NMS

1. A case of Neuroleptic malignant syndrome (NMS)
By Dr. Sunil Thomas George

2. Our case
 A 27 year-old woman was admitted to the hospital in view of decreased response to oral
commands, poor oral intake and inability to move all 4 limbs for the past 7 days.
 Patient was apparently normal prior to this.
 She a known case of schizophrenia for the past 11 years for which she had been reviewed recently
and medications altered 10 days ago.
 On reviewing her previous medical records it is noted that she had been on- Clonazepam (0.25mg
OD), Trihexyphenidyl(2mg OD) and risperidone (2mg OD). HALOPERIDOL (2MG OD) was added 3
days prior to the onset of symptoms.

3.  Physical examination revealed pallor, dehydration, poor dental and oral hygiene.
 Hyperthermia-104 °F (40 °C)
 Generalized rigidity- Cog-wheel rigidity
 Tremors.
 Patient was hypotensive-BP 80/50mmHg and a pulse rate of 119/min.
 Bilateral Pupils equally reacting to light

4.  Bilateral plantar had no response
 Other systemic examination was unremarkable
 Emergency MRI of the brain showed no hemorrhage or infarct

5.  In brief, the history and presentation was:
1. Prior treatment with neuroleptic agents
2. Altered mental status
3. Hyperthermia
4. Tremors
5. Rigidity
6. Dehydration
7. Hypotension
 A provisional diagnosis of Neuroleptic Malignant Syndrome was made

6. Investigations revealed
Investigation Value Reference value
Hemoglobin 10.6 gm/dL 12-15 gm/dL
MCV 82.9 fl 83-101 fl
MCH 26.7 pg 31.5-34.5 pg
MCHC 32.2 % 27-32 %
FBS 131 mg/dl 70-99 mg/dL
PPBS 230 mg/dl <140 mg/dL
HBA1C 9.25 % 4-5.6 %
Creatine Kinase 7921 U/l 34-145 U/l
 Serum electrolyte, RFT and LFT were within normal limits

7. Differential diagnosis
NMS Differential Diagnosis
Diagnosis Key differential characteristics
Central anticholinergic syndrome No rigidity, CPK levels normal
Lithium toxic encephalopathy No fever, CPK levels are normal
Malignant hyperthermia There is history of anesthesia with fluoronade anesthesics
Heat shock related to neuroleptics No diaphoresis, no rigidity
Heat shock
No diaphoresis, no rigidity; History of heat and sun
exposition
CNS Infection Abnormal CSF, usually there is neurological focality
Lethal Catatonia
Semiology can be very similar but there is no history of
neuroleptic administration
Serotonin Syndrome
CPK levels are normal; no leucocytosis; no rigidity, but
clonus and hyperreflexia are present

8. Diagnostic criteria
Our patient had a score of ____ consistent
with a diagnosis of NMS

9. Neuroleptic Malignant Syndrome
Diagnosis

10.  Psychiatry and neurology opinion was obtained and advice followed
 Patient was started on Lorazepam 1 mg IV BD, IV Dantrolene 2.5mg/kg/day , Bromocriptine
2.5mg RT TDS and other supportive measures.
 Over the course of 2 weeks, patient showed significant improvement, being able to take oral
feed, respond to verbal commands, and walk.

11. NMS-Definition
 NMS is a life threatening neurological emergency associated with the use of neuroleptic agents &
characterized by distinctive clinical syndromes :
Mental status changes
Rigidity
Fever
Dysautonomia

12. Incidence
 0.02 to 3 % among patients taking neuroleptic agents
 Age is not a risk factor
 Men > Women

13. Associated medications
 NMS is most often seen with HIGH POTENCY 1st Generation neuroleptic agents
Neuroleptic agents
Haloperidol Fluphenazine

14.  2nd generation antipsychotics
Clozapine Risperidone Olanzapine
 Antiemetics
Metoclopramide
Promethazine

15. Onset
 Develops during the first 2 weeks of neuroleptic therapy.
 Not dose dependent phenomenon.

16. Risk factors
 High doses are however a risk factor.
 Recent rapid dose escalation
 Switch from one agent to another
 Parenteral administration

17. Associated risk factors
 Acute catatonia
 Extreme agitation
 Neurologic diseases (Schizophrenia)
 Acute medical illness (Trauma , Surgery & infection)

18. Antiparkinson medication withdrawal
 Withdrawal of L-Dopa or Dopamine agonist therapy
Reduction of dose
Switch from one agent to another

19.  Distinct disorder from NMS Neuroleptic malignant-like syndrome
Parkinsonism hyperreflexia syndrome
Acute akinesis
Malignant syndrome in Parkinson disease
or
or
or

20. Pathogenesis of NMS
 Cause is unknown
 Dopamine receptor blockade theory is central to most theories of its pathogenesis

21. Parkinson-type symptoms
Rigidity ,Tremor
Interference with nigrostriatal
pathway
Hyperthermia and other signs of
dysautonomia
Central dopamine receptor blockade
in the hypothalamus

22. Alternative theory
Primary skeletal muscle
defect or Direct toxic effect
on muscle
Primary effect on peripheral
muscles

23. Direct changes in the muscle
mitochondrial function
Rigidity and muscle damage

24. Alternative theory #2
Disrupted modulation of
sympathetic nervous system
Increased muscle tone
Metabolism
Unregulated sudomotor &
vasomotor activity

25. Ineffective heat dissipation
Dehydration
Labile blood pressure &
Heart rate
 Dopamine antagonist in this model precipitate symptoms by destabilizing normal dopamine regulation of efferent
sympathetic activity

26. Typical course of clinical manifestations
Mental status changes
Rigidity
Hyperthermia
Autonomic dysfunction
 Fever appearance may be delayed >24hrs leading to diagnostic confusion

27. Progression of changes in mental status
 Agitated delirium with confusion
 Catatonic signs & mutism
 Profound encephalopathy
 Stupor
 Coma

28. Rigidity
 Generalized
 Lead pipe rigidity
 Cog-wheel if superimposed tremor present

29.  Rigidity of respiratory muscles
Tachypnea
Respiratory failure – needing mechanical ventilation

30. Hyperthermia
 >38 ºc
 Fever less consistent with 2nd generation antipsychotics

31. Autonomic instability
 Diaphoresis
 Labile or high blood pressure
 Tachycardia

32. Other motor abnormalities include
 Tremor
 Dystonia
 Opisthotonus
 Trismus
 Chorea
 Sialorrhea
 Dysarthria
 Dysphagia

33. Laboratory abnormalities
 Elevated serum CK: More than 1000 IU/L
Can be as high as 100,000 IU/L

34.  Other non specific lab abnormalities:
 Leukocytosis (10,000 to 40,000)
 Mild elevation in LDH, Transaminases and ALP
 Hypocalcemia
 Hypomagnesemia
 Hypo- and Hypernatremia
 Hyperkalemia
 Metabolic acidosis
 Myoglobinuric renal failure – rhabdomyolysis
 Low serum Iron concentration

35. Diagnostic criteria

36. Complications
 Rhabdomyolysis
 Acute renal failure
 Acute respiratory failure( pulmonary embolism, aspiration pneumonia
 Seizures
 Brain damage
 Myocardial infarction
 DIC
 Hepatic failure
 E.coli fasciitis
 Sepsis

37. Treatment
 Stop causative agent
 ICU - supportive care aimed to avoid complications
A reasonable approach is to start with benzodiazepines along with dantrolene in moderate or severe
cases, followed by the administration of bromocriptine or amantadine

38.  Lorazepam 1-2mg IM or IV every 4 to 6 hours
 IV Dantrolene 1 to 2.5mg/kg to max 10mg/kg/day
 Bromocriptine 2.5mg RT TDS (or) Amantadine 100mg RT up to 200mg BD

39. Prognosis
 Most episodes resolve within 2 weeks. (mean recovery time 7-11 days)

40. Thank you