The diagnosis is made in the presence of the tetrad of altered mental status, muscle rigidity, autonomic dysfunction, and hyperthermia. A high index of suspicion leads clinicians to stop antipsychotic medications and institute supportive measures simultaneously with diagnostic evaluation, given the critical nature of this syndrome. This means that less severe cases (partial NMS, mild NMS) may be seen more often than the original severe and life-threatening presentations. This also makes the diagnosis more challenging, as many other conditions present with some or all of the features of NMS.

An international expert panel has developed consensus-based diagnostic criteria that can be used to help guide clinical assessment, and these have been incorporated into DSM-5.[37][38] Preliminary validation of these consensus criteria has been reported using records from a telephone consultation service.[39]

NMS remains a diagnosis of exclusion. A careful assessment, including physical examination and comprehensive tests, is required to exclude other potential causes.[3][12]

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