Neuroleptic malignant syndrome in clinical practices

Topic: Neuroleptic Malignant Syndrome is a rare but specifi c lethal reaction to neuroleptics / antipsychotics.It occurs in 0.02% to 3.3% of patients in the treatment applying conventional neuroleptic drugs.Neuroleptic malignant syndrome is associated with highly potent antipsychotic drugs. However, it can occur more frequently in patients treated with atypical antipsychotics such as clozapine. Topic position in medical public: Neuroleptic malignant syndrome is critical medical condition, potentially threatening complication associated with side eff ects of neuroleptic drugs. High levels of creatine kinase (CK) and leukocytosis are associated with neuroleptic malignant syndrome. Future action: Neuroleptic malignant syndrome as a psychiatric entity requires permanent research, early diagnosis, adequate therapy, exchange of clinical experiences, and what’s of particular importance, rational antipsychotic administration.


TOPIC
Neuroleptic Malignant Syndrome (NMS) is a rare but specifi c lethal reaction to neuroleptics / antipsychotics.Neuroleptic malignant syndrome related to the treatment of antipsychotic haloperidol was fi rst described in 1960 by the Delay and associates [1].Although estimates incidence of neuroleptic malignant syndrome used to be even 3% of patients treated with antipsychotics, more recent data suggests incidence of 0.01% -0.02% [2].It is most oft en associated with typical highly potent antipsychotic drugs (e.g.haloperidol, fl uphenazine) [3].However, every class of antipsychotics implied, including low potent (e.g.chlorpro-mazine), newer atypical antipsychotics (e.g.clozapine, risperidone, olanzapine) and antiemetic medicines (e.g.metoclopramide, promethazine).Neuroleptic malignant syndrome is characterized by fever, muscle rigidity, altered mental status, autonomic dysfunction and increased creatine kinase [4 -5].
jor role as a trigger for this condition [6].Several arguments support this assumption: • withdrawal of dopaminergic drugs participating in neuroleptic malignant syndrome; • all drugs associated with malignant neuroleptic syndrome caused by dopamine receptor blockade; • seems that the risk of neuroleptic malignant syndrome correlates with affi nity of drugs for binding to dopamine receptors; • dopaminergic drugs are used to treat neuroleptic malignant syndrome, and it is noticed that patients with lesions of the central dopamine pathways develop syndromes sharing many clinical characteristics with neuroleptic malignant syndrome.
Th e central role of dopaminergic hypofunction is further supported by observation that the concentration of dopamine metabolites and homovanillic acid in cerebrospinal fl uid is low in patients with acute neuroleptic malignant syndrome [7].Polymorphisms in the dopamine 2 receptor gene in patients who have recovered from neuroleptic malignant syndrome have been researched in several preliminary studies, although the results are not consistent [8].However, the direct eff ect on peripheral skeletal muscles may have an additional role.Based on autonomic dysfunction observed in the last two decades related to the neuroleptic malignant syndrome and on observed increased values of catecholamine in many cases, it was pointed out that symphatoadrenal dysfunction has a role in contributing to neuroleptic malignant syndrome.Whatever mechanism causes neuroleptic malignant syndrome, pathophysiology of neuroleptic malignant syndrome is probably complicated and includes dysregulation cascade of multiple neurochemical and neuroendocrine system that culminate on the closing stage of hypermetabolic syndrome [9].

Pathogenesis
Neuroleptic malignant syndrome may occur as a result of changes in pre-/or posthypnotic dopaminergic signals.Th ere are two mechanisms: 1. Reduced DA signals as a result of the sudden withdrawal of dopaminergic drugs.2. Initiating the agents which block DA signals [9].
Th ere is great probability that neuroleptic malignant syndrome shall occur aft er starting treatment with antipsychotics or aft er increasing doses of the drug.Initiating neuroleptic malignant syndrome symptom may occur aft er a few hours, but on average, begins from 4 to 14 days aft er starting treatment.

Motor symptoms
Due to inclusion of the basal ganglia, the primary motor characteristic is rigidity or socalled 'lead bar' .Other motor irregularities include akinesia/bradykinesia, dystonia, inability to speak, chorea, dysarthria and tremor [10].

Altered mental status
Alternations in mental status ranging from confusion, delirium and stupor to coma are very common at neuroleptic malignant syndrome [11].

Autonomic instability
Autonomic dysfunction is manifested by respiratory irregularities, cardiac arrhythmia, variable blood pressure, incontinence and diaphoresis [13].

Diagnosis
Despite the available criteria, it is usually hard to distinguish neuroleptic malignant syndrome from frequent extrapyramidal undesired effects and other disorders occurring in similar symptoms; Criteria for researching DSM IV TR require presence of strong muscular rigidity and increased fever aft er the imminent application of antipsychotics.All three main criteria (fever, rigidity, increased serum creatine kinase), or two main and four secondary criteria (tachycardia, variable blood pressure, altered state of consciousness, diaphoresis, leukocytosis) indicate great probability of neuroleptic malignant syndrome if corroboratedclinically [14].Laboratory tests include: • Increased serum creatine kinase (CK); • Other laboratory irregularities [3].
Increased serum creatine kinase: In neuroleptic malignant syndrome, CK is usually higher than 1.000 IU/L and may reach 100.000IU/L.Increased CK value shows rhabdomyolysis as secondary in respect of muscular rigidity.It seems that the level of increased CK is in direct correlation with seriousness of the disease and higher value in accordance with prognosis [2 3].Th e second most consistent fi nding is leukocytosiswith white blood cell count of 10. 000 to 40.000.Laboratory value of leukocytes can be shift ed to left .Lactate dehydrogenase (LDH), alkaline phosphatase, and liver transaminase are frequently leniently increased.Irregularities of electrolytes in terms of hypocalcemia, hypo-or hypernatremia, hyperkalemia and metabolic acidosis are oft en noticed.Myoglobinuric acute renal failure may be the result of rhabdomyolysis.Low concentration value of iron in serum (mid value 5.71μmol/L) is oft en found in neuroleptic malignant syndrome and it is sensitive but not specifi c marker for neuroleptic malignant syndrome in acute patients.
Serious cases of neuroleptic malignant syndrome may be followed by stupor and coma.In these circumstances, lumbar puncture CSF may be implied to evaluate alternative cause and determine whether there is a threatening cerebral edema due to metabolic disorders.
Diff erential diagnosis of neuroleptic malignant syndrome divide into two categories:

FURTHER ACTION
Treatment Neuroleptic malignant syndrome is critical case and may lead to death if not treated.Th e fi rst step includes immediate recognition of neuroleptic malignant syndrome, immediate termination of antipsychotic drugs and exclusion of other medical conditions.Supportive medical care, specifi c pharmacotherapy and electroconvulsive therapy are useful in the overall treatment.Intensive monitoring and supportive treatment require admission to the intensive care unit.Th e following supportive treatment should be provided: • canceling antipsychotic drug administration or precipitating medicine • maintaining cardiorespiratory stability.However, mechanic ventilation and antiarrhythmicdrugs may be required.

Supportive medical care
• maintaining euvolemic state using intravenous fl uids.Unplanned loss of fl uids due to fever and diaphoresis should be also considered.
• decreasing temperature by chilling and using antipyretics.
•decreasing blood pressure, if it is signifi cantly increased

1 .
Conditions associated with neuroleptic malignant syndrome 2. Conditions unrelated to neuroleptic malignant syndrome Conditions associated with neuroleptic malignant syndrome are as following: • Serotonin syndrome • Malignant hyperthermia • Malignant catatonia • Acute lethal catatonia • Central cholinergic syndrome • Metabolic encephalopathy/ encephalitis Conditions unrelated to neuroleptic malignant syndrome: • infection of the central nervous system (meningitis / encephalitis) • Heat stroke • Delirium tremens • Parkinsonism • Acute porphyria • Septic shock • Tetanus • Strychnine intoxication • Pheochromocytoma www.hophonline.orgPharmacotherapy Conventional substances are dantrolene, bromocriptine and amantadine.It seems that clinical preferences determine the use of bromocriptine and/or dantrolene.In patients with strong muscle rigidity, rhabdomyolysis and extreme hypothermia, applying intravenous dantrolene may have advantage, with or without administering bromocriptine.Treatment is continued for at least 10 days.Early termination of treatment can precipitate the recurrence of neuroleptic malignant syndrome.Treatment with depot antipsychotics should be continued 2 to 3 weeks aft er clinical recovery.CONCLUSION NMS as psychiatric and biochemical entity requires: • permanent research including genetic research • early diagnosis • adequate therapy • interchanging clinical experiences • and, most importantly, rational antipsychotic administration.