1. A Rare Yet Serious Condition: Neuroleptic Malignant Syndrome (NMS)
Ravi Parmar
2017/2018 Island Health Pharmacy Resident
Psychiatry Rotation Oct 2017

2. Objectives To define NMS and outline a typical clinical presentation
To discuss the suspected pathophysiology of NMS and medications that are associated with this condition
To outline different treatment options for NMS

3. Definition
NMS is a potentially lethal neurological emergency known to be an adverse reaction to neuroleptic medications that can occur anytime during treatment (e.g. from 1-3 days after initiation or dose change, or after being stable on a dose for years)
Neuroleptic = a drug that depresses nerve functions
Modi et al. Neurocrit Care. 2016

4. Presentation
- Typically evolves over 1-3 days. Each feature is present in % of patients
UpToDate: Neuroleptic Malignant Syndrome

5. Diagnostic Criteria DSM V
Exposure to dopamine antagonist, or dopamine agonist withdrawal, within past 72 hours
Hyperthermia (>100.4°F or >38.0°C on at least 2 occasions, measured orally)
Rigidity
Mental status alteration (reduced or fluctuating level of consciousness)
CK elevation (at least 4 times upper limit of normal)
Sympathetic nervous system lability, defined as at least 2 of the following:
Blood pressure elevation (systolic or diastolic ≥25% above baseline)
Blood pressure fluctuation (≥20 mmHg diastolic change or ≥25 mmHg systolic change within 24 hours)
Diaphoresis
Urinary incontinence
Hypermetabolism, defined as heart rate increase (≥25% above baseline) and respiratory rate increase (≥50% above baseline)
Negative work-up for infectious, toxic, metabolic, and neurological causes.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 5th edition (DSM-5). Washington, DC: American Psychiatric Publishing; 2013.
DSM V 2013

6. Atypical Cases
Milder or atypical cases may rarely present in a manner in which all 4 cardinal features of the tetrad may not occur
These cases are thought to occur more often with low potency agents (e.g. atypical antipsychotics) or in these diagnosed early on
Rigidity may be milder or absent, and although fever is thought to be an essential feature, cases have been reported where it was not present
Diagnosis should be considered when any two of the tetrad of symptoms are present in a patient who is on a potentially contributing agent
UpToDate: Neuroleptic Malignant Syndrome

7. Differential

8. Suggested Workup Requested Test Why Requested Complete Blood Count
To exclude leukocytosis and all kinds of hemolysis and its consequences
Blood cultures
To exclude possibilities of septic shock (coma)
LFTs
To exclude hepatic failure for one reason or another
BUN and creatinine levels
To exclude renal failure
Calcium, phosphate, potassium, and sodium levels
To exclude electrolyte imbalances and hemolysis
CK level
To exclude or prove rhabdomyolysis or other myocytes type necrosis
Serum iron level
Because of rhabdomyolysis and other hemolytic pathologies
Urine myoglobin level
To exclude myoglobinuria
Arterial blood gas analysis
To exclude respiratory failure and metabolic acidosis
Coagulation studies
To exclude hepatic failure and disseminated intravascular coagulopathy
Serum and urine toxicologic screening
To exclude ASA, cocaine and amphetamines poisoning
Oruch et al. Neuropsychiatric Disease and Treatment. 2017

9. Lab Data in Typical Case of NMS
Parameters
Changes
Enzymes and abnormal protein in plasma
LDH
Increased CK
Increased in (50-100% of cases)
ALP
Myoglobin
Myoglobinemia
Serum electrolytes and proteolysis remnants
Phosphate
Hyperphosphatemia
Potassium
Hyperkalemia
Calcium
Hypocalcemia
Magnesium
Hypomagnesemia
Sodium
Hypo or hypernatremia
Oruch et al. Neuropsychiatric Disease and Treatment. 2017

10. Lab Data in Typical Case of NMS
Parameters
Changes
Elements of blood
Leukocytes
Leukocytosis (70-80% of cases)
Blood platelets (thrombocytes)
Thrombocytosis (thrombocytopenia – rarely)
Urine
Protein
Proteinuria (increased protein)
Myoglobin
Myoglobinuria (increased myoglobin)
pH (blood gas analysis)
Decreased (metabolic acidosis)
Oruch et al. Neuropsychiatric Disease and Treatment. 2017

11. Iron Deficiency in NMS
Reduced serum iron may reduce the number of functional dopamine receptors, thereby making patients more vulnerable to even seemingly low dose antipsychotics
In patients with suspected iron deficiency anemia with the requirement of antipsychotic therapy, it would be wise to initiate correction of the iron deficiency and give lower doses of antipsychotics whilst being vigilant of signs of NMS
Patil et al. Int J Appl Basic Med Res. 2014

12. Epidemiology
The incidence of NMS ranges from 0.02 to 3% for patients taking neuroleptic agents
It is seen more often in young adults, however can occur at any age
Males are approximately 50% more likely to be diagnosed at any age (possibly due to higher muscle mass, higher sweat gland output, and increased antipsychotic exposure)
The Canada Vigilance Reaction Outline (CVARO) database estimates 442 reported cases of NMS between Jan 1965 and Sep 2012
Gurrera RJ. Acta Psychiatr Scand. 2017
UpToDate: Neuroleptic Malignant Syndrome

13. Associated Medications
It is most often associated with typical high potency neuroleptics (e.g. haloperidol, fluphenazine)
However, every class of neuroleptic has been implicated, including low potency (e.g. chlorpromazine) and newer atypical antipsychotics (e.g. clozapine, risperidone, olanzapine) as well as antiemetic drugs (e.g. metoclopramide, promethazine)
UpToDate: Neuroleptic Malignant Syndrome

14. Associated Medications
Gautam Bhandari Neuroleptic Malignant Syndrome

15. Pathophysiology
The pathophysiology of NMS is not entirely understood, but it is believed to occur secondary to an acute imbalance or dysregulation of CNS neurotransmitters
The associated medications clearly implicate dopamine systems, but other neurotransmitter systems (GABA, epinephrine, serotonin, acetylcholine) appear to be involved as well
UpToDate: Neuroleptic Malignant Syndrome

16. Pathophysiology

17. Risk Factors Category Variable Pharmacological Treatment
Initial phases of treatment, or change of dosage
Any antipsychotic treatment (particularly high dose or high potency antipsychotic)
Parenteral administration (IV or IM)
Polypharmacy
Other compounds: antidepressants, mood stabilizers (especially lithium), antiparkinsonians
Environmental Factors
Physical restraint
Dehydration
High temperature
Demographics
Age
Multiple co-morbidites
Genetic Liability
Previous NMS
Family hx. of catatonic syndrome
Muscle channelopathy
Tse et al. Current Neuropharmacology. 2015

18. Primary Prevention
Use the lowest effective dose of antipsychotic medications
Avoid rapid escalation of antipsychotics if possible
Avoid abrupt withdrawal of dopaminergic agents
Treat agitation early, and use alternatives to antipsychotics when possible
Avoid dehydration
Strawn JR, Keck PE Jr, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry. 2007; 164:
Strawn et al. Am J Psychiatry. 2007

19. Discontinue offending agent
Treatment
Pharmacotherapy or
ECT
Discontinue offending agent
Supportive Therapy
UpToDate: Neuroleptic Malignant Syndrome

20. Discontinue Offending Agent
The single most critical strategy in the therapeutic management of this potentially lethal condition is to discontinue the suspected pharmacological compound
It is not necessary to delay discontinuation in order to seek confirmatory evidence. One should immediately discontinue the potentially harmful compound upon suspicion of NMS
Tse et al. Current Neuropharmacology. 2015

21. Supportive Therapy
The need for supportive care is NMS is essential, as complications may include:
Dehydration
Electrolyte imbalance
Acute renal failure associated with rhabdomyolysis
Cardiac arrhythmias including torsades de pointes and cardiac arrest
Myocardial infarction
Cardiomyopathy
Respiratory failure from chest wall rigidity, aspiration pneumonia, pulmonary embolism
Deep vein thrombophlebitis
Thrombocytopenia
Disseminated intravascular coagulation
Deep vein thrombosis
Seizures from hyperthermia and metabolic derangements
Hepatic failure
Sepsis
UpToDate: Neuroleptic Malignant Syndrome

22. Supportive Therapy
Cooling blankets and antipyretics (controversial – hyperthermia likely result of anticholinergic and dopaminergic effects of antipsychotics versus prostaglandins) may both be used to reduce fever
Fluid resuscitation and electrolyte correction may be required
Maintaining a slightly alkalotic pH may prevent rhabdomyolysis and AKI
For labile hypertension, calcium channel blockers have been suggested because they may also reverse toxicity at the musculoskeletal level
If immobilized from rigidity, DVT prophylaxis should be initiated
Patients with dysphagia may need a NG tube for administration of fluids, nutrition, and medications
In severe cases, intubation may be needed in patients with muscle rigidity extending to their airway
There have been reports of NMS being successfully treated with supportive therapy alone, however in cases of severe rigidity and hyperthermia, pharmacotherapy is generally required for symptom resolution
Pileggi et al. Annals of Pharmacotherapy. 2016

23. Pharmacotherapy Dantrolene Bromocriptine Benzodiazepines Amantadine
There is limited evidence on whether pharmacological treatments truly reduce symptoms or improve recovery, but options include:
Dantrolene
Bromocriptine
Benzodiazepines
Amantadine
Other agents with anecdotal success include levodopa, apomorphine, and carbamazepine
Pileggi et al. Annals of Pharmacotherapy. 2016
UpToDate: Neuroleptic Malignant Syndrome

24. Dantrolene
Direct skeletal muscle relaxant that disrupts excitation-contraction coupling by blocking calcium efflux from the sarcoplasmic reticulum
Dosage: Intravenously – 1 to 2.5 mg/kg initially; if rapid resolution of hyperthermia and rigidity is observed, may follow with 1 mg/kg q6h up to a max cumulative dose of 10 mg/kg/day, then switch to oral dosage
It is the drug of choice for treatment of malignant hyperthermia, and since 1981 has been routinely used for NMS treatment in more severe cases although efficacy data is controversial
There is an associated risk of hepatotoxicity and LFTs should be done prior to administration
The dose of dantrolene may be weaned over several days to avoid recurrence of NMS
Based on an analysis of 271 case reports, dantrolene in combination with other therapies (e.g. bromocriptine) may be preferred over monotherapy due to lower mortality and longer complete time of remission
Tse et al. Current Neuropharmacology. 2015
Lexicomp: Dantrolene
Pileggi et al. Annals of Pharmacotherapy. 2016

25. Bromocriptine
Ergot derivative with potent agonist activity in the postsynaptic D2 receptor
Used primarily in the treatment of Parkinson's Disease, however in NMS it may counteract dopamine blockade attributed to antipsychotics
Dosage: Oral – 2.5 mg (orally or via gastric tube) every 8-12 hours, increased to a maximum of 45 mg daily, if needed; continue therapy until NMS is controlled, then taper slowly
Because of its ability to cause hypotension, initial dosing tends to begin in the lower end of the dosing range, and upward titration as tolerated is done over several days
Tse et al. Current Neuropharmacology. 2015
Lexicomp: Bromocriptine
Pileggi et al. Annals of Pharmacotherapy. 2016

26. Benzodiazepines
Work through reversal of the hypofunctioning GABAergic system that contributes to NMS symptoms
Of the benzodiazepines, literature supports use of lorazepam, diazepam, and clonazepam as treatment for NMS
Dosages used varied between studies (e.g. lorazepam 1-2 mg IM or IV q4-6h, diazepam 10 mg IV q8h, clonazepam 1 mg q3h)
Can be administered by several different routes (IV, IM, oral, buccal, intranasal, and rectal), so the route and dose can be individualized based on clinical scenario
Patients should be monitored for signs of respiratory depression and/or delirium
Pileggi et al. Annals of Pharmacotherapy. 2016

27. Amantadine
Though the mechanism through which it works is not clearly understood, it is likely a result of both direct increase in dopamine release and reduction in reuptake
It also has anticholinergic-like activity that could shift D2 receptors to high affinity states and functions as a weak NMDA receptor antagonist and has shown to improve dyskinesias associated with levodopa
Dosage: Oral – 100 mg orally or via gastric tube and is titrated upward as needed to a maximum dosage of 200 mg q12h
Generally used as adjunctive treatment in NMS for moderate to severe cases
Pileggi et al. Annals of Pharmacotherapy. 2016
UpToDate: Neuroleptic Malignant Syndrome

28. ECT
When multiple medications have failed, ECT has been used successfully
It has also been suggested that patients with only a partial response to pharmacotherapy could receive a course of ECT to ameliorate the remaining symptoms
It is unclear how this method improves symptoms, but it has been shown to be effective in a variety of other refractory psychological illnesses
Safety concerns include cardiovascular complications, status epilepticus, uncontrolled spontaneous seizures, and aspiration pneumonia as reported through case reports of ECT in NMS
Pileggi et al. Annals of Pharmacotherapy. 2016
UpToDate: Neuroleptic Malignant Syndrome

29. Treatment Algorithm
Pileggi et al. Annals of Pharmacotherapy. 2016

30. Prognosis
Mainly dependent on early diagnosis and active intervention without delay
Most cases resolve within two weeks. Reported mean recovery times are 7 to 11 days (longer if LAIs implicated)
Although the majority of cases can be successfully managed, it is important to be aware that ~ 10% of cases can be fatal, regardless of early diagnosis and treatment
Oruch et al. Neuropsychiatric Disease and Treatment. 2017

31. Restarting Neuroleptics
The population most at risk for developing NMS from antipsychotic use is generally the same population that needs this therapy the most for their underlying condition
Reported rates of recurrence of NMS vary and may be as high as 30%
Following resolution of NMS, the patient should be evaluated for re-challenge with neuroleptics or for management with an alternative agent
If antipsychotic therapy needs to be continued, an agent that has low D2 affinity (e.g. quetiapine) should be selected and started at a low initial dose
Acute recurrence of NMS may depend more on the time between NMS resolution and re-challenge than on the antipsychotic chosen
Analysis of more than 40 re-challenges have suggested success if the washout period from symptom resolution is at least 5 days (another report suggested at least 14 days)
Careful monitoring and slow titration are required regardless of the period
ECT may be a possible treatment option for the underlying illness if patients refuse re-challenge or have severe sequelae
Pileggi et al. Annals of Pharmacotherapy. 2016

32. Summary
NMS is a potentially lethal neurological emergency known to be an adverse reaction to neuroleptic medications
Believed to occur secondary to an acute imbalance or dysregulation of CNS neurotransmitters (especially dopamine systems)
Cardinal symptoms include: fever, muscle rigidity, altered mental status, and autonomic instability
The most important treatment option is stopping suspected contributing medications. Supportive measures are also vital for the numerous potential complications of NMS
Other pharmacologic options include: dantrolene, bromocriptine, benzodiazepines, amantadine, and ECT
Prognosis mainly depends on early diagnosis and active intervention without delay