This document discusses Neuroleptic Malignant Syndrome (NMS), a life-threatening reaction that can occur due to treatment with antipsychotic medications. It defines NMS as a condition characterized by fever, severe muscle rigidity, and changes in mental status and autonomic function. The document outlines risk factors for NMS, diagnostic criteria, treatment recommendations including immediate discontinuation of the causative drug, and supportive care. Dopaminergic medications like bromocriptine may help reduce time to recovery and mortality rates.

1. Neuroleptic Malignant Syndrome

2. Definition NMS is an idiosyncratic, life-threatening complication of treatment with antipsychotic drugs that is characterized by fever, severe muscle rigidity, and autonomic and mental status changes ( Strawn et al 2007)

3. Prevalence Although estimates of the incidence of NMS once ran as high as 3% of patients treated with antipsychotics, more recent data suggest an incidence of 0.01%–0.02% This decrease in frequency likely reflects increased awareness of the disorder, more conservative prescribing patterns, and the shift to use of atypical antipsychotics.

4. Morbidity and Mortality NMS remains a significant source of morbidity and mortality among patients receiving antipsychotics. For example, data from the U.S. Agency for Healthcare Research and Quality indicate that about 2,000 cases of NMS are diagnosed annually in hospitals in the United States, incurring health care costs of $70 million, with a mortality rate of 10%,

5. Differential Diagnosis of Neuroleptic Malignant Syndrome Infectious Meningitis or encephalitis Post infectious encephalomyelitis syndrome Brain abscess Sepsis Psychiatric or neurological Idiopathic malignant catatonia Agitated delirium Benign extrapyramidal side effects No convulsive status epilepticus Structural lesions, particularly involving the midbrain Toxic or pharmacological Anticholinergic delirium Salicylate poisoning Malignant hyperthermia (inhalational anaesthetics, succinylcholine) Serotonin syndrome (monoamine oxidase inhibitors, triptans, linezolid) Substances of abuse (amphetamines, hallucinogens) Withdrawal from dopamine agonists, baclofen, sedative hypnotics, and alcohol Endocrine Thyrotoxicosis Pheochromocytoma Environmental Heatstroke

6. Diagnosis Box 1: Clinical and laboratory features of neuroleptic malignant syndrome* • The development of severe muscle rigidity and elevated temperature associated with the use of neuroleptic medication. • Two or more of the following: diaphoresis, dysphagia, tremor, incontinence, changes in level of consciousness ranging from confusion to coma, mutism, tachycardia, elevated or labile blood pressure, leucocytosis, laboratory evidence of muscle injury (e.g., elevated creatinine phosphokinase). • The symptoms are not due to another substance (e.g., phencyclidine) or a neurologic or other general medical condition. • The symptoms are not better accounted for by a mental disorder (e.g., mood disorder with catatonic features).

7. PCP (Phencyclidine) Angel dust has a reputation for causing psychotic episodes, but what are the true facts behind PCP? PCP, or phenylcyclohexylpiperidine, is a stimulant with strong hallucinogenic properties. It's sold as a white crystalline powder which can be prepared for injection, sniffing, smoking or swallowing. A liquid form, commonly called embalming fluid, can also be found. What are the effects of PCP? Feelings of dreaminess and mild hallucinations Users also experience distortions in their perception of time and space. What are the risks of taking PCP? Even in low doses, PCP can lead to severe psychological trauma Users may feel agitated and paranoid, leading to outbursts of violent behaviour including self-mutilation Large doses can cause respiratory arrest or kidney failure Excessive doses can lead to convulsions and even death It can be difficult to administer safe doses of a drug whose strength wildly fluctuates PCP is frequently laced with other illicit substances (such as marijuana) and the buyer not made aware of its presence. The law and PCP: Phencyclidine is a Class A drug, meaning possession can carry a sentence of up to seven years in prison. Other terms for PCP: Angel dust, ozone, embalming fluid, wack, rocketfuel, elephant tranquiliser, dust, kools, and sherms

8. Definitions Diaphoresis Leukocytosis, A simple and easy way to understand the profuse diaphoresis definition is to think of this condition as simply sweating excessively. Leukocytosis, defined as a white blood cell count greater than 11,000 per mm3 (11 X 109 per L),1 is frequently found in the course of routine laboratory testing. An elevated white blood cell count typically reflects the normal response of bone marrow to an infectious or inflammatory process. Occasionally, leukocytosis is the sign of a primary bone marrow abnormality in white blood cell production, maturation or death (apoptosis) related to a leukemia or myeloproliferative disorder.

9. Significance of elevated levels of serum creatine phosphokinase in febrile diseases: a prospective study. Peak value of blood myoglobin predicts acute renal failure induced by rhabdomyolysis The incidence and significance of elevated serum levels of creatinephosphokinase (CPK) in febrile diseases were studied prospectively in all patients admitted with fever to a department of medicine during 1 year. High serum CPK levels were detected in 70 (28%) of 247 febrile patients but in only six (6%) of 105 afebrile control patients (P =.0001). Elevated CPK levels were not related to any specific diagnosis. Logistic regression analysis identified five factors that correlated both significantly and independently with elevation of CPK values: increased blood urea nitrogen level, low serum phosphate level, a stuporous or comatose state, tremor, and muscle tenderness. Myoglobinuria, detected in 14 patients, was predictive of a fatal outcome, but a high CPK level by itself was not an independent correlate of mortality. In summary, CPK elevation is not uncommon in febrile diseases, but because it does not reflect a specific etiology it does not necessarily indicate that an extensive diagnostic work-up is required. Acute renal failure (ARF) is the most important complication of rhabdomyolysis. Serial measurements of blood myoglobin might be useful for predicting rhabdomyolysis-induced ARF. Methods Thirty patients with rhabdomyolysis were examined. The causes of rhabdomyolysis were trauma, burns, and ischemia, among others. Serial blood myoglobin levels were measured by immunochromatography, and the peak value was determined. The relationship between blood myoglobin levels and the incidence of ARF was evaluated. Results The median peak blood myoglobin level was 3335 ng/mL. Acute renal failure occurred in 12 patients (40%). Nine patients (30%) underwent renal replacement therapy. Peak creatine kinase and peak blood myoglobin levels in the ARF group were significantly higher than those in the non-ARF group. Three patients in the ARF group were treated with renal replacement therapy before occurrence of uremia because of extremely high levels of blood myoglobin (>10 000 ng/mL). Receiver operating characteristic analysis showed that the area under the curve for blood myoglobin that predicted ARF was 0.88, and the best cutoff value for blood myoglobin was 3865 ng/mL. Conclusions The peak value for blood myoglobin might be a good predictor of rhabdomyolysis-induced ARF. Early renal protective therapies should be considered for patients with rhabdomyolysis at high risk of ARF.

10. Diagnosis NMS is often difficult to distinguish from more common extrapyramidal side effects of antipsychotics and from other disorders presenting with similar symptoms. About 16% of cases of NMS develop within 24 hours after initiation of antipsychotic treatment, 66% within the first week, and virtually all cases within 30 days (11). It would be unusual for NMS to occur beyond 1 month after initiation of treatment unless the dose was increased or an additional antipsychotic administered.

11. Length of Recovery Once NMS is diagnosed and oral antipsychotic drugs are discontinued, NMS is self-limited in most cases. The mean recovery time after drug discontinuation is in the range of 7–10 days, with 63% of patients recovering within 1 week and nearly all within 30 days However, the duration of NMS episodes may be prolonged when long-acting depot antipsychotics are implicated. In addition, there have been several reports of patients in whom residual catatonia and parkinsonism persisted for weeks after the acute metabolic symptoms of NMS resolved

12. Risk Factors Several clinical, systemic, and metabolic factors have been correlated with the incidence of NMS, including agitation, dehydration, restraint, pre existing abnormalities of CNS dopamine activity or receptor function, and iron deficiency Nearly all case series of NMS patients have reported physical exhaustion and dehydration prior to the onset of NMS . Elevated environmental temperature has been proposed as a contributing factor in some series, although NMS can occur independent of ambient conditions. A prior episode of NMS has been described in 15%–20% of cases

13. Treatment Supportive Therapy The offending agent must be withdrawn immediately, after which supportive medical therapy is the mainstay of management of NMS Volume resuscitation should be aggressive, especially given that most patients with NMS are dehydrated in the acute phase of the illness. Serial monitoring and correction of electrolyte abnormalities is critical. In extreme hyperthermia, physical cooling measures are paramount, as the peak and duration of temperature elevation are predictive of morbidity and mortality Intensive medical care should include careful monitoring for complications, including cardiorespiratory failure, renal failure, aspiration pneumonia, and coagulopathies, and may involve support of cardiac, respiratory, and renal function

14. Pharmacological Treatments NMS is a self-limited iatrogenic disorder, and in many cases medical management and cessation of antipsychotic medication may suffice to reverse the symptoms. Benzodiazepines. Although a controlled evaluation of NMS risk factors suggests that benzodiazepines do not have a preventive effect, several clinical reports suggest that benzodiazepines, administered orally or parenterally, may ameliorate symptoms and hasten recovery in NMS, particularly in milder cases.

15. Dopaminergic Agents Several dopaminergic drugs, including bromocriptine and amantadine, may reverse parkinsonism in NMS and have been reported in case reports and meta-analyses to reduce time to recovery and halve mortality rates when used alone or in combination with other treatments. Bromocriptine can worsen psychosis and hypotension. It also may precipitate vomiting and thus should be used carefully in patients at risk of aspiration. Premature discontinuation of bromocriptine has resulted in rebound symptoms in some cases. Bromocriptine (Parlodel) is classified as a dopamine agonist drug that lowers prolactin levels. Primarily used in Parkinson's disease patients to lower high prolactin level. Bromocriptine was soon discovered to be of great use in many medical conditions as well as off label uses. Elevation of dopamine levels may lead to a marked increase in sex drive, improvement in mood, alertness, learning ability and creativity. Known off-label uses for dopaminergic drugs such as Bromocriptine include sex drive enhancement and increased ejaculation volume, mood elevation, appetite suppression and fat loss. Amantadine is generally initiated at 200–400 mg/day in divided doses administered orally or through a nasogastric tube. The starting dose of bromocriptine is 2.5 mg orally two or three times a day, increased to a total daily dose of 45 mg if necessary

16. Dantrolene. Because of its efficacy in anaesthetic-induced malignant hyperthermia, the muscle relaxant dantrolene has been used in the treatment of NMS. Dantrolene may be useful only in cases of NMS with extreme temperature elevations, rigidity, and true hyper metabolism Generally, rapid reversal of the hyperthermia and rigidity is observed in patients treated with dantrolene, but symptoms may return if treatment is discontinued prematurely.

17. ECT A review (32) found that ECT was consistently effective even after failed pharmacotherapy and that clinical response often occurred over the course of the first several treatments. Treatment response to ECT was not predicted by age, sex, psychiatric diagnosis, or any particular features of NMS. A typical ECT regimen for acute NMS would include six to 10 treatments with bilateral electrode placement.

18. Antipsychotic Use Following NMS Restarting antipsychotic treatment after resolution of an NMS episode has been associated with an estimated likelihood of developing NMS again as high as 30% At least 2 weeks should be allowed to elapse after recovery from NMS before rechallenge; low doses of low-potency conventional antipsychotics or atypical antipsychotics should be titrated gradually after a test dose; and patients should be carefully monitored for early signs of NMS.

19. References http://www.steroidsclub.eu/bromocriptine-buy-204.html http://www.thesite.org/drinkanddrugs/drugsafety Cohen O, LeiboviciL, MorF, WysenbeekAJSignificance of elevated levels of serum creatine phosphokinase in febrile diseases: a prospective study. Reviews of Infectious Diseases [1991, 13(2):237-42] Kasaoka S, TodaniM, Kaneko T, Kawamura Y, OdaY, TsurutaR, Maekawa T, Peak value of blood myoglobin predicts acute renal failure induced by rhabdomyolysis.Journal of Critical Care [2010, 25(4):601-4]