Pseudobulbar Affect In Patients Research Articles

Resting state fMRI analysis of pseudobulbar affect in Amyotrophic Lateral Sclerosis (ALS): motor dysfunction of emotional expression

Pseudobulbar affect (PBA), referring to exaggerated or inappropriate episodes of laughing and/or crying without an apparent motivating stimulus, has been mainly attributed to bilateral degeneration of corticobulbar tracts. We aimed at exploring brain functional connectivity (FC) correlates of PBA in patients with amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, frequently associated with PBA. Resting state functional MRI (RS-fMRI) independent component (ICA) and seed-based analyses and voxel-based morphometry (VBM) whole-brain analysis were performed on 27 ALS patients (13 with PBA; 14 without PBA) and 26 healthy controls (HC), for investigating functional and structural abnormalities in ALS patients compared to HC and in patients with PBA compared to patients without PBA. Between-patient analysis revealed different FC patterns, especially regarding decreased FC in several areas of cognitive (default mode, frontoparietal, salience) and sensory-motor networks in patients with PBA compared to those without PBA. However, no significant differences were found in gray matter atrophy. Seed-based analysis showed increased FC between middle cerebellar peduncles and posterior cingulate cortex and decreased FC between middle cerebellar peduncles and left middle frontal gyrus in patients with PBA compared to patients without PBA. Our findings suggest that some alterations of fronto-tempo-parietal-cerebellar circuits could be related to PBA in ALS. In particular, the abnormal FC between cerebellum and posterior cingulate cortex and left middle frontal gyrus in patients with PBA compared to patients without PBA highlights a crucial role of the cerebellum in regulating emotion expression in patients with ALS.

The relationship between stress, anxiety, and depression levels and pseudobulbar affect in patients with multiple sclerosis

Background Pseudobulbar affect (PBA) has recently been added to the list of mental disorders commonly observed in patients with Multiple Sclerosis (MS). The emotional changes experienced by MS patients may be associated with other mental problems and adversely affect disease prognosis. However, there are limited studies in the international and national literature on this subject. Aim This study aimed to evaluate the relationship between PBA and stress, anxiety, and depression levels in patients with MS. Design This is a descriptive, relational, and cross-sectional study. Methods A total of 442 MS patients followed in the neurology outpatient clinic of a hospital and registered with the MS Society in Turkey participated in this study. Data were collected using a personal information form, the Turkish version of the Center for Neurologic Study–Lability Scale (CNS-LS), and the Depression Anxiety Stress Scale (DASS). Results In this study, 63.3% of the patients had PBA, 21% had extremely severe depression, 41.6% had extremely severe anxiety, and 24.9% had severe stress. Correlation analysis revealed weak positive correlations between CNS-LS total score and DASS subscale and total scores. Depression, anxiety, and stress levels accounted for 22.5% of the variation in CNS-LS total score. Conclusion The results of this study indicate that a majority of MS patients in Turkey experience PBA, depression, anxiety, and stress, and that PBA is positively associated with depression, anxiety, and stress. Impact statement This study, indicates that should be increased consultation-liaison psychiatry services in Turkey, and MS patients should benefit from comprehensive psychiatric services.

Dextromethorphan-quinidine is helpful for pseudobulbar affect disorder in stroke patients

An informed consent article using Hammond FM, Alexander DN, Cutler AJ, et al. PRISM II: an open-label study to assess effectiveness of dextromethorphan/quinidine for pseudobulbar affect in patients with dementia, stroke or traumatic brain injury. BMC Neurology. 2016;16:89. https://doi.org/10.1186/s12883-016-0609-0 for a patient with pseudobulbar affect following stroke.

Pseudobulbar affect in patients with stroke (P3.3-028)

Pseudobulbar affect in patients with stroke (P3.3-028)

Prediction of Cardiovascular Risk to Guide Primary Prevention

Importance In 2010, the US Food and Drug Administration approved a combination of dextromethorphan hydrobromide and quinidine sulfate with an Orphan Drug Act designation for the treatment of pseudobulbar affect in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). This medication, however, is commonly prescribed off-label for behavioral symptoms in patients with dementia and/or Parkinson disease (PD). Objective To investigate the prescribing patterns of dextromethorphan-quinidine, including off-label prescribing, and trends in associated costs. Design, Setting, and Participants This population-based cohort study of patients prescribed dextromethorphan-quinidine used data from 2 commercial insurance databases. The Medicare Part D Prescription Drug Program data set was used to evaluate prescription number and total spending by the Centers for Medicare & Medicaid Services. Patients were included if they were prescribed dextromethorphan-quinidine from October 29, 2010, when the drug was approved, through March 1, 2017. Main Outcomes and Measures The proportion of patients prescribed dextromethorphan-quinidine with a diagnosis of MS, ALS, or dementia and/or PD, as well as the number of patients with a history of heart failure (a contraindication for the drug). Results In the commercial health care databases, 12 858 patients filled a prescription for dextromethorphan-quinidine during the study period. Mean (SD) age was 66.0 (18.5) years; 67.0% were women; and 13.3% had a history of heart failure. Combining results from both databases, few patients had a diagnosis of MS (8.4%) or ALS (6.8%); most (57.0%) had a diagnosis of dementia and/or PD. In the Medicare Part D database, the number of patients prescribed dextromethorphan-quinidine increased approximately 12-fold, from 3296 in 2011 to 40 448 in 2015. Centers for Medicare & Medicaid Services spending on this medication increased from $4.3 million in 2011 to $137.5 million by 2015. Conclusions and Relevance Despite approval by the US Food and Drug Administration as an orphan-designated drug for pseudobulbar affect related to ALS or MS, this study suggests that dextromethorphan-quinidine appears to be primarily prescribed off-label for patients with dementia and/or PD.

PRISM II: an open-label study to assess effectiveness of dextromethorphan/quinidine for pseudobulbar affect in patients with dementia, stroke or traumatic brain injury.

BackgroundPhase 3 trials supporting dextromethorphan/quinidine (DM/Q) use as a treatment for pseudobulbar affect (PBA) were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). The PRISM II study provides additional DM/Q experience with PBA secondary to dementia, stroke, or traumatic brain injury (TBI).MethodsParticipants in this open-label, multicenter, 90-day trial received DM/Q 20/10 mg twice daily. The primary outcome was the Center for Neurologic Study-Lability Scale (CNS-LS), assessing change in PBA episode frequency and severity. The CNS-LS final visit score was compared to baseline (primary analysis) and to the response in a previously conducted placebo-controlled trial with DM/Q in patients with ALS or MS. Secondary outcomes included change in PBA episode count and Clinical Global Impression of Change with respect to PBA as rated by a clinician (CGI-C) and by the patient or caregiver (PGI-C).ResultsThe study enrolled 367 participants with PBA secondary to dementia, stroke, or TBI. Mean (standard deviation [SD]) CNS-LS score improved significantly from 20.4 (4.4) at baseline to 12.8 (5.0) at Day 90/Final Visit (change, −7.7 [6.1]; P < .001, 95 % CI: −8.4, −7.0). This magnitude of improvement was consistent with DM/Q improvement in the earlier phase-3, placebo-controlled trial (mean [95 % CI] change from baseline, −8.2 [−9.4, −7.0]) and numerically exceeds the improvement seen with placebo in that study (−5.7 [−6.8, −4.7]). Reduction in PBA episode count was 72.3 % at Day 90/Final Visit compared with baseline (P < .001). Scores on CGI-C and PGI-C showed that 76.6 and 72.4 % of participants, respectively, were “much” or ”very much” improved with respect to PBA. The most frequently occurring adverse events (AEs) were diarrhea (5.4 %), headache (4.1 %), urinary tract infection (2.7 %), and dizziness (2.5 %); 9.8 % had AEs that led to discontinuation. Serious AEs were reported in 6.3 %; however, none were considered treatment related.ConclusionsDM/Q was shown to be an effective and well-tolerated treatment for PBA secondary to dementia, stroke, or TBI. The magnitude of PBA improvement was similar to that reported in patients with PBA secondary to ALS or MS, and the adverse event profile was consistent with the known safety profile of DM/Q.Trial registrationClinicaltrials.gov, NCT01799941, registered on 25 February 2013Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-016-0609-0) contains supplementary material, which is available to authorized users.

Dextromethorphan/quinidine for treatment of pseudobulbar affect in patients with dementia: Treatment effects by concomitant antidepressant use in a 12-week open-label trial (PRISM II)

Dextromethorphan/quinidine for treatment of pseudobulbar affect in patients with dementia: Treatment effects by concomitant antidepressant use in a 12-week open-label trial (PRISM II)

Diagnosing pseudobulbar affect in traumatic brain injury.

Pseudobulbar affect (PBA) is defined by episodes of involuntary crying and/or laughing as a result of brain injury or other neurological disease. Epidemiology studies show that 5.3%–48.2% of people with traumatic brain injury (TBI) may have symptoms consistent with (or suggestive of) PBA. Yet it is a difficult and often overlooked condition in individuals with TBI, and is easily confused with depression or other mood disorders. As a result, it may be undertreated and persist for longer than it should. This review presents the signs and symptoms of PBA in patients with existing TBI and outlines how to distinguish PBA from other similar conditions. It also compares and contrasts the different diagnostic criteria found in the literature and briefly mentions appropriate treatments. This review follows a composite case with respect to the clinical course and treatment for PBA and presents typical challenges posed to a provider when diagnosing PBA.

Erratum to: Symptomatic and Palliative Care for Stroke Survivors

J Gen Intern Med Published 2012:27(7):863-60. DOI: 10.1007/s11606-011-1966-4 (c) Society of General Internal Medicine 2012 Erratum to: J Gen Intern Med DOI: 10.1007/s11606-011-1966-4 On page 857 of the original publication, the following statement contains a technical error. Recently, the FDA approved Nuedexta, a fixed-dose combination of the cough suppressant dextromethorphan hydrobromide and the antiarrhythmic quinidine sulfate, for treatment of pseudobulbar affect in patients with amyotrophic lateral sclerosis or multiple sclerosis. Correction: Although the FDA approved Nuedexta based on studies in amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), the approved indication was for treatment of pseudobulbar affect (without restriction to a specific underlying condition).

Memantine may affect pseudobulbar affect in patients with Alzheimer's disease.

Behavioural symptoms are common in moderate to severe Alzheimer's disease (AD) and are improved by memantine with the most pronounced effect on agitation/aggression. Dextromethorphan in combination with quinidine is the only drug approved by US Food and Drug Administration for the treatment of pseudobulbar affect (PBA) on the basis of efficacy in patients with multiple sclerosis or amyotrophic lateral sclerosis. The aim of our study was to evaluate the efficacy of memantine on PBA in patients with AD. In a prospective, double-blind, case-control study to assess PBA with pathological laughter and crying scale patients were administered memantine (final dose of 20 mg daily) or citalopram (20 mg once daily), each for 10 weeks. The number of episodes of involuntary emotional expression, Neuropsychiatric Inventory (NPI) and Overt Aggression Scale-Modified (OAS-M) total scores were also recorded. Furthermore, the platelet serotonin (5-HT) concentration was measured. Although memantine had beneficial effects on PBA, it also had a crucial impact on behavioural symptoms, especially aggression and agitation (to an average of 3.5 times higher end-point scores on OAS-M and increase of NPI total scores for an average of 114% of initial value). Therefore, the study was prematurely stopped. In addition, we had evidenced a drop of platelet 5-HT concentration (to an average of 73% of initial value). Surprisingly, our research showed the opposite action of memantine on neuropsychiatric symptoms as expected. In a limited number of AD patients with PBA, memantine had a beneficial effect on involuntary emotional expression, but it potentiated agitation/aggression, irritability and caused a crucial drop of the platelet 5-HT concentration.

Dextromethorphan and Quinidine Combination in Emotional Lability Associated With Depression

To the Editor: The combination of dextromethorphan and quinidine has been shown effective in the treatment of pseudobulbar affect in patients with amyotrophic lateral sclerosis1 and multiple sclerosis2 and has been tried in the treatment of diabetic neuropathy3 and heroin detoxification.4 Pseudobulbar affect is a disorder of emotional expression characterized by uncontrollable episodes of laughing and/or crying. The dextromethorphan-quinidine combination was developed to maximize brain levels of dextromethorphan, an N-methyl-d-aspartate (NMDA) antagonist, by using quinidine to slow cytochrome P450 2D6 enzymes. The mechanism by which dextromethorphan ameliorates pseudobulbar affect is unknown. Case report. Ms A, a 32-year-old woman with a history of depression, started outpatient treatment in our clinic after an admission following an overdose in April 2010. She had been in psychiatric care since the age of 25 years, when she first attempted suicide. The patient met DSM-IV criteria for a major depressive episode and she was given a diagnosis of major depressive disorder, recurrent, and borderline personality disorder. She was taking bupropion, escitalopram, and clonazepam. She had failed treatment with paroxetine, citalopram, duloxetine, desvenlafaxine, and selegiline patch and had had 5 admissions between 2004 and 2010. During the first year of treatment at our clinic, Ms A was admitted to the inpatient unit twice, for suicidal ideation, and, due to the refractory nature of her depression, referred for electroconvulsive therapy (ECT). During that year, she also failed treatment with therapeutic doses of mirtazapine, venlafaxine, and escitalopram and was tried on adjunct chlorpromazine and topiramate treatment; she received weekly psychotherapy during follow-up. After these interventions and adjustments of medications, Ms A, as of March 2011, was taking clonazepam 1 mg twice daily, fluoxetine 20 mg/d, bupropion 400 mg/d, and levothyroxine 175 μg/d. By April 2011, she had completed 11 sessions of ECT and felt she was not making progress. She was still reporting significant problems in controlling her affective expressions, especially due to her crying outbursts. Ms A began treatment with dextromethorphan and quinidine 20 mg/10 mg daily, at which time she scored 14 on the Center for Neurologic Study Lability Scale5 (a score above 10 is indicative of lability5). As of the time of this report, Ms A has been on treatment with dextromethorphan and quinidine for 1 year and reports significant improvement in her mood lability and crying spells. She has been out of the hospital and continues to go to work daily. She feels that her affective control has allowed her to benefit from her psychotherapy. In the present case, we report the off-label use of the combination of dextromethorphan and quinidine to address emotional lability in a patient with depression. Though the dextromethorphan-quinidine combination is approved only for pseudobulbar affect, it is possible that the underlying altered mechanism for affective expression is also altered in mood disorders. Randomized controlled trials to assess the efficacy of this combination in mood disorders are suggested.

No Relation between Physical Disability Scores and Severity of PBA in MS

Pseudobulbar affect (PBA) is a neurological condition of disinhibition of emotional expression characterized by uncontrollable, exaggerated, and often inappropriate outbursts of laughter and/or crying that may cause severe distress, embarrassment, and social dysfunction. This article discusses results from a study to examine the relationships between physical disability and the severity of PBA in patients with underlying multiple sclerosis.

Pseudobulbar affect: an under-recognized and under-treated neurological disorder

Pseudobulbar affect (PBA) is a neurologic syndrome of emotional affect disinhibition, characterized by uncontrollable, exaggerated, and often inappropriate emotional outbursts, which may cause severe distress, embarrassment, and social dysfunction. However, the US prevalence of PBA remains unknown. An online survey was conducted primarily to estimate the US prevalence of PBA in patients with the six most commonly associated conditions: Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, stroke, and traumatic brain injury. Invitations to participate were randomly sent online to adults (aged ≥ 18 years) registered in the Harris Poll Online Panel who were patients or belonged to a household with a patient diagnosed with one of the six conditions (identified through previous screening by Harris Interactive). Participants were screened for PBA using the Pathological Laughing and Crying Scale (PLACS) and the Center for Neurologic Study-Lability Scale (CNS-LS). PBA estimates were made using a cut-off score of ≥ 13 on the PLACS and two different cut-off thresholds on the CNS-LS, a lower one of ≥ 13 and a more rigorous one of ≥ 21. Existing US prevalence data for the six underlying conditions were used to estimate US prevalence of PBA. Of 38,000 individuals invited to participate, 8876 responded (23%) and 2318 (26%) completed the questionnaire. Mean prevalence of PBA across all six conditions was 10.1%, 9.4%, and 37.5% with the PLACS ≥ 13, CNS-LS ≥ 21, and CNS-LS ≥ 13 thresholds, respectively. Using disease population estimates from government agencies and professional organizations, the estimated US population with PBA ranged from 1.8 to 7.1 million. Among patients who discussed their laughing and/or crying episodes with a physician, 41% were diagnosed, and about half received a medication for their episodes. The overall prevalence of PBA was estimated to be about 10% across these commonly associated underlying neurological conditions and appears to be under-recognized.

Pseudobulbar affect in multiple sclerosis: Toward the development of innovative therapeutic strategies

Pseudobulbar affect (PBA), a condition involving involuntary and uncontrollable episodes of crying and/or laughing, occurs frequently in patients with a variety of neurological disorders, including amyotrophic lateral sclerosis (ALS), stroke, traumatic brain injury, dementia including Alzheimer's disease, and multiple sclerosis (MS). Although PBA results in considerable distress for patients and caretakers, it is underrecognized and undertreated. Agents used to treat psychiatric disorders–particularly tricyclic antidepressants and selective serotonin reuptake inhibitors–are useful in alleviating PBA, but act on diffuse neural networks rather than targeting those involved in emotional motor expression. As a result of their nonspecific activity, these agents are associated with a range of unwanted effects that preclude many patients from using them. Dextromethorphan, a common cough suppressant, specifically targets sigma 1 receptors concentrated in the brainstem and cerebellum, thus providing the possibility of targeting regions implicated in emotional expression. When administered in a fixed combination with quinidine, dextromethorphan is effective in treating PBA in patients with ALS, and preliminary results suggest that this therapy also is effective in treating MS-related PBA.

PII-59Population pharmacokinetic analysis of AVP-923 (30 mg dextromethorphan and 30 mg quinidine)

BACKGROUND AVP-923 is a combination product of 30 mg dextromethorphan (DM) and 30 mg quinidine (Q) for the treatment of pseudobulbar affect in patients with various neurological disorders. AIM To evaluate the population pharmacokinetics (PK) of AVP-923 in 170 subjects (53 healthy and 117 patients). METHODS Plasma samples were collected following oral administration of AVP-923 and concentrations of DM, dextrorphan (DX), and Q were assayed. Urine samples were collected for the determination of DM and DX. Compartmental analyses were performed using ADAPT-II®. Data for all analytes/matrices were modeled simultaneously and the impact of various covariates was investigated (age, gender, body weight, and phenotype). RESULTS The PK of Q was best described by a 1-compartment (CPT) model, while the PK of DM and DX were described by 2-CPT models. The model included a CYP2D6 inhibitory Emax effect driven by Q levels preventing biotransformation of DM to DX and reducing the renal clearances of DM and DX. Age had no effect on the PK of DM. For DX, there was an apparent increase in the central volume of distribution with increasing age. This was likely a reflection of a decrease in the terminal elimination rate constant since total clearance of both DM and DX was unaffected by age. Underlying diseases did not seem to affect the PK of DM or DX. CONCLUSIONS The effect of Q on DM and DX was adequately characterized using an inhibitory Emax function. Clinical Pharmacology & Therapeutics (2005) 79, P51–P51; doi: 10.1016/j.clpt.2005.12.184