Pseudobulbar Affect Versus Depression: Issues in Diagnosis and Treatment

July 31, 2018

The most challenging aspect of pseudobulbar affect is differentiating it from depression. Episodes of uncontrollable, sudden, and even inappropriate emotions may point to neurologic or psychiatric conditions.

Pseudobulbar affect (PBA) is a neurologic condition that is characterized by brief episodes of uncontrollable, sudden, and inappropriate emotions. The syndrome consists of uncontrollable crying or laughing, which usually is incongruent with the patient’s mood. Unfortunately, these involuntary emotional outbursts may be mistaken for symptoms of a mood disorder, such as major depression. Pseudobulbar affect often occurs secondary to a neurologic disorder, such as stroke, Alzheimer disease, traumatic brain injury, multiple sclerosis, and amyotrophic lateral sclerosis.

The prefix pseudo in ancient Greek language is used to represent something that is false. Pseudobulbar affect is appropriately named to describe an affect that may be incongruent with internal emotional states. This disorder was previously called emotional incontinence, pathological crying, and emotional lability. A likely reference to PBA appeared in Charles Darwin’s 1872 book, The Expression of the Emotions in Man and Animals. Charles Darwin stated, “Certain brain diseases, such as hemiplegia, brain-wasting, and senile decay, have a special tendency to induce weeping.”1 Although PBA has been documented in the literature for centuries, it continues to be misdiagnosed and underdiagnosed.

CASE VIGNETTE

Mr. A, aged 52 years, was admitted to the ICU following an ischemic stroke. During the hospitalization he began having sudden, brief, uncontrollable crying episodes. A psychiatric consultation was obtained, and he was started on sertraline for MDD. Unfortunately, he had minimal response to the medication. He continued to have crying episodes at home and was unable to identify a trigger for these outbursts.

Mr. A had no previous psychiatric history; he had a family history of major depression in an aunt. He reported a depressed mood that began shortly after the onset of his unexplained emotional outbursts. Mr. A’s wife was present at all medical visits and insisted that he was depressed as a consequence of the stroke. She believed that he was in denial about his feelings. Mr. A reported that he previously enjoyed spending time with family, friends, and outdoors. However, he began spending all of his time at home and declined family gatherings. Mr. A attributed these behavioral changes to wanting to avoid the embarrassment of an uncontrolled crying episode in public.

AThese symptoms persisted for months, and he obtained a second consultation. During this consultation, his symptoms were further elucidated. The crying outbursts were sudden, involuntary, unpredictable, excessive, and incongruent with mood.

Pseudobulbar affect was diagnosed and Mr. A was started on a new treatment regimen. The symptoms decreased in frequency and intensity. His family and friends were educated about the condition, which decreased his embarrassment when an outburst occurred. Mr. A was able to resume spending time with family, friends, and restarted his outdoor activities.

Etiology

The exact cause of PBA is unknown. It is estimated that approximately 1.8 to 7.1 million individuals are affected in the US.2 An accurate estimate is difficult to obtain because of variable diagnostic criteria and patient populations. Research suggests that PBA affects up to 50% of patients who have experienced a stroke or have amyotrophic lateral sclerosis.3,4

Pseudobulbar is caused by lesions of the medulla oblongata. Although, bulbar refers to the brain stem, the insult does not need to occur in the brain stem to cause PBA. Since PBA is often secondary to a wide variety of neurologic insults or injuries, the focus of research is not on identifying a specific lesion, but on identifying a common circuit. Current evidence suggests that PBA results from the disruption of the cerebro-ponto-cerebellar circuit, which decreases the threshold for the expression of emotion. It is proposed that damage to this circuit, such as from a stroke, may result in a disconnect. This condition has been classified as an affective disinhibition syndrome. The use of neuroimaging and neurophysiological studies of patients with PBA provides a neurological basis of PBA.

The dysfunction of the cerebro-ponto-cerebellar circuit is implicated in PBA. This circuit controls limbic and motor descending pathways to the brainstem and cerebellum. According to this theory, the cerebellum automatically controls emotional expression in response to information received from the cerebral cortex. This was tested using event-related potentials, which is a method to measure transient voltage waveforms in brain tissue. This work supported the prevailing gate control theory of PBA, which consists of sensory and motor abnormalities that result in disinhibition of the cerebellum’s ability to function as a gate control for motor expression of emotions.5 The cortical inputs to this circuit normally serve to inhibit inappropriate affect.

Research also suggests that abnormal glutaminergic and serotonergic neurotransmission may contribute to PBA. However, numerous other neurotransmitters may also be involved given their impact on emotion, such as dopamine, norepinephrine, and acetylcholine. We know that serotonin has many projections throughout the brain, and cell bodies originate in the brainstem raphe nuclei. Glutamate is the main excitatory neurotransmitter in the CNS. The exact etiology of PBA is unknown, but research supports a dysfunction of neural circuits and neurotransmitters that modulate the motor expression of emotion.6

Diagnosis of pseudobulbar affect

The diagnosis of pseudobulbar affect is made upon clinical presentation and patient self-report of symptoms. The following are key diagnostic criteria: involuntary episodes of laughing and/or crying that are sudden, unpredictable, excessive, and exaggerated.

There is a wide differential diagnosis for PBA, but the most challenging aspect is differentiating PBA from MDD (Table). The differential diagnosis should also include the following: frontal lobe disorders, behavioral disturbances associated with Alzheimer disease, stroke, epilepsy, traumatic brain injury, and essential crying, all of which may be the underlying neurological disorder that has created the cerebro-ponto-cerebellar circuit dysfunction that is the cause of the pseudobulbar effect.

The initial criteria for PBA were established by Poeck in 1969, which included: an emotional response inappropriate to a situation, affect is not congruent with emotions, inability to control the duration and severity of symptoms, and emotional expression does not result in relief for the patient.7 These criteria were expanded by Cummings in 2006 to include the following: a change from baseline emotional reactivity, not due to another disorder, not secondary to drug use, causes significant impairment, and affect is incongruent or exaggerated with patients’ subjective experience of their emotions.8

Scales used to further characterize the diagnosis and symptoms of PBA include the Center for Neurologic Study-Lability Scale (a self-report instrument) and the Pathological Laughing and Crying Scale (PLACS), which is administered by a provider and measures sudden episodes of crying or laughing. The major clinical challenge is recognizing the symptoms of PBA, which is often misdiagnosed as a mood disorder.

Differentiating pseudobulbar affect from depression

Pseudobulbar affect is a disorder of affect and major depression is a disorder of mood. The key to differentiate these two disorders is understanding the difference between affect and mood (Table). Affect is an outward expression of a subjectively experienced emotion. A mood is experienced internally. Affect has been defined as “the subjective and immediate experience of emotion attached to ideas or mental representations of objects. Affect is an outward manifestation that can be classified as restricted, blunted, flattened, broad, labile, appropriate, or inappropriate.”9

PBA is characterized by a lack of voluntary control over affective expression, a disorder of disinhibition. It is distinguished from MDD by its the duration of symptoms. PBA symptoms last seconds to minutes, but major depression lasts weeks to months. Patients with PBA will describe sudden, brief, intense, and uncontrollable displays of emotion. The emotional response or affect is considered inappropriate to a situation, exaggerated, involuntary, and often incongruent with mood. The emotional outbursts in PBA do not result in any relief for the patient and are not consistent with previous baseline emotional responses. The diagnosis of PBA is often secondary to neurologic disease, insult, or injury. PBA may occur comorbid with depression, but it is a distinctly different disorder.

MDD presents with symptoms that occur over weeks to months. The affect, such as crying, is consistent with the perceived depressed mood. Those with depression may have discrete emotional outbursts, but these are often elicited by known emotional triggers. Those with depression can identify their psychological triggers and modulate their affective responses, voluntarily. The diagnosis of MDD also includes a history of sleep disturbance, changes in appetite, changes in energy, feelings of guilt and hopelessness. These somatic symptoms are not directly associated with PBA. Major depression is thought to involve numerous and wide spread neural pathways and neurotransmitter systems, but PBA may involve more specific networks that determine the motor control of affect expression.

Treatment

There is no cure for PBA, but treatment can reduce the intensity and frequency of symptoms with the goal of improving well-being. The first step is to provide education to both the patient and his or her family. This will decrease the embarrassment associated with uncontrollable episodes and improve social functioning.

Until recently, the main treatment for PBA was antidepressants. Tricyclic antidepressants, and selective serotonin reuptake inhibitors/serotonin and norepinephrine reuptake inhibitors have been used off-label for treatment. The evidence for increasing serotonin to improve PBA symptoms has been limited to mainly case reports and small trials. It is thought that increasing levels of serotonin may decrease emotional lability and improve PBA symptoms.

The first treatment for PBA was FDA approved in 2010. Nuedexta is a fixed combination dosage capsule with 20 mg of dextromethorphan hydrobromide and 10 mg of quinidine sulfate. Normally, dextromethorphan is rapidly metabolized by CYP2D6 to dextrorphan, which appears to have a similar receptor binding profile. Although the mechanism of how dextromethorphan decreases the number of episodes of involuntary laughing and crying is unknown, it is putatively related to dextromethorphan’s uncompetitive low-affinity antagonism at the N-methyl-D-aspartate (NMDA) glutamate ion channel and/or its potent agonism at the sigma-1 receptor. Moreover, dextromethorphan inhibits the re-uptake of both serotonin and norepinephrine, which may also contribute to its mechanism of action.

The role of low dose quinidine, an antiarrhythmic medication, is to utilize its potent inhibition of the CYP2D6 metabolic enzyme that slows down the metabolism of dextromethorphan and increases brain exposure. Pharmacokinetically, this increases the half-life of dextromethorphan from roughly 2 hours to 13 hours, hence allowing for a low dose and a BID daily dosing schedule.

A 12-week, double-blind, randomized, controlled trial of dextromethorphan/quinidine reported a reduction in the PBA episode rate of 46.9 % to 49.0 %, depending on dextromethorphan dose, compared with placebo.10 The exact mechanism is unknown, but it likely reduces symptoms of PBA through modulation of excitatory neurotransmission in disrupted neural circuits.

Concluding thoughts

PBA is a neurologic condition that is characterized by brief episodes of sudden and uncontrollable emotions. These involuntary outbursts of emotion may be mistaken for symptoms of a mood disorder, such as major depression. PBA is characterized by a lack of voluntary control over affective expression, a disorder of disinhibition. Major depression is thought to involve numerous and wide spread neural pathways, but PBA may involve more specific networks that determine the motor control of affect expression. The recognition and diagnosis of PBA is necessary to ensure appropriate treatment and improved quality of life.

Disclosures:

Drs Lochhead and Nelson are Assistant Clinical Professors and Dr Maguire is Clinical Professor of Psychiatry, University of California Riverside School of Medicine, Riverside, CA.

Dr Lochhead and Dr Nelson report no conflict of interest regarding concerning the subject matter of this article. Dr Maguire has received research grants through UCR from Tera, Otsuka, Allergan, and Inracellular. He also is on the speakers bureau through UCR for Sunovion, Otsuka, Takeda, and Merck.

References:

1. Darwin C. The Expression of the Emotions in Man and Animals. New York; London: D Appelton and Co; 1872.

2. Work SS, Colamonico JA, Bradley WG, Kaye RE. Pseudobulbar affect: an under-recognized and under-treated neurological disorder. Adv Ther. 2011;28:586-601.

3. Kim SW, Shin IS, Kim JM, ET AL. Mirtazapine treatment for pathological laughing and crying after stroke. Clin Neuropharmacol. 2005;28:249-251.

4. Gallagher JP. Pathologic laughter and crying in ALS: a search for their origin. Acta Neurol Scand. 1989;80:114-117.

5. Ahmed A, Simmons Z. Pseudobulbar affect: prevalence and management. Ther Clin Risk Manage. 2013;9:483-489.

6. Lapchak PA. Neuronal dysregulation in stroke-associated pseudobulbar affect (PBA): diagnostic scales and current treatment options. J Neurol Neurophysiol. 2015;6:323.

7. Poeck K. Pathophysiology of emotional disorders associated with brain damage. In: Vinken PJ, Bruyn GW, Eds. Handbook of Clinical Neurology, Vol. 3. Amsterdam: North Holland; 1969: 343-367.

8. Cummings JL, Arciniegas DB, Brooks BR, et al. Defining and diagnosing involuntary emotional expression disorder. CNS Spectr. 2006;11:1-7.

9. Sadock BJ, Sadock VA. Kaplan and Sadock’s Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry (10th ed). Philadelphia: Wolters Kluwer; 2015.

10. Pioro EP, Brooks BR, Cummings J, et al. Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect. Ann Neurol. 2010;68:693-702.

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