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Diagnosis and Management of Pathological Laughter and Crying

2006; Elsevier BV; Volume: 81; Issue: 11 Linguagem: Inglês

10.4065/81.11.1482

1942-5546

Josef Parvizi, David B. Arciniegas, Gary L. Bernardini, Michael Hoffmann, J.P. Mohr, Mark Rapoport, Jeremy D. Schmahmann, Jonathan Silver, Stanley Tuhrim,

Autoimmune Neurological Disorders and Treatments

Patients with various neurologic disorders exhibit exaggerated or inappropriate episodes of laughter, crying, or both without an apparent motivating stimulus or in response to stimuli that would not have elicited such an emotional response before the onset of the underlying disease. During these episodes, patients have difficulty controlling their emotional expression according to the contextual information. In contrast, patients with mood disorders have a pervasive and sustained change in their emotional experience and thus exhibit spells of laughter or crying because of an underlying mania or depression. This article focuses on the clinical presentation, diagnosis, prevalence, and proposed pathophysiological mechanisms of and available treatment options for this clinical phenomenon. Patients with various neurologic disorders exhibit exaggerated or inappropriate episodes of laughter, crying, or both without an apparent motivating stimulus or in response to stimuli that would not have elicited such an emotional response before the onset of the underlying disease. During these episodes, patients have difficulty controlling their emotional expression according to the contextual information. In contrast, patients with mood disorders have a pervasive and sustained change in their emotional experience and thus exhibit spells of laughter or crying because of an underlying mania or depression. This article focuses on the clinical presentation, diagnosis, prevalence, and proposed pathophysiological mechanisms of and available treatment options for this clinical phenomenon. Many patients with neurologic disorders exhibit uncontrollable episodes of laughing, crying, or both that are either exaggerated or contradictory to the context in which they occur. Patients report that their episodes are at best only partially amenable to voluntary control, and unless they experience a severe change of mental status, they often have insight into their problem and judge their emotional display as inappropriate and out of character. The cardinal feature of the disorder is a pathologically lowered threshold for exhibiting the behavioral response of laughter, crying, or both. An affected individual exhibits episodes of laughter and/or crying without an apparent motivating stimulus or in response to stimuli that would not have elicited such an emotional response before the onset of their underlying neurologic disorder. In some patients, the emotional response is exaggerated in intensity but is provoked by a stimulus with an emotional valence congruent with the character of the emotional display. For example, a sad stimulus provokes a pathologically exaggerated weeping response instead of a sigh, which the patient normally would have exhibited in that particular situation. However, in some other patients, the character of the emotional display can be incongruent with, and even contradictory to, the emotional valence of the provoking stimulus or may be incited by a stimulus with no clear valence. For example, a patient may laugh in response to sad news or cry in response to stimuli with no emotional undertone, or, once provoked, the episodes may switch from laughing to crying or vice versa. Various terms have been used interchangeably to describe the problem of laughing and crying in these patients. The most widely used terms are pseudobulbar affect, pathological laughter and crying, emotional lability, emotionalism, and emotional dysregulation. Terms such as forced crying, involuntary crying, pathological emotionality, and emotional incontinence have also been used, although less frequently. In some instances, authors have used the same term for clinically different conditions, and in other instances, different terms have been used synonymously to describe the same clinical presentation. Because the disorder is primarily a problem with laughing and crying rather than exhibiting all kinds of emotional displays, the displays are out of character and disproportionate to the context in which they occur, and the condition can lead to social and personal distress and functional impairment, we use the term pathological laughter and crying (PLC) in this article, which we believe is a clear and concise descriptor of the condition and has historical roots in classical neurology. Accurate estimates of the incidence and prevalence of PLC in the setting of each specific neurologic disorder are lacking. This may be in part due to confusion in the literature about the nosology and terminology of this clinical condition, as described previously. This confusion notwithstanding, there appears to be considerable potential for errors in estimating the incidence and prevalence of impaired emotional regulation. Patients and their family members may be unaware that such episodes develop in the context of neurologic disorders.1Arciniegas DB Topkoff J The neuropsychiatry of pathologic affect: an approach to evaluation and treatment.Semin Clin Neuropsychiatry. 2000; 5: 290-306Crossref PubMed Scopus (62) Google Scholar If clinical researchers do not ask specifically about symptoms of impaired emotional regulation and if the nosological distinctions described previously are not considered, these symptoms may be either unrecognized or misinterpreted as a symptom of a mood disorder. Conversely, some studies have attempted to estimate the prevalence of the problem generally in clinical referral samples, which may lead to overestimates of the incidence and prevalence of this disorder. With these caveats in mind, it is informative to review the reported scope of the problem in some neurologic disorders. Among patients with traumatic brain injury,2Zeilig G Drubach DA Katz-Zeilig M Karatinos J Pathological laughter and crying in patients with closed traumatic brain injury.Brain Inj. 1996; 10: 591-597Crossref PubMed Scopus (64) Google Scholar, 3Tateno A Jorge RE Robinson RG Pathological laughing and crying following traumatic brain injury.J Neuropsychiatry Clin Neurosci. 2004; 16: 426-434Crossref PubMed Scopus (65) Google Scholar the prevalence of this condition during the first year after injury is estimated at 5% to 11%. The disorder occurs in 10% of patients with multiple sclerosis,4Minden SL Schiffer RB Affective disorders in multiple sclerosis: review and recommendations for clinical research.Arch Neurol. 1990; 47: 98-104Crossref PubMed Scopus (382) Google Scholar, 5Feinstein A Feinstein K Gray T O'Connor P Prevalence and neurobehavioral correlates of pathological laughing and crying in multiple sclerosis.Arch Neurol. 1997; 54: 1116-1121Crossref PubMed Scopus (166) Google Scholar, 6Feinstein 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: 69-73PubMed Google Scholar 49% of patients with amyotrophic lateral sclerosis,7Gallagher JP Pathologic laughter and crying in ALS: a search for their origin.Acta Neurol Scand. 1989; 80: 114-117Crossref PubMed Scopus (124) Google Scholar 11% to 34% of patients with stroke,8House A Dennis M Molyneux A Warlow C Hawton K Emotionalism after stroke.BMJ. 1989; 298: 991-994Crossref PubMed Scopus (210) Google Scholar, 9Morris PL Robinson RG Raphael B Emotional lability after stroke.Aust N Z J Psychiatry. 1993; 27: 601-605Crossref PubMed Scopus (86) Google Scholar, 10Kim JS Choi-Kwon S Poststroke depression and emotional incontinence: correlation with lesion location.Neurology. 2000; 54: 1805-1810Crossref PubMed Scopus (225) Google Scholar 5% of patients with Parkinson disease and the noncerebellar type of multiple system atrophy (MSA),11Siddiqui MS Kirsch-Darrow L Fernandez HH Jacobson IV, CE Okun MS Prevalence of pseudobulbar affect in movement disorders and its mood correlates: a prospective study of 754 consecutive patients [abstract].Neurology. 2006; 66 (Abstract P06.156.): A369Google Scholar and 37% of patients with the cerebellar type of MSA.12Parvizi J, Joseph J, Press D, Schmahmann JD. Pathological laughter and crying in multiple system atrophy—cerebellar type. Mov DisordIn press.Google Scholar The scope of the problem in patients with dementia is controversial. In one report,13Haupt M Emotional lability, intrusiveness, and catastrophic reactions.Int Psychogeriatr. 1996; 8: 409-414PubMed Google Scholar the authors defined the problem as simply "observable sudden changes in emotional expressions," which they observed in about 74% of mildly to moderately impaired patients with Alzheimer disease. Starkstein et al14Starkstein SE Migliorelli R Teson A et al.Prevalence and clinical correlates of pathological affective display in Alzheimer's disease.J Neurol Neurosurg Psychiatry. 1995; 59: 55-60Crossref PubMed Scopus (105) Google Scholar used the Pathological Laughter and Crying Scale15Robinson 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: 286-293PubMed Google Scholar in their study of 103 patients with Alzheimer disease. Of these 103 patients, 40 had PLC. Of note, however, 21 of these 40 patients also had an underlying congruent mood disorder. The authors labeled these patients as having "emotional lability," which they defined as "pathological laughing and crying with an underlying mood disorder." Despite the problems associated with accurately estimating the incidence and prevalence of PLC, the limited data available suggest that this problem occurs with a frequency considerably higher than is generally recognized by physicians. In light of the frequency of the neurologic conditions in which impaired regulation of emotional expression develops, numerous patients may be expected to have PLC and might benefit from its identification and treatment. Several scales are available to identify and characterize PLC.15Robinson 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: 286-293PubMed Google Scholar, 16Newsom-Davis IC Abrahams S Goldstein LH Leigh PN The emotional lability questionnaire: a new measure of emotional lability in amyotrophic lateral sclerosis.J Neurol Sci. 1999; 169: 22-25Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 17Smith 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. 2004; 10: 679-685Crossref PubMed Scopus (77) Google Scholar Among these, the 2 most commonly used in clinical research studies are the Pathological Laughter and Crying Scale15Robinson 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: 286-293PubMed Google Scholar and the Center for Neurologic Study-Lability Scale.15Robinson 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: 286-293PubMed Google Scholar, 16Newsom-Davis IC Abrahams S Goldstein LH Leigh PN The emotional lability questionnaire: a new measure of emotional lability in amyotrophic lateral sclerosis.J Neurol Sci. 1999; 169: 22-25Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 17Smith 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. 2004; 10: 679-685Crossref PubMed Scopus (77) Google Scholar The items included in these scales cover the triggering factors, frequency, duration, and involuntariness of PLC events, issues that overlap minimally with items included in scales for the assessment of mood disorders (for example, the Hamilton Depression Rating Scale and the Beck Depression Inventory), supporting the differences in these diagnostic constructs. Assessment scales developed specifically for characterizing the problem of laughing and crying may be useful in clinical trials. Using such scales to screen patients at risk for PLC and to follow their progress may also be practical. However, we strongly believe that the diagnosis of the condition remains a bedside issue. As suggested by the content of assessment scales for this disorder, a single screening question regarding the presence of frequent laughing or crying spells may be sufficient to identify patients with impaired regulation of emotional expression. Once the patient's answer is confirmatory, other routine questions are warranted to discern whether the patient's uncontrollable episodes of laughing or crying are related to an underlying mood disorder. In the clinical setting, PLC is often unrecognized. In cases in which the physician notices spells of uncontrollable laughing or crying, the condition can often be misdiagnosed as a mood disorder. However, a thorough evaluation can lead to proper differentiation of these 2 conditions. Mood is an emotional state sustained over relatively long periods, days to weeks or more. Patients with depression feel depressed most of the time, and thus their emotional display of crying is primarily a reflection of their underlying depressed mood. By contrast, patients with pathological crying exhibit the emotional display in the absence of a pervasive and sustained depressed mood. The crying occurs only paroxysmally and is uncontrollable and involuntary. Such episodes may even occur in the absence of any congruent changes in the mood of the patient. Crying due to depression is associated with signs such as anhedonia, decreased energy, psychomotor slowing, feelings of hopelessness and helplessness, and suicidal ideation as well as poor concentration and anxiety. Likewise, patients with bipolar disease may exhibit laughter or crying during their cycles of cheerfulness, irritability, and depression. In addition, these patients have associated problems of grandios-ity, poor judgment, hyperactivity, pressured speech, poor sleep, and increased energy. Patients with PLC report none of these symptoms and, in fact, are often embarrassed by their episodes of laughing or crying. Importantly, although PLC and mood disorders appear to be different clinical entities, they may coexist in the same patient.12Parvizi J, Joseph J, Press D, Schmahmann JD. Pathological laughter and crying in multiple system atrophy—cerebellar type. Mov DisordIn press.Google Scholar, 15Robinson 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: 286-293PubMed Google Scholar, 18Schiffer RB Herndon RM Rudick RA Treatment of pathologic laughing and weeping with amitriptyline.N Engl J Med. 1985; 312: 1480-1482Crossref PubMed Scopus (224) Google Scholar Robinson et al15Robinson 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: 286-293PubMed Google Scholar reported that almost half of their patients with PLC had coexisting depression. However, resolution of pathological laughing or pathological crying seems to be independent of the resolution of depression in these patients and has no relationship with the changes in anxiety or aggression scores.15Robinson 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: 286-293PubMed Google Scholar A recent study found that all patients with the cerebellar type of MSA who exhibited pathological laughter and/or crying also had depression.12Parvizi J, Joseph J, Press D, Schmahmann JD. Pathological laughter and crying in multiple system atrophy—cerebellar type. Mov DisordIn press.Google Scholar The coexistence of pathological emotional expression (eg, PLC) and pathological emotional experience (eg, mood disorders) is an important observation because it poses limitations in diagnosis and research and will certainly influence the physician's choice of treatment. Pathological laughter and crying often responds to the same treatments used for mood disorders. However, in patients with PLC, the beneficial effects of these medications are evident within days of treatment initiation and occur in response to much lower dosages than those usually prescribed for the treatment of mood disorders.12Parvizi J, Joseph J, Press D, Schmahmann JD. Pathological laughter and crying in multiple system atrophy—cerebellar type. Mov DisordIn press.Google Scholar, 15Robinson 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: 286-293PubMed Google Scholar, 18Schiffer RB Herndon RM Rudick RA Treatment of pathologic laughing and weeping with amitriptyline.N Engl J Med. 1985; 312: 1480-1482Crossref PubMed Scopus (224) Google Scholar, 19Schiffer R Pope LE Review of pseudobulbar affect including a novel and potential therapy.J Neuropsychiatry Clin Neurosci. 2005; 17: 447-454Crossref PubMed Scopus (82) Google Scholar Schiffer et al18Schiffer RB Herndon RM Rudick RA Treatment of pathologic laughing and weeping with amitriptyline.N Engl J Med. 1985; 312: 1480-1482Crossref PubMed Scopus (224) Google Scholar studied the effect of amitriptyline, a tricyclic antidepressant, in 12 multiple sclerosis patients with PLC using a mean dosage of 58 mg/d and compared its effect to that of placebo in a 30-day, double-blind, crossover study. They reported a significant improvement in PLC symptoms in 8 patients taking amitriptyline with no effect on their coexisting depression. Robinson et al15Robinson 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: 286-293PubMed Google Scholar administered nortriptyline in dosages as high as 100 mg/d in 14 stroke patients with PLC and compared its effectiveness to placebo in 14 other patients with stroke. They reported significantly greater improvement of PLC in patients given nortriptyline than in those receiving placebo and no significant change in the depression status of these patients. Selective serotonin reuptake inhibitors have also been used for treatment of PLC. In an open-label study by Seliger et al,20Seliger GM Hornstein A Flax J Herbert J Schroeder K Fluoxetine improves emotional incontinence.Brain Inj. 1992; 6: 267-270Crossref PubMed Scopus (94) Google Scholar all 13 patients (8 with stroke and 5 with multiple sclerosis) who received 20 mg/d of fluoxetine reported a decrease in the number of laughing or crying episodes within 3 to 14 days. Andersen et al21Andersen G Vestergaard K Riis JO Citalopram for post-stroke pathological crying.Lancet. 1993; 342: 837-839Abstract PubMed Scopus (209) Google Scholar compared citalopram, 10 to 20 mg/d, to placebo in 16 consecutive patients with stroke in a crossover study. They found that daily crying episodes decreased by 50% in all 13 patients receiving citalopram compared to only 2 patients who received placebo. In a double-blind, placebo-controlled study, Burns et al22Burns 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: 681-685Crossref PubMed Scopus (105) Google Scholar determined that sertraline in dosages up to 50 mg/d was effective in 13 of 14 patients with PLC and stroke, whereas placebo produced a beneficial response in 9 of 14 patients (P=.041). Muller et al23Muller U Murai T Bauer-Wittmund T von Cramon DY Paroxetine versus citalopram treatment of pathological crying after brain injury.Brain Inj. 1999; 13: 805-811Crossref PubMed Scopus (96) Google Scholar conducted an open-label study of 26 patients with PLC after traumatic brain injury. Thirteen patients were treated with citalopram, and 13 others received paroxetine in a single daily dose of 10 to 40 mg. Significant improvement was seen in 92% of patients, with rapid onset of effect within 1 to 3 days. AVP-923 is a new compound that consists of 30 mg of dextromethorphan and 30 mg of quinidine, which inhibits the metabolism of dextromethorphan by cytochrome P-450 2D6 enzyme. In a recent randomized, double-blind study by Brooks et al,24Brooks BR Thisted RA Appel SH AVP-923 ALS Study Group et al.Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial.Neurology. 2004; 63: 1364-1370Crossref PubMed Scopus (215) Google Scholar 140 patients with amyotrophic lateral sclerosis and PLC were randomized to receive dextromethorphan plus quinidine (n=70) vs dextromethorphan (n=33) or quinidine (n=37) alone in twice-daily doses. The authors reported approximately 2-fold lower scores on the Center for Neurologic Study-Lability Scale in the group that received dextromethorphan plus quinidine compared to the groups receiving only dextromethorphan or quinidine. Moreover, 52% of the patients receiving dextromethorphan plus quinidine were symptom free during the last 2 weeks of the study compared to 23% of patients taking dextromethorphan alone and 12% of patients taking quinidine alone. Statistically significant improvement in quality-of-life and quality-of-relationship scores were seen in the patients receiving the combination treatment compared to those receiving either drug alone. Adverse effects reported in the group receiving dextromethorphan plus quinidine included nausea (33%), dizziness (20%), and somnolence (13%), resulting in a 24% discontinuation rate in the group receiving the combination regimen compared to 6% and 5% in the dextromethorphan and quinidine groups, respectively. In a study by Panitch et al,25Panitch HS Thisted RA Smith RA Pseudobulbar Affect in Multiple Sclerosis Study Group et al.Randomized, controlled trial of dextromethorphan/quinidine for pseudobulbar affect in multiple sclerosis.Ann Neurol. 2006; 59: 780-787Crossref PubMed Scopus (149) Google Scholar 150 patients with multiple sclerosis and PLC were randomized to receive dextromethorphan plus quinidine (n=76) or placebo (n=74). Patients receiving the active compound experienced significant improvement of their PLC symptoms as well as their quality-of-life and relationship scores. Laughing and crying episodes occurred 4.7 times per week in the group receiving dextromethorphan plus quinidine compared to 11.5 episodes per week in the placebo group. Headaches were the most commonly reported adverse effect in both groups, but the only statistically significant adverse event was dizziness (26.3% in the dextromethorphan plus quinidine group vs 9.5% in the placebo group). Discontinuation of the study medication because of adverse events occurred in 16% of the dextromethorphan plus quinidine group compared to 11% in the placebo group. In summary, although several agents have been shown to be effective in the treatment of PLC, head-to-head comparative clinical trials are needed to determine whether any of the aforementioned treatment options are superior in efficacy or adverse-effect profile. Given the therapeutic effect of serotonergic agents in patients with PLC, it has been suggested that a serotonergic dysfunction is responsible for the impaired emotional regulation in these patients.21Andersen G Vestergaard K Riis JO Citalopram for post-stroke pathological crying.Lancet. 1993; 342: 837-839Abstract PubMed Scopus (209) Google Scholar The fact that a chemical agent, such as serotonin, is helpful in treating a condition does not necessarily imply a causal relationship between the agent and the condition. However, understanding how serotonergic substitution can improve emotional experience in patients with mood disorders while also being effective in patients who have pathological regulation of emotional expression is important. The hypothesis proposed by Oppenheim and Siemerling26Oppenheim H Siemerling E Mitteilungen uber Pseudobulbarparalyse und akute Bulbarparalyse.Berl Klin Wochenschr. 1886; : 46Google Scholar in 1886 and subsequently by Kinnier Wilson27Wilson SAK Some problems in neurology, II: pathological laughing and crying.J Neurol Psychopathol. 1924; 4: 299-333Crossref Scopus (128) Google Scholar in 1924 was that impaired emotional regulation results from disinhibition of a presumed brainstem center for laughter and crying due to lesions of the voluntary motor pathways in the descending corticobulbar tracts. As previously published,28Parvizi J Anderson SW Martin CO Damasio H Damasio AR Pathological laughter and crying: a link to the cerebellum.Brain. 2001; 124: 1708-1719Crossref PubMed Scopus (347) Google Scholar this explanation has several limitations. For example, if the inhibitory pathways are damaged in these patients, why do they not laugh or cry constantly, or why do they sometimes exhibit a response contradictory to the emotional valence of the triggering stimulus? Moreover, why do many patients with this condition lack the typical features of pseudobulbar palsy? The hypothesis of disinhibition assumes that a proper operation of emotional expression is based on a balance between inhibitory and excitatory inputs to a presumed brainstem center for laughing and crying. On the basis of the current knowledge of brain anatomy and function, there is no single brainstem center for laughter and crying. Rather, a network of brainstem nuclei is involved in the generation of movements associated with the acts of laughter or crying, and it remains to be determined how this network is regulated by the cerebral cortex. Which cortical structures are involved, and how do they exert their control over the brainstem network? Feinstein et al6Feinstein 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: 69-73PubMed Google Scholar, 29McCullagh 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: 43-48Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar have shown that the involuntary and uncontrollable emotional behavior in patients with multiple sclerosis correlates directly with poor performance in tests of prefrontal function. This suggests that the prefrontal cortices, rather than the primary motor cortices as Oppenheim and Siemerling26Oppenheim H Siemerling E Mitteilungen uber Pseudobulbarparalyse und akute Bulbarparalyse.Berl Klin Wochenschr. 1886; : 46Google Scholar and Kinnier Wilson27Wilson SAK Some problems in neurology, II: pathological laughing and crying.J Neurol Psychopathol. 1924; 4: 299-333Crossref Scopus (128) Google Scholar had suggested, are important for the control of emotional behavior.30Wild B Rodden FA Grodd W Ruch W Neural correlates of laughter and humour.Brain. 2003; 126: 2121-2138Crossref PubMed Scopus (273) Google Scholar However, questions remain. For instance, to what extent and through which pathways do the prefrontal cortices regulate the operation of the brainstem network? Is this regulation made possible through direct corticobulbar pathways or indirectly through additional structures such as the cerebellum, as suggested recently?12Parvizi J, Joseph J, Press D, Schmahmann JD. Pathological laughter and crying in multiple system atrophy—cerebellar type. Mov DisordIn press.Google Scholar, 28Parvizi J Anderson SW Martin CO Damasio H Damasio AR Pathological laughter and crying: a link to the cerebellum.Brain. 2001; 124: 1708-1719Crossref PubMed Scopus (347) Google Scholar, 31Parvizi J, Schiffer R. Pathological crying in a patient with a cerebellar cyst. J Neuropsychiatry Clin Neurosci. In press.Google Scholar A thorough understanding of the etiology and pathophysiology of PLC awaits further elucidation of the neural basis of human emotion and of the neurotransmitters and networks involved in its regulation and coordination. Meanwhile, the recognition, diagnosis, and treatment of this clinical entity is important to help patients and their caretakers enhance their quality of life and relationships.