Sudden outbursts of laughing, crying, or other Emotional Expression without an apparent triggering stimulus have been recorded in the literature for decades.

Confusing nomenclature and a paucity of clinical research, however, have had clinicians wondering whether this syndrome may be both under-recognized and undertreated.

Treatment options, including AntiDepressants, Levodopa, and DextroMethorphan/Quinidine, may show promise in ameliorating symptoms for patients plagued with disorders of Emotional Expression.

A variety of Neurological conditions and disease states are accompanied by PseudoBulbar Affect (PBA), an emotional disorder characterized by uncontrollable outbursts of laughing and crying.

The causes of PBA are unclear but may involve lesions in Neural circuits regulating the motor output of Emotional Expression.

Several agents used in treating other Psychiatric Disorders have been applied in the treatment of PBA with some success but data are limited.

And, these agents are associated with unpleasant side effects due to nonspecific activity in diffuse Neural Networks.

DextroMethorphan (DM), a widely used cough suppressant, acts at Receptors in the BrainStem and Cerebellum, Brain regions implicated in the regulation of emotional output.

The combination of DM and Quinidine (Q), an Enzyme Inhibitor that blocks DM metabolism, has recently been tested in phase III clinical trials.

In patients with Multiple Sclerosis and Amyotrophic Lateral Sclerosis and was both safe and effective in palliating PBA symptoms.

In addition, clinical studies pertaining to the safety and efficacy of DM/Q in a variety of Neurological Disease states are ongoing.

Objective
To evaluate the efficacy and safety of DM/Q (capsules containing DextroMethorphan [DM] and Quinidine [Q]) compared with placebo, taken twice daily, for the treatment of PseudoBulbar Affect over a 12-week period in Multiple Sclerosis patients.

Methods
A total of 150 patients were randomized in a double-blind, placebo-controlled study to assess PseudoBulbar Affect with the validated Center for Neurologic Study-Lability Scale.

Each patient also recorded the number of episodes experienced between visits, estimated quality of life and quality of relationships on visual analog scales, and completed a pain rating scale.

Results
Patients receiving DM/Q had greater reductions in Center for Neurologic Study-Lability Scale scores than those receiving placebo (p < 0.0001) at all clinic visits (days 15, 29, 57, and 85).

All secondary end points also favored DM/Q, including the number of crying or laughing episodes (p < or= 0.0077), quality of life (p < 0.0001), quality of relationships (p = 0.0001), and pain intensity score (p = 0.0271).

DM/Q was well tolerated; only Dizziness occurred with greater frequency than with placebo.

Interpretation
Results in Multiple Sclerosis patients were similar to those of a previous study in Amyotrophic Lateral Sclerosis.

Demonstrating that DM/Q may be beneficial in treating potentially disabling PseudoBulbar Affect in a variety of Neurological Disorders.

PseudoBulbar Affect (PBA), a condition involving involuntary and uncontrollable episodes of crying and/or laughing.

Occurs frequently in patients with a variety of Neurological Disorders, including Amyotrophic Lateral Sclerosis (ALS), Stroke, Traumatic Brain Injury, Dementia including Alzheimer's Disease, and Multiple Sclerosis (MS).

Although PBA results in considerable distress for patients and caretakers, it is underrecognized and undertreated.

Agents used to treat Psychiatric Disorders-particularly Tricyclic Antidepressants and Selective Serotonin Reuptake Inhibitors-are useful in alleviating PBA, but act on Diffuse Neural Networks rather than targeting those involved in Emotional Motor Expression.

As a result of their nonspecific activity, these agents are associated with a range of unwanted effects that preclude many patients from using them.

DextroMethorphan, a common cough suppressant, specifically targets sigma(1) receptors concentrated in the BrainStem and Cerebellum, thus providing the possibility of targeting regions implicated in Emotional Expression.

When administered in a fixed combination with Quinidine, DextroMethorphan is effective in treating PBA in patients with ALS, and preliminary results suggest that this therapy also is effective in treating MS-related PBA.

Pseudobulbar Affect (PBA) is an affective disinhibition syndrome associated with various NeuroPathologies, which is characterized by involuntary and inappropriate outbursts of laughter and/or crying.

The PBA syndrome can be socially and occupationally disabling, and it is largely unrecognized in clinical settings.

Validated instruments to distinguish PBA from other disorders of affective regulation exist and could be used to improve recognition of the disorder.

There is no pharmacological therapy with a Food and Drug Administration indication for PBA, although AntiDepressants and Dopaminergic agents have been reported to show varying levels of treatment success.

Recent evidence suggests that treatment with a fixed combination of Dextromethorphan and the Cytochrome P450 2D6 enzyme inhibitor, Quinidine, can improve PBA.

This review describes the clinical and NeuroPathological features of PBA, and presents an overview of current and future treatment approaches.

PseudoBulbar Affect (PBA) or Pathological Laughing and Crying (PLC) is a disorder of affect that occurs in about 10% of Multiple Sclerosis (MS) patients.

The objective of this study was to validate the CNS Emotional Lability Scale (CNS-LS) in MS patients and to correlate the results with the frequency and intensity of episodes of PLC.

Physicians at seven private practice referral centers in the United States made a diagnosis concerning PLC based on patient interviews.

Clinical coordinators separately administered the CNS-LS, a self-report measure of PLC with seven questions, to MS patients.

Including patients known to exhibit PLC, patients thought to be free of PLC, and newly diagnosed patients where PLC status was unknown, and the physician was blinded as to the results.

A Receiver Operating Characteristic (ROC) curve analysis was performed to define a cut-off best correlating with the physician's diagnosis.

Of 90 MS patients selected to complete the survey, 50 were physician diagnosed with PLC; 40 were without PLC, and 15 of these 90 patients were newly diagnosed with MS (< 6 months).

Scores of 17 or higher corresponded to a sensitivity of 0.94 and a specificity of 0.83 (LR+ = 5.5, LR- = 0.07); 89% of patients were correctly diagnosed. The area under the ROC curve was 0.95.

Symptoms were greater in patients diagnosed as PLC than in non-PLC patients as evidenced by mean number of episodes/week, number of days/week with episodes, duration of an episode and total time in an episode.

Similar results were observed if patients were classified as PLC or non-PLC according to CNS-LS score > or = 17.

Suggesting that the CNS-LS is a valid measure for the assessment of PLC in MS patients and could be a useful instrument for clinical and research purposes.

PseudoBulbar Affect (PBA) is defined as episodes of involuntary crying, laughing, or both in the absence of a matching subjective mood state.

This NeuroPsychiatric Syndrome can be found in a number of Neurological Disorders including Multiple Sclerosis (MS).

The aim of this study was to identify NeuroAnatomical correlates of PBA in Multiple Sclerosis (MS) using a case-control 1.5T MRI study.

MS patients with (n = 14) and without (n = 14) PBA were matched on demographic, disease course, and disability variables.

Comorbid Psychiatric Disorders including Depressive and Anxiety Disorders were absent.

Hypo- and HyperIntense lesion volumes plus measurements of Atrophy were obtained and localized anatomically according to parcellated Brain regions.

Between-group statistical comparisons were undertaken with alpha set at 0.01 for the primary analysis.

Discrete differences in lesion volume were noted in five regions:
1. BrainStem HypoIntense lesions
2. Bilateral Inferior Parietal
3. Medial Inferior Frontal HyperIntense lesions
4. Right Medial Frontal HyperIntense lesions
5. Superior Frontal HyperIntense lesions were all significantly higher in the PBA group

A logistic regression model identified four of these variables (BrainStem HypoIntense, Left Inferior Parietal HyperIntense, and left and Right Medial Inferior Frontal HyperIntense lesion volumes) that accounted for 70% of the variance when it came to explaining the presence of PBA.

In conclusion, MS patients with PBA have a distinct distribution of Brain lesions when compared to a matched MS sample without PBA.

The lesion data support a widely-dispersed Neural Network involving Frontal, Parietal, and BrainStem regions in the pathophysiology of PBA.

Purpose
To characterize the Brain activity and associated Cortical structures involved in PseudoBulbar Affect (PBA), a condition characterized by uncontrollable episodes of Emotional Lability in patients with Multiple Sclerosis (MS).

Methods
Behavioral responses and Event Related Potentials (ERP), in response to subjectively significant and neutral verbal stimuli were recorded from 33 subjects in 3 groups:
1. MS patients with PBA (MS+PBA)
2. MS patients without PBA (MS)
3. Healthy control subjects (HC)

Statistical non-parametric mapping comparisons of ERP source current density distributions between groups were conducted separately for subjectively significant and for neutral stimuli.

Results
Behavioral responses showed more impulsive performance in patients with PBA.

As expected, almost all ERP waveform comparisons between the MS groups and controls were significant.

Source analysis indicated significantly distinct activation in MS+PBA in the vicinity of the SomatoSensory and Motor Areas in response to neutral stimuli, and at Pre-Motor and Supplementary Motor Areas in response to subjectively significant stimuli.

Both subjectively significant and neutral stimuli evoked higher current density in MS+PBA compared to both other groups.

Conclusions
PBA of MS patients involves Cortical structures related to Sensory-Motor and Emotional processing, in addition to overactive involvement of Motor Cortical areas in response to Neutral stimuli.

Significance
These results may suggest that a 'disinhibition' of a "gate control"-type mechanism for Emotional Expression may lead to the lower emotional expression threshold of PseudoBulbar Affect.

Objective
To evaluate Dextromethorphan combined with ultra low-dose quinidine (DMq) for treating PseudoBulbar Affect (PBA) in patients with Amyotrophic Lateral Sclerosis (ALS) or Multiple Sclerosis (MS).

Methods
In a 12-week randomized, double-blind trial, ALS and MS patients with clinically significant PBA (a baseline score ?13 on the Center for Neurologic Studies-Lability Scale [CNS-LS]) were maintained, twice daily, on placebo, DMq at 30/10mg (DMq-30), or DMq at 20/10mg (DMq-20).

Results
In 326 randomized patients (of whom 283, or 86.8%, completed the study), the PBA-episode daily rate was 46.9% (p < 0.0001) lower for DMq-30 than for placebo.

And 49.0% (p < 0.0001) lower for DMq-20 than for placebo by longitudinal negative binomial regression, the prespecified primary analysis.

Mean CNS-LS scores decreased by 8.2 points for DMq-30 and 8.2 for DMq-20, vs 5.7 for placebo (p= 0.0002 and p= 0.0113, respectively).

Other endpoints showing statistically significant DMq benefit included, for both dosage levels, the likelihood of PBA remission during the final 14 days.

And, for the higher dosage, improvement on measures of social functioning and mental health. Both dosages were safe and well tolerated.

Interpretation
DMq markedly reduced PBA frequency and severity, decreasing the condition's detrimental impact on a patient's life, with satisfactory safety and high tolerability.

The findings expand the clinical evidence that DMq may be an important treatment for patients suffering from the socially debilitating symptoms of PBA.