AVP-923 as a novel treatment for pseudobulbar affect in ALS

Summary

Key words: Pseudobulbar palsy; pathologic laughing; pathologic crying; dextromethorphan; quinidine; amyotrophic lateral sclerosis; multiple sclerosis; clinical trial; neurotherapeutics.

Introduction and Overview

Pseudobulbar affect (PBA) is a neurologic condition characterized by the disinhibition or loss of control of the motor expression of emotion (Wilson, 1924). Hallmark symptoms of PBA are uncontrollable crying and/or laughing that is out of context with the social setting (Arciniegas & Topkoff, 2000; Dark et al., 1996). The condition can be severe, unremitting, and persistent (Dark et al., 1996). PBA occurs secondary to neurologic diseases or injuries including amyotrophic lateral sclerosis (ALS) (Gallagher, 1989), multiple sclerosis (MS) (Feinstein et al., 1997), stroke (House et al., 1989), traumatic brain injury (Zeilig et al., 1996), Parkinson's disease (Kaschka et al., 2001), and dementia, including Alzheimer's disease (Starkstein et al., 1995). Other terms used to refer to PBA include pathologic laughing and crying (PLC), emotional lability (EL), and emotional incontinence (Dark et al., 1996).

PBA is caused by structural damage to the brain (Dark et al., 1996), possibly resulting from excitotoxic mechanisms underlying the associated neurologic disorder (Mattson, 2003). The end result is disconnection of the regions of the brain that regulate the motor expression of emotion. Under normal conditions, cortical regions (prefrontal, frontal, temporal, and motor), as well as subcortical limbic structures, send modulated signals to the cerebellum and brainstem to coordinate appropriate displays of emotion (Parvizi et al., 2001; Arciniegas & Topkoff, 2000; Mega et al., 1997; Wilson, 1924). It is hypothesized that abnormally increased excitatory, glutamatergic signaling causes the damage underlying a variety of neurologic disease and injury states (Mattson, 2003; Bittigau & Ikonomidou, 1997; Greenamyre, 1986), including a role in all those listed above that are linked with PBA (Mattson, 2003; Matute et al., 2001; Bittigau & Ikonomidou, 1997).