Stephan C. Mann

Neuroleptic malignant syndrome.

Neuroleptic malignant syndrome is a rare but potentially fatal reaction associated with neuroleptic drugs. It occurs in about 0.2% of patients treated with neuroleptics. Risk factors include previous episodes, dehydration, agitation, and the rate and route of neuroleptic administration. Although NMS has been reported in patients with diverse psychiatric diagnoses, as well as in normal subjects, patients with organic brain disorders or mood disorders, particularly when receiving lithium, may be at increased risk. Standardized criteria for the diagnosis of NMS have been developed and emphasize the classic findings of hyperthermia, muscle rigidity, mental status changes, and autonomic dysfunction. The syndrome lasts 7 to 10 days in uncomplicated cases receiving oral neuroleptics. Treatment consists primarily of early recognition, discontinuation of triggering drugs, management of fluid balance, temperature reduction, and monitoring for complications. Use of dopamine agonists or dantrolene or both should be considered and may be indicated in more severe, prolonged, or refractory cases. Electroconvulsive therapy has been used successfully in some cases and is particularly useful in the post-NMS patient. As a result of these measures, mortality from NMS has declined in recent years although fatalities still occur. Neuroleptics may be safely reintroduced in the management of the majority of patients recovered from an NMS episode, although a significant risk of recurrence does exist, dependent in part on time elapsed since recovery and dose or potency of neuroleptics used. Data drawn from clinical observations and basic studies support the primary role of an acute reduction in brain dopamine activity in the development of NMS. Additional studies of facilitating cofactors may lead to innovative risk-reduction strategies and the development of safer neuroleptic drugs.

An international consensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method.

OBJECTIVE The lack of generally accepted diagnostic criteria for neuroleptic malignant syndrome (NMS) impedes research and clinical management of patients receiving antipsychotic medications. The purpose of this study was to develop NMS diagnostic criteria reflecting a broad consensus among clinical knowledge experts, represented by an international multispecialty physician panel. PARTICIPANTS Eleven psychiatrists, 2 neurologists, 2 anesthesiologists, and 2 emergency medicine specialists participated in a formal Delphi consensus procedure. EVIDENCE A core bibliography consisting of 12 prominent, current reviews of the NMS literature was identified by an objective, comprehensive electronic search strategy. Each panel member was given a copy of these references and asked to examine them before commencing the survey process. CONSENSUS PROCESS After reviewing the core bibliography, panel members were asked to list any clinical signs or symptoms or diagnostic studies that they believed, on the basis of their knowledge and clinical experience, were useful in making a diagnosis of NMS. In subsequent survey rounds, panel members assigned priority points to these items, and items that failed to receive a minimum priority score were eliminated from the next round. Information about individual panel member responses was fed back to the group anonymously in the form of the group median or mean and the number of members who had ranked or scored each survey item. The a priori consensus endpoint was defined operationally as a change of 10% or less in the mean priority score for any individual item, and an average absolute value change of 5% or less across all items, between consecutive rounds. The survey was conducted from January 2009 through September 2009. RESULTS Consensus was reached on the fifth round regarding the following criteria: recent dopamine antagonist exposure, or dopamine agonist withdrawal; hyperthermia; rigidity; mental status alteration; creatine kinase elevation; sympathetic nervous system lability; tachycardia plus tachypnea; and a negative work-up for other causes. The panel also reached a consensus on the relative importance of these criteria and on the following critical values for quantitative criteria: hyperthermia, > 100.4°F or > 38.0°C on at least 2 occasions; creatine kinase elevation, at least 4 times the upper limit of normal; blood pressure elevation, ≥ 25% above baseline; blood pressure fluctuation, ≥ 20 mm Hg (diastolic) or ≥ 25 mm Hg (systolic) change within 24 hours; tachycardia, ≥ 25% above baseline; and tachypnea, ≥ 50% above baseline. CONCLUSIONS These diagnostic criteria significantly advance the field because they represent the consensus of an international multispecialty expert panel, include critical values, provide guidance regarding the relative importance of individual elements, and are less influenced by particular theoretical biases than most previously published criteria. They require validation before being applied in clinical settings.

Malignant Hyperthermia Susceptibility in Neuroleptic Malignant Syndrome

The relationship between neuroleptic malignant syndrome (NMS) and malignant hyperthermia (MH) was investigated using the in vitro skeletal muscle contracture test to screen for MH-susceptibility in NMS patients. The maximum contracture tension which developed following exposure to halothane (1–3%), and incremental doses of fluphenazine (0.2–25.6 mM) was measured in muscle obtained from seven NMS, six MH, and six control patients. Comparison of the cumulative responses to fluphenazine revealed no significant differences among the groups. However, the response (mean ± SEM) to halothane in the NMS group (1.7 ± 0.7 g), which was similar to the response in the MH group (1.5 ± 0.2 g), was significantly greater than the response found in controls (0.2 ± 0.1 g). In addition, live of seven NMS patients could be diagnosed as MH-susceptible, based on the development of muscle contractures greater than 0.7 g in response to 1–3% halothane. In contrast, none of the controls were MH-susceptible. These findings appear to correlate with clinical evidence suggesting an association between NMS and MH.

Residual catatonic state following neuroleptic malignant syndrome.

Neuroleptic malignant syndrome (NMS) is usually a self-limited disorder, with most cases resolving within 2 weeks after antipsychotic drug discontinuation. However, the course of NMS may not always be short-lived. In this report, the authors describe five patients who developed a residual catatonic state that persisted after acute hyperthermic symptoms of NMS had subsided and compare them with 27 similar cases in the literature. Two of our patients recovered gradually with supportive treatment. Three patients were treated with electroconvulsive therapy (ECT). Of these, two showed a positive response, although one died later of intercurrent pneumonia. A third patient did not respond to ECT, but recovered gradually thereafter. Although dopamine agonists or benzodiazepines have been advocated for the treatment of residual symptoms in previous case reports, ECT was the treatment most often associated with a rapid response and no mortality, even in patients refractory to pharmacotherapy. In conclusion, catatonic and parkinsonian symptoms of NMS may persist as a residual state lasting for weeks to months after more fulminant acute symptoms abate. These residual symptoms may be more likely to develop in patients with pre-existing structural brain disorders. Although patients may improve gradually with supportive care or pharmacotherapy, ECT can often be highly effective in treating the residual catatonic state that follows NMS.

Neuroleptic malignant syndrome

Since the initial description of neuroleptic malignant syndrome (NMS) 40 years ago, a wealth of clinical data has accumulated on the manifestations, course, treatment, and pathogenesis of this uncommon but serious and potentially lethal drug reaction. Nevertheless, vigilance must be maintained, as this disorder remains obscure to many practising physicians. Here, we review the clinical features of NMS to enhance patient safety and reduce physician liability whenever antipsychotic drugs are administered.

Reactivity to alcohol stimuli in alcoholics: is there a role for temptation?

Two studies investigated conditioned reactions to alcohol in alcoholics. In the first, alcoholic and control subjects were exposed to alcoholic and non-alcoholic stimuli and physiological parameters were measured. No significant differences were found to indicate that alcoholics reacted differentially to alcoholic stimuli. As this was contrary to other findings, procedural differences were examined. In the second study, a series of case studies, subjects were selected for extreme alcohol dependence and the procedure was varied by persuading the subjects that they might consume the stimuli. Under conditions in which the alcoholic stimulus was available and the subjects were able to consume it, two of the three subjects exhibited responses consonant with conditioned reactions to alcohol stimuli. We conclude that such conditioned reactions do exist but that their prevalence and the conditions under which they can be elicited are unknown. From these studies it appears to us that one of the most important parameters may be that of temptation.

Neuroleptic Malignant Syndrome

The neuroleptic malignant syndrome (NMS) is an evidently underdiagnosed but potentially lethal consequence of treatment with potent neuroleptics. The author presents a detailed review of the clinical characteristics and differential diagnosis of the NMS as described in the world literature. Further studies of the incidence, etiology and pathogenesis of the NMS may enhance knowledge of neuroleptic pharmacology and produce more effective means of prevention and treatment.

Catatonia, Malignant Catatonia, and Neuroleptic Malignant Syndrome

Malignant catatonia (MC) represents a life-threatening neuropsychiatric disorder that was widely reported long before the introduction of antipsychotic drugs. A review of the world literature on MC indicates that although the prevalence of the condition may have declined since the pre-antipsychotic drug era, it continues to occur and represents a syndrome rather than a specific disease. Although most often the outgrowth of a psychiatric disorder, MC may develop in association with diverse neurologic and medical conditions. From this perspective, neuroleptic malignant syndrome (NMS) may be viewed as a drug-related form of this same MC syndrome. Our review also supports the proposed conceptualization of catatonia as a continuum, with milder forms at one end (termed simple or nonmalignant catatonia) and more severe forms involving hyperthermia and autonomic dysfunction (termed malignant catatonia) at the other end. In addition, findings from our review suggest that simple catatonia, MC and NMS share a common pathophysiology involving reduced dopaminergic functioning in the basal ganglia-thalamocortical circuits, consistent with their identity as variants of the larger unitary catatonic syndrome. Electroconvulsive therapy appears to represent the preferred treatment for MC. Antipsychotic drugs should be withheld whenever MC is suspected.

Neuroleptic malignant syndrome and the catatonic dilemma.

To the editor; In their scholarly analysis of published reports of neuroleptic malignant syndrome (NMS) and catatonia, Lang et al. (2014) found 12 variables with statistically significant discriminatory power in differentiating the 2 disorders. Given the seriousness of these disorders, the infrequency of their occurrence, and the general lack of research data and awareness among clinicians, the analysis by Lang et al. to differentiate NMS from catatonia is an important endeavor. However, there are three points we believe are worth emphasizing to supplement their findings. First, we agree that it is important to distinguish the two conditions with respect to treatment. In contrast to catatonia due to other causes, NMS is an iatrogenic reaction to treatment with dopamine antagonists, such that early diagnosis is critical in prompting discontinuation of the triggering drug. In cases of NMS, cessation of treatment with dopamine antagonists is essential for recovery to occur even with supportive treatment alone (Caroff and Mann 1988), whereas lorazepam, followed by ECT if lorazepam fails, is considered necessary and has been highly effective and frequently life-saving for the treatment of catatonia arising from endogenous psychotic disorders (Mann 2003). In this way, reversal of symptoms after drug cessation provides a resolution of the catatonic dilemma and an “external validation” of the diagnosis of NMS, albeit post hoc. However, if symptoms of NMS do not resolve after drug discontinuation, evidence has also been published suggesting several drug treatments, including lorazepam, and ECT may improve recovery (Davis et al. 2000). Second, it is not surprising that Lang et al. found that symptoms of parkinsonism (rigidity and tremor) are more common inNMS than in cases of catatonia. In some cases, NMS, which results from drug-induced dopamine blockade, is clinically indistinguishable from the parkinsonian-hyperthermia syndrome that occurs in patients with Parkinson’s disease following abrupt withdrawal from dopamine agonists (Huddleston and Factor 2013). Mann (2003) previously proposed that symptoms of NMS could be mapped to basal gangliathalamocortical circuits, with parkinsonian symptoms reflecting dopamine blockade in the motor circuit, whereas catatonic features reflect blockade of dopamine in the anterior cingulate-medial orbitofrontal subcortical and the lateral orbitofrontal subcortical circuit. The non-focal effect of dopamine antagonist drugs on brain pathways may be generalized and extend across these parallel circuits resulting in a mix of features in NMS, occupying an intermediate position between, and overlapping symptomatically with, forms of parkinsonism on the one hand, and cases of catatonia on the other (Gelenberg and Mandel 1977). Finally, Lang et al. conclude that NMS may be distinguished from catatonia by the fact that certain catatonic symptoms are significantly less common in NMS, and that features of parkinsonism and hyperthermia correlate with NMS. However, it is unclear whether the cases of catatonia used in their S. N. Caroff (*) : E. C. Campbell Department of Psychiatry, Philadelphia Veterans Affairs Medical Center and the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA e-mail: stanley.caroff@va.gov

Anti–N-Methyl-D-Aspartate Receptor Encephalitis and Risk of Neuroleptic Malignant Syndrome

To the Editor Rozier et al.1 report the case of a girl with seizures complicated by neurological and behavioral deterioration, who was diagnosed with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and treated successfully by tumor resection and immunotherapy. They note that NMDAR-encephalitis and neuroleptic malignant syndrome (NMS) share common symptoms, and they prudently remind clinicians to consider the diagnosis of NMDARencephalitis in this context. The problem of differentiating NMDAR-encephalitis from NMS has been raised in several previous case reports.2-4 In these reports, the authors also note that NMDAR-encephalitis is difficult to distinguish from NMS because of similar features and because encephalitis is often initially missed as a cause of psychosis with patients receiving treatment with antipsychotics before the correct diagnosis is established. Drawingon similar patientswe reported in 1998,4wewant toadd tothescholarly reportofRozieretal.bynoting thatNMS and NMDAR-encephalitis may not always be mutually exclusive, and by proposing that there may be an increased risk of NMS in patients with NMDAR-encephalitis as a complication of treatment with antipsychotics. Although treatmentwith antipsychoticsmay be necessary and effective in some cases of NMDAR-encephalitis to control agitation and facilitate diagnostic investigation, serious antipsychoticinduced adverse reactions, including NMS, may occur. The possibility of a shared underlying pathogenesis betweenNMS andNMDAR-encephalitis, as proposed by Rozier et al., sets the stage for synergistic effects. Among published reports of encephalitis presenting with psychosis, we found that antipsychotics were helpful in controlling behavior in some patients, but drug-induced extrapyramidal symptoms and catatonia or NMS were frequently observed.5 This implies that if a patient with suspected encephalitis develops agitation or psychosis, antipsychotics should be used cautiously at low doses, with carefulmonitoring andpromptdiscontinuation ifNMSoccurs. If the diagnosis of encephalitis is already known, it may be advisable to first attempt behavioral control using benzodiazepines, antiepileptic drugs, or atypical antipsychotics, although there are no controlled data to support this approach.