Involuntary Emotional Expression Disorder Often Misdiagnosed and Untreated


Involuntary Emotional Expression Disorder Often Misdiagnosed and Untreated

Involuntary emotional expression disorder (IEED) tends to be underdiagnosed and misdiagnosed by physicians and often remains untreated, according to a recent study that used a novel method to estimate its prevalence among patients with several different neurological disorders.1

IEED, also known as pseudobulbar affect, emotional lability, and pathological laughing and crying, is characterized by uncontrollable episodes of crying or laughter that are exaggerated or incongruent with the underlying mood. In addition, sudden, angry outbursts may occur in IEED.2 These episodes are often embarrassing and can be socially debilitating for the patient.

IEED has been associated with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), traumatic brain injury (TBI), stroke, and Alzheimer disease (AD) and other dementias. According to some estimates, nearly 2 million persons may be affected in the United States.1


In a study presented on May 1, 2007, at the 59th Annual Meeting of the American Academy of Neurology in Boston, a research team led by Walter Bradley, DM, professor and chairman emeritus of the Department of Neurology, Miller School of Medicine, University of Miami, surveyed over 2000 patients (or their caregivers) with neurological diseases or injuries associated with IEED to determine the prevalence of this disorder.

Bradley and colleagues1 adopted a novel approach, which was to work with Harris Interactive (best known for the Harris Poll) and its online database of a nationally representative sample of American adults. The researchers identified from the Harris Interactive Chronic Illness Panel 2318 patients in whom 1 of 6 underlying neurological conditions (MS, PD, ALS, TBI, stroke, and AD and other dementias) had been diagnosed. Patients or their caregivers were then invited to participate in an online survey designed to estimate the prevalence of IEED in the 6 underlying diseases. Data were weighted to match the disease populations in the United States.

"This way of selecting patients differs from the standard clinic chart review and is perhaps a better way of obtaining community-wide data related to individual diseases and symptoms," Bradley said in an interview with Applied Neurology.

The investigators used 2 clinically validated scales: the Pathological Laughing and Crying Scale (PLACS) and the Center for Neurological Study Lability Scale (CNS-LS) to establish the prevalence of IEED. The surveys also collected information about patient-physician interaction regarding potential diagnosis and treatment of IEED.

The researchers used a cutoff score of 13 on the PLACS and 21 on the CNS-LS to distinguish between persons with or without IEED. The overall prevalence of IEED in the 6 diseases was estimated to be 10.1% (based on a PLACS score of 13 or greater) and 9.5% (based on a CNS-LS score of 21 or greater). These data indicate that between 1.8 and 1.9 million patients with neurological disorders in the United States experience comorbid IEED, based on estimates from various professional and governmental organizations of the number of persons affected by the 6 underlying neurological disorders.

Rates for specific neurological conditions were highest for ALS (32.5%) and lowest for PD (3.6%). Only 59% of patients with IEED symptoms had discussed them with a physician. Of these, fewer than half had received a diagnosis (most often depression) or any treatment.

These results, according to Bradley, show that IEED is a more frequent problem than had previously been thought and that it is underdiagnosed and undertreated by physicians. "This is unfortunate," he said, "because IEED seriously hampers social interactions and can have a significant deleterious effect on patients' and their families' quality of life."


Peter Rabins, MD, MPH, professor of psychiatry and codirector of the Division of Geriatric Psychiatry and Neuropsychiatry at Johns Hopkins University School of Medicine in Baltimore, also thinks that physicians often fail to properly diagnose IEED. One reason, he said, is that crying is the most common manifestation, which is often interpreted as a symptom of depression.

Another reason why IEED may sometimes be difficult to diagnose is that many patients, especially those in the advanced stages of AD, are unable to describe their emotions. "So, what you see is someone who suddenly cries intermittently. It is hard to know whether he is depressed, has IEED, or is having what is called a catastrophic reaction," Rabins said.

He related clues that might help physicians decide whether a particular patient has IEED or some other disorder such as depression. One clue is that patients who are able to describe their emotional state often say that they don't feel particularly sad, or else that they don't feel as sad as their crying would suggest. "In patients with ALS or MS, or even stroke, who also have IEED, the feeling-state doesn't match the expressed emotion," he explained.

Other important differences between depression and IEED also may help physicians differentiate these 2 disorders. In addition to crying, depressed patients typically express thoughts of helplessness, hopelessness, and guilt. These sentiments are usually absent in patients with IEED. Other symptoms that are often present in patients with depression but not in those with IEED include disturbances in sleep or appetite.3

Another typical characteristic of IEED, according to Rabins, is that episodes of crying or laughing come on very suddenly and usually stop very quickly. "These episodes are often triggered by an event that has a minor emotional relevance to it," he said.

In addition, the laughing that may occur in patients with IEED "is not really laughing," commented Hillel Panitch, MD, professor of neurology and director of the Clinical Neurotrials Unit at the University of Vermont College of Medicine in Burlington. "It's just a problem controlling the facial muscles, and it looks like the patient is giving you a big grin when he's really not," he explained.

In patients with MS, the symptoms of IEED typically begin during the later stages of the disease, according to Panitch. "In MS, IEED usually appears after there have been several attacks or relapses, and there is some damage to the pathways that control emotional expression," he said.

IEED also tends to appear during the later stages of AD; however, it can occur at any stage, according to Rabins. "In my clinical experience, IEED can occur at any stage, depending on where the lesions are. So certainly in ALS, but even in MS, some patients who have relatively mild, although definite neurological impairments, can develop symptoms of IEED."


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, which (in combination with 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 and 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.




Bradley WG, Arnold R, Kaye R. Involuntary emotional expression disorder (IEED) prevalence and treatment. Presented at: the 59th Annual Meeting of the American Academy of Neurology; May 1, 2007; Boston.


Cummings JL. Involuntary emotional expression disorder: definition, diagnosis, and measurement scales.

CNS Spectr.

2007;12(4, suppl 5):11-16.


Diagnostic and Statistical Manual of Mental Disorders.

4th ed. Washington, DC: American Psychiatric Association; 2000.


Rabins PV, Arciniegas DB. Pathophysiology of involuntary emotional expression disorder.

CNS Spectr.

2007;12(4, suppl 5):17-22.


Narita N, Hashimoto K, Tomitaka S, Minabe Y. Interactions of selective serotonin reuptake inhibitors with subtypes of sigma receptors in rat brain.

Eur J Pharmacol.



Avanir Pharmaceuticals Presents IEED Prevalence and Updated Zenvia Long-Term Safety Data at AAN Annual Meeting.

Business Wire.

May 1, 2007.


Panitch HS, Thisted RA, Smith RA, et al. Randomized, controlled trial of dextromethorphan/quinidine for pseudobulbar affect in multiple sclerosis.

Ann Neurol.



Miller A, Panitch HS. Therapeutic use of dextromethorphan: key learnings from treatment of pseudobulbar affect.

J Neurol Sci.

2007. [Epub ahead of print].

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