Neuroleptic malignant syndrome requiring intensive care unit admission in two patients with SARS-CoV-2 infection in Portugal

Marina Costa; Ana Raquel Covas; Fábio Neves Correia; Sara Bernardo; Pedro Silveira

doi:10.4266/acc.004632

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Letter to the Editor Neurology Neuroleptic malignant syndrome requiring intensive care unit admission in two patients with SARS-CoV-2 infection in Portugal: Marina Costa, Ana Raquel Covas, Fábio Neves Correia, Sara Bernardo, Pedro Silveira; DOI: https://doi.org/10.4266/acc.004632
Published online: March 13, 2025

Department of Intensive Care Medicine, Hospital de Braga, Braga, Portugal

Corresponding author: Marina Costa Department of Intensive Care Medicine, Hospital de Braga, R. das Sete Fontes, 4710-243 Braga, Portugal, Braga, Portugal Tel: +351-918233014, Email: marina.oliveira.costa@ulsb.min-saude.pt

• Received: December 4, 2024 • Revised: January 26, 2025 • Accepted: January 28, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Neuroleptic malignant syndrome (NMS) is a life-threatening neurologic emergency secondary to the use of antipsychotic agents and is characterized by altered mental status, rigidity, fever, and dysautonomia. When manifestations are severe, admission in an intensive care unit (ICU) is required for monitoring and supportive treatment. This syndrome has an incidence of 0.01% to 3.2% among patients taking neuroleptics, with a mortality rate of 10% to 20% [1,2]. A few cases of NMS have been reported in association with coronavirus disease 2019 (COVID-19) [3,4], highlighting the possibility of a predisposition to NMS when severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen is associated with neuroleptic use. In the following paragraphs, we report two patients admitted to our ICU due to coma probably related to NMS, who had concomitant mild to moderate COVID-19.

A 55-year-old male patient, with prior diagnosis of schizophrenia, presented to the emergency department (ED) with fever (40.1 °C) and flu-like symptoms. He was under treatment with risperidone (4 mg orally [PO] once daily), trazodone (150 mg PO once daily), clonazepam (2 mg PO three times daily), and eslicarbazepine (800 mg PO once daily). He was admitted to the medical ward to treat community-acquired pneumonia superimposed on COVID-19, as he had tested positive for SARS-CoV-2 in a nasal swab 2 days prior. In the ward, he showed rapid deterioration of mental status and respiratory condition, with refractory fever (not less than 39 °C despite pharmacological treatment), muscle rigidity, rhabdomyolysis, acute renal failure (ARF), and leukocytosis 19,060/µl. Cranial computed tomography (CT) scan was normal. He had severe hypernatremia of 198 mmol/L, which was considered secondary to dehydration and severe muscle rigidity. He was admitted to the ICU due to subsequent coma with multifactorial etiology, initiating treatment with dantrolene for NMS and withdrawal of dopamine agonists. The dantrolene protocol consisted of an initial intravenous (IV) bolus of 1.5 mg/kg, followed by a maintenance dose of 1 mg/kg IV every 6 hours. Normothermia was achieved in the first 6 hours of ICU admission, with associated acetaminophen, metamizole, and nonpharmacological cooling measures. Hypernatremia was corrected in the first 48 hours with dextrose 5% infusion. Despite severe muscle rigidity observed as stiffness and resistance in all passive limb movement, he was easily ventilated, with protective parameters and low positive end-expiratory pressure and FiO₂. He remained comatose for 3 days, then showing improvement of mental status and rigidity, allowing extubation on the 4th day of admission, after which we started to wean dantrolene dosing. Despite the improvements in neurological status, there was a gradual increase in rhabdomyolysis parameters, with maxima of 67,000 μg/L of myoglobin and 37,000 U/L of creatine kinase (CK), with concurrent worsening ARF requiring renal replacement therapy for 3 days. He stopped dantrolene after 10 days, following a gradual weaning protocol. He stayed in the ICU for a total of 36 days, showing slow but continuous improvement of neurological status and resolution of rhabdomyolysis and rigidity. His stay was complicated by a nosocomial pneumonia, requiring reintubation and associated with ICU acquired myopathy, leading to a prolonged ventilatory weaning and ineffective cough requiring tracheostomy. He remained stable during his stay in the ward and was discharged to integrated continued care after 61 days in the hospital.

A 77-year-old male patient with prior diagnosis of schizoaffective disorder, treated with clozapine (25 mg+75 mg PO daily) and haloperidol (100 mg intramuscular monthly + 10 drops PO once daily), presented to the ED after a syncope. He presented with fever and ARF and tested positive for SARS-CoV-2. He was admitted to the medical ward due to COVID-19 pneumonia with superimposed bacterial infection. At day 3 of admission, in association with sustained ARF and aggravating rhabdomyolysis, he showed refractory fever, reaching 39.6 °C; hypertension; and behavioral changes that progressed to impaired consciousness with associated acute respiratory failure. Cranial CT scan was normal. He was intubated, admitted to the ICU, and started on a dantrolene protocol (the same as previously stated) and cooling measures. The diagnosis of NMS has been considered in the ward, and he developed associated muscle rigidity and rhabdomyolysis, with a CK of 2,650 U/L and leukocytosis of 25,410/µL. He was not started on dantrolene until ICU admission. He had a sodium level of 153 mmol/L, which was corrected in the first 24 hours. Despite rapid improvement of the respiratory failure, he remained intubated until the 9th day of ICU admission due to a sustained coma with diffuse spasticity. As in the previously reported case, ventilatory parameters were not a problem and the patient did not present thoracic rigidity. When extubated, he was following commands and had spontaneous eye opening and tracking movement, though presenting a slight degree of spasticity on extension of both arms. He was discharged to the ward after 10 days in the ICU and received dantrolene for 25 days. Despite showing improvement of the neurological dysfunction, his stay in the ward was complicated with multiple nosocomial infections, leading to severe frailty and death after 58 days of hospital admission.

NMS is a severe neurologic syndrome associated with the use of dopamine-receptor antagonists or with sudden withdrawal of dopaminergic medication. While uncommon, it is part of the differential diagnosis of fever and altered mental status as it requires timely diagnosis and treatment to prevent mortality. Treatment involves immediate discontinuation of neuroleptic agents, supportive care, and empiric pharmacologic therapy in severe cases, with dopamine agonists such as bromocriptine and muscle relaxants such as dantrolene. The diagnosis of NMS is based on the presence of three major criteria: exposure to dopamine-blocking agent; severe muscle rigidity and fever; and at least two of diaphoresis, dysphagia, tremor, incontinence, altered consciousness, mutism, tachycardia, elevated or labile blood pressure, leukocytosis, and elevated CK. Although it is possible to diagnose the syndrome solely based on clinical criteria, the use of laboratory tests can support the diagnosis and help rule out other etiologies. Lab work is usually consistent with rhabdomyolysis with a profoundly elevated CK, which typically correlates with disease severity, and acutely declining renal function.

Here we describe two cases presenting with febrile illness, altered consciousness, and rigidity, both fulfilling the criteria for NMS. Interestingly, both patients were previously admitted to the ward with the diagnosis of COVID-19, and both required admission to the ICU for coma due to NMS. They showed gradual improvement on rigidity and consciousness with the introduction of dantrolene, withdrawal of antipsychotics, and supportive treatment. Our reported cases add value to previously published studies by enhancing the potential link between entities. It is difficult to confirm or generalize this relationship or to establish scientific corroborative values, mostly due to difficulties confirming NMS diagnosis. Lack of availability of testing to confirm or exclude NMS is the main obstacle for validation of this linkage. However, according to diagnostic criteria for NMS, both patients had a very straightforward diagnosis. We could consider fever as part of SARS-CoV-2 infection, although the pattern was severe and refractory compared to that observed in previous COVID-19 patients. Furthermore, severe hypernatremia was identified in the first patient and could explain his altered consciousness. However, other clinical manifestations could not be explained by either hypernatremia or SARS-CoV-2 infection. We considered muscle rigidity and rhabdomyolysis associated with atypical refractory fever as characteristics of NMS; patient history, medication, clinical manifestations, and lab results also supported the diagnosis. Indeed, the drugs most commonly associated with NMS are high-potency, first-generation antipsychotic agents such as haloperidol. Despite that, every class of antipsychotic drug has been implicated in the etiology of NMS, including low-potency first- and second-generation antipsychotics, such as clozapine, risperidone, and olanzapine. We conclude that both patients were at risk of NMS considering their previous medication, although the second patient likely had higher risk since he was being treated with two antipsychotics.

There have been some reports of NMS presenting in patients with SARS-CoV-2 infection, suggesting a possible link between these diseases and that COVID-19 could increase patient susceptibility to NMS [3,4]. Soh et al. [3] report two cases of NMS diagnosed after ICU admission for severe COVID-19 with associated ARDS. They also consider a potential association with risperidone administration, as in our second reported case, and they highlight a possible causative relation between favipiravir and NMS. Kajani et al. [4] reported a patient who presented to the ED with diagnostic criteria for NMS, in addition to a bilateral pneumonia on chest x-ray related to SARS-CoV-2 infection. Our reported cases, in comparison, presented with mild to moderate COVID-19 requiring ward care and developed NMS a few days after hospital admission. Additionally, our patients were not receiving favipiravir or any other COVID-19-specific pharmacological treatment while in the ward. We believe the unique characteristics of our reported cases might add academic value to the current literature.

The pathophysiology of NMS is complex and poorly understood and so is the link between NMS and SARS-CoV-2 infection. Some studies suggest acute medical illnesses as risk factors for NMS [1]. It is proposed that the COVID-19 virus interacts with ACE2 receptors found in the nervous system to cause neurological symptoms, a possible pathophysiological explanation for NMS in COVID-19 patients [5]. We believe the cases described, in addition to those in recent literature, support the potential connection between NMS and COVID-19, potentiating future research on this possible link and its pathophysiology.

Informed consents were obtained from the patients’ relatives. There was no requirement for IRB approval due to the descriptive nature of the study.

NOTES

CONFLICT OF INTEREST

No potential conflict of interest relevant to this article was reported.

FUNDING

None.

ACKNOWLEDGMENTS

None.

AUTHOR CONTRIBUTIONS

Writing - original draft: MC. Writing - review & editing: all authors.

REFERENCES

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3. Soh M, Hifumi T, Isokawa S, Shimizu M, Otani N, Ishimatsu S. Neuroleptic malignant syndrome in patients with COVID-19. Am J Emerg Med 2020;38:2243.e1-2243.e3.Article PubMed
4. Kajani R, Apramian A, Vega A, Ubhayakar N, Xu P, Liu A. Neuroleptic malignant syndrome in a COVID-19 patient. Brain Behav Immun 2020;88:28-9.Article PubMed PMC
5. Jafari Khaljiri H, Jamalkhah M, Amini Harandi A, Pakdaman H, Moradi M, Mowla A. Comprehensive review on neuro-COVID-19 pathophysiology and clinical consequences. Neurotox Res 2021;39:1613-29.Article PubMed PMC PDF

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Neuroleptic malignant syndrome requiring intensive care unit admission in two patients with SARS-CoV-2 infection in Portugal

DOI: https://doi.org/10.4266/acc.004632

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Neuroleptic malignant syndrome requiring intensive care unit admission in two patients with SARS-CoV-2 infection in Portugal