The epidemiology and pathophysiology of pseudobulbar affect and its association with neurodegeneration

King, Rebecca; Reiss, Jeffrey P.

doi:10.2147/dnnd.s34160

Cited by 13 publications

(11 citation statements)

References 152 publications

(217 reference statements)

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“…Patients with frontotemporal lobar degeneration, which holds pathological overlap with ALS, have also been associated with high levels of pathological laughter ( 43 ), suggesting a shared pathological substrate that would be of interest in future comparative clinical imaging studies. Pharmaceutical agents modulating serotonin/dopamine deficiency, glutamate excess, and sigma type 1 receptor dysfunction have shown varying degrees of efficacy in reducing frequency of PLC episodes ( 1 , 44 ). Future investigation of brainstem-derived neurochemical profiles may help drive therapeutic advances of more efficacious treatment options for managing PLC in ALS patients.…”

Section: Discussionmentioning

confidence: 99%

Brainstem Correlates of Pathological Laughter and Crying Frequency in ALS

Huang

Caga

et al. 2021

Front. Neurol.

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Pseudobulbar affect is a disorder of emotional expression commonly observed in amyotrophic lateral sclerosis (ALS), presenting as episodes of involuntary laughter, or crying. The objective of the current study was to determine the association between frequency of pathological laughter and crying (PLC) episodes with clinical features, cognitive impairment, and brainstem pathology. Thirty-five sporadic ALS patients underwent neuropsychological assessment, with a subset also undergoing brain imaging. The Center for Neurological Study Lability Scale (CNS-LS) was used to screen for presence and severity of pseudobulbar affect (CNS-LS ≥ 13) and frequency of PLC episodes. Presence of pseudobulbar affect was significantly higher in bulbar onset ALS (p = 0.02). Frequency of PLC episodes was differentially associated with cognitive performance and brainstem integrity. Notably pathological laughter frequency, but not crying, showed a significant positive association with executive dysfunction on the Trail Making Test B-A (R2 = 0.14, p = 0.04). Similarly, only pathological laughter frequency demonstrated a significant negative correlation with gray matter volume of the brainstem (R2 = 0.46, p < 0.01), and mean fractional anisotropy of the superior cerebellar peduncles (left: R2 = 0.44, p < 0.01; right: R2 = 0.44, p < 0.01). Hierarchical regression indicated brainstem imaging in combination with site of symptom onset explained 73% of the variance in pathological laughter frequency in ALS. The current findings suggest emotional lability is underpinned by degeneration across distinct neural circuits, with brainstem integrity critical in the emergence of pathological laughter.

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Section: Discussionmentioning

confidence: 99%

Brainstem Correlates of Pathological Laughter and Crying Frequency in ALS

Huang

Caga

et al. 2021

Front. Neurol.

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“…The patient was thus treated empirically for VAN by an intensification of PD, which proved beneficial. Since the patient was recently prescribed a new medication, and no other etiology was found to have caused the patient's emotional lability, it is presumed that the valacyclovir likely caused neurotoxicity, resulting in the patient's unique emotional lability, and the improvement via PD, which has been reported relatively infrequently [5,6,14].…”

Section: Discussionmentioning

confidence: 99%

A Unique Case of Valacyclovir Toxicity and Pseudobulbar Affect in a Patient On Peritoneal Dialysis

Memon

Rose

Akram

et al. 2021

Cureus

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There are a few cases of valacyclovir-associated neurotoxicity (VAN) reported. This case report documents a case of a 55-year-old male presenting with emotional lability or pseudobulbar affect as the predominant or sole manifestation of VAN. A failure to adjust valacyclovir's dose for herpes simplex infection in the setting of dialysis-dependent end-stage renal disease (ESRD) preceded VAN in this patient. The patient presented with involuntary and uncontrollable outbursts of emotion. Computerized tomography (CT) scan identified no underlying cause. A complete neurological examination with cognitive assessment was performed, with no abnormalities. He benefited from the use of aggressive peritoneal dialysis (PD) that was employed to enhance valacyclovir's clearance in this case of intractable VAN. On discharge, the patient was back to baseline mental function.Traumatic brain injury, neoplasm, vascular lesions, metabolic abnormality, neurological disease, herpetic encephalitis, and disorders of mood were ruled out. This led to the hypothesis of encephalopathy due to valacyclovir intoxication. Given that the clinical manifestations were related to ESRD, a dose-adjustment of valacyclovir is imperative in the setting of ESRD to prevent VAN. Our case presents important clinical variations. Firstly, our patient demonstrates that VAN may present with no focal neurological impairment, but pseudobulbar affect. Secondly, aggressive PD was useful in this case for the treatment of VAN as opposed to hemodialysis. We believe that it cleared valacyclovir resulting in the resolution of symptoms.

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“…In ALS-associated PLC, functional and structural neuroimaging studies also supported the role of subcortico-thalamo-ponto-cerebellar network pathways in its pathophysiology, and no correlation with sensory deafferentation. 2,27,[40][41][42][43] Volitional facial movements are generally preserved in patients with emotional facial paresis, due to distinct excitatory pathways from the frontal and temporal cortices and hypothalamus to the periaqueductal gray matter and inhibitory modulation pathways from the lateral premotor cortices areas. 39 Similar pathway dysfunction has been observed in ALS patients secondary to the reduction or lack of inhibitory circuits originating from the frontal cortex due to progressive loss of neurons from the cortical areas ("top-down theory").…”

Section: Are There Different Classifications For the Dlc?mentioning

confidence: 99%

Definitions, phenomenology, diagnosis, and management of the disorders of laughter and crying in amyotrophic lateral sclerosis (ALS): Consensus from ALS and Motor Neuron Disease Scientific Department of the Brazilian Academy of Neurology

Gondim,

Pinto,

Chieia

et al. 2023

Arq Neuropsiquiatr

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The spectrum of neuropsychiatric phenomena observed in amyotrophic lateral sclerosis (ALS) is wide and not fully understood. Disorders of laughter and crying stand among the most common manifestations. The aim of this study is to report the results of an educational consensus organized by the Brazilian Academy of Neurology to evaluate the definitions, phenomenology, diagnosis, and management of the disorders of laughter and crying in ALS patients. Twelve members of the Brazilian Academy of Neurology - considered to be experts in the field - were recruited to answer 12 questions about the subject. After exchanging revisions, a first draft was prepared. A face-to-face meeting was held in Fortaleza, Brazil on 9.23.22 to discuss it. The revised version was subsequently emailed to all members of the ALS Scientific Department from the Brazilian Academy of Neurology and the final revised version submitted for publication. The prevalence of pseudobulbar affect/pathological laughter and crying (PBA/PLC) in ALS patients from 15 combined studies and 3906 patients was 27.4% (N = 1070), ranging from 11.4% to 71%. Bulbar onset is a risk factor but there are limited studies evaluating the differences in prevalence among the different motor neuron diseases subtypes, including patients with and without frontotemporal dementia. Antidepressants and a combination of dextromethorphan and quinidine (not available in Brazil) are possible therapeutic options. This group of panelists acknowledge the multiple gaps in the current literature and reinforces the need for further studies.

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The epidemiology and pathophysiology of pseudobulbar affect and its association with neurodegeneration

Cited by 13 publications

References 152 publications

Brainstem Correlates of Pathological Laughter and Crying Frequency in ALS

Brainstem Correlates of Pathological Laughter and Crying Frequency in ALS

A Unique Case of Valacyclovir Toxicity and Pseudobulbar Affect in a Patient On Peritoneal Dialysis

Definitions, phenomenology, diagnosis, and management of the disorders of laughter and crying in amyotrophic lateral sclerosis (ALS): Consensus from ALS and Motor Neuron Disease Scientific Department of the Brazilian Academy of Neurology

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