Some researchers have proposed competing or complementary hypotheses, however. For example, Gurrera23 proposed that patients who are prone to developing NMS have a vulnerability to a hyperactive and dysregulated sympathetic nervous system, and this trait—together with dopamine system disruption induced by dopamine-blocking agents—produces NMS. Other investigators have implicated serotonin, norepinephrine, gamma-aminobutyric acid and glutaminergic mechanisms.1,12,24,25
4. Are FGAs or SGAs more likely to cause NMS?
NMS is assumed to occur less frequently in patients treated with SGAs than in those receiving FGAs, although this hypothesisis unproven. Isolated reports of NMS have been associated with nearly every SGA.9-11 It is difficult to prove FGA vs SGA liabilities because:
- NMS is rare.
- Dosing practices may be more conser-vative now than in the past.
- Most clinicians are aware of the earlysigns of NMS.
In an epidemiological study of a large database, Stubner et al26 found that patients receiving SGAs had a lower risk of NMS than those treated with haloperidol.26 In this study, the overall rate of NMS was 0.02%.
NMS hotline data. We recently examined which medication classes were implicated in 111 NMS cases reported to the Neuroleptic Malignant Syndrome Information Service hotline (1-888-NMS-TEMP) between 1997 and 2006 (Figure). We included only cases of definite or probable NMS (as diagnosed by hotline consultants) in which a single antipsychotic was administered. Slightly more cases were attributed to FGAs (51%) than SGAs (45%). The remaining cases were attributed to neuroleptics used in medical settings (such as promethazineor prochlorperazine). Because they are now prescribed less often, FGAs accounted for a disproportionate number of NMS cases reported to the hotline. Haloperidol accounted for the majority of FGA cases and 44% of all cases. If we had excluded haloperidol and compared the NMS risk of SGAs to only intermediate- or low-potency FGAs, the relative advantage of SGAs would have been lost. On the other hand, it is clear that SGAs still carry a risk for NMS. Analyses suggest that the SGA-associated classic features of NMS—fever, muscle rigidity, and autonomic and mental status changes—are retained in patients receiving SGAs, although some may not develop the severe rigidity and extreme temperatures common in patients receiving FGAs.9-11 The milder clinical characteristics associated with SGAs may reflect more conservative prescribing patterns or increased awareness and earlier recognition of NMS, which would prevent fulminant presentations.
5. What is the evidence for specific NMS treatments?
NMS is rare, its presentation varies, and its progression is unpredictable. These factors make it difficult to evaluate treatments in controlled clinical trials, and data about the relative efficacy of specific interventions are scarce.
Even so, the notion that NMS represents an extreme variant of drug-induced parkinsonism or catatonia suggests that specific NMS treatments could be based on symptom severity or stage of presentation. We propose a treatment guideline basedon theoretical mechanisms and anecdotal data (Algorithm).2,27-29
Support. After immediate withdrawal of the offending medication, supportive therapy is the cornerstone of NMS treatment.1,2,27
For patients presenting with mild signs and symptoms, supportive care and careful clinical monitoring may be sufficient. Extreme hyperthermia demands volume resuscitation and cooling measures, intensive medical care, and careful monitoring for complications.
Treatment. Despite a lack of consensus on drug treatments for uncomplicated NMS, approximately 40% of patients with acute NMS receive pharmacologic treatments.2
Lorazepam, 1 to 2 mg parenterally, is a reasonable first-line therapy for NMS, especially in individuals with catatonic features.4,15-18,21,30,31 Some investigators recommend higher doses.15 Benzodiazepines are preferred if sedation is required in agitated NMS patients.4,15-18
Dopaminergic agents such as bromocriptine and amantadine enhance dopaminergic transmission to reverse parkinsonian symptoms and have been reported to reduce time to recovery and halve mortality rates when used alone or in conjunction with other treatments.13,27,32,33 Rapid discontinuation of these agents can result in rebound symptoms, although this may be true for any specific drug treatment of NMS.1,31,32
Dantrolene uncouples excitation-contraction coupling by enhancing calcium sequestration in sarcoplasmic reticulumin skeletal muscle and has been used to treat NMS hypermetabolic symptoms. Some reviews found improvement in up to 80% of NMS patients treated with dantrolene monotherapy.27,32-35 Compared with supportive care, time to recovery may be reduced—and mortality decreased by almost one-half—when dantrolene is used alone or in combination with other medications.
Not all case reports have shown that dantrolene, benzodiazepines, ordopaminergic agonists are effective in treating NMS.31,36 In our opinion, only advanced NMS cases—with extreme temperature elevations, severe rigidity, and evidence of systemic hypermetabolism—benefit from dantrolene treatment.1,2
ECT has been used successfully to reduce mortality from NMS and other catatonic-spectrum disorders. It is usually employed after supportive therapy and psychopharmacologic interventions fail.2,15,16,27,37 ECT for acute NMS typically consists of a series of 6 to 10 treatments with bilateral electrode placement. Daily ECT may be needed initially.15