Neuroleptic malignant syndrome (NMS) is a life-threatening reaction to antipsychotic medications characterized by fever, muscle rigidity, and changes in mental status. It occurs in 0.01-0.02% of patients receiving antipsychotics. The classical presentation includes fever, muscle rigidity, altered mental status, and autonomic dysfunction. Diagnosis is based on exposure to antipsychotics, these clinical features, and elevated creatine kinase levels. Treatment involves supportive care, managing symptoms like fever and rigidity, and preventing complications. Outcomes are generally good if treated early, but mortality is around 10%.

1. NEUROLEPTIC MALIGNANT
SYNDROME
Dr. Umar Mushir
PG Resident
Index Medical College Hospital
And Research Centre, Indore.

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. • 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%,

4.  1956 - First case reported.
 1960 – Current name was introduced in a French
study.
 Rare.
• 1960-1997: Incidence 0.2-3.2%
• Current incidence : 0.01 – 0.02%
 Mortality rate – 10%.

5. TYPES
• AFEBRILE NMS
Less Malignant, Short Lasting, Good Prognosis
• CLASSICAL NMS
Malignant, long lasting, guarded prognosis

6. OCCURENCE
• On Neuroleptics
• On withdrawl of neuroleptics or dopaminergic
agonists

7. High Index Of Suspicion
• Patient on neuroleptics
• Altered sensorium
• With or without rigidity (as it may develop later)
• With or without fever (as it may develop later)

8. • >38 C (100.4 F)Fever
• “Lead pipe” in most severe form
Muscle
rigidity
• Drowsiness, agitation, confusion, delirium,
coma
Altered
mental status
• Fluctuations in BP, tachypnoea, tachycardia,
sialorrhoea, diaphoresis, flushing, skin
pallor, incontinence
Autonomic
instability
Clinical Presentation
Classical tetrad of clinical features

9. Diagnostic Criteria according to DSM 5
• Exposure to Dopamine antagonist or dopamine
agonist withdrawal, within past 72 hours
• Hyperthermia ( >100.4 o F on at least two
occasions, measured orally)
• Rigidity
• Reduced or fluctuating levels of consciousness
• CK elevation (at least 4 times upper limit of
normal)

10. Contd…
• Sympathetic nervous system lability- defined as
any two of the following
a. Blood Pressure elevation (systolic or diastolic
>= 25 % above baseline)
b. Blood pressure fluctuation (>=20 mm Hg
diastolic change or >=25 mm Hg systolic
change within 24 hours)
c. Diaphoresis
d. Urinary incontinence

11. Contd…
• Hyper metabolism, 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.

12. Levensons Criteria for diagnosis of NMS
Presence of 3 major or 2 major and 4 minor signs indicate
a high probability of NMS
(J Anaes Clin Phar 2012 Oct-Dec: 28(4):517-519)
MAJOR CRITERIA MINOR CRITERIA
Fever Tachycardia
Rigidity Abnormal Blood Pressure
Elevated CPK Altered sensorium
Diaphoresis
Leucocytosis

13. Pathophysiology
• Precise mechanisms are unproven.
• Antipsychotic-induced dopamine blockade
• Sudden drop in CNS dopaminergic activity
•
Nigro striatal pathway – Muscle Rigidity
Hypothalamus --- Impaired heat regulation
Mesolimbic / mesocortical pathways– altered mental status

14. DIFFERENTIAL DIAGNOSIS
• 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

15. Complications
 Dehydration
 Rhabdomyolysis induced Acute Renal Failure
 Cardiac Arrhythmias & MI
 Cardiomyopathy
 Respiratory Failure (Chest Wall rigidity)
 Thrombocytopenia
 DIC & DVTs
 Seizures
 Hepatic Failure

16. Challenges in Classical NMS
• Management of hyperthermia
• Management of hypotension and dehydration
• Management of severe rigidity
• Management of complications – ARDS and
Cardiac arrest
• Management of other complications arising due
to prolon ICU/ Ward stay like bed sores, hospital
acquired pneumonias, septicemia, etc.

17. Investigations look like….
• FBC – Leucocytosis (WBC 10000-40000)
• CK – elevated (> 1000 IU/L)
• Urine analysis – myoglobinuria indicate poor prognosis.
• ABG – Metabolic acidosis
• Serum iron – reduced ( ? An acute phase response)
• Serum catecholamine - elevated
• CSF – 95% normal.
• Brain imaging – usually normal.
• EEG – generalized slowing.(metabolic encephalopathy)

18. Management of Hyperthermia
• Cold sponging, ice packs, ice water enema
• Antipyretics:
a. Combination of Mephenemic acid (450 mg) +
paracetamol (500 mg)
b. Intra Venous Diclofenac
c. Intravenous Paracetamol
• It may take 2 to 3 days for the temperature to
normalize

19. Management of Hypotension and
Dehydration
• I V central line placement
• I V fluids
• Injection Mephentine 15 mg
• Dopamine / Dobutamine / Noradrenaline

20. Management of Severe Rigidity
• Tablet Bromocriptine 2.5 mg 1 – 1 – 1
gradually increase to 4 – 4 – 4
• Tablet Amantadine 100 mg 1 – 1 – 1
• Dantrolene Sod. Is not available in India
• Consider using Tablet Baclofen 30 mg 1 – 1 – 1

21. Management of Myoglobinuria leading
to acute renal shutdown
• Vigorous hydration – plenty of IV fluids to flush
the kidney
• Isotonic saline boluses of 20 ml / kg should be
initially administered with repeat boluses
depending on the hydration status of the patient
• This should be followed by continuous hydration
with IV fluids
• Maintain blood pressure to an optimum level
• Achievement of urine output goal of 2-3 ml
/kg/hr is recommended

22. • Follow up with mannitol to induce diuresis
supported by administration of IV fluids has
been advocated
• Mannitol causes diuresis, which minimizes
intratubular myoglobin deposition, acts as a free
radical scavanger and reduces tubule cell
damage and may act as direct renal vasodilator
• Raising the pH of the urine to 6.5 or more can be
facilitated by adding sodium bicarbonate

23. Management of complications
• The patient may have to be on assisted
ventilation and may require cardiorespiratory
resuscitation
• A good nursing care, prophylactic use of
antibiotics may be used to prevent some
complications.
• Ondensetron is used to manage vomiting

24. ECT IN NMS
Strawn, J.R., Keck, p., Jr.,Stanley N. Caroff, M.D. Neuroleptic Malignant Syndrome Am J Psychiatry 164:6,
June 2007
• A review 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.

25. Antipsychotic use after NMS
 Estimated risk of 30% of developing NMS again
with re-introduction of antipsychotics.
 Precautions:
▫ At least 2 weeks should be allowed from recovery
before rechallenge.
▫ Low potency conventional antipsychotics/ atypical
antipsychotics.
▫ Start with a low dose and titrate gradually.
▫ Careful monitoring for early signs of NMS.

26. Prognosis
• Most episodes resolve in 2 weeks (>70%)
• Mortality rates 10-20%
▫ Decreased if associated with higher potency agents
compared to lower potency agents
▫ Cause of Death
 Cardiac arrhythmias
 Myocardial infarction
 Seizures
 Pulmonary edema
 Bronchopneumonia
 Renal failure

27. Finally…. Thanks