Authors: Jacob Avila, MD and Jonathan Bronner, MD (EM Attending Physicians, University of Kentucky) // Edited by: Alex Koyfman, MD (EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital, @EMHighAK) and Brit Long, MD (@long_brit, EM Chief Resident at SAUSHEC, USAF)

Your next 3 patients…

#1: 35yo M w/ fever and agitation

#2: 21yo F w/ “jitteriness” s/p a med change

#3: 40yo F from nursing home w/ “stiffness”

Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are two types of pathologies that often give a very confusing picture. They are both associated with psychiatric diseases and are often seen in the setting of polypharmacy,1,2 which give the provider a broad differential to work through when these patients present in the emergency department (ED).2-8 To get a better understanding of how to differentiate between the two, let’s look at each of these diseases a bit more in depth.

SEROTONIN SYNDROME

Why do we care about this disease? We care about this because the medical community often misses it. In a previously published survey study, as many as 85% of physicians didn’t know what SS was.9 While that number is probably much better these days, SS still often goes unrecognized. At least part of the reason why we miss this disease is due to the fact that mild cases can present with non-specific symptoms such as tremors, diarrhea, and tachycardia.4 Often when SS starts advancing from the mild into the moderate category, we may inadvertently treat the condition with more serotonergic medications, further precipitating decline.10 Most importantly, it can be deadly. Unrecognized SS can quickly deteriorate into irreparable kidney damage, respiratory failure, or DIC.8 The mortality rate of severe SS has been reported to be 2-12%.6 Work hour restrictions in the US were first established after a case of missed SS where an intern continued to give serotonergic medications for agitation in a patient with SS, likely resulting in her death.11

So now that we’re scared, how do we not miss this deadly disease? First, let us consider the mechanism for how SS occurs. While most of the total body serotonin is found in the periphery,5 what we care about is the serotonin that causes SS, namely, the serotonin produced in the central nervous system (CNS). The overall level of serotonin in the CNS doesn’t matter as much as how much of it is stuck in the neuronal synapses, causing the effects of SS.7 Serotonin in the CNS is mostly produced in the pons and upper brainstem. Once released, it will bind to post-synaptic receptors and remains viable until it is either degraded by monoamine oxidase (MAO) or removed from the synapse by reuptake pumps.5 In the CNS, serotonin functions by modulating core body temperature, wakefulness, analgesia, sexual behavior, mood, affect, perception, personality, emesis, and eating behavior (among other things).7,12 The broad effects of serotonin are mediated by multiple receptors. There are 7 types of receptors, several of which have unique receptor subclasses. As a whole, this results in around 14 distinct serotonin receptors found throughout the body, though only two are thought to be involved in the mechanism of SS: 5-HT 1A and 5-HT 2A . As far as SS goes, the less important one is 5-HT 1A , which is thought to be responsible for myoclonus, hyperreflexia, and alterations on mental status.5,13-15 The most important receptor in SS is 5-HT 2A ,12,16,17 which increases heart rate, elevates blood pressure and temperature, and has a role in neuromuscular excitement.5,13,15,16 These abnormalities in vital physiologic homeostasis reflect adrenal gland stimulation of catecholamine release12,14,18 and stimulation of the hypothalamus manifesting as fever.5,13,15,16 Using this basic molecular understanding of the neurohormonal pathway, the triad associated with SS – mental status changes, increased neuromuscular tone, and autonomic instability in the setting of an individual who has taken a serotonergic medication – becomes more tangible. 3,4,7,8,17 One of the reasons this disease can be tricky do diagnose is that there is such a variable presentation. Not all patients with SS will present with the classic triad. In fact, the most commonly reported symptom (myoclonus) is only seen in 57% of patients.19

So now that we have an appreciation for the pathophysiology and how SS may present, how do we diagnose it? The first step is to recognize patients at higher risk of developing SS even before they’re exposed to serotonergic medications. Smokers, individuals with cardiovascular disease, and those with liver disease may develop acquired deficits in MAO activity and serotonin metabolism.7,15 Ethanol can stimulate the release of serotonin from neurons,15 and there is an increased incidence of SS in patients on dialysis who are also taking selective serotonin reuptake inhibitors (SSRI’s).12 Patients with defective CYP2C19 and CYP2D6 enzymes (either acquired or congenital) may also be at a higher risk since these enzymes are responsible for the break down of many serotonergic medications. 8,20 So which medications have been known to cause serotonin syndrome? This long list includes MAOI, TCA, SSRI, SNRI, anti-emetics, street drugs/drugs of abuse, diet pills, antibiotics, opioids (including tramadol), dextromethorphan, Benadryl, linezolid, methylphenidate, and lithium.5,13,15,21-25 These medications increase the synaptic concentration of serotonin via multiple mechanisms— by increasing the synthesis or release of serotonin, increasing receptor stimulation, inhibiting serotonin reuptake, or decreasing the breakdown of serotonin. 5,25

Approximately 60% of SS is caused by drug-drug interactions – usually paroxetine and tramadol – while 40% is triggered by a single drug. The most common individual culprits are SSRIs, with opioids coming in second. 26 After ingestion of an offending medication or medication combination, symptoms often begin within hours. 4 In fact, the majority of patients will present with SS 6 hours after administration of the provoking agent.5,27 While the gold standard for the diagnosis is an examination by a medical toxicologist,5, 28 there are methods available to help you diagnose SS at bedside. The Sternbach and Hunter criteria are the most common and most accessible for the Emergency Physician,28, 29 though the Sternbach criteria is less sensitive and specific for serotonin syndrome when compared to the newer Hunter criteria.4,30, 28 The reason for this discrepancy is that the Sternbach criteria are more likely to miss mild, early, or subacute cases of SS. 8 While the Hunter criteria may also miss mild, early or subacute cases of SS, it has been reported to have a sensitivity of 84% and a specificity of 97%.28

Aside from the history and physical exam, there are ancillary tests that can be helpful in diagnosis. While there is no definitive test that can diagnose SS 4,25 a basic laboratory assessment and a CT of the head are helpful in both ruling out other diseases that present similarly to SS as well as monitoring the severity of the patient’s symptoms. 8 Other diseases that should be on your differential when you suspect SS are NMS, malignant hyperthermia, anticholinergic poisoning, sympathomimetic poisoning, opioid withdrawal, CNS infection, sepsis, delirium tremens, and heat stroke. 4-8

Once you’ve arrived at a diagnosis of SS, how should the emergency physician initiate treatment? As with most acute pathologies, you must start with the ABC’s, but in a simultaneous fashion the effort to stop the serotonergic medication is of utmost importance.30 In mild cases, this is usually all that is required. When evaluating a patient in the moderate category you might need to start benzodiazepines for agitation, tachycardia, and hypertension. 4,6 When things start to look bad, you may need to give serotonin antagonists. Although there are no randomized controlled trials supporting its use in this setting,5,30 cyproheptadine – a non-selective histamine H1 receptor and serotonin receptor antagonist – is the drug of choice to treat moderate and severe cases of SS.4, 17, 23 The initial recommended dose is 12 mg, followed by 4-8 mg every 6 hours as needed.4, 5 Some sources recommend starting at 12 mg, then tapering the dose down by 2 mg every 2 hours as needed. 6 The main downsides to this drug is sedation (which may actually assist in the patient’s care) and the fact that it is only available in oral form.5 In an uncooperative, agitated patient any medication by mouth may be difficult to administer. Other options are chlorpromazine (Thorazine),31-33 which can be given IV or IM, olanzapine (Zyprexa)31-33 which can be given IM, dexmedetomidine (Precedex)34 or propofol (Diprivan),34 both of which are given IV. Care must be taken when treating with chlorpromazine, since it has potential to cause serious hypotension and lower the seizure threshold. 6,7

The main things you need to consider when weighing treatment options is the autonomic instability and increased neuromuscular tone. More specifically, the hemodynamics and the temperature of the patient. There are two theories of how the fever develops – central versus peripherally mediated. From the central perspective, serotonin acts to stimulate receptors in the hypothalamus, thus increasing the set point for the body temperature. 5,13,15,16 The peripherally mediated theory suggests that the body’s temperature increases due to the hypermetabolic state caused by increased muscular tone. 6, 7 The truth is that they probably both play a role. Regardless of etiology, fever and hemodynamic instability are of critical therapeutic importance as these are the pathways leading to patient mortality. Up to 14% of patients with SS present with hypotension19 and when the vital organs aren’t perfused, patient outcomes suffer significantly. Impaired temperature regulation can also be deadly due to the sequelae of the fever itself as well as the processes that cause the fever. Patients with uncontrolled muscle spasms spill myoglobin into their serum and suffer renal failure due to rhabdomyolysis.3 If a patient’s muscle rigidity is difficult to control, you should consider intubation and neuromuscular paralysis. If the patient does undergo rapid sequence intubation, care should be taken with the administration of succinylcholine and the potential for elevated serum potassium.3 Typically after discontinuing the offending medication, symptoms are gone within 24 hrs.5,7,27 Still, some SSRI’s have half-lives of 1-2 weeks so symptoms can persist up to 6 weeks after cessation.12

There are a few other SS-inducing medications worthy of special mention. First, not all opioids cause SS. There are two broad classes of opioids called phenanthrenes and non-phenanthrenes. The phenanthrenes are divided into those with an oxygen bridge and those without. The only one in the latter class is dextromethorphan. The phenanthrenes with an oxygen bridge include buprenorphine, codeine, oxycodone, hydrocodone, hydromorphone, morphine, naloxone, and naltrexone. Theoretically speaking, none of these narcotics should cause SS. However, despite the biochemical structure, there have been case reports of SS associated with hydromorphone, buprenorphine, naloxone, and oxycodone. Specifically, synthetic medications such as fentanyl, meperidine, methadone, and tramadol have been associated with SS. On the other hand, there have been no case reports of SS associated with hydrocodone, morphine, or codeine.1 The second class of drugs necessitating mention are triptans. You know those anti-headache medications? They’re serotonin agonists. In 2006 the FDA sent out a warning about the potential for SS when using triptans and SSRI’s or SNRI’s in combination.35 Interestingly, the evidence for this phenomenon is not entirely convincing. Triptans are selective agonists of 5-HT 1B , 5-HT 1D , and 5-HT 1F .36 If you recall, SS is primarily mediated by 5-HT 2a and 5-HT 1A . Additionally, the FDA alert was based off of 29 cases of suspected SS, only 10 of which met Sternbach’s criteria. None of the 29 met the Hunter criteria.37

NEUROLEPTIC MALIGNANT SYNDROME

Neuroleptic malignant syndrome (NMS) is a disease that tends to occur in a similar population as SS and can manifest in a similar manner.38 Previously, NMS was reported to occur in 0.2%-3.2% of patients on neuroleptics,39 but due to increased awareness of the disease and decreased use of 1st generation anti-psychotics the incidence of NMS has declined to 0.01-0.02% of all patients at risk.39 However, even though the incidence is low, the mortality rate has been reported to be as high as 55%.2 There is a certain population of patients that are at higher risk for the development of NMS, and those include dehydrated patients, patients with underlying brain damage and dementia, and those on high dosages of dopaminergic medications.3 As stated previously, the administration of neuroleptics (also known as anti-psychotics) are the medications most commonly associated with NMS. First generation anti-psychotics have an odds ratio of 23.4, while 2nd generation anti-psychotics have an odds ratio of 4.8 for the development of NMS.40 One of the differences between NMS and SS is the time of onset. While SS will usually manifest within 24 hours after the offending medication is administered, only about 16% of patients who develop NMS will do so within 24 hours, and 66% will develop symptoms within the first week.41

So now that we know a little background on NMS, what are the symptoms? In order to understand the symptoms, one must consider the pathophysiology of how NMS affects the body. It is very likely that there are multiple mechanisms involved, but the most probable theory is that dopamine acts as a tonic inhibitor of the central sympathetic nervous system (SNS).42 When the dopamine is removed, the SNS becomes unopposed. The evidence behind this isn’t grade A, but the pathophysiology of the theory makes sense, and multiple studies have found elevated levels of catecholamines in both the serum and the CSF.38,41-43 NMS manifests classically as extrapyramidal symptoms, altered mental status, and autonomic dysfunction.38 The extrapyramidal symptoms appear as Parkinsonian features such as rigidity, tremor, dystonia, and akinesia, and the autonomic dysfunction manifests as tachycardia, diaphoresis, hyperthermia, and labile blood pressure. Just as in SS, getting an adequate history and a medication list is crucial. That being said, often patients in extremis and with altered mental status present without any past medical history, and we then have to rely on the physical exam. The main differentiating feature of SS and NMS are reflexes. SS will typically be hyperreflexic whereas NMS will have rigidity.

The initial treatment of NMS is identical to SS, which includes stopping the offending medication and administering supportive care, including benzodiazepines. However, if that doesn’t work, escalating care may be necessary. This is where the similarities between the treatment of SS and NMS diverge. The three main medications that are given are bromocriptine, amantadine, or dantrolene.41 The two former medications are dopamine agonists, and the latter blocks calcium release. Other options include L-dopa,3 and surprisingly, electroconvulsive therapy has successfully been used in refractory cases.3,41

Summary

Even though both NMS and SS are relatively rare clinical entities, their incidences are expected to increase due to both enhanced awareness as well as a rise in medication administration. 34 Understanding the complex presentations is a critical initial step in identification of the process. If you do suspect SS or NMS, make sure to review the patient’s medications. At the bedside you will need to remember to check reflexes, especially in the lower extremities. These initial clues, along with a few other things, such as autonomic instability, mental status changes, extrapyramidal symptoms, and increased neuromuscular tone, will help you differentiate SS from NMS or from other pathologies and begin treating your patient appropriately.

References / Further Reading

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Silberstein SD, Peres MF, Hopkins MM, et al. Olanzapine in the treatment of refractory migraine and chronic daily headache. Headache 2002; 42: 515–518. Rushton WF, Charlton NP. Dexmedetomidine in the treatment of serotonin syndrome. Ann Pharmacother. 2014;48:(12)1651-4. [pubmed] http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm085845.htm Ahn AH, Basbaum AI. Where do triptans act in the treatment of migraine? Pain. 2005;115:(1-2)1-4. [pubmed] Evans RW, Tepper SJ, Shapiro RE, Sun-Edelstein C, Tietjen GE. The FDA alert on serotonin syndrome with use of triptans combined with selective serotonin reuptake inhibitors or selective serotonin-norepinephrine reuptake inhibitors: American Headache Society position paper. Headache. 2010;50:(6)1089-99. [pubmed] Sokoro AA, Zivot J, Ariano RE. Neuroleptic malignant syndrome versus serotonin syndrome: the search for a diagnostic tool. 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