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?
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%.
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-
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)
• 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.
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
16.
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
19.
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
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
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
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
33. • Central nervous system infections
• Status epilepticus
• Stroke
• Brain trauma
• Neoplasms
• Acute intermittent porphyria
• Tetanus
• Thyroid Storm
• Heat stroke
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
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,
38. • If B.P. is significantly elevated
- Nitroprusside (cutaneous vasodilatation)
- Clonidine
• Heparin or low molecular weight heparin for
prevention of deep venous thrombosis
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
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-
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
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
• Respiratory failure from
chest wall rigidity,
aspiration pneumonia,
pulmonary embolism
• Deep vein thrombosis
(DVT)
• Thrombocytopenia
• Disseminated
intravascular
coagulation (DIC)
• Seizures from
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
56. References
• Eelco FM Wijdicks.
https://www.uptodate.com/contents/neurole
ptic-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
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
Lead-pipe- stable resistance through all ranges of movement
Chorea, dystonia
Clozapine- rigidity is seldom seen. Rather DIAPHORESIS!!
Neuroleptic malignant syndrome can occur as a result of changes in pre- or postsynaptic DA signaling. There are two mechanisms:
1. Reduced DA signaling resulting from sudden withdrawal of dopaminergic agents
2. Introduction of agents that block DA signaling
Serotonin syndrome- Hunter’s criteria and Sternbach’s criteria
