the four major clinical symptoms of nms are hyperthermia , severe muscle rigidity , autonomic dysfunction , and altered mental status .
to date , several diagnostic criteria have been proposed for nms . according to the diagnostic criteria of the fourth edition of the diagnostic and statistical manual of mental disorders , text revision
( dsm - iv - tr),1 the major symptoms are hyperthermia and severe muscle rigidity , and minor symptoms are diaphoresis , dysphagia , tremor , incontinence , changes in level of consciousness ( ranging from confusion to coma ) , mutism , tachycardia , elevated or labile blood pressure , leucocytosis , and laboratory evidence of muscle injury ( eg , elevated creatine kinase [ ck ] ) .
the presence of two or more of the ten minor symptoms is necessary for a diagnosis of nms .
levenson2 suggested that elevated serum ck level is a major symptom used to diagnose nms .
this is in agreement with findings that serum ck is important for detecting nms.3,4 on the other hand , it has been reported57 that elevated ck levels are of relatively little importance in the diagnosis of nms .
however , elevated ck concentrations have been found in over 90% of patients with nms.2,5,8 as elevated ck is prevalent in the early stage of nms,9 clarification of the temporal appearance of serum ck may assist in the diagnosis of nms .
numerous case reports on nms have been published , but there have been no detailed studies on how muscle rigidity develops during nms .
furthermore , the relationship between ck concentration and the degree of muscle rigidity over the time course of nms from onset has not been established . in the present study ,
changes in serum ck and degree of muscle rigidity , and the temporal relationship between these factors , were evaluated in a large number of patients with nms .
between 1985 and 2012 , 38 patients were treated in the authors department for typical nms , characterized by a fever ( temperature > 38c ) , muscle rigidity , altered consciousness , autonomic dysfunction , and abnormal laboratory findings including elevated ck and leucocytosis . in a case of suspected nms
, body temperature and degree of muscle rigidity can be evaluated on a daily basis , but serum ck level can not always be measured this regularly . in order to evaluate temporal alterations in serum ck , measurements must be taken several times during the episode of nms .
serum ck levels could be evaluated only two or three times during the nms episode in 12 of the 38 patients ; therefore , it was difficult to evaluate temporal changes in serum ck in these 12 patients because the number of ck measurements was small .
there were two patients in whom serum ck level could be evaluated first on day 7 after the onset of fever ; therefore , it was difficult to evaluate the first weekly changes of serum ck in these two patients .
overall , 24 patients in whom serum ck level could be evaluated temporally were selected for the present study . as already noted , all 24 patients
had hyperthermia ( temperature > 38c ) , muscle rigidity , altered consciousness , and autonomic disturbances including diaphoresis , tachycardia , labile blood pressure , and hypersalivation , and all cases met the criteria for nms proposed in levenson,2 caroff and mann,5 and the dsm - iv - tr.1 a summary of patient characteristics is shown in table 1
. we have previously reported monoamine levels in cerebrospinal fluid in patients with nms.1012 specifically , cases 13 in table 1 correspond to cases 2 , 4 , and 5 , respectively , in the first of these reports ; cases 49 correspond to cases 14 , 6 , and 11 in the second report ; and cases 1015 correspond to cases 16 in the third report .
cases 1 and 24 have been reported recently.13 the summary of temporal changes in ck and muscle rigidity in individual patients is shown in table 2 . the first day on which fever of unknown etiology is observed
it should be noted that extrapyramidal symptoms persist in some patients with nms after hyperthermia has subsided.14 therefore , when patients become afebrile , disturbance of consciousness improves , and no autonomic dysfunction ( ie , diaphoresis , tachycardia , and labile blood pressure ) is observed , nms is considered to have resolved . taking case 1 as an example ,
was measured first on day 2 , and six times thereafter . including a further measurement after improvement of nms , serum ck
case 1 did not present with muscle rigidity until day 8 after the onset of fever . the nms evaluation scale proposed by sachdev15
was used to monitor temporal changes in muscle rigidity : 0 , nil ( no rigidity ) ; 1 , mild ( slight rigidity present , particularly obvious on recruitment of muscles responsible for jaw clenching ) ; 2 , moderate ( rigidity definitely present to a significant degree but produces no limitation of passive movement ) ; and 3 , severe ( rigidity that produces some limitation of passive movement ) .
the nms scale was proposed by sachdev in 2005 , enabling us to evaluate patients encountered since 2005 directly using this scale . prior to 2005
, we evaluated the temporal degree of muscle rigidity in patients using the ashworth scale16 or the modified ashworth scale17 to evaluate the movement of joints .
the obtained data enabled us to retrospectively evaluate the temporal degree by using the scale proposed by sachdev . because we did not measure body temperature in the days before fever onset in all patients , we retroactively used temperature readings taken on day 3 and day 7 and added them to table 3 .
temporal changes ( mean  standard deviation ) in body temperature , serum ck concentration , and degree of muscle rigidity during the course of nms are shown in table 3 .
all statistical tests were conducted using spss version 11 for windows ( ibm corporation , armonk , ny , usa ) . a one - way analysis of variance with dunnett s post hoc test was used to analyze changes in body temperature , serum ck levels , and degree of muscle rigidity .
baseline values of serum ck were considered to be those after recovery because values before fever were not available .
the relationship between serum ck and degree of muscle rigidity was examined using pearson s correlation coefficient .
between 1985 and 2012 , 38 patients were treated in the authors department for typical nms , characterized by a fever ( temperature > 38c ) , muscle rigidity , altered consciousness , autonomic dysfunction , and abnormal laboratory findings including elevated ck and leucocytosis . in a case of suspected nms
, body temperature and degree of muscle rigidity can be evaluated on a daily basis , but serum ck level can not always be measured this regularly . in order to evaluate temporal alterations in serum ck , measurements must be taken several times during the episode of nms .
serum ck levels could be evaluated only two or three times during the nms episode in 12 of the 38 patients ; therefore , it was difficult to evaluate temporal changes in serum ck in these 12 patients because the number of ck measurements was small .
there were two patients in whom serum ck level could be evaluated first on day 7 after the onset of fever ; therefore , it was difficult to evaluate the first weekly changes of serum ck in these two patients .
overall , 24 patients in whom serum ck level could be evaluated temporally were selected for the present study . as already noted , all 24 patients
had hyperthermia ( temperature > 38c ) , muscle rigidity , altered consciousness , and autonomic disturbances including diaphoresis , tachycardia , labile blood pressure , and hypersalivation , and all cases met the criteria for nms proposed in levenson,2 caroff and mann,5 and the dsm - iv - tr.1 a summary of patient characteristics is shown in table 1
. we have previously reported monoamine levels in cerebrospinal fluid in patients with nms.1012 specifically , cases 13 in table 1 correspond to cases 2 , 4 , and 5 , respectively , in the first of these reports ; cases 49 correspond to cases 14 , 6 , and 11 in the second report ; and cases 1015 correspond to cases 16 in the third report .
cases 1 and 24 have been reported recently.13 the summary of temporal changes in ck and muscle rigidity in individual patients is shown in table 2 . the first day on which fever of unknown etiology is observed
it should be noted that extrapyramidal symptoms persist in some patients with nms after hyperthermia has subsided.14 therefore , when patients become afebrile , disturbance of consciousness improves , and no autonomic dysfunction ( ie , diaphoresis , tachycardia , and labile blood pressure ) is observed , nms is considered to have resolved . taking case 1 as an example ,
was measured first on day 2 , and six times thereafter . including a further measurement after improvement of nms , serum ck
case 1 did not present with muscle rigidity until day 8 after the onset of fever . the nms evaluation scale proposed by sachdev15
was used to monitor temporal changes in muscle rigidity : 0 , nil ( no rigidity ) ; 1 , mild ( slight rigidity present , particularly obvious on recruitment of muscles responsible for jaw clenching ) ; 2 , moderate ( rigidity definitely present to a significant degree but produces no limitation of passive movement ) ; and 3 , severe ( rigidity that produces some limitation of passive movement ) .
the nms scale was proposed by sachdev in 2005 , enabling us to evaluate patients encountered since 2005 directly using this scale . prior to 2005
, we evaluated the temporal degree of muscle rigidity in patients using the ashworth scale16 or the modified ashworth scale17 to evaluate the movement of joints .
the obtained data enabled us to retrospectively evaluate the temporal degree by using the scale proposed by sachdev . because we did not measure body temperature in the days before fever onset in all patients , we retroactively used temperature readings taken on day 3 and day 7 and added them to table 3 .
temporal changes ( mean  standard deviation ) in body temperature , serum ck concentration , and degree of muscle rigidity during the course of nms are shown in table 3 .
all statistical tests were conducted using spss version 11 for windows ( ibm corporation , armonk , ny , usa ) . a one - way analysis of variance with dunnett s post hoc test was used to analyze changes in body temperature , serum ck levels , and degree of muscle rigidity .
baseline values of serum ck were considered to be those after recovery because values before fever were not available .
the relationship between serum ck and degree of muscle rigidity was examined using pearson s correlation coefficient .
the mean age of the study participants ( 12 men and 12 women ) was 38 years ( range 2160 years ) .
there was great variability among the peak ck concentrations , ranging from 495 to 44,880 iu / l . as shown in table 1 , there were only six patients who received intramuscular injections before fever onset .
the mean number of ck measurements in each case was 7.4 ( range 413 ) and the total number of measurements was 177 for the 24 cases . as also shown in table 2 , the most common day for ck concentration to peak was day 2 of nms ( seven cases ) , followed by days 3 , 4 and 5 ( three cases each ) .
mild muscle rigidity was observed in 17 of 24 cases ( 71% ) before the onset of fever . during the course of nms
, the strongest grade of rigidity , 3 , was seen in 20 patients and grade 2 was seen in four patients .
nms resolved in 23 patients without sequelae and one patient ( case 22 ) died .
as shown in table 3 , overall serum ck peaked on day 2 and normalized to 165 iu / l ( mean ) ( normal range 46210 ) on day 12 .
pearson s correlation test demonstrated that serum ck concentration was positively correlated with the degree of muscle rigidity ( r=0.0392 , p < 0.01 [ figure 1 ] ) .
the main findings of this study are : ( 1 ) serum ck peaked on day 2 after the onset of fever and returned to within normal limits by day 12 ; and ( 2 ) mild muscle rigidity was observed before the onset of fever in 17 of 24 cases ( 71% ) and was worst on day 4 .
serum ck is usually elevated following intramuscular injection , strenuous exercise , trauma , muscular injuries , acute psychosis , and restraint .
hence , elevated ck is not specific to nms and is therefore not a reliable diagnostic parameter .
the diagnosis of nms should be based on four clinical symptoms : fever , altered consciousness , muscle rigidity , and autonomic dysfunction .
however , it has been established that elevated ck is found in over 90% of patients with nms.2,5,8 therefore , if patients treated with antipsychotics develop a fever of unknown cause and their serum ck levels are elevated nms should be suspected in addition to other conditions in which serum ck levels are elevated .
if muscle rigidity is observed , the patient has a higher risk of developing nms .
therefore , it is important for diagnosing nms to understand how serum ck concentration and the degree of muscle rigidity change during the course of nms .
harsch18 reported that ck concentration peaked 2448 hours after onset in nine cases of nms , and rosebush and stewart19 reported among 24 episodes of nms a peak on days 2 and 3 after onset in 64% of episodes , on days 4 to 7 in 29% , and on day 1 in 7% .
the present study is the first to examine temporal changes in serum ck in numerous nms cases , and the present results confirm the above findings . muscle rigidity was observed in 17 of 24 cases ( 71% ) before the onset of fever .
velamoor et al20 investigated 222 nms patients previously reported and concluded that mental status change or muscle rigidity was the initial manifestation in 82.3% of cases .
al did not evaluate when the degree of muscle rigidity became most severe ; however , the results of the present study demonstrate a peak on day 4 after the onset of fever .
taken together , in many cases it appears that serum ck concentration rapidly increases after the onset of fever , peaks on day 2 , and normalizes on day 12 .
by contrast , mild muscle rigidity is present at the onset of nms in 71% of cases and peaks on day 4 . on the other hand
, we reported exceptional cases of nms with regard to temporal changes in serum ck and muscle
rigidity.13 as muscle rigidity first appeared after serum ck had normalized in cases 1 and 24 , physicians should be aware of the existence of these uncommon findings .
we calculated pearson s correlation coefficient to assess the relationship between serum ck levels and degree of muscle rigidity and noted a significant positive but weak correlation ( r = 0.198 ) .
serum ck is elevated in numerous situations . to conclude that elevated ck is significantly associated with degree of muscle rigidity ,
it is necessary to rule out other factors including intramuscular injection , strenuous exercise , and acute catatonia .
therefore , at present , we are unable to ascertain whether elevated ck is associated with muscle rigidity .
average body temperature peaked on days 1 and 2 , and gradually decreased during the course of nms in 24 cases .
it is possible that low - grade fever preceded the appearance of hyperthermia ( temperature > 38c ) .
as we did not measure body temperature on the day prior to hyperthermia onset in any cases , it is unclear whether body temperature generally peaks on day 1 or 2 of nms
first , the study was carried out retrospectively to assess the degree of muscle rigidity .
it will be necessary to examine this condition prospectively in a large sample population with nms .
second , serum ck was randomly measured in each patient ; daily measurement of ck is difficult because nms is rare and measurement of serum ck is not a routine examination . in conclusion
mild muscle rigidity was observed in about 71% of 24 cases , and the degree of muscle rigidity was worst on the fourth day , after which it gradually resolved .
the findings of our study confirm physicians empirical knowledge of serum ck concentration and muscle rigidity in nms based on the data accumulated from numerous patients with this syndrome .
 neuroleptic malignant syndrome ( nms ) is a dangerous adverse response to antipsychotic drugs . 
 it is characterized by the four major clinical symptoms of hyperthermia , severe muscle rigidity , autonomic dysfunction , and altered mental state . 
 serum creatine kinase ( ck ) elevation occurs in over 90% of nms cases . in the present study , 
 the detailed temporal changes in serum ck and degree of muscle rigidity , and the relationship between ck concentration and degree of muscle rigidity over the time course from fever onset , were evaluated in 24 affected patients . 
 the results showed that serum ck peaked on day 2 after onset of fever and returned to within normal limits at day 12 . 
 mild muscle rigidity was observed before the onset of fever in 17 of 24 cases ( 71% ) . 
 muscle rigidity was gradually exacerbated and worsened until day 4 after onset of fever . 
 these findings confirm physicians empirical understanding of serum ck concentrations and muscle rigidity in nms based on data accumulated from numerous patients with the syndrome , and they indicate that serum ck may contribute to the early detection of nms . 