Neuroleptic malignant syndrome (NMS) is a rare but potentially life-threatening disorder associated with the use of dopamine receptor antagonists like antipsychotics. It is characterized by a tetrad of symptoms including hyperpyrexia, muscle rigidity, altered mental status, and autonomic dysfunction. Treatment involves immediate withdrawal of the offending agent, aggressive supportive care, and in severe cases, pharmacological interventions like dantrolene or bromocriptine. Prognosis is generally good if diagnosed and treated early, but mortality can result from complications and occurs in around 10% of cases.

1. NEUROLEPTICNEUROLEPTIC
MALIGNANTMALIGNANT
SYNDROMESYNDROME
Dr. Kaushik.P,
Intern, Department of Psychiatry,
M.S.Ramaiah Teaching Hospital

2. INTRODUCTION
 A severe disorder associated with
1. Increase in dose of dopamine
receptor antagonists. (mostly
antipsychotics)
OR
2.Rapid withdrawal of dopaminergic
agents.
 Unpredictable
 Potentially life-threatening.

3.  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%.

4. PRESENTATIONPRESENTATION
CLASSICAL TETRAD OF CLINICAL
FEATURES

5. CLINICAL PRESENTATION CONT..
In addition,
Extrapyramidal motor signs – Tremor,
chorea, akinesia, dystonic movements.
Other symptoms – Dysphagia,
dyspnoea, abnormal reflexes, mutism,
seizures.
NMS associated with atypical antipsychotics –
Core symptoms may be absent.

6. DSM-IV CRITERIA FOR DIAGNOSIS

7. DEVELOPMENT AND COURSE
 Heterogeneous in onset, presentation,
progression and outcome.
 Onset – from hours to days.
 16% : within 24hrs.
 66% : within 1 week.
 Virtually all cases : within 30 days.
 Alteration in mental status and other
neurological signs typically precede systemic
signs. (>80%)

8. DEVELOPMENT AND COURSE
CONT..
 Self-limited in most cases.
 Mean recovery time : 7-10 days.
 63% : within 1 week.
 Nearly all : within 30 days.
 Mortality results from :
 respiratory failure
 cardiovascular collapse
 myoglobinuric renal failure
 arrhythmias
 DIC

9. RISK FACTORS
 Concurrent medical and neuropsychiatric
issues
1.Dehydration
2.Psychomotor agitation
3.Encephalitis and traumatic brain injury
4.Mood disorders
5.Preexisting catatonia
6.History of NMS- in 15%-20% of cases.
7.Low serum iron
 Younger age
 Male gender

10. ANTIPSYCHOTIC-RELATED RISK
FACTORS
 High potency conventional antipsychotics –
higher risk
 Atypical antipsychotics: Less incidence.
 Parental routes
 Higher titration rates
 Higher total doses

11. PATHOPHYSIOLOGY
 Precise mechanisms are unproven.
 Drug induced dopamine blockade, followed
by abrupt discontinuation of the drug
Sudden dopaminergic dysregulation

12. PATHOPHYSIOLOGY
 Supportive evidence for this hypothesis:
1) All drugs associated are dopamine receptor
blockers.
2) Risk of NMS appears to be correlated with the
dopamine receptor binding affinity of drugs.
3) Dopaminergic drugs are used in the treatment of
NMS.
4) Patients with central dopamine tract lesions
develop similar syndromes.
5) Low levels of homovanillic acid (dopamine
metabolite) detected in patients with acute NMS.

13. PATHOPHYSIOLOGY CONT..
 Also family clusters of NMS have found that A1
allele of dopamine D2 receptor gene may be over
expressed in these patients, this allele reduces
the density and function of the dopamine
receptor

14. INVESTIGATIONS
 CBC – Leucocytosis (Upto 40000)
 CK – elevated (> 1000 IU/L)
 Urine analysis – myoglobinuria (indicates poor prognosis)
 ABG – Metabolic acidosis
 Serum iron – reduced (probably an acute phase response)
 Serum catecholamine - elevated
 CSF – 95% normal.
 Brain imaging – usually normal.
 EEG – generalized slowing (metabolic encephalopathy)

15. DIFFERENTIAL DIAGNOSIS
 Primary CNS disorders-
1.CNS Vasculitis
2.Infarctions
3.Infection
4.Status Epilepticus
5.Trauma
6.Tumors
7.Acute Porphyria
 Psychiatric disorders- Idiopathic Lethal
Catatonia

16. DIFFERENTIAL DIAGNOSIS CONT..
 Systemic Disorders-
1.Acute Porphyria
2.Autoimmune disorders
3.Dehydration
4.Heat stroke
5.Hyperthyroidism
6.Infections
7.Tetanus
8.Pheochromocytoma

17. DIFFERENTIAL DIAGNOSIS CONT..
 Medication related disorders-
1.Anticholinergic syndrome
2.Levodopa syndrome
3.Malignant hyperthermia
4.Serotonin Syndrome

18. MANAGEMENT
 Immediate withdrawal of the offending agent.
 Supportive care – mainstay of management
 Aggressive fluid resuscitation
 Monitoring and correction of electrolyte
imbalances.
 Cooling measures (cooling blankets, ice packs, ice
water enema)
 Monitoring for complications – cardiorespiratory
failure, renal failure, aspiration pneumonia,
coagulopathies.
 Dialysis – renal failure
 Ventilator support – respiratory failure

19. MANAGEMENT CONT..
 Pharmacological management
 No general consensus on use of pharmacological
therapies in uncomplicated cases.
 Numerous anecdotal reports and meta-analyses
support the use of several empiric
pharmacological therapies in more severe cases.
 May shorten the course and reduce mortality.

20. MANAGEMENT CONT..
 Dopaminergic agents
 Bromocriptine
 Starting dose - 2.5mg bd/tds by mouth
 Increase dose by 2.5mg every 24hrs.
 Max. dose – 45mg/day
 At least for 10 days (oral antipsychotics)
or 2-3 weeks (depot antipsychotics)
 May worsen psychosis,hypotension and
induce emesis

21. MANAGEMENT CONT..
 Amantadine-
200-400mg/day in divided doses by
mouth in divided doses
 Levodopa-
50-100mg per day intravenous as
continous infusion

22. MANAGEMENT CONT..
 Dantrolene
 Started with 1-2.5mg/kg initial IV bolus
 Then 1mg/kg every 6hrly up to a max. dose of
10mg/kg/day for 8days
 Switching to oral form after first few days for
another 7days
 Discontinued once symptoms begins to resolve.
(Risk of hepatotoxicity)

23. MANAGEMENT CONT..
 Benzodiazepines
 May hasten the recovery in milder cases.
 May control agitation.
 Lorazepam
 Starting test dose 1-2mg IM/IV, if effective
switch to mouth
 Carbamazepine
Reported to have some effect.
 Clonidine

24. MANAGEMENT CONT..
 ECT - good outcome with both unilateral and
bilateral treatments
 can be effective when,
1. Poor response to supportive care and
pharmacological management.
2. When idiopathic malignant catatonia
cannot be excluded.
3. Persistent residual catatonia and
parkinsonism after the resolution of
acute symptoms.

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.
 Considering alternative therapies like ECT
 Start with a low dose and titrate gradually
 Careful monitoring for early signs of NMS.

26. RECOMMENDATIONS
 Conservative use of antipsychotics.
 Cautious use of antipsychotics in patients with
increased risk
 Early diagnosis.
 Prompt discontinuation of offending agents.
 Early supportive care and medical management.

27. REFERENCES