Pseudobulbar Affect: A Call to Action

Transcription

1 Emerging Challenges in Primary Care: 2017 Pseudobulbar Affect: A Call to Action 1 Faculty Gustavo Alva, MD, DFAPA Medical Director, ATP Clinical Research Volunteer Faculty (Assistant Clinical Professor) Department of Psychiatry University of California Riverside, CA 2 Disclosures Gustavo Alva, MD, DFAPA serves on the research support team for Intra-Cellular, Trans-Tech, Novartis, and Neurion. Dr. Alva also serves on the clinical research team for Suven, Neurotrope, Janssen, Allergan, and Lundbeck. 3 1

2 Learning Objectives Review the epidemiology and impact of Pseudobulbar Affect (PBA). Recognize the importance of early recognition of PBA in primary care. Describe diagnostic tools and criteria for objective diagnosis of PBA. Discuss therapeutic options for PBA. 4 PRE-TEST QUESTIONS 5 Pre-test ARS Question 1 In the PRISM registry study, the prevalence of Pseudobulbar Affect was highest in patients with which of the following conditions? 1. Stroke 2. Dementia 3. Multiple sclerosis 4. Traumatic brain injury (TBI) 6 2

3 Pre-test ARS Question 2 In a survey of patients with Pseudobulbar Affect, approximately how many reported being housebound by their symptoms? 1. 10% 2. 20% 3. 30% 4. >40% 7 Pre-test ARS Question 3 Which of the following agents is/are FDAapproved for the treatment of Pseudobulbar Affect? 1. Fluoxetine 2. Citalopram 3. Dextromethorphan 4. Dextromethorphan/quinidine 5. All of the above 8 Pre-test ARS Question 4 A 63-year-old woman with a history of hypertension, dyslipidemia, and ischemic stroke presents complaining of excessive crying. She says the crying started after her stroke, about 6 months ago, and causes her to stay home most days. On questioning, she denies depressive symptoms and says I don t know why I m crying. All of the following might be appropriate at this time, EXCEPT: 1. Administer CNS-Lability Scale 2. Ask patient if laughing or crying episodes match her mood 3. Initiate empiric therapy with SSRI to identify and treat potential pseudobulbar affect 4. If further workup suggests pseudobulbar affect, consider prescribing dextromethorphan/quinidine 9 3

4 Pre-test ARS Question 5 How often do you consider a diagnosis of Pseudobulbar Affect in patients who report repeated episodes of laughing or crying? 1. Never 2. Rarely 3. Sometimes 4. Often 5. Always 10 Pre-test ARS Question 6 Please rate your confidence in your ability to recognize Pseudobulbar Affect in your patient population: 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 11 Pseudobulbar Affect (PBA) Definition and Pathophysiology 12 4

5 Understanding PBA Introduction to PBA: Video courtesy of the National Stroke Association 13 Definition of PBA Involuntary and inappropriate outbursts of crying and/or laughing Episodic (sudden and intense) - Brief (seconds to minutes) - Frequent - Stereotypical (frequency, duration, intensity) Episodes may be incongruent or exaggerated relative to patient s underlying mood 1-3 PBA occurs secondary to a variety of otherwise unrelated neurologic conditions 4 1. Schiffer R, Pope LE. J Neuropsychiatry Clin Neurosci. 2005;17(4): Wortzel HS, et al. CNS Drugs. 2008;22(7): Wilson SAK. J Neurol Psychopathol. 1924;4(16): NUEDEXTA (dextromethorphan HBr and quinidine sulfate) Capsules [prescribing information]. Aliso Viejo, CA: Avanir Pharmaceuticals; PBA: Disconnect Between Affect and Inner State PBA is a disconnect between affect (expression of emotion) and inner feelings Sudden, frequent episodes of uncontrollable crying or laughing that are exaggerated or independent of mood PBA occurs secondary to a variety of unrelated neurologic conditions affecting the brain, such as: Dementia incl. Alzheimer s disease (AD) Stroke Traumatic brain injury (TBI) MS ALS Parkinson s disease 1. Cummings J, Gilbert J, Andersen G. Eur Neurol Rev. 2013;8: Cummings JL, Arciniegas DB, Brooks BR, et al. CNS Spectr. 2006;11: Wortzel HS, Oster TJ, Anderson CA, Arciniegas DB. CNS Drugs. 2008;22:

6 5/3/17 Hypotheses of PBA Pathophysiology PBA may result from Lesions in the corticobulbar tract that disrupt voluntary control of emotional expression and disinhibit, u or release, laughter/crying centers or Network disrupted Lesions in the cortico-ponto-cerebellar circuit that impair cerebellar modulation of affect, which processes information from the cerebral cortex on the social/cognitive context of the triggering stimulus u Involuntary Laughing/ Crying 16 1 Arciniegas DB, Topkoff J. Semin Clin Neuropsychiatry. 2000;5(4): ; 2 Parvizi J, et al. Brain. 2001;124(Pt 9): ; 3 Parvizi J, et al. J Neuropsych and Clin Neurosci. 2009; 21: Putative gate control of emotional expression Somatosensory cortex BA 5, 5, BA BA 40 Normal BA Somatosensory cortex PBA Excitatory Inhibitory Excitatory Inhibitory 17 Haiman G et al. J of Clin Psychopharm PBA Symptoms May Impact Activities and Social Function Patients with PBA: - Reported impaired social and occupational function, embarrassment, social phobia, withdrawal, and isolation impacting both themselves and caregivers - May have interference with physical and/or occupational rehabilitation from an underlying neurologic condition Life situations affected by PBA Ability to make/keep friends 44% Becoming homebound 42% Getting divorced Moving to supervised living It is unknown whether PBA treatment affects these types of social disabilities. 29% 15% Study design: Neurologic patients and their caregivers were surveyed online using a matched sample design (N=1,061; the exact number of PBA patients varied per question). Respondents were asked: To what extent have your/your patient s involuntary episodes of laughing and/or crying ever contributed to the following life situations? This graph shows responses of Main cause, Great deal, or Somewhat using a 5-point scale. Top 3 scores on a 5-point scale: Main cause, Great deal, or Somewhat. 1. Work SS, Colamonico JA, Bradley WG, Kaye RE. Adv Ther. 2011;28: Schiffer R, Pope LE. J Neuropsychiatry Clin Neurosci. 2005;17: Ahmed A, Simmons Z. Ther Clin Risk Manag. 2013;9: Sacco S, Sara M, Pistoia F, Conson M, Albertini G, Carolei A. Arch Phys Med Rehab. 2009;89: Colamonico J, Formella A, Bradley W. Adv Ther. 2012;29:

7 Estimated PBA Symptom Prevalence 19 Pseudobulbar Affect: Historical Background 1872: Charles Darwin wrote that certain brain diseases, such as hemiplegia, brain wasting, and senile decay, have a special tendency to induce weeping : H. Oppenheim coined the term pseudobulbar affect as spasmodic bursts of laughter or weeping associated with brain lesions : S.A.K. Wilson offered the first comprehensive clinical description of pathological laughing and crying (PLC) syndrome and 1985: K. Poeck suggested diagnostic criteria 4,5 1 Darwin C. The Expression of the Emotions in Man and Animals. New York, NY and London: D. Appleton and Company; 1872; 2 Duda JE. CNS Spect. 2007;12(suppl 5):6-10; 3 Wilson SAK. J Neurol Psychopathol. 1924;4(16): ; 4 Poeck K. Ger Med Mon. 1969;14(8): ; 5 Poeck K. Pathological laughter and crying. In: Fredericks JAM, ed. Handbook of Clinical Neurology. Vol 45: Elsevier Science Publishers; An Estimated 7 Million People With Neurologic Conditions Have Symptoms Suggestive of PBA % of patients with CNS-LS 13 Prevalence of PBA symptoms in common neurologic conditions (based on PRISM Registry; n>5,000, 132 centers) % Alzheimer s disease/ Dementia Presence of PBA symptoms (N=5,290) 45% 46% 26% 38% 52% ALS MS Parkinson s Stroke TBI CNS-LS Score of CNS-LS Score of 21+ PBA symptom prevalence was measured using the CNS-LS a in 5,290 outpatients with various neurologic conditions The CNS-LS has been validated as a PBA screening tool in ALS and MS populations only A CNS-LS score of 13 may suggest PBA symptoms and merits further diagnostic assessment a Center for Neurologic Studies Lability Scale. 1. Work SS, Colamonico JA, Bradley WG, Kaye RE. Adv Ther. 2011;28: Brooks BR, Crumpacker D, Fellus J, Kantor D, Kaye RE. PLoS One. 2013;8:e Moore SR, Gresham LS, Bromberg MB, Kasarkis EJ, Smith RA. J Neurol Neurosurg Psychiatry. 1997;63: Smith RA, Berg JE, Pope LE, Thisted RA. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004;5(suppl 1): Smith RA, Berg JE, Pope LE, Callahan JD, Wynn D, Thisted RA. Mult Scler. 2004;10:

8 PRISM Registry Psychotropic Medication Use by CNS-LS Category Psychotropic medication use is higher with increased PBA symptoms (as defined by CNS-LS score) 60% % of patients using medication 50% 40% 30% 20% 10% 0% CNS-LS <13 (N=3,346) 42.9%* CNS-LS 13 (N=1,944) 38.9%* CNS-LS 21 (N=492) 27.9% 22.8%* 18.6%* 9.8% 7.1%* 2.7% 5.0%* a Antipsychotic TCA Non-TCA Psychotropic medication use *P< compared with CNS-LS <13; chi-square test Note: Group with CNS-LS 21 is a subset of the group with CNS-LS 13. a Tricyclic antidepressant. The reasons for use of antipsychotic/antidepressant medications were not captured Brooks BR, Crumpacker D, Fellus J, Kantor D, Kaye RE. PLoS One. 2013;8:e Diagnosing PBA 23 Case #1: Is this PBA? A 54-year-old Hispanic man presents following a recent stroke with residual left hemiparesis: During the visit, he begins to cry When asked about the crying, he says he doesn t know why he s crying He denies symptoms of depression Subsequently demonstrates brief episodes of tearfulness interspersed with laughing 24 8

9 ARS Question Which of the following features of this presentation are consistent with PBA? 1. History of stroke 2. Residual neuromuscular deficits 3. Short and abrupt episodes of crying and laughing 4. All of the above 5. 1 and 3 25 Terminology Often Used to Describe PBA Symptoms Emotional Incontinence Affective Lability Various terms have been used to describe PBA, but these are not necessarily synonymous or interchangeable 1. Miller A. J Neurol Sci. 2006;245: Pathological Laughing and Crying Forced Crying Emotional Lability Emotional Dyscontrol Emotionalism a These terms are not always synonyms of PBA. 26 Recognizing PBA in Your Practice PBA episodes may appear as: EXAGGERATED Disproportionate to the situation and/or mood INCONGRUENT Inconsistent with or opposite to a person s mood Crying may appear as or with: UNPROVOKED Sometimes episodes can occur spontaneously and involuntarily, with little or no visible reason SHORT and ABRUPT Lasting seconds to minutes; sudden onset and no wind down weeping with or without tears sobbing or wailing crying with inarticulate sounds facial grimacing In the nursing facility, many residents may not be able to communicate. Crying may not be crying as commonly known. It can be accompanied by grimacing, other facial expressions, and by vocalizations. 1. Cummings JL, Arciniegas DB, Brooks BR, et al. CNS Spectr. 2006;11: Crumpacker DW, Engelman WA. US Neurol. 2014;10: Wilson SAK. J Neurol Psychopathol. 1924;4: Lieberman A, Benson DF. Arch Neurol. 1977;34: Zarowitz BJ, O Shea T. Consult Pharm. 2013;28: Rottenberg J, Gross JJ, Wilhelm FH, Najmi S, Gotlib IH. J Abnorm Psychol. 2002;111:

10 PBA: Crying What do these episodes look like? PBA: Laughing What do these episodes look like? Ø Laughing video: 29 ARS Question PBA is most often mischaracterized as what? 1. PTSD 2. Depression 3. Bipolar disorder 4. Part of underlying neurologic condition 30 10

11 PBA Is Underdiagnosed and Often Mischaracterized Common mischaracterizations of PBA Depression Just part of condition 28% 33% Bipolar/mood disorder Post-traumatic stress Anxiety Pain a Other Don't know/na 13% 9% 7% 0% 18% 12% Diagnoses received across all disease groups by patients who discussed their laughing and/or crying episodes with a physician and were given a diagnosis (n=227) Underdiagnosed in conditions with related or unrelated neurologic characteristics Dementia, stroke, TBI, MS, ALS a Includes various personality disorders, psychotic disorders, and stress. 1. Chart adapted from Work SS, Colamonico JA, Bradley WG, Kaye RE. Adv Ther. 2011;28: Colamonico J, Formella A, Bradley W. Adv Ther. 2012;29: Crumpacker DW, Engelman WA. US Neurol. 2014;10: Ahmed A, Simmons Z. Ther Clin Risk Manag. 2013;9: Engelman W, Hammond FM, Malec JF. Neuropsychiatr Dis Treat. 2014;10: PBA Is Often Mischaracterized as Depression Make a differential diagnosis that includes the possibility of comorbid conditions Differentiating PBA from depression when crying is present a Patients who frequently cry may have: (1) PBA alone, (2) PBA mischaracterized as depression, (3) PBA with depression, or (4) depression alone PBA Brief episodes (seconds to minutes) Sudden, abrupt, no wind down CRYING Exaggerated Over 75% of those with reaction or PBA symptoms (CNS-LS 13) independent of mood showed at least moderate depression symptoms in a study of 399 patients a Formal diagnosis of PBA or depression can only be made by a qualified HCP. These are not all of the diagnostic features of depression. PBA occurs in the context of a neurologic disease/injury affecting the brain and is not explained by other causes such as medication use. Depression Tonic mood (lasts weeks to months) Ongoing sadness or diminished interest If present, can be modulated b Emotional expression matches patient s mood b Tearfulness/crying is not a DSM-5 criterion for depression diagnosis. 1. Ahmed A, Simmons Z. Ther Clin Risk Manag. 2013;9: Colamonico J, Formella A, Bradley W. Adv Ther. 2012;29: Crumpacker DW, Engelman WA. US Neurol. 2014;10: Brooks BR, Crumpacker D, Fellus J, Kantor D, Kaye RE. PLoS One. 2013;8:e Cummings J, Gilbert J, Anderson G. Eur Neurol Rev. 2013;8: Cummings JL, Arciniegas DB, Brooks BR, et al. CNS Spectr. 2006;11: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed Dementia and Depression 1,2 Dementia Depression Onset Insidious Recent or recurrent Duration Months to years Weeks to months Progression Consciousness Irreversible Generally alert Reversible; relapses common Generally alert, possibly withdrawn History of Depression Usually negative Usually positive Visuospatial Often abnormal Preserved Mood: Sadness/ Guilt/Worthlessness Usually absent Usually present 1. Cefalu C, Grossberg GT. Diagnosis and Management of Dementia. American Academy of Family Physicians; American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition. Text Revision. (DSM-IV-TR ). American Psychiatric Association;

12 Underdiagnosis in Underlying Neurologic Conditions Reasons PBA may be underdiagnosed Patients may not tell their HCPs about their symptoms HCPs may not ask if patients are experiencing uncontrollable episodic crying or laughing PBA episodes may not occur during a medical visit PBA may be mistaken for symptoms associated with the patient s primary neurologic condition 1. Cummings J, Gilbert J, Andersen G. Eur Neurol Rev. 2013;8: Crumpacker DW, Engelman WA. US Neurol. 2014;10: Silver JM, McAllister TW, Arciniegas DB. Am J Psychiatry. 2009;166: Engelman W, Hammond FM, Malec JF. Neuropsychiatr Dis Treat. 2014;10: Colamonico J, Formella A, Bradley W. Adv Ther. 2012;29: Centers for Disease Control and Prevention, National Institutes of Health, Department of Defense, and Veterans Affairs Leadership Panel. June Centers for Disease Control and Prevention. Accessed November 24, Underdiagnosis in Underlying Neurologic Conditions Why PBA may be underdiagnosed in patients with: Dementia Mischaracterized as behavioral disturbances of dementia or mistaken for depression, which may co-exist with PBA. Stroke Mistaken for poststroke depression. May be mistaken for poststroke behavioral change. TBI a May co-occur or be mistaken for depression, PTSD, b or behavioral consequences of TBI. a May result from falls, unintentional blunt trauma, motor vehicle accidents, assaults, or other causes. b Post-traumatic stress disorder. 1. Cummings J, Gilbert J, Andersen G. Eur Neurol Rev. 2013;8: Crumpacker DW, Engelman WA. US Neurol. 2014;10: Silver JM, McAllister TW, Arciniegas DB. Am J Psychiatry. 2009;166: Engelman W, Hammond FM, Malec JF. Neuropsychiatr Dis Treat. 2014;10: Colamonico J, Formella A, Bradley W. Adv Ther. 2012;29: Centers for Disease Control and Prevention, National Institutes of Health, Department of Defense, and Veterans Affairs Leadership Panel. June Centers for Disease Control and Prevention. Accessed November 24, Alzheimer s Dementia Core Multiple cognitive deficits, consisting of memory impairment and 1 1 Aphasia Agnosia Apraxia Executive function Each deficit causes significant impairment in social or occupational functioning 1 Result of cholinergic deficit 2* Healthy Control AD largely involves temporoparietal deficits 3 Clinical Difficulty learning and remembering new information 2 Repetitiveness, anomia 2 Poor orientation to time 2 AD *AD not exclusively due to cholinergic deficit, but also due to amyloid plaques, neurofibrillary tangles, and cell death Images courtesy of Open Access Series of Imaging Studies (OASIS), IDs: OAS1_0011; OAS1_ American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition. Text Revision. (DSM-IV-TR ). American Psychiatric Association; Geldmacher D. In: Weiner MF et al, eds. Textbook of Alzheimer Disease and Other Dementias. 1st ed. American Psychiatric Publishing; 2009: Tarawneh R, Galvin JE. In: Weiner MF et al, eds. Textbook of Alzheimer Disease and Other Dementias. 1st ed. American Psychiatric Publishing; 2009:

13 Vascular Dementia Core Decline in cognitive function from a prior baseline and a deficit in performance in 2 1 Executive/attention Memory (may not always be impaired) 2 Language Visuospatial function Evidence of cerebrovascular disease via neuroimaging 1,3,4 Clinical Focal neurologic signs that may relate to location of vascular lesion 1,3,4 Cognitive deficits may occur in a stepwise fashion 1,3,4 Image courtesy of Dr Jeremy Jones, West Yorkshire Radiology Academy, Leeds, United Kingdom. 1. Gorelick PB et al. Stroke. 2011;42(9): Szoeke CE et al. In: Weiner MF et al, eds. Textbook of Alzheimer Disease and Other Dementias. American Psychiatric Publishing; 2009: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition. Text Revision. (DSM-IV-TR ). American Psychiatric Association; Roman GC et al. Neurology. 1993;43(2): PBA Making a Clinical Diagnosis Do you currently screen, and if so, how? 38 PBA: A Clinical Diagnosis The diagnosis of PBA remains CLINICAL! History: Prior or current neurologic condition (eg, MS, ALS, TBI, stroke) Symptom pattern: episodes of inappropriate laughing/ crying Differential: Rule out depression, anxiety, dementia, etc. No specific laboratory tests 1. Cummings et al.cns Spectr. Jun 2006;11(6):

14 PBA: A Clinical Diagnosis Proposed criteria (Cummings et al.): 1 Change from previous emotional responses Inconsistent with or disproportionate to mood Not dependent on stimulus or excessive relative to stimulus Cause significant distress or impairment Not accounted for by another disorder Not drug-related 1. Cummings et al.cns Spectr. Jun 2006;11(6): Case #2: Is this PBA? A 34-year-old Caucasian woman presents with episodes of mood instability Diagnosed with bipolar disorder (BD) and treated with mood stabilizer Treatment for BD significantly improved mood overall, but she still reports periods of emotional instability Reports episodes of crying, even in the absence of other symptoms of depression Crying episodes impact her function at work Asks if an antidepressant might help 41 ARS Question Which of the following might be appropriate at this time? 1. Add antidepressant to mood stabilizer 2. Administer Mood Disorder Questionnaire 3. Refer to psychiatrist for further evaluation of BD 4. Ask about history of neurologic conditions (eg, TBI) 42 14

15 Case #2: Is this PBA? When asked about neurologic history: Patient was collegiate athlete (soccer, basketball) and continued to play competitive sports through her 20s Reports several sports injuries consistent with TBI 43 ARS Question Which of the following might be appropriate at this time? 1. Request CT of head/neck 2. Administer CNS-Lability Scale 3. Refer to psychiatrist for workup of potential PBA 4. Initiate treatment with SSRI or dextromethorphan/quinidine 44 PBA Assessment Tool: Center for Neurologic Study Lability Scale Using the scale below, write the number that describes the degree to which each item applies to you DURING THE PAST WEEK. Write only 1 number for each item. Applies never 1 Applies rarely 2 Applies occasionally 3 Applies frequently 4 Applies most of the time 5 Assessment Questions Answers 1 2 There are times when I feel fine 1 minute, and then I ll become tearful the next over something small or for no reason at all. Others have told me that I seem to become amused very easily or that I seem to become amused about things that really aren t funny. 3 I find myself crying very easily. I find that even when I try to control my laughter, I am often unable to 4 do so. There are times when I won t be thinking of anything happy or funny at 5 all, but then I ll suddenly be overcome by funny or happy thoughts. I find that even when I try to control my crying, I am often unable to 6 do so. 7 I find that I am easily overcome by laughter. Total Score A score of 13 or greater may suggest PBA The CNS-LS has been validated in ALS and MS patient populations. A CNS-LS score of 13 may suggest PBA symptoms and merits further diagnostic assessment. 1. Moore SR, Gresham LS, Bromberg MB, Kasarkis EJ, Smith RA. J Neurol Neurosurg Psychiatry. 1997;63: Smith RA, Berg JE, Pope LE, et al. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004;5(suppl 1): Smith RA, Berg JE, Pope LE, Callahan JD, Wynn D, Thisted RA. Mult Scler. 2004;10:

16 Treating PBA 46 Treating PBA Goal is to reduce severity and frequency of episodes Primary molecular targets of therapy: Serotonin Norepinephrine Glutamate Drug classes used in PBA: SSRIs TCAs Antipsychotics Glutamate inhibitor (dextromethorphan) Few RCTs in PBA Only 1 FDA-approved medication (dextromethorphan/ quinidine) 47 Treating PBA: SSRIs Drug Disease N Outcomes Fluoxetine MS or stroke 13 Reduced episode rate Fluoxetine TBI or stroke 6 Reduced severity Fluvoxamine ALS, MS, or stroke Paroxetine, citalopram Uncontrolled trials of SSRIs in PBA Reduced episode rate TBI 26 Reduced severity Small studies, unvalidated outcome measures Overall positive outcomes with SSRIs 1. Muller U et al. Brain Inj. Oct 1999;13(10): Seliger et al. Brain Inj. May-Jun 1992;6(3): Sloan et al. Brain Inj. Jul-Aug 1992;6(4): Iannaccone et al. Clin Neuropharmacol. Dec 1996;19(6):

17 Treating PBA: RCTs Controlled trials in PBA1-6 Drug class Disease N Outcomes TCA Stroke 28 Reduced severity SSRI Stroke 20 Reduced severity SSRI Stroke 28 Reduced lability SSRI Stroke 106 Reduced crying DM/Q MS 150 Reduced severity DM/Q ALS or MS 326 Reduced severity Only studies with N 20 included Used severity scales as outcomes measures Response with active treatment greater than placebo in all studies 1. Robinson et al. Am J Psychiatry. Feb 1993;150(2): Brown et al. Acta Psychiatr Scand. Dec 1998;98(6): Burns et al. Int J Geriatr Psychiatry. Aug 1999;14(8): Choi-Kwon et al. Stroke. Jan 2006;37(1): Panitch et al. Ann Neurol. May 2006;59(5): Pioro et al. Ann Neurol. Nov 2010;68(5): FDA-Approved for PBA: Pharmacology of Dextromethorphan/Quinidine Dextromethorphan (DM) hydrobromide (20 mg) Active ingredient in the central nervous system 1 Undergoes rapid and extensive firstpass hepatic metabolism when administered alone Quinidine (Q) sulfate (10 mg) Metabolic inhibitor enabling therapeutic DM concentration 1 Increases bioavailability of DM by more than 20-fold 2 Prolongs elimination half-life of DM from 2 to 13 hours Pharmacokinetics of DM AUC of DM (ng * h/ml) Increased DM bioavailability DM 30 mg 5993 DM/Q NUEDEXTA 1. NUEDEXTA (dextromethorphan HBr and quinidine sulfate) Capsules [prescribing information]. Aliso Viejo, CA: Avanir Pharmaceuticals; Pope LE, et al. J Clin Pharmacol. 2004;44(10): Data on file: STAR Trial. Avanir Pharmaceuticals, Aliso Viejo, CA; Dextromethorphan/Quinidine: Mechanism of Action DM believed to modulate glutamate signaling in 2 ways: The mechanism by which DM exerts therapeutic effects in patients with PBA is unknown. AMPA R, α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor; NMDA R, N-methyl-D-aspartate receptor. 51 NUEDEXTA (dextromethorphan HBr and quinidine sulfate) Capsules [prescribing information]. Aliso Viejo, CA: Avanir Pharmaceuticals;

18 STAR Trial: Pivotal Study Design PBA populations - ALS (n = 197) - MS (n = 129) 64 study sites - North America (47 sites) - Latin America (17 sites) Primary endpoint - Reduction of PBA episode rate Randomized n = 107 N = 326 Double-Blind Phase 12 weeks n = 110 n = 109 DM/Q 30/10 bid DM/Q 20/10 bid Placebo bid NOTE: Only the DM/Q 20 mg/10 mg dosage form is FDA-approved. Open-Label Phase a 12 weeks 1. Arciniegas DB, Topkoff J. Semin Clin Neuropsychiatry. 2000;5(4): Parvizi J, et al. Brain. 2001;124(pt 9): Parvizi J, et al. J Neuropsychiatry Clin Neurosci. 2009;21: Miller A, et al. Expert Rev Neurother. 2011;11(7): a 52 Only the 30 mg /10 mg dose was studied in the open-label phase. Pioro EP, et al. Ann Neurol. 2010;68(5): STAR Trial: Reduction in PBA Episodes Mean Weekly Episode Decrease Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Week 9 Week 10 Week 11 Week 12 0 Mean Change from Baseline (%) * * * NUEDEXTA DM/Q Placebo Reductions from baseline may be seen within the first week of treatment Efficacy was sustained over the course of 12 weeks The need for continued treatment of PBA should be reassessed periodically, as spontaneous improvement of PBA symptoms occurs in some patients Data on file: STAR Trial. Avanir Pharmaceuticals, Aliso Viejo, CA; * * * * * * *P <.05 * * * 53 PBA Episode Remission with DM/Q % Patients Achieving Episode Remission at End of Study Patients (%) P < DM/Q Placebo a Remission = absence of PBA episodes during the patient s final 14 days of the study. Adapted from Pioro EP, et al. Ann Neurol. 2010;68(5):

19 DM/Q: Adverse Events Adverse Drug Events with an Incidence of 3% and 2x Placebo 1 DM/Q n = 107 Placebo n = 109 Diarrhea 13% 6% Dizziness 10% 5% Cough 5% 2% Vomiting 5% 1% Asthenia 5% 2% Peripheral edema 5% 1% Urinary tract infection 4% 1% Influenza 4% 1% Increased gammaglutamyltransferase 3% 0% Flatulence 3% 1% Rates of falls, somnolence, and fatigue were similar to placebo 1. NUEDEXTA (dextromethorphan HBr and quinidine sulfate) Capsules [prescribing information]. Aliso Viejo, CA: Avanir Pharmaceuticals; Data on file: STAR Trial. Avanir Pharmaceuticals, Aliso Viejo, CA. AEs were generally mild to moderate in nature Most were transient and decreased with continued use 2 Precautions to reduce the risk of falls should be taken, particularly for patients with motor impairment affecting gait or a history of falls 55 Summary PBA is common in patients with certain neurologic conditions, including MS, ALS, stroke, and TBI Characterized by episodes of laughing or crying that are inconsistent (or greatly exaggerated) with the patient s mood Episodes are paroxysmal Often misdiagnosed or mischaracterized Symptoms have significant impact on patients function Ask patients about history of neurologic conditions, quality of laughing/crying episodes, and mood CNS-LS can be used to support a diagnosis of PBA and establish baseline for treatment SSRIs, TCAs often used to treat, but only dextromethorphan/ quinidine is FDA-approved for PBA 56 POST-TEST QUESTIONS 57 19

20 Post-test ARS Question 1 In the PRISM registry study, the prevalence of Pseudobulbar Affect was highest in patients with which of the following conditions? 1. Stroke 2. Dementia 3. Multiple sclerosis 4. Traumatic brain injury (TBI) 58 Post-test ARS Question 2 In a survey of patients with Pseudobulbar Affect, approximately how many reported being housebound by their symptoms? 1. 10% 2. 20% 3. 30% 4. >40% 59 Post-test ARS Question 3 Which of the following agents is/are FDAapproved for the treatment of Pseudobulbar Affect? 1. Fluoxetine 2. Citalopram 3. Dextromethorphan 4. Dextromethorphan/quinidine 5. All of the above 60 20

21 Post-test ARS Question 4 A 63-year-old woman with a history of hypertension, dyslipidemia, and ischemic stroke presents complaining of excessive crying. She says the crying started after her stroke, about 6 months ago, and causes her to stay home most days. On questioning, she denies depressive symptoms and says I don t know why I m crying. All of the following might be appropriate at this time, EXCEPT: 1. Administer CNS-Lability Scale 2. Ask patient if laughing or crying episodes match her mood 3. Initiate empiric therapy with SSRI to identify and treat potential pseudobulbar affect 4. If further workup suggests pseudobulbar affect, consider prescribing dextromethorphan/quinidine 61 Post-test ARS Question 5 How often will you consider a diagnosis of Pseudobulbar Affect, after attending this conference, in patients who report repeated episodes of laughing or crying? 1. Never 2. Rarely 3. Sometimes 4. Often 5. Always 62 Post-test ARS Question 6 Please rate your confidence in your ability to recognize Pseudobulbar Affect in your patient population: 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 63 21