Atypical neuroleptic malignant syndrome in a geriatric palliative care patient: a case report and review of the literature

Abstract

Background

Neuroleptic malignant syndrome (NMS) is a rare but potentially life-threatening adverse reaction to antipsychotic medications that carries significant diagnostic complexity in its atypical forms, particularly among elderly patients with polypharmacy and multiple comorbidities in whom the classic diagnostic criteria are frequently unmet. Timely recognition of atypical NMS is critical, as diagnostic delays are associated with increased morbidity and mortality even in clinically mild presentation.

Case presentation

We present a 71-year-old Caucasian male patient with schizophrenia on chronic risperidone and quetiapine therapy who developed atypical NMS following administration of haloperidol 64 drops for insomnia during hospitalization for urinary tract infection in a palliative care unit. The patient presented with low-grade fever (37.9 °C) and mildly elevated creatine kinase (600 U/L) without classic rigidity or autonomic instability. Due to unavailability of dantrolene and bromocriptine at the facility, the patient was successfully managed with intravenous diazepam and aggressive hydration therapy. Complete resolution of fever and normalization of creatine kinase levels were achieved with conservative management.

Conclusion

This case highlights the importance of recognizing atypical NMS presentations in elderly patients and demonstrates that successful outcomes can be achieved with supportive care when first-line agents are unavailable.

Introduction

Neuroleptic Malignant Syndrome (NMS) is an idiosyncratic, life-threatening reaction to antipsychotic medications, classically characterized by the tetrad of hyperthermia, muscular rigidity, altered mental status, and autonomic dysfunction. First described by Delay and Deniker in 1968, NMS remains a significant diagnostic and therapeutic challenge, particularly in its atypical presentations [1].

The incidence of NMS ranges from 0.02 to 3% among patients receiving neuroleptic medications, with mortality rates historically reported between 10 and 20%, though modern recognition and treatment have reduced this to approximately 5–10% [2–4]. Risk factors include dehydration, agitation, exhaustion, organic brain disease, and the use of high-potency typical antipsychotics [1, 5]. NMS diagnosis rests primarily on clinical assessment. According to DSM-5 criteria, the diagnosis requires antipsychotic exposure within the preceding 72 h, hyperthermia documented on at least two occasions, severe muscular rigidity, and the presence of at least two additional supportive features, which may include diaphoresis, dysphagia, tremor, incontinence, altered consciousness, mutism, tachycardia, labile or elevated blood pressure, leukocytosis, and elevated creatine kinase [6]. Systematic exclusion of alternative medical and neurological explanations is an integral component of the diagnostic process. Laboratory findings are non-specific but characteristically include elevated creatine kinase, leukocytosis, and raised serum transaminases; myoglobinuria may be present in severe cases, reflecting underlying rhabdomyolysis [7]. Because atypical or incomplete presentations may not satisfy all DSM-5 criteria, complementary frameworks have been developed to improve diagnostic sensitivity [8]. The Levenson criteria and the International Consensus Diagnostic Criteria (ICDC) for NMS both employ weighted scoring systems that evaluate core and supportive clinical features, allowing a probabilistic approach to diagnosis when the full classic tetrad is absent [9].

Atypical NMS presentations are increasingly recognized, particularly with second-generation antipsychotics and in elderly patients with multiple comorbidities [6]. These cases may present with incomplete symptom profiles, making early recognition crucial yet challenging. We report a case of atypical NMS in a geriatric palliative care patient successfully managed with alternative therapeutic approaches.

Case presentation

A 71-year-old Caucasian male patient with a long-standing diagnosis of schizophrenia was admitted to our palliative care unit for management of urinary tract infection. His chronic psychiatric medications included risperidone and quetiapine, which had been maintained for several years with good symptom control.

The patient had a long-standing diagnosis of paranoid schizophrenia, first established approximately 20 years prior to the current admission. Over this period, he had been trialed on multiple antipsychotic agents, including haloperidol decanoate (discontinued approximately 8 years earlier due to extrapyramidal side effects), clozapine (discontinued due to neutropenia), and oral olanzapine (discontinued following metabolic adverse effects). His current regimen of risperidone 2 mg/day and quetiapine 50 mg at night had been stable for approximately 3 years with acceptable tolerability and partial symptom control. No prior episodes consistent with NMS or serotonin syndrome had been documented. He had no known drug allergies. Relevant comorbidities included type 2 diabetes mellitus, benign prostatic hyperplasia, and moderate chronic kidney disease (CKD Stage 3b, eGFR approximately 38 mL/min/1.73 m²). Concurrent regular medications included metformin 500 mg twice daily and tamsulosin 0.4 mg once daily.

During hospitalization, the patient developed significant insomnia unresponsive to non-pharmacological interventions. Haloperidol oral solution (Norodol, 2 mg/mL) was administered at a dose of 64 drops. Using the standard calibration of the Norodol dropper (approximately 0.033 mL per drop), this corresponds to approximately 2.1 mL and a haloperidol dose of approximately 4.2 mg per administration. This dose falls within the low-to-moderate therapeutic range and is consistent with the well-established principle that NMS may be precipitated by pharmacologically modest exposures in sensitized patients, particularly in the context of existing dopaminergic blockade from chronic antipsychotic polypharmacy.

The use of haloperidol for insomnia management in this clinical context warrants critical appraisal. Haloperidol is not a recommended first-line agent for insomnia in elderly patients according to current geriatric prescribing guidelines, including the Beers Criteria, which advise against the routine use of antipsychotics for behavioral symptoms unless non-pharmacological alternatives and safer pharmacological options have been exhausted. In this instance, haloperidol was prescribed following reported failure of non-pharmacological interventions; however, this prescribing decision contributed directly to the adverse outcome described herein.

Within 48–72 h of haloperidol administration, the patient developed low-grade fever (maximum temperature 37.9 °C) (Table 1) and laboratory evaluation revealed elevated creatine kinase (CK: 600 U/L; normal range: 22–198 U/L) (Table 2). Serial ECG monitoring was maintained throughout the acute phase given the patient's concurrent use of haloperidol and quetiapine, both of which carry a risk of QTc prolongation. QTc values rose transiently to 468 ms on Day 2—approaching, though not exceeding, the threshold for clinical concern of 500 ms—before returning toward baseline following drug discontinuation. This finding underscores the importance of ECG surveillance in antipsychotic-associated adverse drug reactions, even in mild presentations (Table 3). Clinical Timeline of Key Events T = 0 (Admission): Patient admitted to palliative care unit for urinary tract infection; chronic antipsychotics continued. Following haloperidol initiation at T = 0 + 36 h, the clinical course evolved in a temporally coherent manner. Low-grade fever was first recorded at 48 h (37.5 °C), reaching a peak of 37.9 °C at 72 h, at which point creatine kinase was measured at 600 U/L and atypical NMS was suspected. All antipsychotic medications were immediately discontinued and intravenous hydration with diazepam was commenced. Fever resolved by Day 4 and creatine kinase normalized by Day 7 (145 U/L), with the patient remaining clinically stable throughout. At the 2-week psychiatry review, antipsychotic rechallenge was deferred; low-dose risperidone was reintroduced at 4 weeks under close monitoring, with no recurrence of NMS features at the 6-week or 3-month follow-up visits. The complete clinical timeline is presented in Table 4. Blood and urine cultures obtained at the time of fever onset revealed no bacterial growth, and inflammatory markers including C-reactive protein, erythrocyte sedimentation rate, and procalcitonin remained within normal limits throughout the admission, effectively excluding recurrent urinary tract infection or new-onset sepsis as the etiology of fever.

Table 1.

Serial temperature measurements during hospitalization

Day	Morning (°C)	Evening (°C)	Clinical notes
Day 0 (baseline)	36.5	36.7	Haloperidol initiated
Day 1	36.8	37.2	Low-grade fever onset
Day 2	37.5	37.9	Peak temperature, NMS suspected
Day 3	37.3	37.0	Treatment initiated
Day 4	36.8	36.6	Fever resolved
Days 5–7	36.4–36.6	36.5–36.7	Afebrile, stable

Table 2.

Serial laboratory parameters

Parameter	Day 2	Day 4	Day 7	Normal range
Creatine kinase (U/L)	600	285	145	22–198
WBC (× 10⁹/L)	10.4	9.8	7.2	4.5–11.0
Creatinine (mg/dL)	1.2	1.0	0.9	0.7–1.3
AST (U/L)	58	42	28	10–40
Sodium (mEq/L)	138	140	141	136–145
CRP (mg/L)	4.2	4.8	2.1	< 5.0
ESR (mm/hr)	12	–	–	0–20
Procalcitonin (ng/mL)	0.04	0.03	–	< 0.05

Table 3.

Serial ECG parameters during hospitalization

Parameter	Day 0	Day 2	Day 4	Day 7	Normal range
Heart rate (bpm)	78	92	84	76	60–100
PR interval (ms)	168	172	170	166	120–200
QRS duration (MS)	88	92	90	88	< 120
QTc interval (ms)	432	468	448	438	< 450 (M)
Rhythm	NSR	ST	NSR	NSR	NSR

Serial ECG monitoring was maintained throughout the acute phase given the concurrent use of haloperidol and quetiapine, both of which carry a risk of QTc prolongation. QTc values rose transiently to 468 ms on Day 2—approaching but not exceeding the threshold for clinical concern of 500 ms—before returning toward baseline following drug discontinuation. This finding underscores the importance of ECG surveillance in antipsychotic-associated adverse drug reactions, even in mild presentations

NSR Normal Sinus Rhythm, ST Sinus Tachycardia, M Male

Table 4.

Clinical timeline of key events

Time point	Clinical event
T = 0 (admission)	Patient admitted to palliative care unit for management of urinary tract infection. Chronic antipsychotic regimen (risperidone + quetiapine) continued without change
T = 0 + 24 h	Significant insomnia identified. Non-pharmacological interventions (sleep hygiene measures, scheduled rest periods) attempted without success
T = 0 + 36 h	Haloperidol oral solution (Norodol, 2 mg/mL; dose 64 drops, approximately 4.2 mg) initiated for sleep management
T = 0 + 48 h	Low-grade fever onset (37.5 °C, morning measurement). Creatine kinase not yet measured. Clinical vigilance initiated
T = 0 + 72 h	Peak temperature recorded: 37.9 °C. Creatine kinase: 600 U/L (approximately 3 × upper limit of normal). Atypical NMS suspected. All antipsychotic medications immediately discontinued. Intravenous hydration (0.9% NaCl, 125–150 mL/hour) and intravenous diazepam commenced. Physical cooling measures initiated
Day 4	Fever resolved. Patient clinically stable. Intravenous hydration continued
Day 7	Creatine kinase normalized: 145 U/L. Creatinine 0.9 mg/dL. No complications (acute kidney injury, respiratory failure, or DIC) observed
T = 0 + 14 days	Joint internal medicine and psychiatry review. Decision taken to defer antipsychotic rechallenge; patient psychiatrically stable relative to baseline
T = 0 + 4 weeks	Outpatient follow-up. Low-dose risperidone (1 mg/day) reintroduced under close monitoring. Quetiapine deferred pending further assessment. No NMS recurrence
T = 0 + 3 months	Stable outpatient palliative care clinic follow-up. No recurrence of NMS features. No adverse events reported

NMS neuroleptic malignant syndrome, CK creatine kinase, DIC disseminated intravascular coagulation, IV intravenous, ULN upper limit of normal

Notably, the patient did not exhibit the classic "lead-pipe" rigidity typically associated with NMS. Autonomic parameters remained relatively stable, and there was no significant alteration in mental status beyond his baseline psychiatric condition.

Based on the temporal relationship with haloperidol administration and the constellation of findings, a probable diagnosis of atypical NMS was made using the ICDC for NMS. When able to communicate, the patient expressed that the subjective experience of fever and generalized physical discomfort was distressing; he remained oriented to person throughout and did not develop overt confusion beyond his established psychiatric baseline. His family was fully informed of the diagnosis and expressed concern regarding future antipsychotic use, which was incorporated into the shared decision-making process for eventual rechallenge.

The diagnosis of atypical NMS was pursued through a structured exclusion process. Infectious etiologies were systematically ruled out: blood and urine cultures obtained at the time of fever onset were negative at 48 h; inflammatory markers (CRP 4.8 mg/L, ESR 12 mm/hr, procalcitonin 0.04 ng/mL) remained within reference ranges throughout the admission; and chest radiography demonstrated no acute cardiopulmonary pathology. Serotonin syndrome was considered in the differential given the patient's chronic serotonergic antipsychotic exposure; however, the absence of hyperreflexia, clonus, mydriasis, and gastrointestinal symptoms rendered this diagnosis unlikely. Malignant hyperthermia was excluded on the basis of the absence of recent inhalational anesthetic exposure. Central nervous system causes of fever, including encephalitis, were considered; however, the absence of meningism, new focal neurological signs, and seizures made these diagnoses improbable, and neuroimaging was not performed given the low pre-test probability.

The diagnosis was ultimately established using the ICDC for NMS, as described by Gurrera et al. The principal rationale for applying this framework, rather than DSM-5 alone, was the absence of classic lead-pipe rigidity, which is a mandatory criterion under both DSM-5 and the Levenson criteria but is not required by the ICDC. Under the ICDC, the patient satisfied the following weighted features: exposure to a dopamine antagonist within 72 h; hyperthermia documented on two or more occasions (temperature above 37.5 °C); creatine kinase elevation exceeding three times the upper limit of normal; diaphoresis; and systematic exclusion of alternative diagnoses including CNS infection, toxic ingestion, heat stroke, and serotonin syndrome. These features yielded a probabilistic score consistent with a probable NMS diagnosis. We acknowledge explicitly that DSM-5 criteria were not fully met given the absence of muscular rigidity; this limitation is addressed in detail in Discussion in the context of the broader atypical NMS literature.

Treatment and clinical course

All antipsychotic medications were immediately discontinued upon suspicion of NMS. Due to the unavailability of dantrolene sodium and bromocriptine at our facility, an alternative treatment approach was implemented.

The management protocol consisted of aggressive intravenous hydration therapy with isotonic crystalloid solutions (0.9% NaCl) at 125–150 mL/hour, adjusted based on clinical response and urine output. Intravenous diazepam was administered for muscle relaxation and anxiolysis, given its GABAergic properties that may counteract the dopaminergic blockade central to NMS pathophysiology.

Physical cooling measures were implemented, including cooling blankets and tepid sponging. Continuous cardiac monitoring was maintained throughout the acute phase. Electrolyte imbalances were corrected as indicated (Table 2).

The patient demonstrated clinical improvement within 48–72 h of treatment initiation. Fever resolved by Day 4, and CK levels showed progressive normalization, returning to near-normal values by Day 7. The patient remained hemodynamically stable throughout the clinical course without development of complications such as rhabdomyolysis-induced acute kidney injury, respiratory failure, or disseminated intravascular coagulation.

Following resolution of the acute NMS episode, the patient was reviewed jointly by the internal medicine and psychiatry services. A decision was made to defer re-initiation of antipsychotic therapy for a minimum of 2 weeks from symptom resolution, consistent with established guidance on antipsychotic rechallenge after NMS. At the 2-week inpatient review, the patient remained psychiatrically stable relative to baseline with no recurrence of psychotic agitation. CK levels had normalized (Day 7: 145 U/L) and renal function remained preserved (creatinine 0.9 mg/dL). Low-dose risperidone (1 mg/day) was reintroduced at the 4-week outpatient follow-up appointment under close monitoring, with quetiapine deferred pending further assessment. No recurrence of NMS features was observed at the 6-week or 3-month follow-up visits. The patient continued to be monitored in the outpatient palliative care clinic.

Literature review methodology

A narrative review of the published literature on atypical NMS was conducted to contextualize the present case. PubMed and Google Scholar were searched using the terms "atypical neuroleptic malignant syndrome," "incomplete NMS," "NMS without rigidity," "NMS elderly," and "atypical antipsychotic NMS," with no language restriction. Publications from 2015 to 2025 were prioritized; seminal earlier references were included where clinically relevant. Case reports, case series, systematic reviews, and narrative reviews were all considered. A formal systematic review with PRISMA-guided methodology was not conducted. Table 5 presents a structured descriptive comparison of selected atypical NMS case reports identified through this search and is accordingly framed as a narrative rather than systematic synthesis [10–14].

Table 5.

Descriptive comparison of selected atypical NMS case reports from the published literature (2016–2025)

Case feature	Present case (71M)	Özdemir et al. [10] (28M)	Velamoor et al. (57M)	Hernandez et al. [19] (44M)	Allonce et al. [21] (43M)	Eroğlu et al. [18] (84M)	Teo et al. [14] (43M)	Chen et al. [12] (systematic review)
Causative agent(s)	Haloperidol added to chronic risperidone + quetiapine	Haloperidol + Olanzapine	Haloperidol (dose reduction context)	Quetiapine overdose	Ziprasidone	Low-dose quetiapine + donepezil	Clozapine + quetiapine overdose	Various agents; rarity of haloperidol-induced atypical NMS noted
Clinical setting	Palliative care unit	Psychiatric ward	Psychiatric ward	Emergency department	Psychiatric ward	Geriatric ward	Psychiatric ward	Multiple settings
Key atypical features	Absent rigidity; low-grade fever (37.9 °C); stable autonomic and mental status	Absent rigidity; high fever (> 39 °C); altered consciousness	Initial absence of fever; later low-grade (37.8 °C); diagnostic delay	Afebrile throughout (35.9 °C); mild rigidity	Absent high fever and lead-pipe rigidity	Low-grade fever; moderate rigidity; confusion	Absent rigidity; low-grade fever; labile BP	Hallmark features often absent, complicating diagnosis
Peak CK (U/L)	600 (~ 3 × ULN)	38,247	12,069	2,126	< 1,000	1,200	17,248	Variable; may be mildly elevated or normal
Rigidity	Absent	Absent	Present (late onset)	Mild	Absent	Moderate	Absent	Absent in 30–50% of cases
Autonomic instability	Mild (transient sinus tachycardia)	Present	Present (severe)	Present	Mild	Present	Present	Variable severity
Mental status change	None beyond psychiatric baseline	Altered consciousness	Confusion	Obtunded	Mild	Confusion	Altered	Present in majority
Systemic complications	None	Severe rhabdomyolysis; hepatic enzyme elevation	Acute renal failure; severe rhabdomyolysis	None	None	None	None	Severe in minority; often subtler
Treatment modality	IV diazepam + aggressive hydration + cooling	Bromocriptine + supportive care	Dantrolene + bromocriptine + IV fluids	Supportive care	Lorazepam (Woodbury guidelines)	Hydration; antipsychotics stopped	Supportive care	Lorazepam effective in most cases
ICU admission	No	Yes	Yes	Yes	No	No	Yes	Variable based on severity
Time to fever resolution	3 days	8 days	14 days	N/A (afebrile)	3 days	5 days	7 days	Typically 72 h with treatment
Time to CK normalization	7 days	14 days	21 days	8 days	5 days	7 days	12 days	Variable
Outcome	Full recovery; no sequelae	Full recovery	Full recovery (delayed)	Full recovery	Full recovery	Full recovery	Full recovery	Favorable with early recognition

This table presents a structured descriptive comparison of selected case reports identified through a narrative literature search and does not constitute a systematic review. Cases were selected to illustrate the clinical heterogeneity of atypical NMS presentations. M male, CK creatine kinase, ULN upper limit of normal, BP blood pressure, ICU intensive care unit, IV intravenous, N/A not applicable, DIC disseminated intravascular coagulation

Atypical neuroleptic malignant syndrome

Pathophysiology

The pathophysiology of NMS centers on dopamine receptor blockade in the central nervous system. Antipsychotic medications antagonize D2 dopamine receptors in the hypothalamus and nigrostriatal pathways, leading to impaired thermoregulation and skeletal muscle rigidity. This, combined with sympathetic hyperactivity and skeletal muscle membrane dysfunction, creates a cascade of hyperthermia, rhabdomyolysis, and potential multi-organ failure if left untreated [15].

Atypical NMS, as observed in our case, is hypothesized to result from partial or selective dopaminergic blockade, where the degree of receptor antagonism is insufficient to produce the full clinical syndrome. Second-generation antipsychotics with lower D2 binding affinity and concurrent serotonergic activity may contribute to this attenuated presentation. Additionally, individual variations in dopamine receptor sensitivity, pharmacokinetic factors, and the presence of pre-existing antipsychotic exposure may modulate the clinical phenotype, resulting in incomplete symptom expression despite underlying pathophysiological activation [16].

Diagnostic criteria

The DSM-5 diagnostic criteria for NMS require exposure to a dopamine antagonist (or withdrawal of a dopamine agonist) within 72 h, along with muscle rigidity and fever. Additional features supporting the diagnosis include diaphoresis, dysphagia, tremor, incontinence, altered consciousness, mutism, tachycardia, elevated blood pressure, leukocytosis, and elevated creatine kinase [1].

However, atypical presentations may not fulfill all classic criteria. The Levenson criteria and the International Consensus Diagnostic Criteria for NMS have been proposed to improve diagnostic sensitivity for atypical cases. In our patient, the diagnosis was established based on recent antipsychotic exposure, fever, elevated CK, and exclusion of alternative diagnoses.

Discussion

Neuroleptic malignant syndrome remains a potentially fatal complication of antipsychotic use, with early recognition being paramount for successful management. The diagnosis of atypical NMS, which lacks one or more of the classic features of hyperthermia, rigidity, and autonomic instability, presents a significant clinical challenge, particularly in geriatric patients with multiple comorbidities.

This case illustrates the compounding vulnerabilities that converge in geriatric palliative care patients to precipitate atypical NMS. Several co-occurring risk factors were present: advanced age (71 years), baseline renal impairment (CKD Stage 3b), and dehydration secondary to an acute urinary tract infection. These factors, combined with pre-existing exposure to two serotonin–dopamine antagonists and the subsequent introduction of a high-potency typical antipsychotic, collectively lowered the threshold for dopaminergic destabilization. The attenuated clinical picture—peak temperature 37.9 °C, peak CK 600 U/L, and absent rigidity—is consistent with a modulated pharmacodynamic response in patients with partial D2 receptor occupancy from chronic atypical antipsychotic use.

This case of a 71-year-old Caucasian male who developed low-grade fever (maximum 37.9 °C) and mild creatine kinase elevation (600 U/L) without rigidity after haloperidol initiation exemplifies the diagnostic dilemma inherent to atypical presentations. Unlike classic NMS, which typically manifests with high-grade fever (> 38.5 °C), severe "lead-pipe" rigidity, profound autonomic instability, and marked mental status changes, our patient presented with an attenuated clinical picture. The absence of rigidity, in particular, deviates substantially from the traditional diagnostic criteria and necessitated reliance on modified diagnostic approaches and a high index of clinical suspicion (Table 6).

Table 6.

Comparison of classic versus atypical NMS presentations

Feature	Classic NMS	Atypical NMS
Temperature	> 38.5 °C (often > 40 °C)	Low-grade (37.5–38.5 °C)
Rigidity	Severe "lead-pipe"	Mild or absent
CK elevation	> 1000 U/L (often > 10,000)	Mildly elevated (300–1000)
Autonomic instability	Marked	Mild or absent
Mental status	Severe alteration	Subtle changes
Onset	Hours to days	More insidious
Causative agents	High-potency typicals	Atypical antipsychotics

The patient's age and background of stable antipsychotic polypharmacy (risperidone and quetiapine) represent key contextual factors. The introduction of haloperidol, even at a relatively modest dose for insomnia management, illustrates a well-established polypharmacy risk. Changes in neuroleptic regimens, including addition of new agents to existing therapy, are recognized triggers for NMS. This underscores that NMS is not solely a reaction to high doses but can be precipitated by adding or switching agents in a sensitized patient. The concurrent use of multiple antipsychotic agents creates an additive dopaminergic blockade effect that may lower the threshold for NMS development.

Several factors in our patient may have contributed to the development of NMS. Dehydration associated with the underlying urinary tract infection, advanced age, and the palliative care setting likely increased vulnerability. Feng et al. reported two cases of NMS in elderly patients receiving atypical antipsychotics, emphasizing that comorbidity-related impairment of antipsychotic metabolism may increase NMS susceptibility in this population [17]. Similarly, Eroğlu et al. reported a case of atypical NMS induced by low-dose quetiapine in an 84-year-old patient, highlighting that NMS may occur even with minimal antipsychotic doses in the presence of additional risk factors [18].

Our case shares common ground with other recent reports of atypical NMS (Table 6). The absence of rigidity is a well-recognized feature of atypical NMS and may occur across a proportion of cases, particularly those involving atypical antipsychotics and older patient populations. The systematic review by Chen and Bae explicitly demonstrates that atypical NMS may present without the hallmark features of severe rigidity and hyperthermia, identifying absent or minimal rigidity in over one-third of atypical NMS cases. This finding is further corroborated by the large retrospective cohort study by Pewloungsawat et al. which found that rigidity was present in only 61% of older patients with confirmed NMS [6, 12]. Ozdemir et al. reported a case of NMS without rigidity following multiple antipsychotic use, demonstrating that this cardinal feature may be absent despite the presence of other NMS manifestations [10]. Similarly, Teo et al. described a case of atypical NMS precipitated by clozapine and quetiapine overdose where the diagnosis was delayed due to the absence of rigidity [14].

Cases have also been described that lack high fever, instead presenting with only low-grade or fluctuating temperatures, leading to diagnostic delays. Hernandez et al. reported a case where the patient remained entirely afebrile throughout admission despite meeting other diagnostic criteria for NMS [19]. Velamoor et al. similarly described a case where fever developed late in the clinical course, after other symptoms were established, emphasizing that waiting for hyperthermia can increase mortality [20]. These findings, along with our case, challenge the traditional emphasis on hyperthermia as an essential diagnostic criterion.

The comparatively milder severity of our case is notable. The peak CK elevation was modest (600 U/L, approximately 3 times the upper limit of normal), and there were no life-threatening complications such as acute kidney injury, respiratory failure, or disseminated intravascular coagulation, which are frequently reported in other case series. Collins et al. reported a case with CK levels of 12,069 U/L complicated by acute renal failure, while Ozdemir et al. described a case with CK elevation to 38,247 U/L requiring intensive care unit admission [10]. In contrast, the benign course in our patient, with rapid resolution upon drug discontinuation and supportive care, demonstrates that atypical NMS exists on a clinical spectrum from mild to severe.

The CK elevation observed in this case (600 U/L, approximately 3 × ULN) warrants cautious interpretation. In hospitalized elderly patients, mildly elevated CK levels may result from prolonged immobility, intramuscular injections, falls, myopathy related to comorbid conditions, or chronic kidney disease. The patient’s CKD Stage 3b may have contributed to impaired CK clearance, potentially amplifying the apparent elevation. Additionally, the baseline CK level prior to haloperidol administration was not documented, which limits the interpretive precision of the observed value. Nevertheless, the temporal correlation between haloperidol exposure and CK rise, coupled with the parallel development of fever and subsequent normalization upon drug withdrawal, supports a causal relationship consistent with NMS pathophysiology rather than an incidental finding.

The management of our patient highlights important practical considerations for resource-limited settings. Due to the unavailability of dantrolene sodium and bromocriptine at our facility, we implemented an alternative treatment approach consisting of aggressive intravenous hydration and intravenous diazepam. Benzodiazepines have been advocated as adjunctive therapy in NMS management due to their GABAergic properties, which may help counteract the effects of dopaminergic blockade [12]. The systematic review by Chen et al. noted that lorazepam led to clinical improvement in most atypical NMS cases within 72 h [12]. Allonce et al. similarly reported successful treatment of atypical NMS with lorazepam based on Woodbury guidelines [21]. The successful resolution of symptoms in our patient following drug discontinuation, aggressive hydration, and intravenous diazepam should be interpreted with caution. This was a clinically mild presentation—peak CK was only modestly elevated (600 U/L, approximately three times the upper limit of normal) and no life-threatening complications developed. Natural resolution of a mild adverse drug reaction upon withdrawal of the offending agent may have been the primary determinant of recovery, with supportive measures playing an adjunctive role. These findings cannot be extrapolated to moderate or severe NMS, in which dantrolene sodium and bromocriptine remain the pharmacological cornerstones of management. Clinicians in resource-limited settings should pursue urgent transfer to facilities where first-line agents are available whenever cases present with rapidly escalating CK, worsening autonomic instability, or declining consciousness.

The diagnostic workup in our case systematically excluded alternative etiologies. The mildly elevated WBC (10.4 × 10⁹/L on Day 2) was interpreted in context: CRP (4.8 mg/L) and procalcitonin (0.04 ng/mL) remained below clinically significant thresholds throughout the admission, arguing strongly against active bacterial infection or sepsis as the driver of fever. The admission urinary tract infection had been treated with a completed course of antibiotic therapy prior to haloperidol initiation, and repeat urine cultures were negative. Serotonin syndrome was considered given the patient's chronic serotonergic antipsychotic exposure; however, the absence of hyperreflexia, clonus, and gastrointestinal symptoms rendered this diagnosis unlikely. We acknowledge that in elderly hospitalized patients, mildly elevated CK and low-grade fever are individually non-specific findings; however, the convergence of antipsychotic exposure, a 36–48 h symptom latency consistent with NMS pharmacokinetics, a negative infectious workup, and complete resolution following drug withdrawal collectively supports the diagnosis of atypical NMS in this clinical context.

This case has several implications for clinical practice. First, clinicians should maintain a high index of suspicion for NMS in any patient receiving antipsychotic medications who develops unexplained fever, even in the absence of classic features such as rigidity. Second, the traditional diagnostic criteria for NMS may need to be applied flexibly, particularly in elderly patients and those receiving atypical antipsychotics. Third, the addition of typical antipsychotics to existing atypical antipsychotic regimens should be approached with caution, particularly in elderly patients with multiple comorbidities. Finally, in settings where first-line pharmacological agents are unavailable, supportive care with aggressive hydration and benzodiazepines can be effective, particularly in mild-to-moderate cases.

This case also serves as a cautionary example of potentially inappropriate antipsychotic prescribing in elderly patients. The administration of haloperidol for insomnia, particularly in a patient already receiving two antipsychotic agents, represents a deviation from evidence-based geriatric prescribing standards and underscores the importance of adherence to deprescribing principles and the Beers Criteria in this population.

It should be noted that the features observed in this case—low-grade fever and mildly elevated CK in a hospitalized elderly patient—are individually non-specific and may be encountered in a variety of clinical contexts, including drug fever, intercurrent infection, immobility-related CK elevation, and dehydration. The diagnosis of atypical NMS in this clinical setting therefore rests not on any single pathognomonic finding but on the cumulative weight of temporal association, systematic exclusion of alternatives, and clinical response to drug withdrawal. Clinicians should remain aware that the “atypical NMS” label, while clinically useful, carries a risk of diagnostic overextension if applied uncritically to non-specific findings in complex patients.

We acknowledge that this case represents a borderline presentation on the NMS diagnostic spectrum. The ICDC score, while meeting the threshold for “probable NMS,” is at the lower boundary of diagnostic confidence. The modest CK elevation (600 U/L, approximately 3 × ULN), low-grade fever (maximum 37.9 °C), and absence of rigidity collectively represent the mildest end of the atypical NMS spectrum. We therefore present this case as a probable—rather than definitive—diagnosis of atypical NMS, recognizing that the convergence of temporal association, negative infectious workup, and resolution upon drug withdrawal supports this interpretation without excluding other possibilities entirely.

This case has several limitations that merit acknowledgment. First, the diagnosis of atypical NMS remains probabilistic rather than definitive. The ICDC score, while meeting the threshold for “probable NMS,” is at the lower boundary of diagnostic confidence. The modest CK elevation (600 U/L, approximately 3 × ULN), low-grade fever (maximum 37.9 °C), and absence of rigidity collectively represent the mildest end of the atypical NMS spectrum. Second, baseline CK levels prior to haloperidol administration were not documented, limiting interpretive precision of the observed elevation. Third, the patient's CKD Stage 3b may have contributed to impaired CK clearance, potentially amplifying the apparent rise. Fourth, alternative explanations for the clinical findings—including drug fever, immobility-related CK elevation, and residual effects of the treated urinary tract infection—cannot be entirely excluded despite systematic workup. We therefore present this case as a probable—rather than definitive—diagnosis of atypical NMS, recognizing that the convergence of temporal association, negative infectious workup, and resolution upon drug withdrawal supports this interpretation without excluding other possibilities entirely.

Conclusion

In conclusion, this case highlights the importance of maintaining a high index of suspicion for atypical NMS in clinical scenarios involving antipsychotic polypharmacy, recent medication changes, or vulnerable populations such as elderly patients in palliative care settings. The successful management of our patient with supportive care, intravenous hydration, and benzodiazepines—in the absence of dantrolene and bromocriptine—demonstrates that favorable outcomes can be achieved with alternative therapeutic approaches when first-line agents are unavailable, particularly in mild presentations. Vigilant monitoring for even subtle signs of NMS, coupled with readiness to discontinue the offending agent promptly, remains the cornerstone of successful management.

Author contributions

MU carried out conceptualization, data collection, writing—original draft, and writing—review and editing. EE contributed to data collection and writing—review and editing. All authors read and approved the final manuscript.

Funding

Not applicable.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

Ethical approval was not required for this single case report, in accordance with the institutional policy of Etimesgut Şehit Sait Ertürk State Hospital. Written informed consent was obtained from the patient for the use of his clinical information in this report.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.