JNNP Online First, published on June 1, 2017 as 10.1136/jnnp-2017-315622 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2017-315622 on 1 June 2017. Downloaded from Neurodegeneration RESEARCH PAPER Laughter, crying and sadness in ALS Nimish J Thakore,1 Erik P Pioro1,2 ► Additional material is ABSTRact are prevalent in amyotrophic lateral sclerosis (ALS), published online only. To view Background Pseudobulbar affect (PBA) is prevalent in where estimates range from 15% to >50%,1 8 and please visit the journal online both negatively affect quality of life (QoL).1 9 There (http:// dx. doi. org/ 10. 1136/ amyotrophic lateral sclerosis (ALS), but there is limited jnnp- 2017- 315622) information on its associations and course. is little information on the interplay or overlap of Objectives Explore prevalence, associations, course and these phenomena. 1Department of Neurology, manifestations of PBA in outpatient cohort of patients The aim of this study of a large cohort of patients Neuromuscular Center, with ALS and examine its relationship to depression. with ALS using self-report measures of PBA and Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA Methods Self-reported measures of PBA and depression is threefold: (1) examine the prevalence, 2Department of Neurosciences, depression (Center for Neurologic Study-Lability Scale associations and course of PBA in ALS; (2) explore Lerner Research Institute, (CNS-LS) and Patient Health Questionnaire (PHQ-9), associations, if any, that differentiate laughter from Cleveland Clinic, Cleveland, respectively) were obtained from consecutive patients crying in PBA; and (3) examine the relationship of Ohio, USA with ALS using tablet devices in waiting rooms PBA and depression, and if self-report instruments (Knowledge Program). effectively distinguish these two phenomena. A Correspondence to Nimish J Thakore, Department Results PBA (CNS-LS ≥13) was seen in 209/735 previous report describes the prevalence and associ- 9 of Neurology, Neuromuscular patients (28.4%). PBA was associated with bulbar ations of depression in this cohort. Center Neurological Institute, onset and dysfunction, upper motor neuron dysfunction, Cleveland Clinic, Cleveland, cognitive impairment, depression and lower quality of Ohio 44195, USA; thakorn@ METHODS ccf. org life. A multivariable model that included lower bulbar This was an exploratory observational study of PBA and gross motor subscores, female gender, younger age and depression in ALS, specifically addressing ques- Received 10 January 2017 and shorter duration of disease predicted PBA with 74% tions listed above. The cohort consisted of consec- Revised 16 March 2017 accuracy. CNS-LS scores increased only slowly with time. utive patients with ALS seen at a neuromuscular Accepted 12 April 2017 Women with PBA reported more crying than men. Crying centre between August 2006 and January 2015. (but not laughter) correlated with depression, and crying was associated with poorer quality of life. Exploratory Data source, participants and measures factor analysis of pooled questions of CNS-LS and PHQ-9 Under a quality initiative called Knowledge Program identified three underlying factors (laughter, crying and (KP),10 all neurology patients at our institution are depression) loaded on appropriate questions of the requested to provide patient-reported outcomes respective instruments. (PROs) during routine clinic visits using wireless Conclusion This study identifies associations of tablet devices in waiting rooms. Live data thus PBA and additionally findsP BA (especially crying- obtained inform clinical care. The practice of predominant PBA) more prevalent in women with ALS. collecting PROs is standard of care in neurology at http://jnnp.bmj.com/ Although the two self-report instruments (CNS-LS and our institution, and no additional consent is sought. PHQ-9) discriminate well between PBA and depression, These data accumulate in the KP Data Registry there is significant overlap between depression and that also includes some discrete elements of the crying in PBA. Studies of PBA should stratify for gender, patient’s electronic health record. Disease-spe- examine crying and laughter as separate outcomes and cific instruments used for ALS include a self-ad- adjust for depression. ministered version of the Revised ALS Functional Rating Scale (ALSFRS-R)11 and Center for Neuro- on September 26, 2021 by guest. Protected copyright. logic Study-Lability Scale (CNS-LS). ALSFRS-R is a widely used 12-question five-level instrument that INTRODUCTION measures function in ALS in the domains of bulbar, Pseudobulbar affect (PBA) is a treatable but fine motor, gross motor and respiratory function under-recognised neuropsychiatric phenomenon (three questions each),12 with a score of 48 repre- observed in a wide range of neurological disor- senting normal function. CNS-LS is a seven-ques- ders.1 PBA manifests with uncontrollable episodes tion five-level measure of PBA that includes four of laughter or crying that are excessive for or questions about laughter and three questions about incongruent with the underlying emotion and situ- crying.5 Total CNS-LS score can range from 7 to ation. Depression, on the other hand, is a pervasive 35, with a score of ≥13 implying clinically identi- disorder of mood characterised by sadness, anhe- fiable PBA (sensitivity 0.84 and specificity 0.81 in donia, worthlessness, suicidal thoughts and cogni- ALS).5 Generic outcomes measured in all neurolog- tive and somatic symptoms. Depression as well as ical disorders include Patient Health Questionnaire To cite: Thakore NJ, Pioro EP. PBA is typically diagnosed by a formal or structured (PHQ-9) andEuroQol five dimensions question- J Neurol Neurosurg Psychiatry Published Online First: [please interview and/or direct observation, and guidelines naire (EQ-5D). PHQ-9 is a nine-question four-level 2 include Day Month Year]. assist clinicians to differentiate the two conditions. instrument that incorporates Diagnostic and Statis- doi:10.1136/jnnp-2017- Additionally, various self-report instruments may be tical Manual for Mental Disorders, Fourth Edition 315622 used to screen for these conditions.3–7 Both states criteria for major depressive disorder.4 Total PHQ-9 Thakore NJ, Pioro EP. J Neurol Neurosurg Psychiatry 2017;0:1–7. doi:10.1136/jnnp-2017-315622 1 Copyright Article author (or their employer) 2017. Produced by BMJ Publishing Group Ltd under licence. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2017-315622 on 1 June 2017. Downloaded from Neurodegeneration score can range from 0 to 27, with a score of ≥10 implying at (sum of answers 1, 3 and 5) are presented in figure 1. Mean least moderate depression. EQ-5D is a brief five-question three- (SD) CNS-LS score was 10.86 (4.49), whereas median score level generic QoL index that includes a visual analogue scale was 9, and first and third quartiles were 7 and 13, respectively. (VAS) component.13 For this study, the KP Data Registry was The reported threshold for diagnosing PBA in ALS (13 points) queried by dates (2006–2015), diagnosis (International Clas- that we used for further analyses was reached or exceeded by sification of Diseases, ninth version, code 335.20) and depart- 209 of 735 patients (28.4%). In total, 293 (39.9%) reached a ment/centre evaluated (Neuromuscular) to obtain the dataset for liberal threshold of 11 points, but only 95 (12.9%) and 37 (5%) analysis. Corresponding patient charts were manually reviewed reached stringent thresholds of 17 and 21 points, respectively. for additional information including date of onset of weakness, The prevalence of PBA remained similar if we excluded patients site of onset (bulbar or extremity/other), clinical impression of with longer duration from onset (>2 years). cognitive dysfunction and clinical syndrome, namely typical ALS, upper motor neuron (UMN)-predominant disease or Associations of PBA lower motor neuron (LMN)-predominant disease. ALSFRS-R 14 Univariate associations of PBA are reported in columns 3–5 of ‘pre-slope’ was computed by dividing (initial ALSFRS-R minus table 1. PBA (CNS-LS ≥13) was significantly associated with 48) by months from weakness onset. female gender (37.8% vs 21.4% in males), bulbar onset (42.6% vs 23.2% in non-bulbar onset), lower ALSFRS-R score (espe- Statistical methods cially bulbar subscore) and more rapidly progressive disease. Distribution of CNS-LS scores and prevalence of PBA Prevalence of PBA increased with increasing UMN dysfunction (CNS-LS ≥13) were described. Univariate associations of PBA (10%, 29% and 39% for LMN-predominant disease, typical with categorical and continuous variables were examined using ALS and UMN-predominant disease, respectively). Only 1 of 12 Pearson’s χ2 test and Wilcoxon rank-sum test, respectively. (8%) patients with PMA had PBA compared with 10 of 25 (40%) Logistic regression with bootstrap validation was used for multi- patients with PLS. PBA was more prevalent in patients with cogni- variable prediction of PBA. In patients with repeated measures, tive dysfunction (37.9%) than those without (26.1%). Significant change in CNS-LS over time was estimated using a mixed model dysarthria/dysphagia (bulbar subscore ≤9) was observed in 69% that included a time term. The relative prevalence of laughter of patients with PBA compared with only 31% of those without. and crying was explored by centring and scaling corresponding Additionally, PBA was significantly associated with poorer objec- subscores by population means and SD, respectively (z-scores).15 tive (EQ-5D) and subjective (VAS) QoL, and with more prev- Patients with PBA were empirically classified into those who alent use of dextromethorphan-quinidine, antidepressants and cried more (crying-z-score > laughter-z-score), and those who baclofen. For a higher threshold of PBA (CNS-LS ≥17), several laughed more (laughter-z-score > crying-z-score), and asso- univariate associations were similar. An optimal multivariable ciations of these subgroups were examined. The association logistic regression model for PBA (CNS-LS ≥13) is presented between CNS-LS/PBA and PHQ-9/Depression/major depressive in figure 2 and online supplementary table S1 .