Neuroleptic malignant syndrome in Huntington disease

Abstract

Background and Purpose

Despite the wide use of dopamine receptor blocking agents (DRBAs) in Huntington disease (HD), neuroleptic malignant syndrome (NMS) is rarely described in this population. The aim of this study was to assess NMS prevalence in a large cohort of HD patients and explore the main associated risk factors.

Methods

In 2023, an HD patient was admitted to our neurology department due to NMS. Starting from the case description, we performed a narrative review of the literature of NMS cases in HD, reviewed data from the fifth dataset of the Enroll‐HD (a longitudinal, observational, global study of families with HD) study (PDS5) selecting HD patients treated with DRBAs and/or tetrabenazine (TBZ) who presented at least one of the core symptoms of NMS (rigidity and hyperthermia), and collected data to investigate prevalence of NMS and identify risk factors.

Results

In the Enroll‐HD PDS5 dataset, we identified 5108 of 11,569 HD patients who were undergoing DRBA and/or TBZ treatment. Only one patient, a Caucasian man of 46 years, undergoing clozapine and valproate treatment, had a registered diagnosis of NMS.

Conclusions

NMS in HD patients is seldom described. This could be due to an underestimation of this condition. There are no available objective NMS diagnostic criteria at present, and the existence of atypical forms of NMS further complicates diagnosis. Advanced disease stage, rigid–akinetic phenotype, abrupt therapy changes, polytherapy, and dehydration are key risk factors, most of which are preventable through awareness and caution in managing medications in the HD population.

INTRODUCTION

Huntington disease (HD) is the most frequent neurodegenerative chorea in adults, caused by an autosomal dominant inherited CAG trinucleotide expansion in the gene HTT (Online Mendelian Inheritance in Man: 613004) that encodes for the huntingtin protein on chromosome 4. HD is characterized by striatal degeneration that leads to thalamocortical hyperactivation due to an imbalance in the dopaminergic striatal pathway [1]. Additionally, in HD early hypothalamic degeneration occurs, as shown by postmortem studies [2, 3, 4] and neuroimaging studies through brain magnetic resonance imaging, which revealed gray matter density loss in the hypothalamus occurring up to 1 decade before clinical diagnosis [5, 6]. Through positron emission tomography studies, using a D2–D3 receptor‐specific tracer and a marker of microglial activation, Politis et al. [7] demonstrated the downregulation of D2 and/or D3 receptors in the hypothalamus. These findings partly explain the dysautonomic symptoms (e.g., thermoregulatory defect) along with dysregulation of wake–sleep cycle, increased thirst and hunger, progressive weight loss, and endocrine dysfunction [6, 8, 9].

Neuroleptic malignant syndrome (NMS) is characterized by central hyperthermia, muscle rigidity, autonomic nervous system instability, and changes in mental status [10]. The most used diagnostic criteria for NMS are outlined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DMS‐5; Table 1). Disrupted dopamine transmission is pivotal in the pathogenesis of NMS. Dopamine depletion in the tuberoinfundibular pathway causes body temperature dysregulation, and its effect on the nigrostriatal system results in rigidity; alterations in the mesocortical circuit impact mental status. The circuits are not always involved at the same degree, and NMS may have atypical presentations (more frequently caused by second‐generation antipsychotics) without hyperthermia or rigidity [11].

TABLE 1.

Diagnostic criteria for neuroleptic malignant syndrome based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.

1. Major symptoms Exposure to dopamine‐blocking agent, or dopamine agonist withdrawal within 72 h Muscle rigidity Hyperthermia (body temperature >38°C, measured minimum 2 times orally)

2. Minor symptoms Tachycardia Diaphoresis Incontinence Elevated or labile blood pressure Altered levels of consciousness Tremor Dysphagia Mutism Leukocytosis Elevated creatinine phosphokinase (>4 times)

3. Exclusion criteria Negative workup for infectious, toxic, metabolic, and neurological causes

Dopamine receptor blocking agents (DRBAs) and tetrabenazine (TBZ) are commonly used in treating hyperkinetic movement disorders, including HD [12, 13]. NMS is a rare side effect of DRBAs, but other compounds affecting dopaminergic transmission such as TBZ have also been linked to this condition [14, 15, 16]. It remains uncertain whether the risk of developing NMS in patients with HD is higher compared to the general population [14]. The aim of this study was to explore the prevalence of NMS in a large cohort of HD patients and describe its clinical characteristics and associated risk factors in cases reported in the literature and in our case report.

CASE REPORT

We present the case of a 45‐year‐old woman (Table 2), who developed the first symptoms of HD by the age of 29 years. The symptom onset consisted of gait disturbances and frequent falls. In the course of the disease, she presented rigidity, bradykinesia, involuntary movements, and psychiatric disturbances (bipolar disorder). She progressively developed severe dystonia, insomnia, cognitive decline, and dysphagia. The clinical diagnosis of HD, Westphal variant, was confirmed genetically at the age of 41 years. She was initially treated with quetiapine 25 mg once daily (qd). From 2022, she was treated with valproic acid 200 mg twice daily (bid), olanzapine 5 mg bid, quetiapine 50 mg qd, and zolpidem 10 mg qd. At home, the patient was not autonomous in daily activities; she was unable to walk, her movements were limited to a few steps from the bed to the chair with assistance, and her speech was unintelligible. She suffered from insomnia and agitation.

TABLE 2.

Patient data from the literature review and our case report.

Publication	Age, years/Sex	Disease onset (years)	HD clinical features	Therapy at baseline	Medication at NMS onset (days)	NMS clinical features				CPK, IU/L	Outcome
						Hyperthermia	Rigidity	Mental status	Autonomic sign
Burke 1981	33/M	27–classic variant	Chorea, mild cognitive decline	TBZ, alpha methyltyrosine	Long period of TBZ (210)	Yes	No	Delirium	Diaphoresis	3375	Recovered
Mateo 1992	53/F	39–classic variant	Chorea, severe cognitive decline, bedridden	Haloperidol	Withdrawal of haloperidol, starting TBZ (21)	Yes	Yes	Altered level of consciousness	Tachycardia, diaphoresis	1804–2850	Recovered
Ossemann 1996	52/M	44–classic variant	Chorea, severe cognitive decline, dehydration, bedridden	TBZ, clonazepam	Increase of TBZ (14)	Yes	Yes	Not reported	Not reported	3108–42,350	Death: bacterial pneumonia
Gaasbeek 2004	33/M	16–Westphal variant	Rigidity, dysphagia, weight loss, depression, dehydration	Clozapine	Withdrawal of clozapine, starting fluoxetine (14)	Yes	Yes	Visual hallucinations	Not reported	7072	Death: acute intestinal obstruction
	34/M	16–Westphal variant	Rigidity, hypokinesia, cognitive decline, depression, dehydration	Fluoxetine	Withdrawal of fluoxetine, starting pimozide (17)	Yes	Yes	Not reported	Tachycardia, diaphoresis	14,400	Recovered
	30/M	17–classic variant	Chorea, dysarthria, cognitive decline, dehydration	TBZ, benzodiazepine	Increase TBZ (17)	Yes	No	Agitation	Tachycardia, diaphoresis	14,000	Recovered
	45/F	31–classic variant	Chorea, mute, totally dependent, dehydration, bedridden	TBZ, haloperidol, clorazepate	Withdrawal TBZ, increase haloperidol (4)	Yes	No	Agitation	Tachycardia, diaphoresis	2779	Recovered
Gahr 2010	55/M	45–classic variant	Chorea, dysarthria, weight loss, moderate cognitive decline, behavior disorders	Risperidone, sertraline, tiapride, trimipramine, melperone	Withdrawal of risperidone, starting aripiprazole (2)	Yes	Yes	Not reported	Tachycardia, tachypnea	33,980	Recovered
Moreno 2012	43/M	30–classic variant	Rigidity, bradykinesia, chorea, psychiatric symptoms	Olanzapine, diazepam, escitalopram	Reducing olanzapine (90)	Yes	Yes	Not reported	Tachycardia, diaphoresis	2742	Recovered
Nozaki 2014	81/F	69–classic variant	Chorea, explosive speech, cognitive decline	Tiapride	Starting TBZ (36)	Yes	Yes	Altered level of consciousness	Tachycardia, urinary incontinence, tachypnea	999	Recovered
Our case	45/F	29–Westphal variant	Rigidity, bradykinesia, chorea, dysphagia, bipolar disorder, cognitive decline, dehydration, bedridden	Olanzapine, quetiapine, valproic acid, zolpidem	Withdrawal of quetiapine, starting haloperidol (after hours)	Yes	Yes	Altered level of consciousness	Diaphoresis, tachypnea, tachycardia	>11,000	Recovered

Abbreviations: CPK, creatinine phosphokinase; F, female; HD, Huntington disease; M, male; NMS, neuroleptic malignant syndrome; TBZ, tetrabenazine.

After an occasional administration of five drops of haloperidol 2 mg/mL for psychomotor agitation, she developed fever up to 40°C, severe muscle stiffness, profuse diaphoresis, tachypnea (up to 35 breaths per minute), tachycardia (100 beats per minute), and stupor within a few hours. After initial stabilization, alternative causes of acute change in mental status with generalized hypertonia and hyperthermia were considered. Chest radiograph and abdominal ultrasound imaging showed no signs of infection. Blood, urine, and cerebrospinal fluid cultures were normal. Brain computed tomography was unremarkable. Thus, infections and parenchymal brain abnormalities were ruled out. Laboratory tests showed elevated creatine phosphokinase (CPK; up to 11,000 IU/L), lactate dehydrogenase (821 IU/L), alanine aminotransferase (224 IU/L), and aspartate aminotransferase (133 IU/L). It is relevant to note that, in the week prior to the hospitalization, the patient was treated with antibiotics for influenzalike symptoms and diarrhea; the infectious state, and dehydration, due to dysphagia and diarrhea, were probably the precipitating factors of NMS. Neuroleptic drugs were discontinued and intravenous (IV) diazepam (10 mg three times daily), IV dantrolene sodium (150 mg/day for 10 days), and high‐volume IV fluids were administered. Fever regressed and muscle rigidity improved in 1 week. In 3 weeks, CPK levels dropped to the normal value. During hospitalization, the patient manifested frequent episodes of psychomotor agitation and insomnia, managed by gradual introduction of clonazepam, zopiclone, phenobarbital, and quetiapine (the latter reintroduced after 15 days since discontinuation). Hospitalization lasted approximately 1 month, during which she underwent surgery for percutaneous gastrostomy due to dysphagia and the resulting risk of aspiration. At discharge, the patient was transferred to a nursing home.

MATERIALS AND METHODS

This paper encompasses a narrative review of the literature and the retrospective study of the data from the fifth dataset of the Enroll‐HD study (PDS5). We described the clinical presentation and potential risk factors of NMS in HD patients through a case report and through a narrative review of the literature (Table 2). For the publication of the clinical case, we received approval from the caregiver. Furthermore, we explored the prevalence of NMS in a large cohort of HD patients reported in the Enroll‐HD registry. The literature review was conducted by two authors (A.F. and B.R.), under supervision of a senior neurologist (M.P.). The search was performed on PubMed and Embase using the keywords “Huntington's disease,” “neuroleptic malignant syndrome,” “malignant hyperthermia/hyperpyrexia,” and “tetrabenazine AND neuroleptic malignant syndrome.” We included patients who satisfied the following criteria: (i) genetically confirmed diagnosis of HD; (ii) ongoing DRBA and/or TBZ treatment at the time of NMS onset; (iii) presented with hyperthermia and/or rigidity, which represent the cardinal features of NMS according to DMS‐5, thus including both typical and atypical forms. We reviewed six case reports and one case series [14, 17, 18, 19, 20, 21, 22], identifying 10 patients for whom we collected demographic and clinical data.

We investigated NMS prevalence in HD patients through the collection of data generously provided by the participants in the Enroll‐HD study (https://www.enroll‐hd.org), version PDS5 (periodic dataset 5). Enroll‐HD is a global, multicenter clinical research platform funded by the CHDI Foundation, where data are collected annually from all research participants as part of a longitudinal observational study, including manifest and premanifest HD gene carriers, genetically negative subjects, and family controls. Data are monitored for quality and accuracy using a risk‐based monitoring approach. This study did not require institutional review board (IRB) approval because it utilized precollected, deidentified data from the Enroll‐HD database. Each study site that collected data received its own approval for the study from the local or national coordinator site IRB, and all participants, or their authorized representatives in the case of inability, gave their written informed consent for participation in the study and the distribution of deidentified data for research purposes. Dataset access can be requested by qualified researchers at https://enroll‐hd.org/for‐researchers. Participants enrolled into the study attend a yearly assessment of motor, cognitive, functional, and psychiatric conditions, in addition to comorbidity and pharmacological/nonpharmacological treatment updates. Reportable events are also registered, but only suicide attempts, completed suicide, mental health events requiring hospitalization, and death are systematically captured in Enroll‐HD [23]. The data contained in Enroll‐HD PDS5 was extracted from the Enroll‐HD electronic data capture database on 31 October 2020. It contains data on 21,116 Enroll‐HD participants from 55,975 Enroll‐HD visits (baseline and follow‐up from July 2012 to October 2020). Most participants in Enroll‐HD PDS5 are diagnosed with HD (10,947 at baseline and 11,569 at last follow‐up), but others are subjects carrying HD gene expansion not yet HD symptomatic. The database also includes HD‐negative family members and family members not HD related who did not contribute to our analyses. Of these 11,569 HD symptomatic patients, we selected patients undergoing DRBA (first/second generations of antipsychotic drugs) and/or TBZ treatment. A flowchart illustrating the selection of patients from the Enroll‐HD PDS5 dataset is shown in Figure 1. To identify NMS cases in this cohort, we used the keywords "neuroleptic malignant syndrome," "NMS," "rigidity," "hyperthermia," and "fever" as filters, to include both typical and atypical forms of NMS. The keywords were searched both in the “comorbidity” section and in the “events” section. The first reports patient comorbidities, whereas the latter reports reasons for hospitalization, which mainly include psychiatric causes, suicide, suicide attempts, or other undefined causes. Among the cases of fever, we only included cases of unspecified fever, excluding all infectious, rheumatic, or other causes of fever.

FIGURE 1.

Flowchart of patient identification from the fifth dataset of the Enroll‐HD study. DRBA, dopamine receptor blocking agent; HD, Huntington disease; TBZ, tetrabenazine.

RESULTS

From the analysis of Enroll‐HD PDS5 data, we identified 5108 of 11,569 HD patients who were undergoing DRBA and/or TBZ treatment. Using the keywords "neuroleptic malignant syndrome," "NMS," "rigidity," and "hyperthermia," we found only one correspondence in the “comorbidity” section, which referred to an episode of NMS occurring before Enroll‐HD PDS5 registration; no keywords were identified in the “events” section. The patient in question was a Caucasian man of 46 years, with a psychiatric onset of disease at age 28 years, who developed NMS while undergoing treatment with clozapine 300 mg qd and valproate 1500 mg qd. The time interval between the onset of NMS and the diagnosis of HD has not been reported. Furthermore, we found five cases of unspecified fever in the “comorbidity” section; all patients were undergoing polytherapy with drugs that included tetrabenazine, DRBA, and others (olanzapine, haloperidol, tiapride, quetiapine).

DISCUSSION

The loss of dopamine D2 and D3 receptors in the basal ganglia and in the hypothalamus [7] may expose HD patients undergoing treatment with DRBA or/and TBZ to an increased risk of developing NMS. However, according to the available data, it is unclear whether the prevalence of this condition is higher in these individuals compared to the general population [14, 19]. In the Enroll‐HD dataset, only one of 5108 HD patients treated with DRBAs and/or TBZ was diagnosed with NMS, while undergoing treatment with clozapine. In this database, all psychiatric events that lead to hospitalization are systematically collected (suicide attempts, suicide, mental health events including depression, psychotic disorders, aggression). Despite the frequent use of antipsychotics and TBZ to treat both motor and psychotic symptoms, the adverse events associated with these therapies, including NMS, are not systematically reported. Furthermore, it is important to note that some patients, mostly those treated with second‐generation neuroleptic agents and/or TBZ, may present an atypical form of NMS (i.e., hyperthermia without rigidity) [17, 19, 24, 25], overlooked due to the incomplete manifestation of symptoms. For instance, five HD patients treated with DRBAs and/or TBZ reported unspecified fever, raising the possibility of an atypical form of NMS. Another potential reason for a missed diagnosis is that hyperkinetic movements such as chorea, dystonia, myoclonus, or a pre‐existing rigidity may mask tardive motor side effects. Therefore, systematically recording adverse events related to neuroleptic treatment would help avoid underestimation and underdiagnosis of this dangerous condition. Unexplained fevers should be thoroughly investigated and categorized to ensure they are not a result of the medications used. For instance, in the Enroll‐HD PDS5 dataset, we found the term “neuroleptic malignant syndrome” in the “comorbidity” section, reported as an episode that occurred before dataset registration and not in the “events” section, which included reasons for hospitalization. The main reported reasons for hospitalization include psychiatric causes, suicide, or suicide attempts but other events are not systematically described, including NMS, which is a rare but potential cause of hospitalization. This can partly explain the very low rate of NMS diagnosis in the dataset.

In the general population, the main risk factors that lead to NMS are both clinical and environmental, such as physical restraint, dehydration, high temperature, iron deficiency, and the type and management of pharmacological treatment [16]. Considering the patient from our case report and the data obtained through the literature review, we identified 11 cases of NMS in HD patients (mean age at HD onset = 33 years), three with the Westphal variant (Table 2). On average, they had a long clinical history and an advanced stage of HD at the onset of NMS (mean NMS onset time after HD diagnosis = 12.8 years); almost all patients (9/11) were either bedridden, dysphagic, or dehydrated, showed signs of akinetic rigidity, were undergoing polytherapy, or showed a combination of these conditions. The remaining two presented only mild HD signs; however, one of the patients had a long clinical history of HD and oncologic comorbidity [22]. The clinical characteristics described in this cohort are all known risk factors of NMS; however, compared to the general population, multiple risk factors are often present in late stage HD patients.

Antipsychotics block D2 dopamine receptors with different affinity and potency [26]. There is no clear epidemiological data showing that atypical antipsychotic drugs have a lower risk of inducing NMS [27, 28]. Furthermore, even if higher doses are correlated with increased risk of NMS, it can occur even with low doses, indicating that possibly the risk is related more to individual susceptibility than to DRBA dosage [10, 11]. The development of NMS is also time‐independent, as it can develop immediately after the administration of the drug or after many months at the same dosage. Based on the data gathered from the literature review and our case report, only three patients developed NMS within hours or days after drug treatment modification, whereas the majority of patients did after at least 2 weeks and up to months after. This can hinder clinicians from identifying the causal link between the treatment switch and the first signs of NMS.

TBZ has weak affinity toward D2 receptors, selectively depletes VMAT2, with higher affinity for dopaminergic vesicles, and is approved for the treatment of choreic dyskinesias in HD [29]. Although TBZ has a different mechanism of action and has fewer side effects than DRBAs, cases of tardive syndromes and NMS under TBZ treatment have been described [30]. In patients described in literature, five developed NMS associated with TBZ, either during long‐term treatment and after dosage modification or after introduction of TBZ. Two of five developed atypical NMS, without rigidity. As highlighted by our case and the literature review, all but the aforementioned patient manifested NMS during drug therapy modification, especially change of drugs, or even slight dose increases of a drug already in use. Moreover, four of 11 patients were under polytherapy. These observations confirm that treatment manipulation is one of the main pharmacological triggers of NMS, in addition to polytherapy, particularly when combining antipsychotic agents, tetrabenazine, antiseizure medication, mood stabilizers, and/or other antidepressants [31]. Atypical NMS forms must be taken into consideration, as they can manifest with only one of the two core symptoms; this was the case in three patients who manifested hyperthermia without rigidity. Rigidity, isolated hyperthermia, altered mental status, mutism, catatonia, and dysautonomia are all part of a wide range of clinical manifestations with which NMS can manifest itself [11]. That these symptoms may occur individually makes their detection more challenging. In patients with a long history of HD, there is progressive dysregulation of dopaminergic pathways and concurrent degeneration of the hypothalamus, a critical structure for autonomic functions such as thermoregulation, thirst, hunger, and circadian rhythm regulation, significantly increasing their risk of developing NMS [1, 2, 3, 4, 5, 6, 7, 8, 9]. These pathophysiological changes not only contribute to an increased susceptibility to clinical risk factors such as immobility, rigidity, dehydration, and weight loss, but also make them more vulnerable to dopaminergic agents due to the underlying degeneration. Consequently, therapeutic changes must be cautious and gradual, and made under close monitoring, especially in patients with a long clinical history. Polypharmacy, or the use of multiple medications, should be minimized when possible, and potential drug interactions should be carefully evaluated. Addressing physical stressors such as dehydration and malnutrition is essential; ensuring patients maintain adequate hydration and receive proper nutrition can significantly reduce the risk. Regular checkups and a multidisciplinary approach can help mitigate these risk factors effectively.

The main limitation of this study is the relative scarcity of the information obtained, which does not allow generalizability of the results. Probably this scarcity of reported information is partly explained by the absence of well‐defined criteria for NMS spectrum and thus the clinical challenge in recognizing it, and partly because these events are not carefully transcribed in the Enroll‐HD register. Consequently, this leaves little space for the analysis of the characteristics of NMS in HD. Given the potential danger of this condition for patients, larger studies are necessary to gain a better understanding of the prevalence and risk factors of NMS in HD patients.

CONCLUSIONS

HD patients have increased risk of developing NMS due to progressive dysregulation of dopaminergic pathways and hypothalamic degeneration. The prevalence of NMS in this population is unknown, mostly due to underdiagnoses and underreporting of atypical presentations, and partly to the masking effects of HD symptoms. Systematic recording of adverse events and thorough investigation of unexplained fevers are essential to increase sensitivity to this condition. Finally, the data highlight the importance of careful review and management of medications throughout the disease course, avoiding abrupt changes, and addressing clinical risk factors such as dehydration and malnutrition to reduce the risk of NMS in HD patients. Regular monitoring and a multidisciplinary approach are essential for effective prevention and control of NMS.

AUTHOR CONTRIBUTIONS

Antonio Funcis: Conceptualization; investigation; writing – original draft; writing – review and editing; formal analysis; supervision; data curation; methodology. Beatrice Ravera: Conceptualization; investigation; writing – original draft; methodology; writing – review and editing; data curation; supervision; formal analysis. Paola Zinzi: Formal analysis; data curation. Marcella Solito: Data curation. Martina Petracca: Data curation; supervision. Paolo Calabresi: Writing – review and editing; supervision. Anna Rita Bentivoglio: Conceptualization; data curation; formal analysis; writing – original draft; writing – review and editing; methodology; supervision.

CONFLICT OF INTEREST STATEMENT

None of the authors has any conflict of interest to disclose.

Funcis A, Ravera B, Zinzi P, et al. Neuroleptic malignant syndrome in Huntington disease. Eur J Neurol. 2024;31:e16442. doi: 10.1111/ene.16442

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.