A brief overview on Neuroleptic Malignant Syndrome presented for the PGs and the faculty of Dept. of Medicine, Govt. Medical College Kannur, Kerala, India

1. NEUROLEPTIC MALIGNANT
SYNDROME
Dr. Sumesh Balachandran
Assistant Professor
Dept. of Psychiatry
Govt. Medical College Kannur, Kerala

2. CONTENTS
 Case Vignette
 Introduction
 Diagnosis
 Pathophysiology
 Risk factors
 Causative drugs
 Laboratory findings
 Differential Diagnosis
 Management
 Prognosis
 Conclusion

3. Case Vignette
• A 45 year old woman
• History of BPAD and hypertension
• Hospitalized with depressed mood of one month’s duration.
• In prior episodes, she had received antidepressants, lithium
and ECT.
• On admission, she was excited with idiosyncratic behavior
with confused speech and thought.

4. • Two doses of haloperidol were administered.
• Her excitement subsided.
• She became grandiose, garrulous and paced
continuously.
• Lithium carbonate was prescribed and fluphenazine
hydrochloride (5 mg Q.D.S. daily) was added.
• Within 48 hours, she exhibited bilateral cogwheel
rigidity
• Improved with IM promethazine hydrochloride.

5. • The next day, she became tremulous, had persistent cogwheel
and her temperature rose to 100 F.
• Contemplating neurotoxicity, both lithium and fluphenazine
were discontinued.
• Her condition worsened and she became mute, tremulous and
rigid and diaphoretic.
• B.P. and heart rate increased, temperature rose to 103.5 F.

6. • Lungs clear
• Abdomen- soft, non- tender, nil bowel sounds
• No meningism or focal neurological deficit
• Pupils – normal, reactive
• No clonus
• Reflexes normal
• WBC count was 13,500/ cubic mm and CPK was 1486 IU/l. All
other investigations WNL (including CT Brain and EEG).
How will you manage this case?

7. • Neuroleptic Malignant Syndrome
• Syndrome malin des neuroleptiques

8. Introduction
• Rare but potentially life-threatening idiosyncratic reaction
• First description (Delay et al. )- 1960 - Haloperidol
• Incidence – 0.02 to 3 %
• Males > females (3:2)
• Age - < 20 years and > 65 years
• A retrospective study conducted in India showed an
incidence of 0.14%.
Chopra MP, Prakash SS, Raguram R. The neuroleptic malignant syndrome: an Indian
experience. Compr Psychiatry. 1999 Jan-Feb. 40(1):19-23.

9. • NMS usually occurs after exposure to an neuroleptic drug.
• On an average, onset is 4-14 days after the start of therapy
• 90% of cases occur within 10 days.
• NMS can occur years into therapy.
• Once the syndrome starts, it usually evolves over 24-72 hours.
• Mnemonic- “ F.E.V.E.R.”

10. Diagnostic criteria (DSM 5) (all 3 major or 2 major
and 2 minor)
• Major criteria (all required)
1. Exposure to dopamine antagonist
or dopamine agonist withdrawal
with 72hours
2. Muscle rigidity
3. Hyperthermia (>100.4 deg. F or >
38 deg. C, measured orally on at
least two occasions)
• Nierenberg and colleagues’
criteria
• Levenson’s criteria
• Caroff and Mann’s criteria
• Hope’s criteria
• Minor (at least 2 required)
1. Diaphoresis
2. Dysphagia
3. Tremor
4. Incontinence
5. Altered levels of consciousness
6. Mutism
7. Tachycardia
8. Elevated or labile B.P.
9. Leukocytosis
10. Elevated CPK (> 4 times)

11. 70 %
Altered
consciousness
Autonomic instability
Generalized rigidity
with tremors
Hyperthermia
NMS

12.  Altered mental state
• Perplexity
• Delirium
• Stupor
• Coma

13.  Rigidity
• Generalized and extreme
• Lead pipe rigidity
• Superimposed on tremors  cog- wheel
• Generalized tremors
• Dyskinesia, dysarthria and myoclonus
• Catatonic symptoms (mutism, posturing, waxy
flexibility, catalepsy)

14.  Autonomic instability
• Tachycardia (in 88 percent)
• Labile or high blood pressure (in 61 to 77
percent),
• Tachypnoea (in 73 percent)
• Dysrhythmias
• Incontinence
• Diaphoresis- profuse (“greasy” sweat)

15.  Hyperthermia
• 100 to 105 degrees F
• May not be evident with second generation
antipsychotics
• May be fluctuating

17. • “Atypical” NMS:
- DSM 5 criteria not met
- Milder form
- Only hyperthermia and/or rigidity
- Clozapine, Aripiprazole and paliperidone

18. Pathophysiology
• Secondary to decreased dopamine (DA) activity in
central nervous system (CNS):
• • Blockade of dopamine type 2 receptors (D2
receptors)
• • Decreased availability of DA itself.
• Direct effect on peripheral skeletal muscles may play
an additive role

20. • Hypothalamic D2 receptor blockade results in an
elevated temperature set point
• Impairment of heat-dissipating mechanisms (eg.
cutaneous vasodilatation, sweating)
• Nigrostriatal blockade results in muscular rigidity.

21. • Peripherally, antipsychotics lead to increased calcium
release from the sarcoplasmic reticulum
• Increased contractility, which can contribute to
hyperthermia, rigidity, and muscle cell breakdown.
• Removing tonic inhibition from the sympathetic
nervous system.
• The resulting sympathoadrenal hyperactivity and
dysregulation leads to autonomic dysfunction.

22. • Animal model studies- orexin-A (an excitatory
neuropeptide) can cause thermogenesis in a
manner unrelated to muscle activity.
• Orexin-1 receptor plays a role in the effects of
psychotropics on dopamine pathways
• And probably the clinical effects of these agents
(therapeutic and side effects).

23. Risk factors
• Genetics
• Young Males
• Dehydration/ malnutrition
• Exposure to high ambient temperatures
• Agitation or excitement
• Catatonic features, past or present
• Tardive dyskinesia, akathisia, EPS

24. Risk factors (contd..)
• Past history of NMS
• Sudden dose escalation of antipsychotics
• High potency antipsychotic or two or more
antipsychotics
• High potency antipsychotic with an
antidepressant or mood stabilizer (lithium)
• IM antipsychotic or depot antipsychotic
• Recent alcohol abuse with liver dysfunction

25. Risk factors (contd..)
• Alcohol use
• Trauma
• Infections
• Thyrotoxicosis,
• Premenstrual/ Post partum phase

26. Early signs
• Rapidly developed extra-pyramidal signs of
tremors, rigidity, dyskinesia to low or modest
doses of an antipsychotic
• Mania with fever
• Within 24 hours of initial - Catatonia
antipsychotic administration - Sialorrhoea
- Autonomic
instability

27. Pharmacological agents
Withdrawal of:
• Levodopa (L-DOPA)
• Tolcapone/entacapone
• Dopamine agonists (e.g.
bromocriptine)
• Amantadine
• Clozapine
Intoxication with:
• Disulfiram
• Steroid
• Anticholinergics
• Cocaine
Introduction of:
• Neuroleptics:
Phenothiazines,
butyrophenones,
thioxanthenes
• “Atypical” antipsychotics:
clozapine, olanzapine,
risperidone, quetiapine
• Metoclopramide
• Promethazine

29. Abnormal laboratory findings
• Very high CPK
- 1000 – 10000 IU/L
• Low serum iron (11- 32 µmol/L)
- sensitive marker
- 5.17 µmol/L
• High LDH
• Leukocytosis with a left shift (10,000 to 40,000)

30. Abnormal laboratory findings
• Proteinuria
• Myoglobinuria
• Thrombocytosis
• Metabolic acidosis
• Liver transaminases
elevated
• Diffuse EEG slowing
• High CSF proteins
• Dyselectrolemia
- Hypocalcaemia,
- Hypomagnesaemia
- Hyperkalemia
- Hyper/ hyponatremia

32. Differential Diagnosis
• Other neuroleptic induced reactions
- Dystonia
- Akathisia
- Dyskinesias
- Pseudoparkinsonism
• Malignant Catatonia
- prodrome of excitement and agitation with hyperthermia prior to
the onset of rigidity
- episodes of catatonia while a patient is not taking neuroleptics
- Serotonin syndrome - Clonus and hyperreflexia, hypertonia
- Malignant hyperthermia

33. • Central nervous system infections
• Status epilepticus
• Stroke
• Brain trauma
• Neoplasms
• Acute intermittent porphyria
• Tetanus
• Thyroid Storm
• Heat stroke
• Sepsis
• Pheochromocytoma
• Drug intoxication

34. Management
• Mainly supportive!!!
• Prevent complications
• ICU care is quintessential
• Discontinue all antipsychotics

35. • Assessment of the airway, breathing, and
circulation (ABCs)
• Assess safety and restrain if needed (chemical
preferred)
• Thiamine, dextrose (or rapid glucose
determination), and/or naloxone, in case of
alcohol withdrawal, hypoglycemia, and opioid
overdose
• Take a detailed drug history

36. Conservative management

37. • Circulatory and ventilatory support as needed.
• Antipyretics
• Evaporative cooling
• Ice packs (axilla)
• Cooled intravenous (IV) fluids
• Cooling blankets
• Ice water gastric lavage
• Prophylactic intubation for patients with excessive
salivation, swallowing dysfunction, coma, hypoxemia,
acidosis, and severe rigidity with hyperthermia

38. • If B.P. is significantly elevated
- Nitroprusside (cutaneous vasodilatation)
- Clonidine
• Heparin or low molecular weight heparin for
prevention of deep venous thrombosis

39. • Consultations – eclectic team approach
- Neurologist
- Nephrologist
- Cardiologist
- Psychiatrist

40. • Aggressive fluid resuscitation and alkalization
of urine
• Sodium bicarbonate
- prevent acute renal failure and
- enhance excretion of muscle breakdown
products

41. Pharmacotherapy

42. • Benzodiazepines
- For mild NMS
- Lorazepam -1 to 2 mg IM or IV every four to
six hours
- Diazepam 5 to 10 mg IV every eight hours.

43. • Bromocriptine mesylate
- Dopamine agonist
- 2.5 mg orally two or three times a day, increased by
2.5 mg per 24 hours to a total daily dose of 45 mg.
- Can worsen psychosis and hypotension.
- Precipitate vomiting - should be used carefully in
patients at risk of aspiration.
- Premature discontinuation results in rebound
symptoms
- Safe in pregnancy
- Continue for 10 days followed by a slow taper to
minimize relapse

44. • Dantrolene
- Direct acting skeletal muscle relaxant
- 1–2.5 mg/kg body weight administered
initially
- followed by 1 mg/kg every 6 hours if rapid
resolution of the fever and rigidity is observed
- Maximum dose- 10 mg/kg
- Taper or switch to oral dantrolene after the
first few days.
- Oral dantrolene doses - 50 to 200 mg/d

45. - Continue for 10 days followed by a slow taper to
minimize relapse
- Side effects may include impairment of
respiratory or hepatic function
- Only in cases of NMS with extreme temperature
elevations, rigidity, and true hypermetabolism
• With depot neuroleptics, treatment should be
continued up to 2–3 weeks beyond clinical
recovery.

46. • Amantadine
- Dopamine agonist
- Initial dose is 100 mg orally or via gastric tube
- Titrate upward as needed to a maximum dose of
200 mg every 12 hours
- Caution- worsening of psychosis
- Levodopa, combined with the dopadecarboxylase
inhibitor carbidopa- effective in reversing
hyperthermia

47. • Serial follow-up of CK and myoglobulin levels.
• Do not suddenly withdraw treatment despite
recovery.
• High chances of recurrence
• With depot neuroleptics, treatment should be
continued up to 2–3 weeks beyond clinical
recovery.

48. • Electro-convulsive therapy (ECT)
- Can help with the alteration of temperature,
level of consciousness, and diaphoresis.
- Effective if symptoms are refractory to
supportive care and pharmacotherapy
- Idiopathic malignant catatonia due to an
underlying psychotic disorder
- persistent residual catatonia and parkinsonism
after resolution of NMS
• Six to 10 treatments with bilateral electrode
placement

49. - It may also be useful in treating the underlying
psychiatric disease in patients who are unable to
take neuroleptics.
- ECT with anesthesia has generally been safe
- No increased incidence of malignant
hyperthermia from succinylcholine
administration.
• Risks- cardiac arrest, ventricular fibrillation and
status epilepticus

50. What will happen if you don’t
intervene?
• Dehydration
• Electrolyte imbalances
• Acute renal failure
associated with
rhabdomyolysis
• Cardiac arrhythmias
including torsade de pointes
and cardiac arrest
• Myocardial infarction
• Cardiomyopathy
• Sepsis
• Reversible dilated
myocardiopathy ( Takotsubo
myocardiopathy)
• Respiratory failure from
chest wall rigidity, aspiration
pneumonia, pulmonary
embolism
• Deep vein thrombosis (DVT)
• Thrombocytopenia
• Disseminated intravascular
coagulation (DIC)
• Seizures from hyperthermia
and metabolic
derangements
• Hepatic failure

51. Restarting of antipsychotics
• Likelihood of developing NMS again as high as
30%
• reports of previous episodes should be
checked for accuracy
• indications for antipsychotics should be clearly
documented
• alternative medications should be considered
• risk factors should be reduced

52. • At least 2 weeks should be allowed to elapse
after recovery from NMS before rechallenge.
• 6 weeks for depot injections
• Low doses of low-potency conventional
antipsychotics or atypical antipsychotics
should be titrated gradually after a test dose.
• Patients should be carefully monitored for
early signs of NMS.
• Documented written consent

53. Prognosis
• Resolve within 2 weeks (reported mean
recovery times are 7–11 days).
• Cases persisting for 6 months with residual
catatonia and motor signs are reported.
• Risk factors for a prolonged course are depot
antipsychotic use and concomitant structural
brain disease.

54. Prognosis
• Most patients recover without neurologic
sequelae
• Except where there is severe hypoxia or
grossly elevated temperatures for a long
duration.
• Reported mortality rates for NMS are 5–20%.
• Disease severity and the occurrence of
medical complications are the strongest
predictors of mortality.

55. Conclusion
• Neuroleptic malignant syndrome is rare but life-
threatening medical emergency
• A diagnosis of exclusion
• Following usage of neuroleptics and abrupt withdrawal
of some drugs.
• Tetrad: Altered mental state, Rigidity, Hyperthermia
and Autonomic dysfunction
• Due to blockade of D2 receptors
• No pathognomonic lab tests.
• Early recognition and prompt treatment has shown
encouraging outcome (reduced mortality).

56. References
• Eelco FM Wijdicks.
https://www.uptodate.com/contents/neuroleptic-
malignant-syndrome- 2019
• Stanley NC, Cabrina EC. Drug- Induced Extrapyramidal
Syndromes. Psychiatric Clinics of North America
2016;Vol 3, No 3: 399- 400
• Vivian Ngo, Alfredo G, David L, et al. Emergent
Treatment of Neuroleptic Malignant Syndrome Induced
by Antipsychotic Monotherapy Using Dantrolene. Clin
Pract Cases Emerg Med. 2019 Feb; 3(1): 16–23.
• Oruch R, Pryme IF, Engelsen BA, Lund A. Neuroleptic
malignant syndrome: an easily overlooked neurologic
emergency. Jan 2017 Volume 2017:13 Pages 161—175

57. References (contd.)
• P. Adnet, P. Lestavel, R. Krivosic‐Horber. Neuroleptic malignant
syndrome. BJA: British Journal of Anaesthesia, Volume 85, Issue 1, 1
July 2000, Pages 129–135
• Jeffrey RS, Paul EK, Stanley NC. Neuroleptic Malignant Syndrome.
Am J Psychiatry 164:6, June 2007: 870- 876.
• Brian DB. Neuroleptic Malignant Syndrome: A Review for
Neurohospitalists. 2011 Jan; 1(1): 41–47
• Max Fink, Allan Taylor. Catatonia: A clinician’s guide to diagnosis
and treatment. 2003: 45- 51.
• Caroff SC, Mann SC, et al. Catatonia: From Psychopathology to
Neurobiology. 2004: 105-115
• Theodore IB. Neuroleptic Malignant Syndrome. Dec 2018 Medscape
• Lurdes Tse, Alasdair M. Barr, Vanessa Scarapicchia Fidel Vila-
Rodriguez. Neuroleptic Malignant Syndrome: A Review from a
Clinically Oriented Perspective. Current Neuropharmacology, 2015,
13, 395-406.

58. Thank You