Psychosomatics 2013:]:]]]–]]]

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Case Reports Serotonin Syndrome and Stiff-Person Syndrome: Diagnostic Challenges in Psychosomatic Medicine Sean Bordelon, M.D., Robert Brett Lloyd, M.D., Ph.D., Lisa J. Rosenthal, M.D. F.A.P.M.

Introduction Serotonin syndrome is high on the list of potentially fatal psychiatric diagnoses that psychosomatic medicine specialists are asked to assess. When diagnostic criteria are based solely on clinical syndromes, evaluation can be challenging, especially in critically ill patients. We present a patient with symptoms indicative of serotonin syndrome, but after 2 weeks of persisting symptoms and reconsideration of the diagnosis, she was also determined to have Stiff-Person Syndrome (SPS). It is not known if there are biologic connections between these disorders, but they share several core features.1,2 SPS is an autoimmune condition that results in the formation of autoantibodies against glutamic acid decarboxylase (GAD), an important enzyme in the formation of gamma-aminobutyric acid (GABA).3 The condition typically presents with progressive limb and axial muscular rigidity and spasticity that fluctuates with time and also with emotional state. Serotonin syndrome is a toxidrome involving single doses or combinations of serotonergic agents, which presents with hyperreflexia and clonus in the lower extremities, delirium, and motor hyperactivity. We describe the case of a critically ill woman with a history of panic disorder who had symptoms congruent with both serotonin syndrome and SPS and highlight the similarities and differences in the evaluation and management of both. Case Report Ms. L, a 60-year-old Caucasian woman with late-life onset of panic symptoms and fear of falling, had a medical history notable for hypertension and obesity Psychosomatics ]:], ] 2013

and a surgical history of elective bilateral knee replacements 9 years before presentation; multiple falls during subsequent rehabilitation led to a progressive fear of falling. Her husband reported escalating episodes of panic, which were accompanied by progressive rigidity and shaking in her axial skeleton, knees, and proximal lower extremities. For 5 years, she had some symptomatic relief on 40 mg citalopram daily and 1 mg clonazepam as needed once per week. The month before admission, she began having up to 3 panic attacks weekly, and in response, her psychiatrist switched her to sertraline by cross titration over a 2week period (every 4 d citalopram was reduced by 10 mg whereas sertraline was increased by 50 mg to the target dose of 200 mg daily). She independently also began using herbal passion-flower for her mood. The week before admission, she was taking up to 3 mg clonazepam daily, and the episodes of “panic” progressed to 3 days of “continuous body shaking.” She subsequently presented to an outside hospital in a confused, disoriented state with marked tremulousness, inducible clonus (number of beats not specified in records), lower extremity hyperreflexia, diaphoresis, fever of 1071F, pulse 130 beats/min, respiratory rate 36 breaths/min, and a pulse oximetry of 92% and declining. Bowel sounds and pupils were within normal limits. She was intubated, started on cyproheptadine, and clonazepam continued for

Received May 30, 2013; revised July 29, 2013; accepted July 30, 2013. From Department of Psychiatry and Behavioral Sciences, Northwestern University, Chicago, IL; Send correspondence and reprint requests to Sean Bordelon, M.D., Department of Psychiatry and Behavioral Sciences, Northwestern University, 446 East Ontario St, Suite 7-100, Chicago, IL 60611. e-mail: [email protected] & 2013 Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved

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Case Reports presumed serotonin syndrome. Initial laboratory tests were remarkable for white blood cell count of 24.1  109 per liter and lactic acidosis (lactate 12.8 mg/dL; pH 7.24; PaCO2 13 mm Hg) with an elevated creatine phosphokinase at 1163 IU/L that later peaked at 22,000 IU/L before returning to normal levels. A computed tomography scan of the head was negative for acute intracranial abnormalities and a lumbar puncture and CSF analysis was negative for standard measures. Electroencephalography demonstrated generalized moderate slowing that correlated with her delirium, but there was no epileptiform activity or electrical correlation with the shaking episodes. After 3 days of cyproheptadine, tizanidine, clonazepam, and lorazepam, she was extubated after showing signs of improvement of cognitive and motor symptoms. One week after her initial presentation, she was slowly tapered off clonazepam, lorazepam, and cyproheptadine. Despite resolution of confusion, she had a return of severe, frequent episodes of muscle spasms and hypertonicity with marked anxiety. She was again intubated for impending respiratory failure. After this second week, she became febrile and tachypneic and was transferred to our tertiary care academic medical center for further evaluation and management. On admission, cyproheptadine was restarted by the intensive care unit team with the concern that serotonin syndrome had not yet resolved, and benzodiazepines were reinstated. She was given 10 mg of lorazepam equivalents daily and placed on a propofol drip (0.04 mg/kg/min) to maintain sedation. The consultation–liaison service was then consulted for management of serotonin syndrome along with reported anxiety during attempts to wean sedation. Her physical examination during temporary weaning of propofol was positive for continuous spasms of her proximal lower extremities and her axial musculature that increased with physical stimulation. She was hyperreflexic bilaterally in her knees and ankle, but had no spontaneous or inducible clonus and was without ocular clonus. She was oriented only to person, she followed one-step commands, and became significantly hypertensive, tachypneic, and tachycardic with attempts to wean propofol. It was difficult to obtain a thorough cognitive examination, as propofol could only be stopped briefly. Repeat electroencephalography results were negative for the moderate, generalized slowing found initially. 2

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Several factors prompted reconsideration of the differential diagnosis and evaluation for potential co-morbidity. Her husband reported very unusual panic symptoms accompanied by stiffness and falling, and she had prolonged symptoms 2 weeks after discontinuation of normal doses of serotonergic agents. In addition, axial spasticity was more prominent during our examination in the absence of clonus. After consultation by the neurology service, electromyography showed continuous agonist-antagonist muscle contractions, and anti-GAD65 serum levels were 4 30 IU/mL. Ms. L was diagnosed by the neurology team with SPS, and treated with pulse dose and tapering of methylprednisolone as well as intravenous immunoglobulin for 5 days. In the interim, muscle spasms were controlled with 10 mg of diazepam twice daily and 30 mg of baclofen 3 times daily with significant improvement. One week later, she was extubated successfully. She was discharged after 3 weeks to an acute rehabilitation facility for further management. She is currently doing well in rehabilitation, and her symptoms have been controlled on baclofen and diazepam. She is also receiving intravenous immunoglobulin with good response.

Discussion Serotonin Syndrome On initial presentation to the outside hospital, Ms. L appeared to have classic symptoms of serotonin syndrome. She had elevated risk during cross titration of antidepressants and recent initiation of passionflower. Passion-flower, an herbal supplement, has been shown to contain extracts that reversibly inhibit monoamine oxidase-A enzymes and could potentially increase the risk of serotonergic crisis.4 Serotonin toxicity develops extraordinarily quickly, typically within 6 hours after ingestion of the offending medication in more than half of patients studied.2 Overdoses with single serotonergic agent and combinations of multiple agents have been shown to produce the reaction, though inhibitors of monoamine oxidase-A are typically linked to severe cases.5 Numerous medications and herbal substances have been associated with the syndrome, potentially through primary effects on the 5-hydroxytryptamine2A receptor.2 Though mild cases typically resolve quickly once agents are Psychosomatics ]:], ] 2013

Bordelon et al. discontinued, in severe cases, the clinical course may be prolonged based on factors other than dose, metabolism, and clearance of the inciting agent(s). Serotonin syndrome may present with different degrees of severity. At the mild end of the spectrum, serotonin syndrome presents with akathisia, inducible clonus, shivering or tremor, delirium, and mild autonomic nervous system hyperactivity. In more severe cases, there is hyperreflexia with sustained clonus, tachycardia, hyperthermia, diaphoresis, mydriasis, increased bowel sounds, seizures, and frank delirium (Table). The neuromuscular findings are typically most prominent in the lower extremities, and horizontal ocular clonus is also possible.2 More recently, Dunkley et al. suggested a simplified diagnostic classification that uses spontaneous, inducible, or ocular clonus; tremor; diaphoresis; agitation; and hyperreflexia to guide diagnosis.6 The hypertonicity, sustained clonus, and significant hyperthermia result in common laboratory abnormalities, including elevated serum aminotransferases and creatine phosphokinase, renal failure, and metabolic acidosis. Death may occur by a variety of causes including cardiopulmonary arrest and disseminated intravascular coagulopathy.2 Treatment of serotonin syndrome is largely supportive, including aggressive hydration and interventions targeting hyperthermia, autonomic instability, and agitation. Offending medications should be

TABLE.

discontinued immediately. Benzodiazepines are essential in the management regardless of severity and should be instituted as soon as the syndrome is recognized. Benzodiazepines may reduce the agitation and hypertonicity responsible for significant morbidity from serotonin syndrome and may also counter the hyperadrenergic response of the syndrome. In animal models, benzodiazepines are effective in attenuating the lifethreatening hyperthermia and they increase survival times.7 Restraints are discouraged owing to the worsening of muscle contractions, acidosis, and hyperthermia. Cyproheptadine, a serotonin antagonist, is used in cases with more severe symptomatology, although several case reports also describe the use of chlorpromazine and olanzapine, potentially effective owing to antagonism at 5-hydroxytryptamine2A. Symptoms of serotonin syndrome typically resolve within 24 hours with appropriate treatment, though prolonged courses of illness are possible in severe cases and independent of inciting dose.2 SPS In 1956, Moersch and Woltman described 14 individuals who shared a debilitating, unusual condition described as “stiff-man syndrome.” Patients presented with involuntary limb and axial muscular rigidity that fluctuated with time, but generally followed a progressive

COMPARISON OF STIFF-PERSON SYNDROME AND SEROTONIN SYNDROME

Findings

Stiff-Person Syndrome

Serotonin Syndrome

Motor effects

Rigidity and spasms

Location

Axial musculature and proximal lower extremities 10%–20% co-morbidity Severe cases

Hyperreflexia (inducible, spontaneous, or ocular clonus), shivering, and possible rigidity Lower extremities more prominent than upper extremities (ankle/ knee reflex) Severe cases Moderate to severe cases

Rare—only in severe cases

Delirium common, even in mild presentations

N/A Gradual (years) Episodic and progressive worsening

Increased motility and diarrhea Rapid (within hours) Usually resolves within 24 h, may last several weeks in severe/ protracted cases History of serotonergic agent ingestion

Seizures Autonomic instability, hyperthermia Delirium, cognitive changes Gastrointestinal Onset Course Correlation Treatment: Benzodiazepines Treatments: other

Anti-GAD antibodies, history of autoimmune disease Essential in all cases to reduce hypertonicity Essential in all cases to reduce hyperthermia, hypertonicity, and and spasticity hyperadrenergic effects IVIG (first line), baclofen Cyproheptadine

GAD ¼ glutamic acid decarboxylase; IVIG ¼ intravenous immunoglobulin.

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Case Reports course. The observations recorded are dramatic: some patients were reduced to a stiff-legged, waddling gait, during which, one was said to “fall like a wooden man.”8 Several autoimmune diseases have been associated with SPS, including pernicious anemia, thyroiditis, vitiligo, and most commonly, diabetes mellitus.3 By 1988, Solimena et al. proposed the underlying mechanism as formation of autoantibodies that targeted linear and conformational epitopes of the GAD65 isoform. Other antigens have been found since then, including amphiphysin, GABA-A receptor–associated protein, and gephyrin, but 60%–80% of individuals with SPS have high titers of anti-GAD antibodies. The result is a blockade and impairment of GABA signaling without structural changes in the GABA-ergic neurons.9 Even after the discovery of anti-GAD antibodies, SPS remains a clinical diagnosis. Since initially created by Gordon et al. in 1967,10 the diagnostic criteria have been refined to the 2009 Dalakas criteria. These include (1) axial muscle stiffness, (2) painful spasms triggered by emotional stress or startle, (3) positive serology for GAD65 autoantibodies, (4) characteristic continuous motor unit activity in agonist and antagonist muscles by electromyography, (5) response to diazepam, and (6) all in the absence of another neurologic syndrome that would better explain the patient's symptoms.9 The stiffness and periodic aching of SPS is typically the first sign of the illness, and the onset is usually insidious. Patients with anti-GAD-positive SPS tend to have rigidity that more frequently affects the caudal musculature.3 As the condition progresses, ambulation and basic daily activities become increasingly difficult.11 The rigidity frequently fluctuates, and ranges from simply increased tone to “boardlike” stiffness. Sudden loud noises, feelings of intense emotion, or the anticipation of falling have been documented as possible triggers for superimposed spasms. These triggers can also initiate worsening rigidity, and falls can result.3,12 electromyography readings typically show a prolonged, steady tonic activity, characterized as “continuous motor unit activity.” The recordings are essentially identical to voluntary muscle contraction, except that the patient has no conscious control.3,13 It is noteworthy that Ms. L had worsening ambulation for several years before presentation, and after further inquiry, her husband described the panic episodes as anxiety accompanied by falling and stiffness. In severe cases, disease symptoms can progress to the point of stiffness lasting more than an hour with severe 4

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autonomic changes, termed “status spasticus.”13 This acute presentation shares similar symptoms to serotonin syndrome, including hypertonicity and spasms, autonomic changes, and severe anxiety (Table). Spasms of the diaphragm and other muscles involved in respiration can lead to sudden apnea, cyanosis, respiratory arrest, and ultimately, death. Both respiratory causes and severe autonomic instability likely contribute to mortality in status spasticus. The sustained hypertonicity and spasticity may impair ventilation and cause rhabdomyolysis, leading to laboratory abnormalities that are similar to serotonin syndrome, including acidosis, elevated creatine phosphokina, hyperthermia, and acute renal failure. Severe cases necessitate hospitalization in the intensive care unit and 10% of individuals have died suddenly and unexpectedly.12,14 The mainstay of management is currently a 2-fold approach targeting both the autoimmune aspect and the resulting severe GABA deficiency. The autoimmune disease is treated with several cycles of intravenous immunoglobulin, which may be effective for up to 1 year at a time. Early on, it was realized that GABA-ergic medications, including benzodiazepines and baclofen, are highly effective at controlling symptoms including muscle stiffness, seizures, and anxiety. In certain cases, analgesics or tizanidine may be required for muscle spasms9 and patients' level of functioning and ability to ambulate safely must be addressed in rehabilitation.3 More recently, plasma exchange and rituximab have also been used as second-line treatments for the autoimmune disorder. Case Discussion There is little, if any, known connection between SPS and serotonin syndrome, though it is likely that Ms. L had both conditions during her protracted hospital course. Her presentation at the first hospital was representative of serotonin syndrome. As mentioned, the cross titration of serotonergic agents in the setting of starting passion-flower, possessing monoamine oxidase-A inhibition properties, could have made her susceptible. She had inducible clonus in the lower extremities, severe autonomic instability, and confusion, which are all indicative of serotonin syndrome. She had a prominent delirium during this time, which is typically present in the setting of serotonin syndrome (Table). Her presenting symptomatology would fulfill Psychosomatics ]:], ] 2013

Bordelon et al. either Sternbach or Hunter's criteria for serotonin syndrome.6 Additionally, she had good response to both benzodiazepines and cyproheptadine with abatement of the clonus and delirium after the first 2 weeks. Her ongoing symptoms despite treatment suggested either a complicated, prolonged case of serotonin syndrome, SPS alone as a separate but similar syndrome, or co-morbid serotonin syndrome and SPS. Before hospitalization, her anxiety was largely fear of falling, had onset after age 50, and her symptoms were temporally related to episodes of increasing rigidity and spasms in proximal appendicular muscles with concurrent anxiety. Her presentation at our hospital was striking for prominent axial muscle rigidity with superimposed spasms induced by movement. Though she had hyperreflexia in the lower extremities, both her clonus and delirium abated. In SPS, delirium is not a prominent symptom, unless there is significant hypoxia, and myoclonus is not as common as muscular rigidity and spasticity (Table). Her unusual history of panic attacks and ongoing symptoms, including prominent axial symptoms in the absence of clonus, prompted us to reconsider the diagnosis and request assistance from the neurology critical care team. She did later meet the Dalakas criteria for SPS, based on symptoms and electromyography and antibody tests as well as response to benzodiazepines.9 In this case, the different presentations support both syndromes co-morbid in the same individual. It is notable that benzodiazepines are essential in the overall management of both syndromes (Table). In serotonin syndrome, benzodiazepines play a critical role in blunting the hyperadrenergic responses and in reducing hypertonicity and hyperthermia that may lead to significant morbidity and mortality.6 In SPS, benzodiazepines are also essential for both their muscle-relaxant properties and the central nervous system GABA-deficiency repletion. Benzodiazepines

may help to reduce significant hypothermia also found in SPS. Baclofen, a GABAB receptor agonist is often used as an adjunct to decrease spasticity in SPS.9 As benzodiazepines are essential in both, response is not pathognomonic for either disorder and does not differentiate between conditions. Conclusion Both serotonin syndrome and SPS are important in the differential diagnosis of patients presenting with autonomic instability and neuromuscular hyperexcitability, and practitioners of psychosomatic medicine should be aware of the subtle presentations of each condition. Psychiatric presentations of autoantibody-mediated conditions continue to be characterized and are important in the differential diagnosis of critically ill patients. In this case, Ms. L had underlying SPS superimposed on an acute episode of serotonin syndrome in the setting of a medication change. It is unclear to what extent she was susceptible to serotonin syndrome, in relation to the SPS. Regardless, this case report demonstrates important diagnostic considerations in 2 emergencies with prominent psychiatric symptoms. Further study into the pathophysiology of both conditions may clarify the relationship between these disorders and aid in earlier detection and treatment of these life-threatening illnesses. Acknowledgments: The authors wish to acknowledge the wonderful clinical contributions by Drs. James Guth and Neil Rosenberg on the neurology intensive care service, aiding in diagnosis and successful treatment of this patient. Disclosure: The authors disclosed no proprietary or commercial interest in any product mentioned or concept discussed in this article.

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5. Insel TR, Roy BF, Cohen RM, Murphy DL: Possible development of the serotonin syndrome in man. Am J Psychiatry 1982; 139:954–955 6. Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM: The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM 2003; 96:635–642 7. Taylor MA, Fink M: Catatonia in psychiatric classification: a home of its own. Am J Psychiatry 2003; 160: 1233–1241

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Case Reports 8. Moersch FP, Woltman HW: Progressive fluctuating muscular rigidity and spasm (“stiff-man” syndrome); report of a case and some observations in 13 other cases. Proc Staff Meet Mayo Clin 1956; 31:421–427 9. Hadavi S, Noyce AJ, Leslie RD, Giovannoni G: Stiff person syndrome. Pract Neurol 2011; 11:272–282 10. Gordon EE, Januszko DM, Kaufman L: A critical survey of stiff-man syndrome. Am J Med 1967; 42:582–599 11. Evoli A: Antibody-phenotype correlation in stiff-person syndrome. Neurology 2008; 71:1938–1939

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12. Henningsen P, Clement U, Kuchenhoff J, Simon F, Meinck HM: Psychological factors in the diagnosis and pathogenesis of stiff-man syndrome. Neurology 1996; 47: 38–42 13. Meinck HM, Thompson PD: Stiff man syndrome and related conditions. Mov Disord 2002; 17:853–866 14. Mitsumoto H, Schwartzman MJ, Estes ML, et al: Sudden death and paroxysmal autonomic dysfunction in stiff-man syndrome. J Neurol 1991; 238:91–96

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Serotonin syndrome and stiff-person syndrome: diagnostic challenges in psychosomatic medicine.

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