STROKE CLINICAL UPDATES. Approach to Patients with Pseudobulbar Affect in Stroke

Transcription

1 STROKE CLINICAL UPDATES Approach to Patients with Pseudobulbar Affect in Stroke Introduction Pseudobulbar Affect (PBA) is a relatively common disorder of emotional expression that occurs in many neurological disorders including amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, dementia, parkinsonian disorders (particularly progressive supranuclear palsy) and traumatic brain injury. Estimates of the prevalence vary widely and depend on the method of ascertainment 1-4 (Table 1). Because PBA manifests most commonly as crying, it is often misinterpreted by clinicians as depression, resulting in inappropriate counseling and management. When severe, the disorder can be quite dramatic, and can have a major impact on patients quality of life. Effective treatments are now available, making accurate diagnosis very important. Case Mr. Jones is a 57 year old man with atrial fibrillation who suffered a right frontal subcortical stroke about three years ago, which presented with left arm and face weakness. He recovered to the point of minimal deficits. Six months ago he suffered a second stroke with symptoms of severe expressive aphasia and was hospitalized for a week. During the hospital stay he was unable to express himself beyond a few short words or phrases and had good comprehension. It was also noted that he would cry loudly at various times during the day including while watching television and nearly every time his family came to see him. His family would tend to distract him by talking about current events and then he would stop. When his doctors would ask if he felt depressed, he would shake his head and sometimes say no. Nevertheless he was placed on a selective serotonin reuptake inhibitor. After a day, the episodes seemed to decrease a bit in frequency. He comes to your office for follow-up, six months after the second stroke. His language has significantly improved. He can easily express his wants and desires and participate somewhat in conversation, but he has not returned to work, partly because of his continued bouts of crying. He says that he sometimes worries that he will have another stroke and becomes concerned that he could lose his ability to support his family. When this happens, he breaks into an almost instantaneous bout of crying, which lasts for thirty seconds to a minute or two. This also happens very reliably every time he looks at a picture of his daughter, who just started college, or when he speaks to her on the phone. Whenever he sees something emotionally moving on television, particularly programs about families or medical illnesses, he has similar episodes of crying. These events occur several times a day. About once a week, he will have an

2 episode of uncontrollable laughing, usually prompted by a stray thought about something mildly funny. He finds the episodes embarrassing which cause him to curtail some of his social activities. His work involves many meetings, where he could not function with the threat of these episodes. He wonders if he is depressed, and admits that these episodes are frustrating and that his inability to get back to work gets him down. However, he feels quite positive about life, he is eager to get back to work, and he enjoys the time he spends with his family and friends. He is eating and sleeping well and is pursuing his hobbies. He has continued to take the medications he started in the hospital, including the selective serotonin reuptake inhibitor. In the office, you ask him to tell you about his daughter, and he begins by saying Well, she s so smart and I love, then he immediately breaks out into a severe bout of loud crying which lasts about 45 seconds. After it resolves he says Sorry, now you see what I m talking about. Interpretation This case illustrates many of the typical features of Pseudobulbar Affect (PBA). The disorder can occur from lesions in many parts of the brain, but bifrontal dysfunction is very common. Although sometimes described in the literature as being associated with no appropriate stimulus 5, episodes of PBA are more commonly stimulated by appropriate triggers. What makes the events pathological is that they are very powerful, with a rapid onset, and they are nearly impossible to control once they start. The disorder can manifest as crying or laughing, but crying is more common both within and across individuals. Some patients have predominantly laughing episodes. Cognitive or language deficits may make it difficult to obtain much information from the patient. As in this case, the link between the events and emotional stimulation is not recognized, and physicians often interpret these episodes as manifestations of depression. In Mr. Jones case he has some appropriate concern about his situation, but no anhedonia or vegetative signs indicating significant depression. Episodes of crying and/or laughing can often be elicited in the doctor s office by asking patients to talk about the types of thoughts or images that bring them on and the feelings associated with them. Counseling and Non-Pharmacological Management Counseling around the diagnosis is appropriate. It is helpful to explain that the brain has specific mechanisms to control emotions, and that neurological disease can impair these mechanisms. When this happens, stimuli that would normally induce a milder reaction would be controllable instead of leading to very strong expressions that develop too quickly and can t be controlled. It can be thought of as an increase in emotional reflexes. To choose a therapy, one must first assess the impact of the problem. Episodes that occur infrequently, don t bother the patient, and don t interfere with important work or

3 social activities, may not need treatment at all. In such cases, understanding the episodes and being able to explain them to friends and family are all the patient may need. For mild or infrequent episodes, attempts to improve emotion regulation may also be helpful, particularly when specific images or thoughts reliably stimulate episodes. Emotions are regulated through multiple mechanisms, including avoidance (which Mr. Jones is doing), but also reappraisal, meaning to think about a stimulus so that it does not produce as much feeling 6. In Mr. Jones case, he might practice replacing his concerns with more positive thoughts about his family, such as his knowledge that his daughter will soon become independent. Practical steps like the patient purchasing life-insurance may help. If he knows he is going to watch a movie that could provoke a reaction, he might actively work on thinking about some technical aspects of the filming or acting. While these techniques have not been formally studied for management of PBA, they may be effective for some patients. A behavioral therapist or speech pathologist can help patients to learn these strategies. Pharmacological Treatment For more frequent episodes, and/or in situations where the episodes clearly interfere with function, as in Mr. Jones case, medications should be considered. Several treatments have been used in the literature, most commonly antidepressants (Table 2). Small placebo controlled trials have indicated that selective serotonin reuptake inhibitors and tricyclic antidepressants can be of benefit 7,8,9,10,11. However, these agents have never been tested in large trials, and thus they are not FDA-approved for treatment of PBA. The only approved pharmaceutical treatment of PBA is the combination preparation of dextromethorphan (DM) 20 mg with quinidine (Q) 10 mg taken twice daily. The combination, DM/Q, has been evaluated in three large double-blind placebo controlled trials (Table 3). The first tested DM/Q 30mg/30mg against placebo twice daily in Amyotrophic Lateral Sclerosis (ALS) 12 and the second tested the same preparation in Multiple Sclerosis (MS) 13. The third 14 tested both a higher and lower dose of DM (30 mg or 20 mg) with a lower dose of Q (10 mg) in a combined group of ALS and MS patients. All three trials showed efficacy, including complete resolution of symptoms in a substantial portion of patients. Adverse effects were infrequent and lowest in the STAR trial, occurring in less than 13% of patients taking the drug. Although there was a statistically significant prolongation of QT interval with DM/Q treatment, the effect was small and there were no proarrhythmic events in any of the studies. Because DM/Q is effective in two different neurological disorders, it is approved for treatment of PBA from any etiology, including stroke. No published studies thus far have specifically evaluated its efficacy in stroke. Because the drug was recently developed,

4 there are also no large studies of long-term use to date. The components, dextromethorphan and quinidine, have long been available and there are no indications of long-term risk, especially because the quinidine dose is much lower than typical therapeutic doses for cardiac dysrhythmias. The drug should be considered a safe, generally well-tolerated agent for the treatment of PBA. The choice of drug in clinical practice should be dictated by the overall context. PBA can certainly occur in the context of depression, which is common in stroke and other neurological disorders. In this situation, it is reasonable to reassess the PBA symptoms after treatment for depression has been started. If the PBA symptoms do not resolve or the clinical history does not indicate depression, treatment with DM/Q should be considered. The main concerns regarding safety of DM/Q relate to quinidine, which is associated with QT prolongation and torsade de pointes at the higher doses typically used to treat cardiac arrhythmias. Torsades de pointes is an abnormality of cardiac conduction that is associated with a high risk of potentially fatal arrhythmias. The risk of arrhythmia with DM/Q may be higher in patients already at risk for torsade de pointes (e.g., those with a family history of this disorder). In patients who are known to be at increased risk, ECG to evaluate QT interval is recommended prior to starting DM/Q and three to four hours after the first dose. The drug is also contraindicated in those with an atrioventricular block without a pacemaker. Drug interactions of concern include monoamine oxidase inhibitors (contraindicated; increased risk of drug reaction including serotonin syndrome) and other drugs that are metabolized by the hepatic CYP2D6 system. This includes antidepressants. So in a case such as Mr. Jones, who does not seem to be depressed, it is best to stop the antidepressant before starting DM/Q. In patients who have depression, as well as PBA, and are not being adequately controlled by their antidepressant, addition of DM/Q may be indicated. However this should be done with increased caution and monitoring for symptoms such as serotonin syndrome. Additionally, an ECG is advised. Faculty Howard J. Rosen, M.D. Professor of Neurology Memory and Aging Center University of California, San Francisco 675 Nelson Rising Lane, Suite 190 Box 1207 San Francisco, CA hrosen@memory.ucsf.edu Phone: Disclosure Statement Dr. Rosen has no financial disclosures to report.

5 REFERENCES: 1. Schiffer R, Pope LE. Review of pseudobulbar affect including a novel and potential therapy. J Neuropsychiatry Clin Neurosci. Fall 2005;17(4): Rosen HJ, Cummings J. A real reason for patients with pseudobulbar affect to smile. Ann Neurol. Feb 2007;61(2): Wortzel HS, Oster TJ, Anderson CA, Arciniegas DB. Pathological laughing and crying : epidemiology, pathophysiology and treatment. CNS Drugs. 2008;22(7): Brooks BR, Crumpacker D, Fellus J, Kantor D, Kaye RE. PRISM: a novel research tool to assess the prevalence of pseudobulbar affect symptoms across neurological conditions. PLoS One. 2013;8(8):e Poeck K. Pathological laughing and weeping in patients with progressive balbar palsy. Ger Med Mon. Aug 1969;14(8): Gross JJ. Antecedent- and response-focused emotion regulation: divergent consequences for experience, expression, and physiology. J Pers Soc Psychol. Jan 1998;74(1): Lawson IR, MacLeod RD. The use of imipramine ("Tofranil") and other psychotropic drugs in organic emotionalism. Br J Psychiatry. Mar 1969;115(520): Schiffer RB, Herndon RM, Rudick RA. Treatment of pathologic laughing and weeping with amitriptyline. N Engl J Med. Jun ;312(23): Andersen G, Vestergaard K, Riis JO. Citalopram for post-stroke pathological crying. Lancet. Oct ;342(8875): Robinson RG, Parikh RM, Lipsey JR, Starkstein SE, Price TR. Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study. Am J Psychiatry. Feb 1993;150(2): Choi-Kwon S, Kim JS. Poststroke emotional incontinence and decreased sexual activity. Cerebrovasc Dis. 2002;13(1): Brooks BR, Thisted RA, Appel SH, et al. Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial. Neurology. Oct ;63(8): Panitch HS, Thisted RA, Smith RA, et al. Randomized, controlled trial of dextromethorphan/quinidine for pseudobulbar affect in multiple sclerosis. Ann Neurol. May 2006;59(5): Pioro EP, Brooks BR, Cummings J, et al. Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect. Ann Neurol. Nov 2010;68(5):

6 Table 1 Condition Range of prevalence estimates ALS 2-60% MS 7-95% Stroke 11-52% Alzheimer s disease 10-74% Parkinsonian Disorders, including PSP 7-50% b Traumatic Brain Injury 5-80%

7 Table 2 Authors N Drug tested Dose tested Outcome Anderson et al, Lancet, Citalopram mg/d 50% in crying Lawson and MacLeod, Br J. Psych, Imipramine mg/d Improvement vs. placebo Robinson et al, Am J. Psych, Nortriptyline Max 100 mg/d Improved PLACS score Schiffer et al, NEJM, Amitriptyline Max 75 mg/d 8/10 significant improvement Choi-Kwon et al, Stroke, Fluoxetine 20 mg/d Sig improvement in crying scores Murray et al, J. Clin Psych, Sertraline Max 100 mg/d Improved emotionalism

8 Table 3 Authors, Journal, Yr N Disorder DM/Q dose Outcome Brooks et al, Neurology, ALS 30mg/30mg BID Improved CNS-LS vs DM or Q alone Panitch et al, Ann Neurol, MS 30mg/30mg BID Improved CNS-LS vs placebo Pioro et al, Ann Neurol, ALS/MS 30mg/10mg or 20mg/10mg BID Improved CNS-LS vs placebo