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Serotonin Syndrome Preceding Pseudoseizures in an Adolescent
Letters eridemia apparently as a result of exposure to fluoxetine and later to venlafaxine extended-release, both within moderate dosage ranges while working effectively and without other variables or noticeable side effects. The abnormality was incidentally found because labwork was retested after having mildly elevated baseline readings. The initial elevation was fortunate, as monitoring likely would not have occurred otherwise. This is the second such case reported by this clinician over the past 18 months,6 thus raising concern about the etiology, incidence, and potential underreporting and secondarily hidden risks for venlafaxine and SSRI-induced acute hypertriglyceridemia. Both cases included fluoxetine as the first antidepressant medication used upon discovery of the abnormality. Consequently, it is necessary to consider that fluoxetine and/or norfluoxetine may in some manner prime hepatic triglyceride manufacturing to increase in an ongoing delayed fashion either directly, as a rebound phenomena, or as a predisposing factor prior to the use of another antidepressant medication. In summary, it is possible that routine monitoring of lipid profiles needs to occur with the use of venlafaxine or an SSRI even in individuals without physical complaints, obvious side effects, or histories of abnormal lipid profiles. There is no known reason to explain this induced effect or the specific physiologic etiology. Further investigation is warranted. Marshall Teitelbaum, M.D. Palm Beach Gardens, FL
References
1. Hozumi Y, Kawano M, Miyata M: Severe hypertriglyceridemia caused by tamoxifentreatment after breast cancer surgery. Endocr J 1997; 44:745–749 2. Melkersson KI, Hulting AL, Brismar KI: El-
evated levels of insulin, leptin, and blood lipids in olanzapine-treated patients with schizophrenia or related psychoses. J Clin Psychiatry 2000; 61:742–749 3. Scheen AJ: How I study hypertriglyceridemia. Rev Med Liege 1998; 2:103–105 4. Suga S, Tamasawa N, Kinpara I, et al: Identification of homozygous lipoprotein lipase gene mutation in a woman with recurrent aggravation of hypertriglyceridaemia induced by pregnancy. J Intern Med 1998; 4:317–321 5. Tozuka M, Yamauchi K, Hidaka H, et al: Characterization of hypertriglyceridemia induced by L-asparaginase therapy for acute lymphoblastic leukemia and malignant lymphoma. Ann Clin Lab Sci 1997; 27:351–357 6. Teitelbaum M: Severe and moderate hypertriglyceridemia secondary to citalopram and fluoxetine. Psychosomatics 2000; 41:448– 449
Serotonin Syndrome Preceding Pseudoseizures in an Adolescent TO THE EDITOR: Serotonin syndrome is a potentially fatal complication of treatment with certain medications, most notably the selective serotonin reuptake inhibitors (SSRIs). There is no proven effective drug treatment.1 The syndrome, documented in both adults and children, is manifested by changes in mental status (confusion, restlessness, and agitation), neuromuscular symptoms (ataxia, shivering, myoclonus, and hyperreflexia), and autonomic dysfunction. The author presents a complex case in which serotonin syndrome immediately preceded conversion disorder, with seizures, often referred to as pseudoseizures. Case Report Ms. A. is a 17-year-old Asian-American female with a 3-year history of acting out behavior including running away, promiscuity, and alcohol abuse. Despite multiple referrals to mental health services in the past, she had always refused care. In an emergency department (ED) visit for self-inflicted
Psychosomatics 42:5, September-October 2001
hand injuries (she had punched a wall in anger), she claimed that she was being physically abused at home. She told ED staff that if forced to continue living with her parents she would kill herself. She was briefly hospitalized on an inpatient psychiatry ward; during the 7day stay she revealed a 2-year history of sexual abuse at the hands of her older brother, who no longer lived in the home. She also reported her father had physically abused her and that she “hated” him. She described numerous symptoms of posttraumatic stress disorder (PTSD), including transient dissociative episodes. With a depressed, irritable mood and symptoms consistent with PTSD, I recommended antidepressant therapy as well as individual insight-oriented psychotherapy. After two sessions, Ms. A. reluctantly agreed to start paroxetine (10 mg daily). Three days after the initiation of paroxetine, her parents brought her to the ED because she had been “shaking.” This had started, although quite mildly, the day she began the paroxetine and had gradually worsened. Her last dose of paroxetine had been about 12 hours prior to presentation. Ms A. claimed she could not control these movements and that she had difficulty walking. Her movements consisted of severe coarse tremor, which involved all four extremities and her head and was worse in the lower extremities. She could suppress them for only a few seconds with great effort. She was shivering intensely. Her muscle tone was markedly increased and she had bilateral hyperreflexia. She demonstrated significant ataxia on attempts to perform a finger-to-nose test. Her gait had been so impaired that her father had to carry her from the car to the ED. Her pulse was 104 and her temperature 100.8⬚F; other vital signs were normal. She was alert and responsive, 441
Letters oriented in all fields, and answered questions appropriately. She denied any illicit drug use, specifically amphetamines or MDMA (“Ecstasy”). She denied any deliberate or accidental overdose of the paroxetine. There was no aura, no bladder or bowel dysfunction, and no alteration of consciousness. There was a history of possible absence seizures as a toddler but no subsequent seizures. She was not taking any other medications, including antipsychotics, monoamine oxidase inhibitors, or pain medication. Differential diagnosis included serotonin syndrome, drug-induced extrapyramidal reaction, akathisia, drug allergy, seizure activity, and substance intoxication or withdrawal. She received two doses of diphenhydramine 25 mg intramuscular (IM) injection with no benefit. Intravenous (IV) hydration was initiated with normal saline. She was given diazepam IV in 5 mg aliquots over several minutes, for a total of 20 mg. This resulted in an effective cessation of her muscle movements, and she fell asleep. Although sleeping, her increased muscle tone, myoclonus, and hyperreflexia were still evident. Vital signs normalized. A complete blood count revealed a slightly elevated white blood cell count but all other lab studies (electrolytes, blood urea nitrogen, creatinine, liver function, and thyroid studies) were normal. A urine toxicology screen (the results of which were not available until several days later) was negative. Ten hours later (the next morning), she was performing activities of daily living with little help, and her vital signs were normal. Overnight she had required an additional 2 mg IV lorazepam for her symptoms. Given her recent initiation on SSRI treatment and the neuromuscular involvement, the episode was thought best explained by serotonin syndrome. Complete recov442
ery from serotonin syndrome occurs in 70% of cases within 1 day of cessation of the offending agent,2 and it appeared her symptoms were resolving. She was prescribed cyproheptadine at 8 mg/day, as there is some evidence of its benefit in this syndrome.1 That afternoon, however, the nurses noted that her symptoms (tremors, ataxia) had returned and were quite severe. By this time it was approximately 30 hours since her last dose of paroxetine. She was given an additional IV (4 mg lorazepam), but she did not respond immediately as she had earlier. Her “involuntary movements” had a different quality. She was not shivering, and her upper extremities were much more involved than her legs. Rather than purposeless motion, the movements now looked like punches and kicks. Her head swung through its full range of motion from left to right. Ms. A. could walk to the bathroom without difficulty now, but upon returning to her bed, the violent, thrashing movements would return. The symptoms began when several of her high school friends came to visit, then worsened when her father entered the room. She was able to suppress these different movements much more easily than those of the prior evening. She insisted, though, that she was not producing the movements voluntarily. There was no myoclonus, no hyperreflexia, and her vital signs were normal. There was no fluctuation in level of consciousness. She did not bite her tongue, and she did not lose control of her bowel or bladder. Ms. A. was transferred to a hospital with electroencephalograph (EEG) capabilities. After examining the patient and the EEG, the neurologist concluded the movements were not due to seizures. The thrashing movements continued, causing great distress to nursing personnel who felt the patient was medically unstable. The neu-
rologist, though, documented that the patient could stop moving if sternly given such a command. The patient got no additional benzodiazepines at this facility. Again, the movements would worsen in the presence of her father. She was transferred to inpatient psychiatry; her diagnosis was conversion disorder, with seizures. She still had occasional episodes, with the same volitional quality, when asked questions about her father and brother. These movements would cease after a few minutes, without intervention. She interacted appropriately on the ward, but she frequently requested discharge in order to spend time with her friends. She was discharged 2 days later. Three days later, at outpatient follow-up, Ms. A. insisted that she had no voluntary control over the movements she had experienced. She claimed that they still occurred, although less severely, in the presence of her father. A phone call to her mother confirmed this information. The day after this follow-up appointment, Ms. A. required hospitalization for suicidal threats, claiming continued physical abuse at home. Subsequent social work investigation did substantiate the charges of physical abuse by her father and sexual abuse by her older brother. Since removal from the home and transfer to a residential treatment facility, the movements have not returned. Discussion During the first hours of Ms. A.’s hospitalization, her symptoms were clearly consistent with serotonin syndrome. Even when she was asleep, her clonus and increased muscle tone persisted. The second constellation of symptoms is much more confusing. The involuntary movements were distinctly different, resolved when she walked, and oc-
Psychosomatics 42:5, September-October 2001
Letters curred primarily in the presence of or when asked questions about her father. The differential diagnosis included malingering, factitious disorder, conversion disorder, anxiety disorder, or neurologic disorder. Malingering to obtain benzodiazepines was considered, but the movements persisted even when the patient understood these would no longer be prescribed. Malingering in order to remain hospitalized was also considered; however, this individual had repeatedly requested to leave the inpatient psychiatric unit in order to be with her friends. In factitious disorder, the motivation for the symptoms is to assume the patient role but this individual demonstrated a history of actually avoiding medical care. While many individuals demonstrate increased psychomotor activity (such as tremor) when anxious, this individual’s involuntary movements involved her whole body and consisted of purposeful actions like punching and kicking. Certainly, clinicians cannot rely solely on “bizarre” symptoms (prone position, pelvic thrusting, genital manipulation, etc.) to make the diagnosis of pseudoseizures. Frontal lobe partial complex seizures can produce such symptoms.3 However, Ms. A. could suppress the movements, they were temporally re-
lated to the presence of her father (either physically or if asked questions about him), and they did completely resolve when she was removed from the home. Did the serotonin syndrome precipitate the pseudoseizures? She received a great deal of attention from her parents and from hospital staff due to her dramatic initial presentation. Unconsciously, this may have satisfied fantasies to be “rescued.” It also, to some degree, shifted her father’s role from aggressor to “hero” (he carried her from the car to the hospital). The loss of muscle control during serotonin syndrome might have reminded her of the helplessness experienced while she was being sexually abused, and her pseudoseizures might have been a protective dissociative phenomenon.3 From a biological perspective, Ms. A. met criteria for PTSD and had a history of dissociative episodes. Both animal models and the clinical benefit of SSRIs suggest that serotonin may modulate PTSD symptoms. Additionally, serotonin agonists have been shown to evoke PTSD symptoms in some veterans with that diagnosis.4 If indeed this individual’s pseudoseizures were a form of dissociation, it is conceivable that excessive stimulation of the 5HT1 and 5HT-2A receptors, thought to be
Psychosomatics 42:5, September-October 2001
the etiology of the serotonin syndrome,5 might have contributed. There are few data on biological precipitants of dissociative and conversion symptoms; further research is warranted. Literature review revealed no other cases of serotonin syndrome immediately preceding pseudoseizures or other conversion symptoms. Jeffrey M. Benzick, M.D. U.S. Air Force Medical Corps, Mental Health Clinic, Osan Air Base, South Korea The opinions expressed in this article are those of the author and do not reflect policy of the U.S. Air Force, the Department of Defense, or any other government agency.
References
1. Fuller MA, Sajatovic M (eds): Serotonin syndrome, in Drug Information Handbook for Psychiatry. Cleveland, Lexi-Comp Inc., 1999, pp 1351–1352 2. Gillman PK: The serotonin syndrome and its treatment. J Psychopharmacol 1999; 13 100– 109 3. Bowman ES: Pseudoseizures. Psychiatr Clin North Am 1998; 21 650–657 4. Kaplan HI, Sadock BJ (eds): Posttraumatic stress disorder, in Comprehensive Textbook of Psychiatry. 6th Ed, Baltimore, MD, Williams & Wilkins, 1995, pp. 1229–1231. 5. Mason PJ, Morris VA, Balcezak TJ: Serotonin syndrome: Presentation of two cases and review of the literature. Medicine 2000 79: 201–209
443
References
1. Hozumi Y, Kawano M, Miyata M: Severe hypertriglyceridemia caused by tamoxifentreatment after breast cancer surgery. Endocr J 1997; 44:745–749 2. Melkersson KI, Hulting AL, Brismar KI: El-
evated levels of insulin, leptin, and blood lipids in olanzapine-treated patients with schizophrenia or related psychoses. J Clin Psychiatry 2000; 61:742–749 3. Scheen AJ: How I study hypertriglyceridemia. Rev Med Liege 1998; 2:103–105 4. Suga S, Tamasawa N, Kinpara I, et al: Identification of homozygous lipoprotein lipase gene mutation in a woman with recurrent aggravation of hypertriglyceridaemia induced by pregnancy. J Intern Med 1998; 4:317–321 5. Tozuka M, Yamauchi K, Hidaka H, et al: Characterization of hypertriglyceridemia induced by L-asparaginase therapy for acute lymphoblastic leukemia and malignant lymphoma. Ann Clin Lab Sci 1997; 27:351–357 6. Teitelbaum M: Severe and moderate hypertriglyceridemia secondary to citalopram and fluoxetine. Psychosomatics 2000; 41:448– 449
Serotonin Syndrome Preceding Pseudoseizures in an Adolescent TO THE EDITOR: Serotonin syndrome is a potentially fatal complication of treatment with certain medications, most notably the selective serotonin reuptake inhibitors (SSRIs). There is no proven effective drug treatment.1 The syndrome, documented in both adults and children, is manifested by changes in mental status (confusion, restlessness, and agitation), neuromuscular symptoms (ataxia, shivering, myoclonus, and hyperreflexia), and autonomic dysfunction. The author presents a complex case in which serotonin syndrome immediately preceded conversion disorder, with seizures, often referred to as pseudoseizures. Case Report Ms. A. is a 17-year-old Asian-American female with a 3-year history of acting out behavior including running away, promiscuity, and alcohol abuse. Despite multiple referrals to mental health services in the past, she had always refused care. In an emergency department (ED) visit for self-inflicted
Psychosomatics 42:5, September-October 2001
hand injuries (she had punched a wall in anger), she claimed that she was being physically abused at home. She told ED staff that if forced to continue living with her parents she would kill herself. She was briefly hospitalized on an inpatient psychiatry ward; during the 7day stay she revealed a 2-year history of sexual abuse at the hands of her older brother, who no longer lived in the home. She also reported her father had physically abused her and that she “hated” him. She described numerous symptoms of posttraumatic stress disorder (PTSD), including transient dissociative episodes. With a depressed, irritable mood and symptoms consistent with PTSD, I recommended antidepressant therapy as well as individual insight-oriented psychotherapy. After two sessions, Ms. A. reluctantly agreed to start paroxetine (10 mg daily). Three days after the initiation of paroxetine, her parents brought her to the ED because she had been “shaking.” This had started, although quite mildly, the day she began the paroxetine and had gradually worsened. Her last dose of paroxetine had been about 12 hours prior to presentation. Ms A. claimed she could not control these movements and that she had difficulty walking. Her movements consisted of severe coarse tremor, which involved all four extremities and her head and was worse in the lower extremities. She could suppress them for only a few seconds with great effort. She was shivering intensely. Her muscle tone was markedly increased and she had bilateral hyperreflexia. She demonstrated significant ataxia on attempts to perform a finger-to-nose test. Her gait had been so impaired that her father had to carry her from the car to the ED. Her pulse was 104 and her temperature 100.8⬚F; other vital signs were normal. She was alert and responsive, 441
Letters oriented in all fields, and answered questions appropriately. She denied any illicit drug use, specifically amphetamines or MDMA (“Ecstasy”). She denied any deliberate or accidental overdose of the paroxetine. There was no aura, no bladder or bowel dysfunction, and no alteration of consciousness. There was a history of possible absence seizures as a toddler but no subsequent seizures. She was not taking any other medications, including antipsychotics, monoamine oxidase inhibitors, or pain medication. Differential diagnosis included serotonin syndrome, drug-induced extrapyramidal reaction, akathisia, drug allergy, seizure activity, and substance intoxication or withdrawal. She received two doses of diphenhydramine 25 mg intramuscular (IM) injection with no benefit. Intravenous (IV) hydration was initiated with normal saline. She was given diazepam IV in 5 mg aliquots over several minutes, for a total of 20 mg. This resulted in an effective cessation of her muscle movements, and she fell asleep. Although sleeping, her increased muscle tone, myoclonus, and hyperreflexia were still evident. Vital signs normalized. A complete blood count revealed a slightly elevated white blood cell count but all other lab studies (electrolytes, blood urea nitrogen, creatinine, liver function, and thyroid studies) were normal. A urine toxicology screen (the results of which were not available until several days later) was negative. Ten hours later (the next morning), she was performing activities of daily living with little help, and her vital signs were normal. Overnight she had required an additional 2 mg IV lorazepam for her symptoms. Given her recent initiation on SSRI treatment and the neuromuscular involvement, the episode was thought best explained by serotonin syndrome. Complete recov442
ery from serotonin syndrome occurs in 70% of cases within 1 day of cessation of the offending agent,2 and it appeared her symptoms were resolving. She was prescribed cyproheptadine at 8 mg/day, as there is some evidence of its benefit in this syndrome.1 That afternoon, however, the nurses noted that her symptoms (tremors, ataxia) had returned and were quite severe. By this time it was approximately 30 hours since her last dose of paroxetine. She was given an additional IV (4 mg lorazepam), but she did not respond immediately as she had earlier. Her “involuntary movements” had a different quality. She was not shivering, and her upper extremities were much more involved than her legs. Rather than purposeless motion, the movements now looked like punches and kicks. Her head swung through its full range of motion from left to right. Ms. A. could walk to the bathroom without difficulty now, but upon returning to her bed, the violent, thrashing movements would return. The symptoms began when several of her high school friends came to visit, then worsened when her father entered the room. She was able to suppress these different movements much more easily than those of the prior evening. She insisted, though, that she was not producing the movements voluntarily. There was no myoclonus, no hyperreflexia, and her vital signs were normal. There was no fluctuation in level of consciousness. She did not bite her tongue, and she did not lose control of her bowel or bladder. Ms. A. was transferred to a hospital with electroencephalograph (EEG) capabilities. After examining the patient and the EEG, the neurologist concluded the movements were not due to seizures. The thrashing movements continued, causing great distress to nursing personnel who felt the patient was medically unstable. The neu-
rologist, though, documented that the patient could stop moving if sternly given such a command. The patient got no additional benzodiazepines at this facility. Again, the movements would worsen in the presence of her father. She was transferred to inpatient psychiatry; her diagnosis was conversion disorder, with seizures. She still had occasional episodes, with the same volitional quality, when asked questions about her father and brother. These movements would cease after a few minutes, without intervention. She interacted appropriately on the ward, but she frequently requested discharge in order to spend time with her friends. She was discharged 2 days later. Three days later, at outpatient follow-up, Ms. A. insisted that she had no voluntary control over the movements she had experienced. She claimed that they still occurred, although less severely, in the presence of her father. A phone call to her mother confirmed this information. The day after this follow-up appointment, Ms. A. required hospitalization for suicidal threats, claiming continued physical abuse at home. Subsequent social work investigation did substantiate the charges of physical abuse by her father and sexual abuse by her older brother. Since removal from the home and transfer to a residential treatment facility, the movements have not returned. Discussion During the first hours of Ms. A.’s hospitalization, her symptoms were clearly consistent with serotonin syndrome. Even when she was asleep, her clonus and increased muscle tone persisted. The second constellation of symptoms is much more confusing. The involuntary movements were distinctly different, resolved when she walked, and oc-
Psychosomatics 42:5, September-October 2001
Letters curred primarily in the presence of or when asked questions about her father. The differential diagnosis included malingering, factitious disorder, conversion disorder, anxiety disorder, or neurologic disorder. Malingering to obtain benzodiazepines was considered, but the movements persisted even when the patient understood these would no longer be prescribed. Malingering in order to remain hospitalized was also considered; however, this individual had repeatedly requested to leave the inpatient psychiatric unit in order to be with her friends. In factitious disorder, the motivation for the symptoms is to assume the patient role but this individual demonstrated a history of actually avoiding medical care. While many individuals demonstrate increased psychomotor activity (such as tremor) when anxious, this individual’s involuntary movements involved her whole body and consisted of purposeful actions like punching and kicking. Certainly, clinicians cannot rely solely on “bizarre” symptoms (prone position, pelvic thrusting, genital manipulation, etc.) to make the diagnosis of pseudoseizures. Frontal lobe partial complex seizures can produce such symptoms.3 However, Ms. A. could suppress the movements, they were temporally re-
lated to the presence of her father (either physically or if asked questions about him), and they did completely resolve when she was removed from the home. Did the serotonin syndrome precipitate the pseudoseizures? She received a great deal of attention from her parents and from hospital staff due to her dramatic initial presentation. Unconsciously, this may have satisfied fantasies to be “rescued.” It also, to some degree, shifted her father’s role from aggressor to “hero” (he carried her from the car to the hospital). The loss of muscle control during serotonin syndrome might have reminded her of the helplessness experienced while she was being sexually abused, and her pseudoseizures might have been a protective dissociative phenomenon.3 From a biological perspective, Ms. A. met criteria for PTSD and had a history of dissociative episodes. Both animal models and the clinical benefit of SSRIs suggest that serotonin may modulate PTSD symptoms. Additionally, serotonin agonists have been shown to evoke PTSD symptoms in some veterans with that diagnosis.4 If indeed this individual’s pseudoseizures were a form of dissociation, it is conceivable that excessive stimulation of the 5HT1 and 5HT-2A receptors, thought to be
Psychosomatics 42:5, September-October 2001
the etiology of the serotonin syndrome,5 might have contributed. There are few data on biological precipitants of dissociative and conversion symptoms; further research is warranted. Literature review revealed no other cases of serotonin syndrome immediately preceding pseudoseizures or other conversion symptoms. Jeffrey M. Benzick, M.D. U.S. Air Force Medical Corps, Mental Health Clinic, Osan Air Base, South Korea The opinions expressed in this article are those of the author and do not reflect policy of the U.S. Air Force, the Department of Defense, or any other government agency.
References
1. Fuller MA, Sajatovic M (eds): Serotonin syndrome, in Drug Information Handbook for Psychiatry. Cleveland, Lexi-Comp Inc., 1999, pp 1351–1352 2. Gillman PK: The serotonin syndrome and its treatment. J Psychopharmacol 1999; 13 100– 109 3. Bowman ES: Pseudoseizures. Psychiatr Clin North Am 1998; 21 650–657 4. Kaplan HI, Sadock BJ (eds): Posttraumatic stress disorder, in Comprehensive Textbook of Psychiatry. 6th Ed, Baltimore, MD, Williams & Wilkins, 1995, pp. 1229–1231. 5. Mason PJ, Morris VA, Balcezak TJ: Serotonin syndrome: Presentation of two cases and review of the literature. Medicine 2000 79: 201–209
443