JS, Choi S, Kwon SU, Seo YS. Inability to control anger or aggression after stroke. Neurology 2002;58:1106 –1108. 15. Kim JS, Choi-Kwon S. Poststroke depression and emotional incontinence: correlation with lesion location. Neurology 2000; 54:1805–1810. 16. 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 1994;25:1050 –1052. 17. Achari AN, Colover J. Posterior fossa tumors with pathological laughter. JAMA 1976;235:1469 –1471. 18. Wisoff JH, Epstein FJ. Pseudobulbar palsy after posterior fossa operation in children. Neurosurgery 1984;15:707–709. 19. Tei H, Sakamoto Y. Pontine infarction due to basilar artery stenosis presenting as pathological laughter. Neuroradiology 1997;39:190 –191. 20. Bhatjiwale MG, Nadkarni TD, Desai KI, Goel A. Pathological laughter as a presenting symptom of massive trigeminal neuromas: report of four cases. Neurosurgery 2000;47: 469 – 472. 21. Parvizi J, Anderson SW, Martin CO, et al. Pathological laughter and crying: a link to the cerebellum. Brain 2001;124: 1708 –1719. 22. McCullagh S, Moore M, Gawel M, Feinstein A. Pathological laughing and crying in amyotrophic lateral sclerosis: an association with prefrontal cognitive dysfunction. J Neurol Sci 1999; 169:43– 48. 23. Feinstein A, O’Connor P, Gray T, Feinstein K. Pathological laughing and crying in multiple sclerosis: a preliminary report suggesting a role for the prefrontal cortex. Mult Scler 1999;5: 69 –73. 24. Arciniegas DB. A clinical overview of pseudobulbar affect. Am J Geriatr Pharmacother 2005;3(suppl A):4 – 8; quiz 16 –17. 25. Moore SR, Gresham LS, Bromberg MB, et al. A self report measure of affective lability. J Neurol Neurosurg Psychiatry 1997;63:89 –93. 26. Nahas Z, Arlinghaus KA, Kotrla KJ, et al. Rapid response of emotional incontinence to selective serotonin reuptake inhibitors. J Neuropsychiatry Clin Neurosci 1998;10:453– 455. 27. Allman P, Hope RA, Fairburn CG. Emotionalism following brain damage: a complex phenomenon. Postgrad Med J 1990; 66:818 – 821. 28. Wild B, Rodden FA, Grodd W, Ruch W. Neural correlates of laughter and humour. Brain 2003;126:2121–2138. 29. Cummings JL, Arciniegas DB, Brooks BR, et al. Defining and diagnosing involuntary emotional expression disorder. CNS Spectr 2006;11:1–7. 30. Schiffer RB, Herndon RM, Rudick RA. Treatment of pathologic laughing and weeping with amitriptyline. N Engl J Med 1985;312:1480 –1482. 31. Seliger GM, Hornstein A, Flax J, et al. Fluoxetine improves emotional incontinence. Brain Inj 1992;6:267–270. 32. Andersen G, Vestergaard K, Riis JO. Citalopram for post-stroke pathological crying. Lancet 1993;342:837– 839. Rosen and Cummings: Pseudobulbar Affect 95 33. Robinson RG, Parikh RM, Lipsey JR, et al. Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study. Am J Psychiatry 1993;150:286 –293. 34. Burns A, Russell E, Stratton-Powell H, et al. Sertraline in stroke-associated lability of mood. Int J Geriatr Psychiatry 1999;14:681– 685. 35. Murai T, Barthel H, Berrouschot J, et al. Neuroimaging of serotonin transporters in post-stroke pathological crying. Psychiatry Res 2003;123:207–211. 36. Kim SW, Shin IS, Kim JM, et al. Mirtazapine treatment for pathological laughing and crying after stroke. Clin Neuropharmacol 2005;28:249 –251. 37. Udaka F, Yamao S, Nagata H, et al. Pathologic laughing and crying treated with levodopa. Arch Neurol 1984;41:1095–1096. 96 Annals of Neurology Vol 61 No 2 February 2007 38. Wolf JK, Santana HB, Thorpy M. Treatment of “emotional incontinence” with levodopa. Neurology 1979;29:1435–1436. 39. Ramasubbu R. Lamotrigine treatment for post-stroke pathological laughing and crying. Clin Neuropharmacol 2003;26: 233–235. 40. Palmer GC. Neuroprotection by NMDA receptor antagonists in a variety of neuropathologies. Curr Drug Targets 2001;2: 241–271. 41. Su TP, Hayashi T. Understanding the molecular mechanism of sigma-1 receptors: towards a hypothesis that sigma-1 receptors are intracellular amplifiers for signal transduction. Curr Med Chem 2003;10:2073–2080. 42. Kamei H, Kameyama T, Nabeshima T. Effects of sigma receptor ligands on conditioned fear stress. Methods Find Exp Clin Pharmacol 1998;20:613– 618.