Pseudobulbar : When patients laugh or cry, but don’t know why

Disruption of neural circuitry undermines voluntary control of affect

seudobulbar affect (PBA) is a disorder of affective expression that manifests as stereotyped and frequent Poutbursts of crying (not limited to lacrimation) or laugh- ter. Symptoms are involuntary, uncontrolled, and exaggerated or incongruent with current . Episodes, lasting a few seconds to several minutes, may be unprovoked or occur in response to a mild stimulus, and patients typically display a normal affect between episodes.1 PBA is estimated to affect 1 to 2 million people in the United States, although some studies suggest as many as 7 million,1,2 depending on the evaluation method and threshold criteria used.3 Many terms have been used to describe aspects of PBA (Table 14 and Box, page 585-10). This abundance of often con- flicting terminology is thought to have impeded efforts to © SIMONE GOLOB/CORBIS categorize disorders, determine their Benjamin Frock, MD prevalence, and evaluate clinical evidence of potential ther- PGY-1 Resident apeutic options.11 Vanderbilt University School of Medicine Nashville, Tennessee Andrew Williams, MD Where to look for PGY-1 Resident Oregon Health & Science University PBA has been most commonly described in 6 major neuro- Portland, Oregon logic disorders: Jason P. Caplan, MD • Alzheimer’s disease Professor and Chair of • amyotrophic lateral sclerosis (ALS) Creighton University School of Medicine • (MS) Phoenix Regional Campus Phoenix, Arizona • Parkinson’s disease • • (TBI).

Disclosures Dr. Caplan has served as a consultant to Avanir Pharmaceuticals, an independent subsidiary of Otsuka America, Inc., manufacturer of the formulation of / discussed Current Psychiatry in this article. Drs. Frock and Williams report no financial relationships with any company whose 56 September 2016 products are mentioned in this article or with manufacturers of competing products. Of these disorders, most studies have Table 1 found the highest PBA prevalence in patients The study of PBA has yielded with ALS and TBI, with lesser (although sig- a long list of descriptive terms nificant) prevalence in Parkinson’s disease (Table 2, page 59).1,12 These “big 6” diagnoses Affective lability are not a comprehensive list, as many other Emotional dyscontrol disease states are associated with PBA (Table 3, page 59).12-14 Emotional incontinence As PBA has become better defined and more widely recognized, additional sequelae Emotionalism have been described. PBA’s sporadic and Excessive emotionality unpredictable nature and the potential Forced or crying embarrassment and distress of public out- Inappropriate hilarity bursts may lead to an agoraphobia-like Involuntary emotional expression disorder response.15 People with PBA report a signifi- Labile affect cantly worse subjective assessment of gen- Pathological affect eral health, quality of life, relationships, and Pathological laughter and crying Clinical Point Pathological weeping work productivity compared with people PBA’s unpredictable with similar primary underlying diagnoses Pseudobulbar crying without PBA.16 PBA: pseudobulbar affect nature and potential Source: Reference 4 embarrassment of public outbursts 2 Pathways: ‘Generator’ and may lead to an ‘governor’ basis pedunculi, and continues on to the agoraphobia-like Despite the many and varied injuries and anteroventral basis pontis. The basis pontis illnesses associated with PBA, Lauterbach then serves as an afferent relay center for response et al10 noted patterns that suggest dysregu- cerebellar activity. Projections from the pons lation of 2 distinct but interconnected brain then regulate the emotional circuitry primar- pathways: an emotional pathway controlled ily at the level of the PAG.10 by a separate volitional pathway. Lesions Lesions of the volitional pathway have to the volitional pathway (or its associated been correlated with conditions of PBA, feedback or processing circuits) are thought whereas direct activation of the emotional to cause PBA symptoms. pathway tended to lead to emotional labil- To borrow an analogy from engineering, ity or the crying and laughing behaviors the emotional pathway is the “generator” observed in dacrystic or gelastic .10 of affect, whereas the volitional pathway is The pivotal nature of the regulation the “governor” of affect. Thus, injury to the occurring at the PAG has guided treat- “governor” results in overspill, or overflow, ment options. Neurotransmitter recep- of affect that usually would be suppressed. tors most closely associated with this region include glutamatergic N-methyl-d- The emotional pathway, which coordinates aspartate (NMDA), muscarinic M1 to M3, the motor aspect of laughing or cry- γ-aminobutyric acid (GABA)-A, dopamine ing, originates at the frontotemporal cortex, D2, norepinephrine α-1 and α-2, sero- relaying to the amygdala and hypothala- tonin 5-HT1B/D, and sigma-1 receptors. mus, then projecting to the dorsal , Volitional inhibition of the PAG is medi- which includes the midbrain-pontine peri- ated by acetylcholine and GABA balance Discuss this article at aqueductal gray (PAG), dorsal tegmentum, at this location.10 www.facebook.com/ CurrentPsychiatry and related brainstem.

The volitional pathway, which regulates the When to screen for PBA emotional pathway, originates in the dorsal Ask the right question. PBA as a disease and lateral frontoparietal cortex, projects state likely has been widely under-reported, Current Psychiatry through the internal capsule and midbrain under-recognized, and misdiagnosed (typi- Vol. 15, No. 9 57 Box From Darwin to IEED, nomenclature has evolved over time

harles Darwin5 was among the first to was related to motor disinhibition resulting Cacknowledge the correlation between from bilateral corticobulbar lesions that neurologic insult and dysregulated emotional disengaged a brainstem “faciorespiratory expression, writing in 1872 that “certain brain center” from cortical levels of control. In disease, such as hemiplegia, brain-wasting, 1963, Poeck et al8 proposed diagnostic Pseudobulbar and senile decay, have a special tendency to criteria for PLC. induce weeping.” More recently, Cummings et al9 proposed affect In 1886, Oppenheim and Siemerling6 “involuntary emotional expression disorder” proposed the terms “pseudobulbar affect” (IEED) in 2006 as an umbrella term for (PBA) and “” (a separate disorders having “involuntary outbursts or and distinct state that includes dyscontrol crying and/or laughing” as a primary feature. of facial muscles, resulting in , To distinguish more sufficiently between , and dysphonia) in their descriptions purely affective etiologies of these features of patients with bilateral forebrain injury that (PBA) and disorders that include dysfunction appeared to mimic brainstem dysfunction. of both mood and affect, Lauterbach et Wilson7 in 1924 proposed that al10 divided IEED into 2 subtypes: PLC and pathological laughing and crying (PLC) emotional lability. Clinical Point A single question might best refine cally, as a primary ).9 Three presence and severity of PBA symptoms.1 A the likelihood that factors underscore this problem: 7-question, patient self-administered tool, a patient has PBA: • Patients do not specifically report the CNS-LS is graded on a 5-point Likert ‘Do you ever cry symptoms of affective disturbance (perhaps scale. A score ≥13 has high sensitivity and because they lack a vocabulary to separate specificity for diagnosis of PBA, compared for no reason?’ concepts of mood and affect) with physician diagnosis. • Physicians do not ask patients about Another option, the 16-question separations of mood and affect Pathological Laughing and Crying Scale, • Perhaps most importantly, PBA lacks a is a clinician-administered screening tool. general awareness and understanding. Again, a score ≥13 is consistent with symp- Co-occurring mood disorders also may toms required for a PBA diagnosis. thwart PBA detection. One study of PBA in Alzheimer’s found that 53% of patients with symptoms consistent with Treating PBA symptoms PBA also had a distinct mood disorder.17 This Until recently, most pharmacotherapeutic suggests that a PBA-specific screening test is interventions for PBA were based on off- needed for accurate diagnosis. label use of tricyclic (TCAs) A single question might best refine the or selective serotonin reuptake inhibitors likelihood that a patient has PBA: “Do you (SSRIs). From 1980 to 2010, only 7 of 22 case ever cry for no reason?” In primary psy- reports or trials of TCAs or SSRIs for PBA chiatric illness, crying typically is associ- were randomized, double-blind, and pla- ated with a specific trigger (eg, depressed cebo-controlled. Five had 12 to 28 patients, mood, despair, anxiety). A patient’s inabil- and 2 had 106 and 128 patients, respectively. ity to identify a trigger for crying suggests Only 1 controlled trial included a validated the pathological separation of mood and symptom severity scale, and none included affect—the core of PBA, and worthy of fur- a scale validated for PBA.18 ther investigation. In particular, imipramine and nortrip- tyline were studied for managing PBA Clinical rating scales that correlate to dis- in patients with stroke; , in ease severity appear to be the most effec- patients with MS; and various SSRIs, in tive in identifying PBA. The PRISM study, patients with stroke.11 Response of PBA to date the largest clinic-based study of PBA symptoms to therapy was symptoms, used the Center for Neurologic greater in all placebo-controlled trials than Current Psychiatry 58 September 2016 Study-Liability Scale (CNS-LS) to gauge the response to placebo.18 As seen in pharmaco- Table 2 Prevalence of PBA in the 6 most common underlying disease states CNS-LS ≥21 (%) [consistent with CNS-LS ≥13 (%) moderate or [consistent with severe PBA] symptoms of PBA] N Traumatic brain injury 16.4% 52.4% 590 Amyotrophic lateral sclerosis 12.0% 44.8% 125 Multiple sclerosis 12.0% 45.8% 1,215 Alzheimer’s dementia 9.4% 37.8% 1,799 Stroke 6.6% 29.3% 757 Parkinson’s disease 5.5% 26.0% 804 Average 9.3% 36.7% 5,290

CNS-LS: Center for Neurological Study-Liability Scale; PBA: pseudobulbar affect Source: References 1,12 Clinical Point

Table 3 Response of PBA therapy of , the lower burden of Other disease states and injuries symptoms to adverse effects and overall better tolerabil- that have been associated antidepressant ity of SSRIs resulted in their preferred use with PBA therapy was greater over TCAs. In some cases, the side effects of Acute demyelinating in all placebo- TCAs can be leveraged for therapeutic gain. Central pontine myelinolysis controlled trials than If insomnia is a problem, a nighttime dose Cerebral aneurysms response to placebo of a TCA could ameliorate this. Similarly, if Cerebral arteriovenous malformations a patient has sialorrhea, the anticholinergic effect of a TCA may show some benefit.19 Cerebral tumors Chemotherapy Dextromethorphan plus quinidine. Corticobasal degeneration Dextromethorphan has long been of inter- Deep brain stimulation est for a variety of neurodegenerative dis- eases. Studies of its efficacy were largely Herpes unsuccessful, however, because rapid Huntington’s disease metabolism by cytochrome P450 (CYP) 2D6 prevented CNS penetration.20 Quinidine is Lipid storage diseases an avid inhibitor of CYP2D6, even at very Neurosyphilis low dosages. Adding quinidine to dex- Normal pressure tromethorphan limits metabolism, allow- Primary lateral sclerosis ing dextromethorphan to accumulate to a Progressive supranuclear palsy plasma concentration sufficient to penetrate Wilson’s disease the CNS.12 In 2010, the combination agent PBA: pseudobulbar affect dextromethorphan hydrobromide (20 mg)/ Source: References 12-14 quinidine (10 mg) (DM/Q) became the first treatment to receive FDA approval for man- aging PBA.11 and serotonin neurotransmission and ion channel function.20 Sigma-1 receptors are Mechanism of action. The exact mecha- concentrated in the brainstem and parts of nism of DM/Q in PBA remains unknown. the cerebellum that are thought to coordi- Dextromethorphan is an agonist of sigma-1 nate motor emotional responses. Agonism receptors and a relatively specific noncom- of sigma-1 receptors on glutamatergic neu- petitive antagonist of NMDA receptors. It rons has been proposed to limit release of Current Psychiatry also has been shown to modulate glutamate glutamate from the presynaptic neuron Vol. 15, No. 9 59 that quinidine may be used to reduce abuse Related Resource of dextromethorphan.20 As such, the abuse • Bush D, Klein L (directors). Beyond laughter & tears: A jour- potential of DM/Q appears to be low. ney of hope. Madpix Flims, W2O Films; 2016. The most common adverse effects Drug Brand Names reported with DM/Q are diarrhea, dizzi- Amitriptyline • Elavil Imipramine • Tofranil 12 Dextromethorphan Moxifloxacin • Avelox ness, and cough. Notably, patients who hydrobromide (20 mg)/ • Pamelor received DM/Q in the STAR trial were more quinidine sulfate (10 mg) likely to report dizziness than those receiv- Pseudobulbar • Nuedexta affect ing placebo (10.3% vs 5.5%), but patients receiving placebo were more likely to fall.21,22 Package labeling warns that DM/Q while also limiting downstream transmis- causes dose-dependent QTc prolongation.21 sion of glutamatergic signal in postsynaptic Quinidine can be associated with signifi- neurons. cant QTc prolongation when dosed at anti- arrhythmic levels, although mean plasma Clinical trials. Two large trials have dem- concentrations found with the 10 mg of Clinical Point onstrated efficacy of DM/Q in PBA. STAR quinidine in the approved DM/Q formu- Compared with was a 12-week, double-blind, placebo- lation are 1% to 3% of those associated controlled trial with 326 patients diag- with typical dosages used in antiarrhyth- placebo, DM/Q use nosed with ALS or MS who showed PBA mic therapy. Electrophysiology studies was associated with symptoms (CNS-LS score ≥13). Compared of quinidine 10 mg dosed every 12 hours significantly reduced with placebo, DM/Q use was associated have demonstrated a mean QTc increase at daily episodes of PBA with significantly reduced (P < .01) daily steady state of 6.8 milliseconds, compared episodes of PBA at 2, 4, 8, and 12 weeks.20 with 9.1 milliseconds for a reference control at 2, 4, 8, and The effect was rapid, with 30% fewer PBA (moxifloxacin).12,21 12 weeks episodes after the first week (P < .0167). At Although this would seem to indicate a 12 weeks, 51% of patients on DM/Q had relatively low risk of clinically significant been symptom-free for at least 2 weeks. QTc prolongation at these ultra-low dosages The PRISM II study examined the effi- of quinidine, it may be advisable to obtain cacy of DM/Q in managing PBA in 102 an initial pre-dose and post-dose ECG and individuals with dementia, 92 with stroke, longitudinally monitor the QTc interval in and 67 with TBI. After 30 and 90 days, patients with conditions that predispose CNL-LS scores were significantly reduced to cardiac arrhythmias. Because quinidine (P < .001) compared with baseline scores.20 inhibits CYP2D6, use caution when pre- scribing and monitoring other medications Prescribing information. Dextro­ metabolized by this pathway. methorphan—typically in the form of cough syrup—has been implicated as a References 1. Brooks BR, Crumpacker D, Fellus J, et al. PRISM: a novel substance of abuse. A placebo-controlled research tool to assess the prevalence of pseudobulbar trial demonstrated that co-administering affect symptoms across neurological conditions. PLoS One. 2013;8(8):e72232. doi: 10.1371/journal. quinidine with dextromethorphan limits pone.0072232. measures of positive reinforcement, such 2. Cruz MP. Nuedexta for the treatment of pseudobulbar affect: a condition of involuntary laughing and crying. P T. as euphoria and drug liking. This suggests 2013;38(6):325-328. continued on page 63 Bottom Line Pseudobulbar affect (PBA) is characterized by paroxysmal affective outbursts that are (1) out of proportion to, and out of context with, patients’ mood state and (2) outside of their control. PBA is caused by brain illnesses and injuries that disrupt neural circuitry that underpins the volitional control of affect. FDA-approved dextromethorphan and Current Psychiatry 60 September 2016 quinidine in combination has demonstrated significant reduction in PBA symptoms. continued from page 60

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