Oh Shacka - Dantrolene for Neuroleptic Malignant Syndrome?

You are in a community emergency department when a middle-aged woman is brought in by her husband for worsening confusion over the last two days.  The charge nurse comes and asks if it should be a stroke page because the patient has “slurred speech”.   You rush into the room, NIHSS card in hand ready to wheel the patient off to CT and are confronted by a worrisome picture.  The patient is burning man re-incarnate - She is laid out on the stretcher with all 4 limbs stiff and outstretched, is febrile to 39.4 and tachycardic to the 140’s.  Her blood pressure is normal. She can answer some of your questions (says she has trouble “saying” words) but is definitely confused.  You think that this might be good old sepsis, but something about her sets your tox-sense tingling …. and you ask her husband immediately for a medication list which contains a number of pro-serotonergic anti-depressants and a single anti-psychotic. 

Could this be serotonin syndrome?  Could this be NMS?  You  send off a CK level (which comes back at > 1000), initiate a sepsis work-up, get a head CT and phone a friend.  Your tox expert by phone helps you with this by asking a single question:  Well, does she have myoclonus  (SS) or is she rigid (NMS)?  Rigid has it, and you create a mnemonic for future reference:

Oh SHACKA this patient might have NMS:

Now that you think that this is like NMS, how is it best treated?  You have memorized for your board exams that bromocriptine is the treatment for NMS, but your toxicology friend reminds you that bromocriptine can worsen the symptoms of serotonin syndrome [1], and given this patient’s med list and possible mixed-picture, may not be the best idea. What about dantrolene?  Well, what about it?

Clinical question:  What is the mechanism of action for dantrolene? Does dantrolene have any proven effectiveness in the treatment of neuroleptic malignant syndrome? 

Literature Review: 
    Neuroleptic malignant syndrome is a rare, and potentially life-threatening adverse reaction to anti-dopaminergic anti-psychotic medication.  There are multiple established diagnostic criteria - the Levenson Criteria and DSM-IV - that are largely described by the mnemonic above. 

from Guzofski et. al. [2]

The exact pathophysiology of NMS is unknown, but the muscle rigidity (which looks a lot like Parkinsonism) is thought to be secondary to inhibition of dopamine-mediated signalling (as such this can also occur in Parkinson's patients in the setting of dopamine withdrawal).  This muscle rigidity can cause muscle

damage and subsequent rhabdomyolysis.  The hyperthermia may be the result of either (or both) the muscle rigidity or by direct effects of dopamine D2-receptor blockade on the hypothalamus.  Hyperthermia can become life-threatening, and thus the treatment, in addition to cessation of the offending agent, is to pharmacologically relax and cool down the patient.

Bromocriptine, a dopamine agonist, is sometimes used.  But as discussed above, if there is a serotinergic component to the patient's presentation, this could worsen serotonin syndrome.  Benzodiazepines and IV fluids are the mainstay of supportive care. 

            Dantrolene, the mainstay of treatment for malignant hyperthermia, has also been proposed and has been used for the treatment of NMS.  Dantrolene acts as a direct skeletal muscle relaxant by blocking calcium release from the sarcoplasmic reticulum [3].  As such, the main side effect is muscle weakness, but no reports of respiratory or airway compromise have been reported (at least in healthy volunteers) [3].  Given this mechanism, it is unclear why it would be helpful for NMS.  Like most things in toxicology, the majority of data regarding the efficacy (or lack thereof) of dantrolene in the treatment of NMS comes from case series and case reports. In 2007, a study published in Critical Care attempted to pool the results of 271 Case Reports to assess the effectiveness of dantrolene for the treatment of NMS [4].  From these 271 case reports, the authors collected patient data including gender, age, diagnosis, triggering medication, dosage, time of incidence, diagnostic criteria met, other laboratory parameters and whether the patients received dantrolene therapy alone, dantrolene + other medications, only other medications, or only supportive care.  The "other medications" and the scope of "supportive care" was not specified (or necessarily the same) between case reports.  The outcomes of the study were the following: reported improvement within 24 hrs, complete time to remission and overall mortality.  The authors found that dantrolene monotherapy was associated with a higher likelihood of improvement within 24 hrs and shortest time (9.4 +/- 12.7 days) to complete remission than dantrolene+ other medication, other medication or supportive therapy alone.  If this was not confusing enough (for example, why would dantrolene alone be better than dantrolene+other medication), the dantrolene monotherapy also had an overall higher mortality (16.2% vs. 7.3% for d+other, 8.9% for "other", and 2% for supportive care).  Given the innumerable caveats to pooling the data only from case reports and the difficult to interpret results, it is unclear whether dantrolene therapy is effective, helpful or potentially harmful in the treatment of NMS.  It is possible that patients who received dantrolene who were either 1) not very sick and so got better quickly or 2) very sick, in which case they received other medications (therefore the longer time to remission) or mismanaged by giving dantrolene alone leading to higher overall mortality.

Clinical Takehome: Know your hyperthermic toxidromes because they are not made better with antibiotics.  Regarding NMS, dantrolene has unproven effectiveness but lack of rigorous evidence that it causes harm.  Benzodiazepines and fluids will be your mainstay of treatment, give bromocriptine if you are confident in your diagnosis. Boom shaka laka.

References:
[1]Boyer, E. W., & Shannon, M. (2005). The serotonin syndrome. New England Journal of Medicine, 352(11), 1112-1120.
[2] Peralta, M. D. (2006). Neuroleptic malignant syndrome, with attention to its occurrence with atypical antipsychotic medication: a review. Jefferson Journal of Psychiatry, 20(1), 7.
[3] Krause, T., Gerbershagen, M. U., Fiege, M., Weisshorn, R., & Wappler, F. (2004). Dantrolene–a review of its pharmacology, therapeutic use and new developments. Anaesthesia, 59(4), 364-373.
[4]Reulbach, U., Dutsch, C., Biermann, T., Sperling, W., Thuerauf, N., Kornhuber, J., & Bleich, S. (2007). Managing an effective treatment for neuroleptic malignant syndrome. Crit Care, 11(1), R4.

Submitted by Maia Dorsett [@maiadorsett], PGY-3
Faculty Reviewed by Evan Schwarz [@TheSchwarziee]