Intravenous formulations of diazepam and lorazepam contain propylene glycol which in large doses may cause renal insufficiency; their use in patients with rhabdomyolysis-induced renal failure should be judicious.
Dantrolene is a muscle relaxant chemically derived from phenytoin but lacking antiepileptic activity which may cause severe weakness, respiratory failure, and hepatotoxicity. Its use is contraindicated in patients taking calcium channel blockers, as the combination may result in cardiovascular collapse. The most significant long-term sequelae of disease among survivors are rhabdomyolysis-induced renal failure and permanent neurocognitive dysfunction.
Other complications include ICU-acquired infections sepsis and pneumonia and immobilization-related venous thromboembolism. The family should be advised about the expected prognosis as well as the possible long term sequelae including death and updated at regular intervals regarding progression of disease. NMS is caused by exposure to antidopaminergic medications in susceptible patients. More recent estimates based on large studies appear to reflect a much lower incidence, approximately 0.
Why certain patients appear to be susceptible while others are not is poorly understood. Furthermore, some patients will develop symptoms of NMS after a dosage change to a longstanding medication or even in the absence of any recent dosage change. Experts have speculated that perhaps there is abnormal dopaminergic activity at baseline in the brains of certain patients with psychotic disorders, and that this may contribute to the appearance of NMS, but few data exist to support this hypothesis yet.
Genetic studies of NMS have been inconclusive thus far despite reports of familial patterns in the literature. The exact pathogenesis of symptoms in NMS is unknown. The leading hypothesis regarding the causative mechanism of antidopaminergic medications in NMS is central dopamine deficiency due to dopamine receptor blockade in the central nervous system.
This hypothesis is based on the known pharmacologic effects of the antipsychotic medications, as well as the pharmacologic link between these medications and others which have also caused NMS. Additionally, reports of clinical improvement with bromocriptine a dopamine agonist support this hypothesis, although reports have been inconsistent. This pharmacologic hypothesis has led some authors to refute the concept that NMS is an idiosyncratic syndrome; by definition, idiosyncratic reactions do not have a pharmacologic basis of effects.
In addition to the complications noted above, one of the major complicating factors for this disease stems from the nature of the affected patient population. Psychotic patients may become hazardous to themselves or others in the absence of therapy. Patients must be monitored carefully for signs of worsening psychiatric diseases and care should be managed by an appropriate psychiatric specialist.
Additionally, drug reactions to bromocriptine, benzodiazepines, or dantrolene may occur as noted above. Lasting effects of NMS may include rhabdomyolysis-induced renal failure and irreversible neurocognitive deficits.
The remainder of the clinical findings generally resolve with therapy. There is no specific laboratory testing for NMS. Genetic studies have been inconclusive thus far.
NMS cannot be prevented in all patients without a better understanding of the mechanisms of the disease. However, the incidence has decreased with declining use of the potent antipsychotic medications. Although causative relationships have not been elucidated, it may be prudent for patients on antidopaminergic agents to avoid excessive environmental heat as well as dehydration when feasible , which have been associated with NMS in some patients.
In patients with a known history of NMS, recurrence can be prevented by avoidance of antidopaminergic medications. For patients with psychosis in whom therapy is essential, reintroduction of medical therapy should be at least 2 weeks after recovery from NMS, and only with the informed consent of patient and family.
Generally a small test dose of medication is administered, followed by very slow dose escalation with careful observation for symptoms of NMS. This process should generally be guided by a psychiatric professional. J Clin Psychiatry. A review of NMS and its association with atypical antipsychotic medications; although overall lower risk than typical antipsychotics, the atypical medications are responsible for a larger number of cases due to increased prescribing practices.
Curr Neuropharmacol. A recent review of NMS, including discussion of an expanded list of causative agents, mechanistic theories, management and complications, and outcomes. Margetic, B, Margetic, BA. Pharmacoepidemiol Drug Saf. A review of past and present controversies in NMS. There are case reports of rapid dose titrations occurring safely, however these involved small numbers of acutely unwell patients, being titrated on quetiapine [ 29 ] and olanzapine [ 30 ].
However the titration rates of the patients included in the study were variable and in some antipsychotic polypharmacy occurred. To date, our study is the only one available whereby an attempt to define rapid dose escalation mathematically based on comparison of cumulative dose over two time periods has occurred. This method allows comparison of dose escalation not only between different antipsychotics but also over different periods of time of titration.
Provided doses are converted to chlorpromazine equivalents and cumulative doses over the first half of the titration schedule are compared to the second half, a ratio of dose escalation can be calculated. The individual dose escalation rate can then be compared to standard practice seen for clozapine and quetiapine allowing a more scientific evaluation of dose titration to be made. This method although limited by comparison only to standardised UK titration schedules, represented the best way to pragmatically define rapid dose escalation.
Our study suggests that a rapid rate of anti-psychotic dose escalation, although likely to be an important risk factor, is not universally observed in cases of NMS. Cumulative dose of antipsychotic may be equally important. It is worth noting that mean daily and mean cumulative antipsychotic doses were markedly higher both at day 15 and day 30 in the non rapidly escalating NMS cohort compared to the cohort who underwent rapid escalation.
Individuals with high cumulative antipsychotic dose had a higher peak mean CK value during their episode of NMS. Only five cases There have been some reports of NMS induced by second generation antipsychotics, having a propensity for atypical clinical presentations. However interestingly in our cohort all patients who were exposed to clozapine in the 30 day period prior to their episode of NMS were noted to have rigidity as a feature of their presentation.
This highlights the importance of a high level of clinician suspicion, vigilance and the importance of repeated review and reassessment in order to diagnose and initiate treatment of NMS promptly.
Prescribers should be vigilant with regards to dose escalation of all psychotropic medications, particularly antipsychotics. Our study although limited by its small sample size and retrospective nature represents a pragmatic attempt to review antipsychotic dose escalation as a trigger for NMS. The heterogeneity of the condition, combined with its rarity makes NMS difficult to research. Our case series reflects the complexity of the condition and by its retrospective nature allows it to be practicable to current clinical practice and adds to the limited evidence basis available.
Our findings indicate that it is not easy to predict what rate of antipsychotic dose escalation if any will result in the development of NMS.
Indeed, the rate of dose escalation amongst less than half the cases 5 cases Our findings also indicate that prescribers should also be mindful of cumulative antipsychotic dose and be aware of prescribing large doses of medication over prolonged periods of time. It is clear that more work on both the heterogeneous presentation of NMS and its aetiology both antipsychotic-related and other related factors is warranted. A detailed review of a large series of patients with NMS perhaps recruited internationally matched to controls, with a particular focus on cumulative antipsychotic dose as well as rate of dose escalation, would be helpful in order to further enhance understanding of this condition.
He has multiple research interests including psychopharmacology and individuals with high readmission rates.
He is an honorary senior clinical lecturer at the University of Glasgow. Daniel Smith is a reader in mental health and honorary consultant psychiatrist at the University of Glasgow. He has multiple research interests including bipolar illness and multimorbidity. J Annales Medicos-Psychologiques. Google Scholar. Journal of Clinical Psychiatry. J Clin Psychopharmacol. Dave M: Two cases of risperidone induced neuroleptic malignant syndrome ltr. Am J Psychiatry.
Psychopharmacol Bull. Arch Intern Med. Patterson JF: Neuroleptic malignant syndrome associated with Metoclopramide. Southern medical Journal. Madakasira S: Amoxapine induced neuroleptic malignant syndrome. Drug Intelligence and Clinical Pharmacy. CAS Google Scholar. Article PubMed Google Scholar. Heyland D, Sauve M: Neurloeptic malignant syndrome without the use of neurleptics. Can Med Ass J. Neurologic Clin. Article Google Scholar. Gurrera RJ: Sympathoadrenalhyoactivity and the aetiology of neuroleptic malignant syndrome.
Gurrera RJ: Is neuroleptic malignant syndrome a neurogenic form of malignant hyperthermia?. Clin Neuropharmacology. British Journal of Anaesthetics. Arch Gen Psychiatry. Human Psychopharmacology.
Caroff S, Mann S: Neuroleptic malignant syndrome. Medical Clinics of North America. ActaPsychiatrica Scandinavia. Berman BD: Neuroleptic malignant syndrome: a review for neurohospitalists. The Neurohospitalist. J NeurolNeurosurg Psychiatry. FloiaPsychiatricaetNeurologica Japonica. British Journal of Psychiatry. J Psychopharmacol. The BMJ Best Practice recommends waiting for at least 2 weeks before reinitiating antipsychotic medication.
Since this gentleman had already tried various antipsychotic medications, there were limited options available when ascertaining an alternative antipsychotic medication. Expert opinion from the hospital medicine pharmacy specialist was sought, and they advised rechallenge with oral risperidone as this medication was previously tolerated by the patient.
Due to a lack of evidence in the literature pertaining to restarting depot medication after an episode of NMS, the importance of avoiding this was stressed by the pharmacy specialist. Currently, the patient has been discharged from the psychiatric inpatient unit on risperidone with appropriate safety netting advise and risk management in place. Regular community mental health team reviews and home treatment team follow-up should assist in medication compliance and frequent monitoring of his mental health.
Learning Points. Tachycardia should raise the suspicion of NMS. Diaphoresis is also very common and not often thought of as a hallmark sign of NMS. Elevation of CK is frequent but is not always extreme and may actually be absent in some cases. Waiting for rigidity or the development of fever may delay the diagnosis of NMS in patients taking clozapine.
In the absence of fever with the presence of other core symptoms of NMS, an atypical presentation should be considered. Patient Perspective. Patient or next of kin not wishing to provide any comments. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Read the winning articles. Journal overview. Academic Editor: Lut Tamam. Received 18 Jan Revised 17 Mar Accepted 19 Mar Published 29 Apr Abstract Neuroleptic Malignant Syndrome NMS associated with the use of first-generation antipsychotics is a widely known phenomenon.
Introduction There are extremely few reported cases of clozapine associated NMS without fever. Patient Information The patient is a year-old male well known to mental health services with an established diagnosis of paranoid schizophrenia. Clinical Findings and Timeline On commencing clozapine at Diagnostic Assessment In this case, the important differential diagnoses considered were sepsis, anticholinergic syndrome, and malignant hyperthermia.
Investigations and Treatment The patient was transferred to the medical ward for a thorough physical health evaluation following his injury on the psychiatric unit. Discussion The pathophysiology of NMS at a receptor level involves a decrease in central dopaminergic activity at the Dopaminergic D2 receptor.
Additional Points Learning Points. References M. Belvederi Murri, A. Guaglianone, M. Bugliani et al. Simon, M. Hashmi, and A.
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