Atypical Presentation of Ziprasidone-Induced Neuroleptic Malignant Syndrome: A Case Report

Abstract

Neuroleptic malignant syndrome (NMS) is a severe adverse reaction associated with neuroleptic or antipsychotic drugs. This case report discusses a 43-year-old man with a history of bipolar disorder and polysubstance abuse who presented with altered mental status, autonomic dysfunction, and muscular rigidity. The patient had recently started on ziprasidone, a second-generation antipsychotic, leading to an atypical presentation of NMS. Unlike classic findings associated with NMS induced by first-generation antipsychotics, this case lacked high fever, lead pipe rigidity, or elevated creatine kinase levels greater than 1000 on initial presentation. The delay in diagnosis was attributed to the milder symptoms and absence of typical findings, resulting in extensive diagnostic workup and interventions. The patient responded positively to treatment with lorazepam based on the Woodbury severity stage guidelines. This case underscores the complexity of diagnosing NMS induced by second-generation antipsychotics and highlights the need for awareness and tailored treatment approaches for atypical presentations.

Introduction

Neuroleptic malignant syndrome (NMS) is a rare but lethal adverse reaction to neuroleptic or antipsychotic drugs. Similar to malignant catatonia, it can cause autonomic dysfunction and muscular rigidity. Key differentiating factors include a history of neuroleptic or antipsychotic use within 2 weeks, high fevers, and high creatine kinase (CPK) levels.^1,2 Recognition and treatment of catatonia and malignant catatonia are crucial because both may progress to neuroleptic malignant syndrome and be fatal without treatment. ³ Neuroleptic malignant syndrome diagnostic criteria is often apparent when discussing NMS induced by first-generation antipsychotics (FGA) but may not be met when discussing newer antipsychotics or second-generation antipsychotics (SGA). This is due to the lack of classic findings including high fever, lead pipe rigidity, or CPK greater than 1000, all of which are commonly seen in cases of NMS. ⁴ This can result in delayed diagnosis and treatment.

Patient Information

A 43-year-old Caucasian man presents from jail for altered mental status. His medical history included polysubstance abuse and bipolar disorder treated with clonazepam and lithium with unclear compliance to medications. One year prior, he was admitted for altered mental status and tremors of the jaw with concern for seizure. He was evaluated for toxic, metabolic, or infectious causes; all were negative. No further seizures occurred while hospitalized. He was discharged at his baseline mentation with a diagnosis of first-time seizure. On this presentation, he was noted to have a change in mental status of 3-day duration. Symptoms included mutism, fixed gaze, urinary incontinence, and poor oral intake. Minimal history was obtained as the patient was transported by correctional officers unfamiliar with the patient.

Clinical Findings

Vitals on presentation were significant for temperature of 98°F, respiratory rate of 24, and blood pressure of 163/98. Physical examination was significant for ill- and toxic-appearing male, with dry mucous membranes, dilated but reactive pupils, and normal cardio and pulmonary examination. He had increased muscle tone and dysarthria. Initial laboratory values included a white blood cell count of 20.7, total creatine kinase 939, ammonia 33, acetaminophen <2.0, lithium level <0.2, salicylate level <1.7, and ProCal 0.05. Urine drug screen was positive for barbiturates and cannabinoids. Computed tomography (CT) of the head without contrast, CT Angio perfusion, CT Angio head/neck, and chest x-ray were all unremarkable. The initial concern was for a postictal state secondary to seizure; therefore, neurology was consulted, and the patient was started on levetiracetam. Later in the evening, the patient appeared more sluggish and less responsive with a decreased ability to follow commands. So levetiracetam was held. The following day the patient’s abnormal mental status and muscle tone persisted. Laboratory values showed an increase in CK to 1769, with persistent leukocytosis. Further evaluation with an electroencephalogram (EEG), lumbar puncture (LP), and magnetic resonance imaging (MRI) of the brain were all unremarkable. He was diagnosed with urinary retention which required straight catheterization multiple times over 3 days. On day 3, he was found to be hypertensive, tachypneic, tachycardic, and febrile at 100.4. Rigidity was more pronounced with some providers commenting on cogwheel rigidity and soon developed jaw tremors. An infectious workup included blood cultures and a chest x-ray (CXR) was completed. Chest x-ray showed right lower lobe infiltrates concern for pneumonia versus pneumonitis. Piperacillin-tazobactam was started for aspiration pneumonia. A nasogastric tube was inserted for nutritional intake. Following these interventions, it was discovered that the patient was started on ziprasidone 60 mg BID intramuscular 2 weeks before hospital presentation. He was discharged from a psychiatric unit 7 days before his arrest where the jail nurse believes ziprasidone was started. The reasoning for the admission to the psychiatric facility was not known. Based on the Woodbury severity score, he was started on lorazepam for NMS. There was some improvement which included decreased rigidity and verbal responses to simple questions after starting treatment. On day 5, the patient showed stabilization of body temperature, blood pressure, and respiratory rate. His mutism had resolved and he could now follow commands. After 48 hours of treatment with lorazepam, he was noted to be back to baseline. He was weaned off lorazepam and discharged back to jail.

Discussion

The diagnosis of NMS based on the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) includes exposure to dopamine antagonist, or dopamine agonist withdrawal within 72 hours, hyperthermia, rigidity, mental status alteration, CPK elevation, sympathetic nervous system lability, and hypermetabolism with a negative workup for infectious, toxic, metabolic, and neurological causes. ⁵ Although the exact mechanism of NMS may not be known, it is believed to be due to dopamine receptor blockade acting as a trigger. The atypical symptoms or milder symptoms associated with SGA may be associated with lower binding of the D2 receptors in the basal ganglia and hypothalamus. ⁶

Ziprasidone is often initiated in the treatment of schizophrenia, bipolar mania, and acute agitation in patients with schizophrenia. Second-generation antipsychotics are often used as adjunct therapy to mood stabilizers such as lithium. This is considered the first line in the maintenance therapy in bipolar disorder, because it has been shown to reduce recurrent manic episodes compared with placebo. ⁷ It remains uncertain whether the patient recently experienced a manic episode prompting changes in medication, or if poor compliance was a contributing factor. Typical adverse reactions and symptoms associated with starting ziprasidone include tardive dyskinesia, somnolence, and dizziness. Ziprasidone toxicity can present with seizures, somnolence requiring intubation, body temperature regulation, and suicide. While our patient exhibited few of these manifestations, adverse drug reactions to ziprasidone are more frequently encountered during the initial phase of medication initiation, unlike the presentation observed in this case. ⁸ In this case, the patient was being managed with ziprasidone 60 mg twice daily, which is considered a moderate dose. Neuroleptic malignant syndrome can develop at any point without a specified dosage threshold. It is believed that, akin to FGA, a higher dosage of SGAs may elevate the risk of NMS development. Presently, there is insufficient systematic data demonstrating a specific dosage associated with an increased likelihood of NMS occurrence. ⁹

Neuroleptic malignant syndrome is a rare occurrence since medical staff awareness and the introduction of SGA. Previous reports show rates of 0.01% to 3.2% of patients taking neuroleptic medications, with rates even lower in patients taking SGA. ¹⁰ This case is considered atypical as the patient never developed a high fever (greater than 104°F), nor strict/lead pipe muscle rigidity, and his CK level was less than 1000 on presentation. The patient also exhibited waxing and waning of his mentation which further challenged the neurologist and psychiatrist involved in the case. In the previous reports of SGA-induced NMS, such fluidity in mental status has not been reported. Often the patient’s mental status gradually improves or clinically worsens based on the etiology (withdrawal of anti-psychosis or the increase).

Before confirming the diagnosis, other etiologies must be ruled out, in particular seizure activity or postictal state. Due to his lack of improvement with time and lack of seizure activity on EEG, this was ruled out. Also, the patient tested positive for barbiturates, making overdose a concern but due to lack of improvement with time and gradual worsening in the following days, this was less likely. Other potential diagnoses were contemplated, including lithium intoxication or clonazepam withdrawal. However, considering the patient’s presentation, characterized by autonomic dysfunction that progressively deteriorated during his hospitalization alongside increased rigidity, clonazepam withdrawal or non-compliance became less likely. Although lithium toxicity was also considered, the patient’s low lithium levels rendered this possibility improbable. Infectious etiologies were also ruled out during his hospital course. Previous studies show that SGA-induced NMS may present with milder symptoms, leading to a more expansive range of presentation. ¹¹

For this patient, his delay in treatment was due to the atypical presentation, which included frequent volatile mental status changes and a lack of common findings in NMS. This led to a more extensive workup, invasive interventions, and complications such as urinary straight catheterization, nasogastric tube placement, LP, multiple brain imaging, and empiric antibiotics.

The treatment guidelines used for the management of this patient included the Woodbury severity stage guidelines, as seen in Table 1. In 1992, Dr Woodbury was the first to show success using benzodiazepine in the early stages of NMS. ¹² This was first noticed in adolescents but was also applied to our patient. With these guidelines, our patient met the criteria of stage 2 with some progression to stage 3 due to worsening of autonomic changes. The patient did not meet the criteria to be treated with dantrolene or bromocriptine, only lorazepam. Previous retrospective studies show that when implemented, the Woodbury severity stage can help categorize the severity of the patient and aid in treatment, particularly in cases where symptom management and supportive care may not be enough. Those categorized as severe showed better outcomes when treated with dantrolene, bromocriptine, or electroconvulsive therapy.^13,14

Table 1.

Woodbury Severity Stage for NMS.

Severity stage	Clinical findings
Stage I	Drug-induced parkinsonism: This stage represents the mildest form of NMS and is characterized by drug-induced parkinsonism symptoms, such as tremors, rigidity, and bradykinesia (slowness of movement). These symptoms are similar to those seen in Parkinson’s disease.
Stage II	Hyperthermia and autonomic instability: In stage II, additional symptoms start to manifest, including high fever (hyperthermia) and autonomic instability. Autonomic instability refers to disruptions in the functioning of the autonomic nervous system, leading to irregularities in blood pressure, heart rate, and sweating.
Stage III	Altered mental status: Stage III is characterized by a significant alteration in mental status. Patients may experience confusion, disorientation, agitation, delirium, or even psychosis. This stage represents a more severe progression of NMS.
Stage IV	Generalized rigidity and myoclonus: In stage IV, the symptoms progress to generalized rigidity, where muscle stiffness affects the entire body. Myoclonus, which refers to sudden, involuntary muscle jerks or spasms, may also be present. This stage represents a critical point in the severity of NMS.
Stage V	Coma and autonomic dysregulation: Stage V represents the most severe form of NMS. Patients in this stage may experience a coma or a significantly altered level of consciousness. Autonomic dysregulation continues to be a prominent feature, with severe disruptions in blood pressure, heart rate, and other autonomic functions.

Treatment with lorazepam was initiated at a lower dose due to concern for airway protection following CXR findings. Once back to his baseline, lorazepam was titrated down until completely off. He was discharged and was advised to discontinue ziprasidone.

Conclusion

This case highlights the complexity of diagnosing ziprasidone-induced NMS. Second-generation antipsychotics can cause a milder presentation and patients may not develop the key features of NMS that are commonly present with FGA. Although milder, cases can become so severe that intensive care/critical care intervention may be warranted. Treatment recommendations and clinical evidence remain limited and vary depending on the severity of symptoms. Woodbury severity stage may be beneficial when deducing the initiation of benzodiazepine, dantrolene, or bromocriptine.