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Neuroleptic malignant syndrome is a fulminant and life-threatening toxidrome that occurs in an estimated 0.07% to 3.23% of patients treated with antipsychotic medication.1,2 Patients typically present with fever, rigidity, changes in mental status and autonomic instability, often after the start of antipsychotic medication or an increase in dosage....
Citations
... 10 Various mechanisms of the induction of the acute phase response in NMS are autoantibody production, virusdrug interaction, heat stress, muscle break-down and psychological stress. 15 However, there is an upward trend in CPK, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), interleukin-6 (IL-6), alpha-1 antichymotrypsin (ACT), and fibrinogen, the levels of iron (Fe) and albumin levels(AL) decrease. Such responses correspond to the APR activation. ...
... Such responses correspond to the APR activation. 15 The positive values of APR, ESR, CRP, IL-6, ACT, and fibrinogen peaked after 72 h. In NMS, serum levels of negative APRs, such as serum AL and Fe are low, but gradually redouble and reach the normal range, along the lines of clinical improvement. ...
... This transient APR profile is consistent with the changes in temperature, creatine kinase (CK) levels and the clinical course of the syndrome, suggesting that APR may directly contribute to the pathophysiology of NMS. 15 A sudden drop in Fe levels is regularly observed in connection with NMS, which is a key manifestation of APR. 16 As mentioned in some publications, APR is considered less important than CPK, 11 although APR may be involved in the pathogenesis of NMS, suggesting a possible role in disease initiation. ...
Key Clinical Message
In some patients, neuroleptic malignant syndrome is accompanied significant high levels of erythrocyte sedimentation rate (ESR), C‐reactive protein (CRP).
Abstract
Neuroleptic malignant syndrome (NMS) is an idiosyncratic life‐threatening adverse reaction and usually triggered in response to antipsychotic drugs. In addition, leukocytosis and increased muscle enzymes levels (especially creatine phosphokinase) are observed in NMS. In addition, a transient increase in different types of acute phase reactants in NMS has been mentioned. This article describes a woman treated with haloperidol, perphenazine, escitalopram, and alprazolam because she developed catatonic symptoms after psychological stress. She suffered from NMS symptoms and had elevated CRP and ESR levels, among other signs and symptoms. Given the COVID‐19 pandemic and reports of co‐occurrence of catatonia and NMS and COVID‐19 and elevated erythrocyte sedimentation rate (ESR) and C‐reactive protein (CRP), this patient was a diagnostic dilemma. After consultation with the consultation‐liaison psychiatry units, she was managed adequately with electroconvulsive therapy and lorazepam.
... It seems likely that the body's response to elevated body core temperature is similar in all hyperthermic disorders. Severe NMS and MH have previously been proposed as neuro-immunological or inflammatory disorders [24][25][26][27]. ...
... Neuroleptic malignant syndrome (NMS) is a severe adverse effect tied to typical antipsychotics such as haloperidol and fluphenazine [71]. The underlying pathophysiology of NMS is not well understood [24]. The cause is believed to be a blockade of dopamine-D2 or D1 receptors in the corpus striatum and hypothalamus (POAH) [32]. ...
... Additional evidence includes the direct relationship between dopamine receptor affinity and risk of NMS, the effectiveness of dopamine agonists as reversal agents, and clinical similarity between NMS and syndromes characterized by dopaminergic hypoactivity [32,72]. Finally, some authors have proposed similarities to "acute-phase responses," leading to suggestions that immune or sympathoadrenal dysfunction characterized by loss of hierarchical integration and control may be responsible [24,27,32]. ...
Humans maintain core body temperature via a complicated system of physiologic mechanisms that counteract heat/cold fluctuations from metabolism, exertion, and the environment. Overextension of these mechanisms or disruption of body temperature homeostasis leads to bodily dysfunction, culminating in a syndrome analogous to exertional heat stroke (EHS). The inability of this thermoregulatory process to maintain the body temperature is caused by either thermal stress or certain drugs. EHS is a syndrome characterized by hyperthermia and the activation of systemic inflammation. Several drug-induced hyperthermic syndromes may resemble EHS and share common mechanisms. The purpose of this article is to review the current literature and compare exertional heat stroke (EHS) to three of the most widely studied drug-induced hyperthermic syndromes: malignant hyperthermia (MH), neuroleptic malignant syndrome (NMS), and serotonin syndrome (SS). Drugs and drug classes that have been implicated in these conditions include amphetamines, diuretics, cocaine, antipsychotics, metoclopramide, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and many more. Observations suggest that severe or fulminant cases of drug-induced hyperthermia may evolve into an inflammatory syndrome best described as heat stroke. Their underlying mechanisms, symptoms, and treatment approaches will be reviewed to assist in accurate diagnosis, which will impact the management of potentially life-threatening complications.
... 10 It has also been suggested that acute phase response may cause NMS. 11 It is known that vaccination and administration of antigens to the body stimulate macrophages and dendritic cells, resulting in an acute phase response by increasing the release of inflammatory cytokines. The plasma levels of a number of microminerals including Fe can cause changes in disorders of homeostasis during the acute phase response. ...
... 15 Due to the decrease in serum albumin, the amount of free olanzapine may increase, causing a dose increase-like response. In an article by Anglin et al 11 , it was suggested that viral infection might lead to decreased tolerance to drugs by changing immune regulation, and accordingly NMS might be associated with a virus-drug interaction by triggering a fulminant acute phase response of a predisposing viral disease to antipsychotic drugs. 11 Soh et al reported NMS in 2 patients followed up due to SARS-CoV-2 pneumonia. ...
... In an article by Anglin et al 11 , it was suggested that viral infection might lead to decreased tolerance to drugs by changing immune regulation, and accordingly NMS might be associated with a virus-drug interaction by triggering a fulminant acute phase response of a predisposing viral disease to antipsychotic drugs. 11 Soh et al reported NMS in 2 patients followed up due to SARS-CoV-2 pneumonia. The first case was associated with the use of fentanyl, propofol, midazolam, and favipiravir, while the second case was associated with the use of favipiravir and risperidone. ...
Neuroleptic malignant syndrome is characterized by muscle stiffness, hyperthermia, autonomic dysfunction, elevation in serum creatine phosphokinase, and changes in consciousness, which usually occur due to the side effects of life-threatening neuroleptic and antipsychotic drugs, and it can cause high mortality. A few cases of neuroleptic malignant syndrome associated with coronavirus disease 2019 infection and vaccination have been reported in the literature. Our case presented with epileptic seizure and neuroleptic malignant syndrome signs 10 days after receiving a single dose of the BNT162b2 vaccine when under low-dose olanzapine treatment with a diagnosis of autism and epilepsy. According to the laboratory test, the creatine kinase value was very high, there was hyponatremia, and the iron value was low. The patient died. Our aim in reporting this case is to draw attention to the possibility that coronavirus disease 2019 vaccines may trigger neuroleptic malignant syndrome, which can be a fatal complication in patients taking antipsychotics, albeit very rare among the large vaccinated population.
... Problemet er kort sagt at legemidler som om mulig gjør mer skade enn nytte (31)(32)(33)(34), ikke faktasjekkes, idet helsevesenet (ved for eksempel Helsedirektoratet) ofte ikke anerkjenner eller bruker ny forskning (35). ...
... Regardless of the trigger mechanism (dopaminergic antagonism, dysautonomia, direct muscle toxicity of NL, etc.), the physiopathology of NMS is complex and involves a cascade of dysfunctions in multiple neurochemical and neuroendocrine systems, leading to end-stage hypermetabolic syndrome [8,[17][18][19]. NMS is classically [1] characterized by four cardinal signs: hyperthermia, muscular rigidity, dysautonomia, and altered mental status. ...
Background: Neuroleptic malignant syndrome (NMS) is a rare but potentially life-threatening neuropsychiatric emergency. The aim of our study was to update our bedside procedures by investigating NMS cases managed in the intensive care unit (ICU).Methods: This retrospective study included all NMS patients admitted to our hospital between January 2012 and December 2019. The variables analyzed included demographics, diagnosis, therapeutics, and outcomes.Results: This study included 20 patients, with an average age of 36.6 years. The male to female ratio was 1:4. No patient had a history of NMS, and 60% of the patients had schizophrenia. First-generation neuroleptics (NLs) were the most commonly prescribed drugs (80%). The mean time between the introduction of NLs and onset of symptoms was 7.6 days. Rigidity was observed in 90% of the patients, hyperthermia and neuropsychic syndrome in 65%, and dysautonomia in 50%. The creatine phosphokinase level in all patients was four times the normal value. Mechanical ventilation was required in 20% of the patients and hemodialysis in one patient. None of the patients received specific therapy. The mean duration of ICU stay was 10 days. The mortality rate was 10%,, mainly associated with renal failure. The analysis of the predictors of mortality was limited by the size of our cohort.Conclusion: NMS is a rare condition requiring multidisciplinary implementation of contextualized and updated procedures. Early detection and supportive treatment could improve the prognosis in resource-limited settings, where specific treatments are not available. Predictive risk factors should be investigated in larger multicenter cohorts.
... Neuroleptic malignant syndrome is a fulminant and lifethreatening disorder that occurs in patients treated with antipsychotic medication. Although the pathophysiology of neuroleptic malignant syndrome is not fully understood, it involves a central hypodopaminergic state and an acute phase reaction as an immune response [1]. We report a case of this syndrome after COVID-19 vaccination. ...
... 6 However, other mechanisms have also been postulated to be involved in the pathophysiology of NMS, including adrenergic hyperactivity and neuroimmunological reactions. 7,8 NMS is characterized most commonly by muscle rigidity, altered mental status, high fever, and autonomic dysfunction. Common laboratory findings include increased creatine kinase (CK), leukocytosis, increased serum aminotransferases, altered electrolyte levels (hyperkalemia, hypo-hypernatremia, or hypocalcemia), increased lactate dehydrogenase (LDH), and metabolic acidosis. ...
Objective:
Neuroleptic Malignant Syndrome (NMS) is a potentially fatal, idiosyncratic reaction to antipsychotics. Due to low incidence of NMS, research on risk factors of mortality associated with NMS is limited.
Methods:
Two authors independently searched Medline/Embase/Cochrane/CINAHL/PsychINFO databases for case reports with author-defined NMS published in English until 05/30/2020. Demographic, clinical, treatment and outcome data were independently extracted following PRISMA guidelines. NMS severity was rated using the Francis-Yacoub scale. Mortality risk factors were identified using a multivariable regression analysis including all characteristics that were significantly different between NMS cases resulting vs not resulting in death.
Results:
683 cases with NMS were analyzed (median age=36 years, males=62.1%). In a multivariable model, independent predictors of NMS mortality were lack of antipsychotic discontinuation (odds ratio (OR)=4.39 95% confidence interval(CI)=2.14-8.99; p<0.0001), respiratory problems (OR=3.54 95%CI=1.71-7.32; p=0.0004), severity of hyperthermia (Unit-OR=1.30, 95%CI=1.16-1.46; p<0.0001), and older age (Unit-OR=1.05, 95%CI=1.02-1.07; p=0.0014). Even in univariate, patient level analyses antipsychotic formulation was not related to death (oral antipsychotic (OAP): n=39/554 (7.0%) vs long-acting injectable (LAI): n=13/129 (10.1%); p=0.2413). Similarly, death with NMS was not related to antipsychotic class (first-generation antipsychotic: n=38/433 (8.8%) vs second-generation antipsychotic: n=8/180 (4.4%); p=0.0638). Non-antipsychotic co-treatments were not associated with NMS mortality.
Conclusion:
Despite reliance on case reports, these findings indicate that presence of respiratory alterations, severity of hyperthermia and older age should alert clinicians to a higher NMS mortality risk, and that antipsychotics should be stopped to reduce mortality, yet when NMS arises on LAIs, mortality is not increased vs OAPs.
... Increased levels of acute phase reactants such as α-1 antichymotrypsin and fibrinogen, elevated ESR, Creactive protein, and IL-6 cytokine levels, decreased negative acute phase reactants as albumin, serum Fe indicate that an inflammatory reaction occurs in NMS (3,4). Based on these findings, Anglin et al. (2010) speculate that there may be a neuroimmunological involvement in these cases. The authors argue that NMS and acute phase response have common findings of fever, tachycardia, diaphoresis, unstable blood pressure, tissue injury, altered consciousness, and leukocytosis (5). ...
... Based on these findings, Anglin et al. (2010) speculate that there may be a neuroimmunological involvement in these cases. The authors argue that NMS and acute phase response have common findings of fever, tachycardia, diaphoresis, unstable blood pressure, tissue injury, altered consciousness, and leukocytosis (5). The NLR is a relatively new and simple marker used to measure systemic inflammation (6). ...
Objective: Neuroleptic malignant syndrome (NMS) is a rare but severe side effect of antipsychotic medication. Neutrophil-lymphocyte ratio (NLR) is a simple marker used to measure systemic inflammation.
Method: In this case report we explore the relationship of inflammation in the etiology of NMS. In our case involving NMS, although there was no leukocytosis, the NLR was increased up to systemic infection levels.
Conclusion: We hypothesized that systemic inflammation may take a role in developing NMS. If so, NLR could be a new marker of NMS that may be able to provide more sensitive results than leukocyte levels.
... Les mécanismes physiopathologiques du SMN [6][7][8][9] ne sont pas complètement élucidés, mais plusieurs hypothèses étiopathogéniques intriquées existent, selon lesquelles l'antagonisme dopaminergique induit par les antipsychotiques semble être le primum movens. Quel que soit le mécanisme d'initiation, la physiopathologie du SMN est complexe, impliquant une cascade de dysfonctionnements dans plusieurs systèmes neurochimiques et neuroendocriniens aboutissant à un syndrome d'hypermétabolisme à la phase finale (figure 1). ...
Le syndrome malin des neuroleptiques (SMN) est une urgence neuropsychiatrique diagnostique et thérapeutique rare et potentiellement mortelle en l’absence de prise en charge adaptée et précoce, reposant essentiellement sur un traitement symptomatique et spécifique. Exigeant une forte suspicion clinique pour le diagnostic et le traitement, le SMN est à juste titre un syndrome plus souvent considéré que véritablement diagnostiqué, et, du fait de sa faible incidence, les données factuelles le concernant, dans la littérature, sont limitées. Cette mise au point physiopathologique et thérapeutique a pour objectifs d’améliorer le raisonnement clinique et de réduire la marge d’incertitude du praticien en proposant un protocole actualisé, contextualisé et personnalisable.
... 19 Low levels of serum iron, a negative acute phase reactant, have been noted in NMS 20 and a neuroimmunological hypothesis has been proposed to explain the pathophysiology of NMS. 21 Low serum iron has also been found not only in malignant catatonia but also in nonmalignant acute catatonia episodes. 22,23 One would hence speculate that the positive acute phase reactant, C-reactive protein (CRP), is likely to be elevated in catatonia. ...
Catatonia is a psychomotor syndrome defined by a constellation of predominantly motor symptoms. The aim of the present study was to determine whether recently admitted psychiatric patients with catatonia exhibited higher serum C-reactive protein (hs-CRP) levels compared to non-catatonic psychiatric patients and healthy controls (HCs). Recently admitted psychiatric patients were screened and evaluated for the catatonia syndrome using the Bush-Francis Catatonia Rating Scale and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). The study sample was formed by 150 individuals (39 male and 111 female), including 51 catatonic patients, 55 non-catatonic patients, and 44 HCs. Serum hs-CRP levels were processed with the enzyme-linked immunosorbent assay. Serum levels of creatine kinase (CK), adrenocorticotropic hormone (ACTH), immunoglobulin G (IgG), complement component 3 (C3), and complement component 4 (C4) were also determined. There was a significantly higher percentage of patients with high inflammatory levels (hs-CRP > 3000ng/ml) in the catatonic (43.1%) than in the non-catatonic (14.5%) or HCs group (9.1%) (χ 2 =18.9, P < .001). Logistic regression showed that catatonic patients had significantly higher hs-CRP levels compared to non-catatonic patients even after controlling for other clinical and laboratory variables (OR = 3.52, P = .015, 95% CI 1.28-9.79). Multiple linear regression analysis revealed that log-transformed hs-CRP was independently predicted by body mass index and log-transformed C4, ACTH, and Cortisol in catatonic patients. Findings of the present study suggest that catatonia is specifically linked to a higher level of systemic inflammation, not merely attributable to the overall psychopathology, or alterations in the stress level and complement system.
