Emergent Treatment of Neuroleptic Malignant Syndrome Induced by Antipsychotic Monotherapy Using Dantrolene

Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal complication resulting from neuroleptic drug therapy. Presentation of NMS can vary, and diagnosis relies primarily upon medical history and symptomatology. Due to the potential delay in diagnosis, emergency physicians should remain vigilant in recognizing the symptoms of NMS and be prepared to initiate immediate treatment following diagnosis. Dantrolene, which has been used for spasticity and malignant hyperthermia, has been reported as a potential treatment for NMS and led to off-label use for NMS. We report two cases of NMS induced by antipsychotic monotherapy for which dantrolene was administered.


INTRODUCTION
Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal complication of antipsychotic drug therapy. 1,2 It occurs in 0.002-3% of patients taking neuroleptic drugs, including patients of both genders and all age groups. 3,4 It is characterized by hyperthermia, blood pressure fluctuation, muscle rigidity, altered mental status, and tachycardia. 3 Lab values typically show leukocytosis, elevated transaminases, metabolic acidosis, myoglobinuria, elevated creatine and blood urea nitrogen levels. Electrocardiogram (ECG) changes can reveal prolonged PR, QRS, and QT intervals as well as ST and T-wave abnormalities. 3 The presentation of NMS is varied and may include some or all of these criteria.
Although formal diagnostic criteria have been proposed (Table 1), there is no universally-accepted criteria; the diagnosis of NMS is one that relies heavily on history and symptomatology rather than laboratory and diagnostic testing. [4][5][6] Once the diagnosis of NMS has been suspected, treatment should be immediately initiated following current available guidelines to reduce morbidity and mortality associated with delays in treatment. 7 However, while removal of the causative agent and supportive home. Family reported a history of hallucinations and a recent medication change to haloperidol (Table 3). In the ED the patient presented lethargic with a Glasgow Coma Scale (GCS) of 4, foaming from the oropharynx, and rigid. Vitals included an intravesical temperature of 109.6°F, blood pressure of 143/129 millimeters mercury (mmHg), pulse of 133 beats per minute (bpm), respiratory rate of 12 breaths per minute and irregular, and 100% saturation on high oxygen flow via nasal cannula. The patient's total creatine kinase was 28.482 units per liter (U/L) and troponin of 0.75 nanogram per milliliter (ng/mL) with ECG revealing lateral depressions. The patient was intubated for airway protection and immediately cooled with evaporative cooling measures. Additionally, the patient's rhabdomyolysis was managed with vigorous hydration. The cardiology team determined the patient was not stable enough for urgent cardiac catheterization, and heparin drip was started. Given the patient's hyperthermia and muscle rigidity, NMS was suspected and an intravenous one milligram per kilogram (mg/kg) bolus dantrolene was administered in the ED. He was admitted to the intensive care unit (ICU) with a diagnosis of NMS, rhabdomyolysis, respiratory failure, and non-STelevation myocardial infarction. The ICU treatment team began bromocriptine at a dose of 2.5mg per nasal gastric tube every six hours per neurology recommendations and cooling through Arctic Sun 5000 Temperature Management System™.
He also experienced multi-organ insult including hepatic shock and acute renal failure. Furthermore, he continued to experience labile temperatures with episodic fevers ( Figure  1). However, blood and urine cultures and cerebrospinal fluid (CSF) analysis were unremarkable. Additionally, he had acute loss of consciousness with wavering mentation, likely secondary to toxic metabolic encephalopathy, with GCS ranging from 4-11. After several failed multiple attempts for extubation, the patient subsequently required tracheostomy. He was discharged to an extended care facility for tracheostomy care after four weeks of inpatient management.

Case Two
A 21-year-old male with past medical history of autism and psychiatric disorder on risperidone was brought to the ED by his family with concern of altered mental status. The family reported that the patient had been somnolent, nonverbal, febrile, and had developed an unsteady gait. The patient was presenting one-week post treatment with a depot dose of risperidone (Table 4). In the ED, the patient was nonverbal with a GCS of 11, rigid, somnolent but able to follow basic commands, and displayed masked facies. Vitals included a temporal temperature of 99.3°F, blood pressure of 146/97 mmHg, pulse of 125 bpm, respiratory rate of 20 breaths per minute and oxygen saturation of 98% at ambient air. Laboratory examination was significant for creatine kinase 1092 U/L. Urine drug screen, comprehensive metabolic panel, hematology, and CSF analysis were unremarkable. The patient's ECG revealed sinus tachycardia with a heart rate of 102 bpm but was otherwise normal.
The patient was started on an intravenous 1mg/kg bolus of dantrolene, followed by 1mg/kg intravenously every six hours in the ED. He was admitted to the ICU for close monitoring. On hospital day two, he began to show improvement in alertness and cognition but remained mostly somnolent with no improvement in muscle rigidity, and he spiked a fever of greater than 102.3°F ( Figure 2). After four days, the intensive care team and neurology adjusted the dantrolene regimen to 40mg intravenously every six hours. Dantrolene was discontinued after 15 days and he was started on a 2.5mg dose of bromocriptine twice per day, which was subsequently adjusted to 5mg every eight hours.
By hospital day six, he was following basic commands and showing progressive symptomatic improvement. The patient continued to improve and by hospital day 10 demonstrated significant improvement in both gross and fine motor skills. He  The patient was discharged and restarted on clozapine.   tachycardia, metabolic acidosis, elevated creatine kinase, etc. 10 In our case series, one patient presented with the most frequently reported NMS symptoms, hyperthermia and rigidity, while the second patient presented with only a mild fever and rigidity but also had an altered mental state, elevated blood pressure and elevated creatinine kinase, which led to the NMS diagnosis. Therapeutic approaches tend to vary as they are often implemented in a trial fashion rather than evidencebased practice. 10 Primary treatment consists of withdrawal of the neuroleptic and supportive therapy such as hydration and cooling measures ( Table 5). 8 Medical therapy using dantrolene was first used for NMS in 1981 and has been cited in several reports as a useful treatment for NMS, particularly if the neuroleptic was a monotherapy. 10 However, some studies have reported that dantrolene offers no significant benefit when compared to supportive therapy alone. Due to the low incidence rate of NMS, a randomized, controlled trial has not been feasible leading to a continued lack of consistency in treatment. 10 There are several differences between our two cases that reveal firsthand the lack of consistency in treatment guidelines. The first patient received a bolus of dantrolene before being transferred immediately to the ICU for further management. Within the ICU setting, neurology and the intensive care team discontinued dantrolene and started bromocriptine. In contrast, the second patient remained in the ED for 12 hours and received two doses of dantrolene before being transferred to the ICU where dantrolene was continued until hospital day 15. He then was switched to bromocriptine. The differences in medical therapy seem to result from general practice differences between departments and specialists. Whereas dantrolene is commonly used for spasticity and malignant hyperthermia by ED providers, neurologists and intensivists favor bromocriptine as the medical therapy for management of NMS. This change in medical therapies used for NMS management during a hospital course has been reported previously. 1,11 The common theory of pathogenesis of NMS is dopamine blockade with subsequent disruption of the hypothalamus and corpus striatum, leading to temperature deregulation and muscle contractions. 19 Dopamine pathways play a crucial role in hypothalamus function and temperature regulation, which can be disrupted by dopamine receptor antagonists such as haloperidol and risperidone. 20 Derangement of hypothalamic function can cause hyperthermia, arrhythmias, and irregular blood pressure and respiration. Additionally, dopamine blockade in the corpus striatum can lead to increased muscular rigidity and may lead to the occurrence of non-traumatic rhabdomyolysis. A recent study found that rhabdomyolysis and acute kidney injury were the most common complications in NMS -30.1% and 16.1%, respectively. 21 Additionally, acute kidney injury was associated with 2.3 times increased odds of death. 21 was subsequently discharged on hospital day 18 with continued bromocriptine treatment and close follow-up.

DISCUSSION
Recent literature suggests that both diagnosis and treatment of NMS remain challenging. 11,18 While NMS is primarily recognized by hyperthermia and peripheral muscle rigidity, presentation can often vary. Additional symptoms may include altered mental state, irregular blood pressure, Volume III, no.  Although the use of dantrolene in the setting of NMS is widely reported due to its effectiveness in spasticity and malignant hyperthermia, its pathophysiological effects are unclear. It is known that dantrolene directly relaxes skeletal muscle by inhibiting both ryanodine receptor binding and calcium release from intracellular storage in the sarcoplasmic reticulum. As an inhibitor of calcium release, it is suggested that dantrolene may also treat or prevent neuronal injury. 22 The binding of dantrolene to ryanodine receptors in the brain protects neurons from the disruptions in calcium that occur in NMS. There is evidence that dantrolene may have effects in the thermoregulation areas of the brain to thereby reduce hyperthermia. 23 Additionally, dantrolene promptly reduces muscular rigidity, which in turn decreases hyperthermia in NMS patients and prevents myoglobinuric acute kidney injury secondary to spontaneous rhabdomyolysis common in NMS patients. 9,24 Despite the inconsistencies in NMS presentation and treatment, emergency physicians need to be prepared to rapidly assess and treat patients presenting with NMS symptomatology to avoid poor outcomes. Unfortunately, previous studies lack consistency in neuroleptic dosage, scales for reporting rigidity, and a temporal sequence of NMS symptomatology, further complicating an accurate NMS diagnosis (Table 2). 10 As our case series shows, the first patient presented with hyperthermia and rigidity typical of NMS and went on to develop serious complications, which greatly lengthened his recovery time. Complications secondary to NMS include acute kidney injury, respiratory failure, myocardial infarction, and toxic encephalopathy. Furthermore, such serious complications predict a poor prognosis. Therefore, prompt treatment should follow high suspicion for NMS and is imperative to avoid increased morbidity and mortality.
Our case series demonstrates that dantrolene may be effective in treating NMS because it affects both muscular and central nervous systems, especially if NMS was caused by neuroleptic monotherapy. Fortunately, in our case series both patients were brought in by family members who reported recent doses of neuroleptic monotherapy, which led to a faster diagnosis of NMS and treatment strategies including the use of dantrolene.

CONCLUSION
Our case series provides emergency physicians with critical examples of NMS symptomatology that presented in an ED and the potential benefit of using dantrolene for NMS resulting from neuroleptic monotherapy. Additionally, it is our hope that our case series will contribute to the growing body of knowledge regarding NMS presentation and treatment and encourage future studies to further explore NMS diagnostic criteria and appropriate treatment regiments.
Documented patient informed consent and/or Institutional Review Board approval has been obtained and filed for publication of this case report.

Conflicts of Interest:
By the CPC-EM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.