Although no one knows for certain what causes IEED, several theories exist about which brain areas and neurotransmitters may be involved in its development. "Because it occurs in so many different disease states, it is hard to say what areas of the brain are affected and which neurotransmitters are involved," Panitch stated. "But there is probably some kind of a disconnection between the frontal lobes, which normally keep emotions under control, and the brain stem and cerebellum, where these reflexes are mediated."
Emotional expression, including spontaneous crying and laughing, is normally under conscious or semiconscious control by the higher cortical centers, mostly in the frontal lobes, said Panitch. "In many of these conditions [in which IEED can occur], there is bilateral, subcortical disease, so there is a release of the brain stem reflexes," he explained. "What all these conditions have in common, of course, is a loss of cortical and subcortical control of descending tracts into the brain stem."
In an article published in the May 2007 supplement to CNS Spectrums, Rabins and coauthor David Arciniegas, MD, associate professor at the University of Colorado School of Medicine in Denver, offer some specific hypotheses about the pathophysiology of IEED.4 According to the authors, there is accumulating experimental and clinical evidence suggesting that the cerebellum plays an important role in emotional behavior and in visceral-autonomic responses. "The cerebellum receives projections from a number of cortical areas via the basis pontis, and lesions of the pons or the cerebro-ponto-cerebellar pathways produce emotional dysfunction," they write.4
Bidirectional connections between the cerebellum and the hypothalamus have been identified. It seems likely that the cerebellum plays an essential role in modulating motor, visceral, and behavioral responses via these connections, Rabins and Arciniegas argue. "These hypothalamocerebellar projections are posited to participate in cerebellar modulation of somatic motor as well as non-motor responses, while the cerebellohypothalamic connections may be involved with nonsomatic processes, including cardiorespiratory, immune, and emotional regulation."4
Deficits in specific areas of this complex cortico-limbic-subcortico-thalamic-ponto-cerebellar (CLSTPC) network may cause significant disruptions in a number of functions and can lead to disturbances in emotional experience and expression, including IEED, the authors contend.
As for the biochemistry of IEED, it has been suggested that s1 receptors located on the surface of the cerebellum and brain stem may play an important role. Giving rise to this theory was the observation that selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), both of which are known to be at least partially effective in controlling the disorder, possess significant agonist activities at s1 receptor sites.5 Moreover, the drug dextromethorphan(Drug information on dextromethorphan), which (in combination with quinidine(Drug information on quinidine)) has been found to effectively alleviate the symptoms of IEED, is also a potent s1 receptor agonist.
s1 Receptors are concentrated in the brain stem and cerebellum and limbic and motor CNS regions—all components of the CLSTPC network, Rabins and Arciniegas point out. The s1 receptor agonist dextromethorphan may effectively modulate 2 of the neurotransmitter systems, glutamate and serotonin, in parts of the CLSTPC network, and may thereby improve regulation of affect, the authors propose.4
Medications that have been used for the past 20 years or so for treating the symptoms of IEED include TCAs, such as amitriptyline(Drug information on amitriptyline) and nortriptyline(Drug information on nortriptyline), in relatively low doses. There are reports of success with TCAs going back to the 1980s, but they are not very effective, according to Panitch.
More modern antidepressants such as SSRIs also have been used, especially in situations in which the principal symptom is crying. They may be effective, Panitch said. "But nothing really appears to be as effective as a new compound [marketed as] Zenvia [dextromethorphan/quinidine (DM/Q)], which is currently being developed by Avanir Pharmaceuticals," he added.
Dextromethorphan is the therapeutically active ingredient in the combination agent to which Panitch referred and otherwise is a commonly used cough suppressant. The enzyme inhibitor quinidine increases the bioavailability of dextromethorphan. The drug combination is believed to help regulate excitatory neurotransmission in 2 ways: through presynaptic inhibition of glutamate release via s1 receptor agonist activity and through postsynaptic glutamate response modulation, as an uncompetitive, low-affinity N-methyl-d-aspartate antagonist.6
The efficacy and safety of the DM/Q combination was investigated by a research team headed by Panitch in a randomized controlled trial that was published in the May 2006 issue of the Annals of Neurology.7 A total of 150 patients with MS and comorbid IEED were randomly selected to receive either DM/Q capsules (30 mg/30 mg) or placebo twice a day for 12 weeks.
Patients receiving DM/Q had greater reductions in CNS-LS scores than those receiving placebo (P < .0001) at all clinic visits (days 15, 29, 57, and 85). Moreover, the number of crying or laughing episodes decreased (P = .0077), and significant improvements in quality of life (P < .0001) and quality of relationships (P = .0001) were documented.
Panitch and colleagues also tested the safety and efficacy of the DM/Q combination in patients with ALS, TBI, and PD and found the results to be very encouraging.8 "We've found it very effective and also very safe," he told Applied Neurology. He did point out, however, that the FDA has reservations about DM/Q.
In October 2006, the FDA issued an "approvable letter" outlining some safety concerns regarding the use of Zenvia for the treatment of IEED. To address these concerns, the drug's manufacturer intends to initiate a confirmatory phase 3 trial using a newer formulation with a lower dose of quinidine.6
Because of these developments, "it might be some time" before this new medication becomes available for use outside a clinical trial, Panitch noted. Nevertheless, physicians should be aware of the existence of IEED, he said, and should not automatically assume that everyone with frequent episodes of crying is depressed. Some of these persons—especially those with ALS, AD, or TBI or who are stroke patients—may be experiencing IEED.