Pseudobulbar affect: the spectrum of clinical presentations, etiologies and treatments

Figures & data

Figure 1. Proposed brain circuitry involved in emotional expression, and its hypothesized dysfunction in pseudobulbar affect (PBA).

Normally (A), an emotional motor expression network including cortico–ponto–cerebellar afferentation (upper blue arrows) enables the cerebellum to act as a ‘gate-control’ for the motor expression of emotion (lower blue arrows). Inputs to this network (green and red arrows) include an inhibitory influence from sensory cortices. In PBA (B), reduced inhibitory influence at the cortical level (broken red cortical arrows) results in increased aberrant activation within the network (broken blue arrows), giving rise to the motor manifestations of pathological laughing/crying.

Figure 2. Circuitry of the cerebellum, including interactions that may be involved in a gating function relevant to emotional expression.

In brief, mossy fibers (from, for instance, the pontine nuclei) synapse with granule cells, which in turn distribute signals, via parallel fibers, to several cells types. Of these, only Purkinje cells generate cerebellar cortical efflux (to the deep cerebellar nuclei). Among cerebellar interneurons, stellate cells, basket cells and Lugaro cells are all inhibitory, while climbing fibers (from the inferior olivary nucleus) are strongly disinhibitory. For their part, Golgi cells are remarkable for inhibiting granule cells.

Table 1. Placebo-controlled trials of pharmacotherapeutic options in pseudobulbar affect.

Drug class	Study (year)	Active drug vs placebo	Study design	PBA setting	N	Main findings	Ref.
Tricyclic antidepressants	Schiffer et al. (1985)	Amitriptyline	Crossover; 1 month per treatment	MS	12	Reduced episode rate	[18]
	Robinson et al. (1993)	Nortriptyline	Parallel-group; 6 weeks	Stroke	28	Reduced severity on validated scale (PLACS)	[17]
Selective serotonin reuptake inhibitors	Andersen et al. (1993)	Citalopram	Crossover; 3 weeks per treatment	Stroke	16	Reduced episode rate	[22]
	Brown et al. (1998)	Fluoxetine	Parallel-group; 10 days	Stroke	20	Reduced severity on unvalidated scale	[23]
	Burns et al. (1999)	Sertraline	Parallel-group; 8 weeks	Stroke	28	Reduced lability on unvalidated scale	[58]
	Choi-Kwon et al. (2006)	Fluoxetine	Parallel-group; 6 months	Stroke	91	Reduced crying on unvalidated scale	[59]
Antiglutamatergics	Panitch et al. (2006)	DMQ	Parallel-group; 12 weeks	MS	150	Reduced severity on validated scale (CNS-LS); reduced episode rate	[63]
	Pioro et al. (2010)	DMQ	Parallel-group; 12 weeks	ALS or MS	326	Reduced severity on validated scale (CNS-LS); reduced episode rate	[68]

ALS: Amyotrophic lateral sclerosis; CNS-LS: Center for Neurologic Study–Lability Scale; DMQ: Dextromethorphan/quinidine; MS: Multiple sclerosis; PBA: Pseudobulbar affect; PLACS: Pathological Laughter and Crying Scale.

Schiffer R, Herndon RM, Rudick RA. Treatment of pathological laughing and weeping with amitriptyline. N. Engl. J. Med.312(23), 1480–1482 (1985).

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Robinson RG, Parikh RM, Lipsey JR, Starkstein SE, Price TR. Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study. Am. J. Psychiatry150(2), 286–293 (1993).

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Andersen G, Vestergaard K, Riis JO. Citalopram for post-stroke pathological crying. Lancet342(8875), 837–839 (1993).

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Brown KW, Sloan RL, Pentland B. Fluoxetine as a treatment for post-stroke emotionalism. Acta Psychiatr. Scand.98(6), 455–458 (1998).

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Choi-Kwon S, Han SW, Kwon SU, Kang DW, Choi JM, Kim JS. Fluoxetine treatment in poststroke depression, emotional incontinence, and anger proneness: a double-blind, placebo-controlled study. Stroke37(1), 156–161 (2006).

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Panitch HS, Thisted RA, Smith RA et al. Randomized, controlled trial of dextromethorphan/quinidine for pseudobulbar affect in multiple sclerosis. Ann. Neurol.59(5), 780–787 (2006).

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Pioro EP, Brooks BR, Cummings J et al. Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect. Ann. Neurol.68(5), 693–702 (2010).

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