Affective Pseudobulbar Syndrome: An Emotional Disorder Transversal to Neurodegenerative Pathologies
Year: 2025
Type: article
Abstract: Dear Editor, Pseudobulbar affect (PBA) is an emotional disorder characterized by stereotyped and uncontrolled explosions of affection or emotional expressions such as laughing and crying that are inappropriately exaggerated concerning the context and not congruent with the mood. This symptomatology lasts from a few seconds to several minutes even several times a day.[1] PBA is transversal to many neurodegenerative pathologies such as Alzheimer’s dementia (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), Traumatic brain injury (TBI), stroke, and cerebellar lesions. PBA is currently poorly recognized and poorly treated, with an estimated 2 million affected individuals in the USA.[2] The causes of PBA are not completely clarified, there are several hypotheses, the general one according to the theory of Rabins and Arciniegas, PBA would be caused by various factors such as the interruption of the cortico-limbic-subcortoco-thalamic-ponto-cerebellar network, often related to lesions of descending corticobulbar fibers inhibiting emotional and motor areas, lesions of the brainstem and cerebellar white matter that modulate emotions and neurotransmitter anomalies of serotonin (5HT) and glutamate (GLU).[3,4] 5HT plays a role in emotional modulation. Serotonergic neurons are present in the cortico-limbic areas including the cerebellum. The quality of life is affected by PBA with negative effects on the rehabilitation process, social and occupational functioning, and the quality of relationships. PBA can lead to depression, anxiety, and stress not only for the patient but also for the caregiver.[1,3] The differential diagnosis is with psychiatric disorders (bipolar disorder, depression, anxiety, personality disorders with affective dysregulation, alcohol or substance intoxication), and some neurological disorders (epilepsy and convulsive states). PBA is mistaken for psychiatric disorders such as depression and masked by the symptoms of associated neurodegenerative diseases. Symptoms such as tiredness, anorexia, insomnia, discomfort and feelings of despair, and asthenia are superimposable on depressive symptoms. Depressive symptoms classically last from weeks to months, but a PBA episode lasts only seconds or minutes.[1] So mood disorders can present with some emotional lability, but the affection is congruent with mood and the episodes last longer than the excesses of PBA. Anxiety disorders such as panic disorder can occur with episodic manifestations of affection associated with autonomic reactivity, but the individual will have an internal sense of anxiety. However, an additional confusing factor in the diagnosis is PBA which can be comorbid with disorders such as depression or anxiety.[5] A recent systematic review and meta-analysis study revealed that failure to correctly diagnose or recognize PBA exposed patients to incorrect or insufficient therapies. The highest prevalence in neurodegenerative diseases was found in ALS at 38.5%, whereas in AD at 16.4%, and at PD 16.5%.[5] Although PBA according to the Pseudobulbar Affect Registry Investigating Symptom Management study, which aimed to estimate the prevalence of PBA in neurological pathologies, is less present in movement diseases compared to conditions such as ALS and TBI,[6] some studies on PD have shown that the prevalence of PBA would increase with disease progression.[4,7] There are different scales for the diagnosis and evaluation of PBA symptoms: The Center for Neurological Study lability Scale (CNS-LS) and the Pathological Laughing and Crying Scale (PLACS).[8] The CNS-LS is a self-report measure for PBA. It consists of a subscale for laughter (four items), each item is scored on 5 points (1 never applies, 5 most of the time applies), and is a reliable instrument (it has a sensitivity of 0.84 and a specificity of 0.81). The PLACS is administered by a healthcare professional. It quantifies aspects of pathological affect, including the duration of episodes, inadequacy to emotions, and degree of discomfort. It is composed of 16 items, 8 items are related to pathological laughter and 8 to pathological crying. The scores for each individual item range from 0 (normal condition) to 3 (frequent or high emotional lability). The PLACS distinguishes individuals with PBA with a sensitivity for PBA of 0.88 and a specificity of 0.96.[9,10] In 2010, the US Food and Drug Administration (FDA) approved the combination of dextromethorphan bromide (20 mg) and quinidine sulfate (10 mg) 1 capsule every 12 hours for maintenance therapy for PBA.[11] Dextromethorphan is a noncompetitive agonist of the N-Methyl D-Aspartate receptors, an agonist of the s1 receptors and an antagonist of the a3 b4 nicotinic receptor, it has an inhibitory action on the reuptake of serotonin and norepinephrine. Dextromethorphan has a low and variable bioavailability when administered alone due to rapid first-pass metabolism and subsequent elimination by cytochrome 450 CYP 2D6 liver enzymes. The association with quinidine sulfate, an inhibitor of CYD 2D6, increases the bioavailability of dextromethorphan.[12-13] It has been shown that dextromethorphan/quinidine (DMQ) binds to the 5HT transporter SERT and to the serotonergic receptor 5HT1B/D, partially modulating 5HT neurotransmission.[13] The anti-GLUergic effect of DMQ is effective in restoring inhibitory neurotransmission from the cortex to the brainstem, compensating for the dyscontrol of emotional expression in PBA.[14-16] DMQ is well tolerated. Adverse effects are diarrhea, nausea, dizziness, drowsiness, cases of prolongation of the QTc interval and slowing of the heart rate has been recorded.[11,17] DMQ is contraindicated in patients with a history of atrioventricular block, heart failure, prolonged QTc interval, and in patients with a history of thrombocytopenia, hepatitis, and bone marrow depression. The use of MAO oxidase inhibitors is contraindicated due to risks of potential drug interactions with the risk of serotonin syndrome.[18] In 52–a week of open-label multicenter study in patients with PBA associated with various neurological disorders, DMQ was generally well tolerated.[19] Off-label antidepressant class drugs such as SSRIs and tricyclic antidepressants (TCA) have been used to treat PBA with moderate benefits, as reported by open-label clinical studies and case reports14, but they do not appear to have been effective in acute forms of PBA.[18] SSRIs and TCAs with their widespread serotonergic action would act by increasing the availability of 5HT also in the cortico-limbic and cerebellar pathways, without being selective on the circuits involved in motor and emotional expression.[20] The mean dose of SSRIs in clinical trials for the treatment of PBA is sertraline 50 mg/day, for fluoxetine and citalopram 20 mg/day[21] for fluoxetine and citalopram 20 mg/day, while for TCAs, amtriptyline and nortriptyline from 20 to 100 mg/day.[22] SSRIs and TCAs remain an off-label therapeutic choice in patients who do not respond to treatment with DMQ. PBA is a neurological condition that is not very common, but still underestimated in the AD and PD population. Often mistaken for a psychiatric pathology. But unlike the psychiatric patient, the patient affected by PBA, except in advanced neurodegenerative states, has a fair amount of insight (sickness awareness), and the inability to control involuntary outbursts of pathological laughter and crying leads to serious embarrassment and inadequacy of the patient and the caregiver, with a decrease in the quality of life, which can lead to disruptions in their social life, including isolation and loss of work and marital divorce, with consequent demoralization and nervous depression. It is important to educate not only health professionals but also patients’ families and caregivers, with psychoeducational and informative support programs for social awareness, offered by various associations for dementia, MS, and Parkinson’s disease and through integrated management clinical care pathways. For example, care in the territory must provide assistance to the patient and families (specialist visits, primary care from the general practitioner, psychological and social assistance). Support for both patients with PBA and their caregivers is essential not only to reduce their care burden and health decline but also to prevent prejudice and social stigma. Early diagnosis and adequate treatment of PBA is important, to improve the quality of life of the patient already affected by the neurodegenerative pathology. Author contributions Sole author; not applicable. Data availability statement Not applicable. Declaration for AI use Nil. Declaration of use of copyright tools Not Applicable. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
Source: Journal of Psychiatry Spectrum
Author: Davide Cristina
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W4411780286