NMS / Serotonin syndromes

Serotonin syndrome and neuroleptic malignant syndrome: distinguishing features

Serotonin syndrome (SS)

Serotonin syndrome is an acute onset, severe toxic syndrome caused by a sudden pathologic increase in CNS serotonergic transmission. In the CNS, serotonin acts on 7 groups of serotonin receptor families (5-HT1–5-HT7), and it is hypothesized the neurologic manifestations of serotonin syndrome occur largely via activation of the postsynaptic 5-HT1a receptor system. Many cases of serotonin syndrome occur in patients taking multiple serotonergic medications (reported in 16.1%) or large doses of a single drug (15.4%).

Symptoms are characterized by a triad of neuron-excitatory features, which include (a) neuromuscular hyperactivity -- tremor, clonus, myoclonus, hyperreflexia and, in advanced stages, pyramidal rigidity; (b) autonomic hyperactivity -- diaphoresis, fever, tachycardia and tachypnea; (c) altered mental status -- agitation, excitement and, in advanced stages, confusion.

• The diagnosis is based on Sternbach's criteria.

  • • Recent addition or increase in a known serotonergic agent

    • Absence of other possible etiologies (infection, substance abuse, withdrawal, etc.)

    • No recent addition or increase of a neuroleptic agent

    • At least three of the following symptoms:

    • Mental status changes (confusion, hypomania)

      • Agitation

    • Myoclonus

      • Hyperreflexia

      • Diaphoresis

      • Shivering

      • Tremor

      • Diarrhoea

      • Incoordination

      • Fever

Hunter Serotonin Toxicity Criteria: Decision rules

In the presence of a serotonergic agent:

1. 1. IF (spontaneous clonus = yes) THEN serotonin toxicity = YES

2. ELSE IF (inducible clonus = yes) AND [(agitation = yes) OR (diaphoresis = yes)] THEN serotonin toxicity = YES

3. ELSE IF (ocular clonus = yes) AND [(agitation = yes) OR (diaphoresis = yes)] THEN serotonin toxicity = YES

4. ELSE IF (tremor = yes) AND (hyperreflexia = yes) THEN serotonin toxicity = YES

5. ELSE IF (hypertonic = yes) AND (temperature > 38.C) AND [(ocular clonus = yes)

6. OR (inducible clonus = yes)] then serotonin toxicity = YES

7. ELSE serotonin toxicity = NO

The constellation of symptoms are observed within hours to days (<13 hours) following the administration of drugs that elevate serotonin concentration in combination or in overdose. The drugs most frequently contributing to this condition are the combination of a monoamine oxidase inhibitor and the addition of a selective serotonin reuptake inhibitor. Serotonin syndrome (SS) is a serious potentially life-threatening condition

It arises when pharmacological agents increase serotonin neurotransmission at postsynaptic 5- hydroxytryptamine 1A and 5-hydroxytryptamine 2A receptors through increased serotonin synthesis, decreased serotonin metabolism, increased serotonin release, inhibition of serotonin reuptake or direct agonism of the serotonin receptors.

Multiple medications and supplements have been implicated in this syndrome, including serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), bupropion, monoamine oxidase inhibitors, triptans, opioid analgesics, tramadol, lithium, illicit drugs such as LSD, cocaine, and amphetamines, herbal supplements (eg, St. John's wort and ginseng), dextromethorphan, ritonavir, linezolid, and some antinausea medications (eg, metoclopramide, ondansetron, and granisetron). The etiology is often the result of therapeutic medication use, intentional overdosing of serotonergic agents or complex interactions between medications that directly or indirectly modulate the serotonin system.

For example in a patient taking: tramadol + venlafaxine + mirtazepine: In this case, serotonin syndrome resulted from coadministration of tramadol, venlafaxine, and mirtazapine. It is likely that the activation of 5-HT(1A) receptors by mirtazapine, the combined serotonin reuptake inhibition by venlafaxine and tramadol, as well as possible serotonin release by tramadol, contributed to the development of SS in this case.

• • Onset within 24 hours. H/o SSRI use and the use of migraine medication (triptans) or an MAOI or dextromethorphan.

  • Treatment agents: IVF, Benzodiazepine, Cyproheptadine

  • Resolution Within 24 hours

It is crucial to avoid inadvertent administration of new proserotonergic medications, especially fentanyl for analgesia in the ICU. Benzodiazepines are an essential component of management of the neurologic hyperactivity and cardiovascular instability. If patients do not respond to administration of intravenous benzodiazepines, cyproheptadine, a 5-HT-1a and 5-HT-2a receptor antagonist should be added. The autonomic hyperactivity can be striking, and there are limited data to guide management of severe autonomic dysfunction. Administration of benzodiazepine and cyproheptadine can improve blood pressure. Reasonable strategies in addition to benzodiazepines for management of the hemodynamic dysfunction include carefully avoiding hypovolemia (which has the tendency to exacerbate hypotension and tachycardia) and the use of intravenous opiates such as hydromorphone and propofol for sustained, severe hypersympathetic features. “Traditional” antihypertensive medications may be required. Intravenous calcium channel blockers, including diltiazem, nicardipine, and clevidipine, can be effective.

Clinical vignette.

68-year-old woman with anxiety, depression, and neuropathic pain presented to a community hospital with a sudden change in mental status. Minutes after having last been seen well, she was found agitated, rummaging through bedroom drawers, and not answering questions. Home medications included gabapentin, hydroxyzine, ondansetron, tramadol, and sertraline. On arrival to the emergency department her agitation was severe enough that she was intubated. Her initial evaluation was notable for tachycardia, low-grade fever, toxicology screen positive for opioids (not prescribed), and an unremarkable CT head and CT angiography (CTA) of the head and neck. Empirical antimicrobials for possible CNS infection were started.

Three days later she was transferred to the medical ICU of a tertiary care hospital. Her initial neurologic examination, performed 5 minutes after stopping infusions of propofol, fentanyl, and dexmedetomidine, was notable for spontaneous eye opening and visual orientation but she was not following commands. Her pupils were 5mm and briskly reactive with other brainstem reflexes intact. She had normal tone, no adventitious movements, localized to pain with both arms, and had diffuse hyperreflexia including the jaw jerk and sustained ankle clonus. She developed intermittent fevers to as high as 103° F. Continuous electroencephalogram (EEG) did not show seizures, lumbar puncture revealed normal cerebral spinal fluid (CSF), and MR imaging of the brain was unremarkable. Three days after transfer, serotonin syndrome was suspected. Accordingly, fentanyl infusion was changed to hydromorphone, and enteral cyproheptadine was started as a 12 mg load followed by 8 mg every 6 hours. Midazolam, propofol, and dexmedetomidine infusions were continued. Two days after starting cyproheptadine the hyperreflexia resolved, and within 4 days she was following commands. Her subsequent course was complicated by severe pneumonia with sepsis and ARDS, during which cyproheptadine was weaned. Signs of recurrent serotonin syndrome in the form of hyperreflexia with ankle clonus, asterixis, myoclonus, and chorea were apparent after deep sedation for ARDS was weaned. Cyproheptadine was restarted with rapid resolution of these abnormalities over 2 days, then weaned off over the course of a week. Despite a 2-month hospitalization that required tracheostomy and percutaneous gastrostomy, the patient fully recovered within 1 month after discharge.

MAOI-Induced Hypertensive Crisis

Pt. has acute HTN crisis. Has h/o MAOI use and either antihistamines, nasal decongestants, or consumption of tyramine-rich foods (pickled foods, cheeses). May also have taken MAOI and TCA concurrently.

Neuroleptic malignant syndrome (NMS).

NMS, occurring in 0.02% to 3% of all patients taking antipsychotic medications, is the most serious and life-threatening adverse reaction of these widely used medications. In-hospital mortality associated with NMS is reported as 3% to 20%. The exact neuro-pharmacologic pathophysiology is unknown, but there is clearly an association between decreased activity of dopamine D2 receptors and subsequent severe sympathetic and neuromuscular hyperactivity.

The classic tetrad involves the autonomic nervous system, (fever in 100%), the extrapyramidal system (rigidity), and encephalopathy which evolves over a period of 1-3 days. The main difference is that with the neuroleptic malignant syndrome the onset of symptoms and resolution of symptoms usually takes days to weeks, the muscular rigidity is often "lead pipe," and rhabdomyolysis and metabolic acidosis are more common. The classic tetrad of symptoms is most commonly associated with typical antipsychotics, whereas NMS associated with the atypical antipsychotics and antiemetics can often have absence of hyperpyrexia and severe rigidity. In fact, the NMS like syndrome occurring in association with atypical antipsychotics and antiemetics frequently seems similar to malignant catatonia (MC), suggesting that the 2 disorders lie in different locations along the spectrum of disorders associated with dopamine predominant dysregulated monoaminergic neurotransmission.

Seen more commonly with high potency neuroleptics such as haloperidol, olanzapine. Can also occur with metoclopramide and promethazine.

• • Idiosyncratic; can occur with 1st dose or after several years of use.

  • Higher risk with higher doses, rapid dose escalation, parenteral administration.

  • Host risk factors: Underlying psychosis, catatonia, concomitant use of lithium. NMS occasionally secondary to antiemetics or withdrawal of drugs for Parkinsonism (L-dopa)

• Other etiologies include L-dopa withdrawal, tetrabenazine, phenelzine, tricyclic antidepressants, and metoclopramide.

Clinical Features:

• • Days to weeks after starting an antipsychotic.

• The key to diagnosis is that NMS occurs only after exposure to a neuroleptic drug. On average, onset is 4-14 days after the start of therapy; 90% of cases occur within 10 days. However, NMS can occur years into therapy. Once the syndrome starts, it usually evolves over 24-72 hours.

  • Hyperpyrexia, muscular rigidity, agitation, tachycardia, HTN, tremor, incontinence, and an altered level of consciousness that may progress to coma. There is autonomic instability.

    • Fever of >38°C is essential for diagnosis, >40° C is seen in almost half of patients.

  • 20% mortality rate.

  • Rhabdomyolysis > elevated CK, Cr, leukocytosis, hyperkalemia, myoglobinuria, and low serum iron.

Labs: CPK, UA, urine myoglobin, UDS. CBC, CMP, ECG.

• • Increased LDH

  • Increased CK (50-100% of cases)

  • Increased AST and ALT

  • Increased alkaline phosphatase

  • Hyperuricemia

  • Hyperphosphatemia

  • Hyperkalemia

  • Myoglobinemia

  • Leukocytosis (70-98% of cases)

  • Thrombocytosis

  • Proteinuria

  • Decreased serum iron

  • Increased CSF protein

  • Hypocalcemia

  • Myoglobinuria

  • Metabolic acidosis

Tx:

• • ABC

  • Stop the antipsychotic agent.

  • Cooling blanket

  • Supportive therapy

  • VS, I/O

  • Transfer to ICU

  • Give Bromocriptine to overcome dopamine receptor blockade.

    • Bromocriptine 2.5 mg po tid may increase to 5 - 10 mg po tid for 7-10 days, then taper dose over 3 days to D/C.

    • Dantrolene (dose of 1–2.5 mg/kg with maximum daily dose of 10 mg/kg/d) should be considered when rigidity and hyperthermia are immediately life-threatening. Although dantrolene will treat these symptoms, it fails to treat the underlying dysautonomia and encephalopathy and therefore is best considered as adjunctive therapy. The mean recovery time is 7 to 11 days. Dantrolene is a skeletal muscle relaxant that can relieve muscle rigidity and improve the prognosis.

    • Give diazepam to reduce muscle rigidity.

• Electroconvulsive therapy (ECT) is a therapeutic option when pharmacotherapy fails but the use of succinylcholine is associated with cardiac arrhythmias and hyperkalemia and should be avoided during the ECT procedure.

• In most cases, atypical antipsychotics can be restarted safely approximately 4 weeks after resolution of symptoms, but there should be close follow-up, as recurrence can be as high as 10% to 20%.