A Typical Neuroleptic Malignant Syndrome Presenting with Hyponatremia

Rustem O; Ercan Y; Ozer O

doi:10.37871/jbres2171

ISSN: 2766-2276

2025 August 27;6(8):1138-1142. doi: 10.37871/jbres2171.

Subject area(s)

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Case Report

A Typical Neuroleptic Malignant Syndrome Presenting with Hyponatremia

Rustem O^1*, Ercan Y² and Ozer O³

¹Neurology Clinic, Diyarbakir, Selahaddin Eyyubi StateHospital, Turkey
²Internal Medicine Clinic, Diyarbakir, Selahaddin Eyyubi StateHospital, Turkey
³Emergency Medicine Clinic, Diyarbakir, Selahaddin Eyyubi StateHospital, Turkey

*Corresponding authors: Rustem O, Department of Neurology, Selahaddin Eyyubi StateHospital, Neurology Clinic, Diyarbakir, Turkey E-mail:

Received: 26 June 2025 | Accepted: 13 August 2025 | Published: 27 August 2025

How to cite this article: Rustem O, Ercan Y, Ozer O. A Typical Neuroleptic Malignant Syndrome Presenting with Hyponatremia. J Biomed Res Environ Sci. 2025 Aug 27; 6(8): 1138-1142. doi: 10.37871/jbres2171, Article ID: jbres1757

Keywords

Neuroleptic malignant syndrome
Venlafaxine
Hyponatremia

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Abstract

Neuroleptic Malignant Syndrome (NMS) is a rare but potentially fatal neurological complication of medications affecting the central dopaminergic system, especially antipsychotic agents. According to one theory, decreased dopamine activity in the central nervous system plays a role in the pathogenesis of NMS. Clinically, patients exhibit resistant fever, neurological and autonomic findings, and laboratory changes. In this article, we aimed to present a case of neuroleptic malignant syndrome due to a single dose of venlafaxine, which presented with hyponatremia and high fever.

Introduction

Neuroleptic Malignant Syndrome (NMS) is a rare but life-threatening condition that is particularly associated with the use of Antipsychotics (APs) and other drugs that affect the dopaminergic system [1,2]. The first description of NMS was made by Deniker and Delay in 1960. The reported incidence of NMS has varied over the years. Considering the number of people using neuroleptic agents, the incidence of NMS is rare. Estimates are around 0.1% of people taking antipsychotics [3,4]. Many studies suggest that the pathophysiology of NMS is due to sudden decreases in central dopaminergic activity resulting from blocked D2 dopamine receptors in the nigrostriatal, hypothalamic, mesolimbic, and cortical pathways [5-7]. The typical clinical presentation of NMS is characterized by high fever that is resistant to treatment, neurological findings, and autonomic dysfunction [3,8]. In laboratory tests, the most noticeable changes are serum Creatine Phosphokinase (CPK) levels. They are usually 4-5 times higher than normal values. Apart from CPK elevation, white blood cell count increases, and electrolyte disturbances occur [9,10]. In the literature, atypical cases have been reported that do not fully meet the DSM (Diagnostic and Statistical Manual of Mental Disorders) criteria for NMS that show mild hyperthermia and/or neurological findings or no symptoms at all [3,9]. Based on this information, we aimed to discuss our case of atypical neuroleptic malignant syndrome presenting with hyponatremia and fever after venlafaxine.

Case

A 58-year-old female patient was brought to the emergency department with syncope and high fever. Her medical history included hypertension, major depression, and psychosis. The medications she used were: nebivolol, amlodipine, olanzapine, imipramine, and venlafaxine. Among these drugs, the patient had been using all of them for many years, except venlafaxine, and symptoms started on the 3rd day of venlafaxine use. On initial physical examination, vital signs were as follows: blood pressure, 168/82 mmHg; heart rate, 108 beats/min; respiratory rate, 22 breaths/min; and body temperature, 40.5°C. In the emergency department, the patient was conscious, oriented, and cooperative, and a detailed neurological examination was normal.

Blood tests: WBC: 16,000/mm3, sodium 110 mmol/L, CPK (creatinine phosphokinase) 1812 u/L, LDH (lactate dehydrogenase) 597 u/L. Other tests, including C-Reactive Protein (CRP), were standard. No pathology was detected in cranial imaging. The COVID PCR test, which was performed three times at twelve-hour intervals, resulted in negative results.

The patient was admitted to the internal medicine intensive care unit due to euvolemic hyponatremia. Hypertonic fluid, a proton pump inhibitor, low-molecular-weight heparin, ceftriaxone, paracetamol, nebivolol, amlodipine, and metamizole were initiated as treatment. In her follow-up, despite the maximum doses of paracetamol and metamizole, her fever continued. Although the patient's sodium level increased to the desired level and remained stable for a specific period of time, a deterioration in her general condition and a regression in her Glasgow Coma Scale score were observed on the second day of her hospitalization. Autonomic findings, such as tachypnea, tachycardia, pallor, and excessive sweating, were added to the clinic. A neurologist was consulted due to changes in the patient's state of consciousness and the emergence of neurological findings such as dysarthria and dysphagia. Neurological examination revealed findings such as confusion, pathological reflexes, dysphagia, and dysarthria. The patient's follow-up cranial imaging was normal. An infectious disease specialist was consulted for central nervous system infections. The patient was taken to the 3rd level intensive care unit, empirical treatment was started until meningoencephalitis was excluded, and a lumbar puncture was planned for meningoencephalitis. But the patient was intubated due to rapid deterioration in the clinic within hours. The patient developed cardiac arrest in the following hours, and despite all interventions, the patient was declared dead.

As a result, the patient was considered to have neuroleptic malignant syndrome based on persistent fever, neurological findings, recent venlafaxine use, elevated serum creatine phosphokinase, and many laboratory changes and imaging studies.

Discussion

In general, NMS is a rare but highly mortal condition that develops due to antipsychotics [3,11]. It has been reported in the literature that many drug groups other than antipsychotic agents can cause NMS [3,12-15]. Therefore, NMS diagnosis should be kept in mind in the differential diagnosis of patients with persistent fever, neurological findings, and high CPK despite not using antipsychotic drugs. The clinical picture typically develops 24-72 hours after treatment initiation [3]. We would like to begin our discussion with the patient's laboratory values, which were determined in the emergency department and served as the primary indication for hospitalization. When our patient came to the emergency department, he was hyponatremic (110 mmol/L) and his CPK was high (1812 u/L). Most likely, severe hyponatremia was the most misleading laboratory result in the diagnosis. The patient's general condition was primarily thought to be due to hyponatremia, and differential diagnosis and treatment were planned according to hyponatremia. Although not as common as WBC and CPK elevations, electrolyte disorders (hypocalcemia, hypomagnesemia, hypophosphatemia/hyperphosphatemia, hypo/hyperkalemia, hypo/hypernatremia) and LDH, ALP/AST elevations are frequently reported in NMS [9].

According to literature data, the most significant laboratory abnormality in NMS is the CPK level. In 95% of cases, the CPK level is determined to be at least 4-5 times higher [9]. However, it is known that CPK may be high in cases such as intramuscular injection and trauma. This elevation is usually around 1000 u/l. Another common laboratory change in the literature is an increase in leukocyte count (WBC). The increase in leukocyte count is present in 78% of cases and is usually above 15,000 cells/mm3 [3,9,16]. In our patient, both CPK and WBC values were high, supporting the literature data. Fever is one of the significant criteria in NMS [3]. In a systematic review, hyperthermia was present in 88% of cases [17]. Although the degree of hyperthermia is variable, body temperatures of up to 42°C have been reported in some cases [18]. As in our patient, hyperthermia in NMS is resistant to treatment. In addition to medical therapy, supplementary methods such as mechanical cooling, cooling blankets, and ice packs may also be necessary. Due to the lack of animal models for NMS, it is challenging to determine the cause of altered thermoregulation. Recently, it has been thought that hyperthermia is due to multiple causes. One of these is heat production resulting from the rigidity that develops in patients. Based on this theory, several successful studies have reported hyperthermia and a decrease in CPK with treatment directed at rigidity [19,20]. Another theory that contributes to hyperthermia in NMS is the activation of the sympathetic nervous system [21]. Activation of the sympathetic nervous system can produce heat through proteins that degrade brown fat and skeletal muscle, a process similar to that induced by amphetamines [22-24]. Additionally, activation of the sympathetic nervous system may impair heat dissipation through cutaneous vasoconstriction [25,26]. Finally, there is evidence that increases in acute-phase reactants are associated with NMS [27]. Central release of prostaglandins in areas such as the preoptic area accounts for the hyperthermia, catatonia, and labile blood pressure commonly reported with NMS [28].

Another misleading factor in our case was the neurological state. Generally, neurological symptoms (e.g., altered consciousness, tremor, sialorrhea, akinesia, dystonia, trismus, myoclonus, dysarthria, dysphagia, rhabdomyolysis) are essential in diagnosis and prognosis in NMS. Rigidity was detected in 86% of patients in a study conducted by Lang FU, et al. [17]. As is known in the literature, atypical NMS cases can occur without rigidity, as in our case [29]. Another common feature in NMS, as in our patient, is altered mental status. Although there is no characteristic mental status finding in NMS, a change is almost always observed. These changes may be agitation, delirium, mutism, or coma [17,30]. In our patient, we observed that although consciousness was normal in the first days, mutism and delirium were particularly prominent during follow-up. Additionally, many other neurological symptoms were not observed in our patient, particularly in the initial days.

Finally, autonomic dysfunction findings are observed in many patients with NMS. Similar to the literature data, our patient exhibited tachycardia, labile blood pressure, and excessive sweating during follow-up. In a study conducted by Lang FU, et al. [17] 62% of NMS patients experienced tachycardia, 44% had sweating, and 42% exhibited instability of blood pressure.

NMS is typically a condition that develops due to antipsychotics. However, as in our patient, there is data that it can also develop due to different agents. Venlafaxine is an agent from the Selective Norepinephrine Reuptake Inhibitor (SNRI) group. There has been an increase in the number of NMS or extrapyramidal side effects associated with venlafaxine [31-33].

In conclusion, we would like to emphasize that neuroleptic malignant syndrome should be included in the differential diagnosis for patients presenting with electrolyte disorders, persistent fever, and neurological findings who also exhibit CPK elevation. Additionally, atypical NMS cases without rigidity have been reported.