5. Thinking
Thinking requires a process of consideration,
rumination and deliberation, which constitutes
clinical thought.
The whole art of medicine depends on the
stimuli that enter the mind of the physician, the
processes that go on in the mind, and the
material produced by that mind as a result.
Sustain - clinical neurology
6. REVIEW OF LITERATURE
“THE WORLD IS NOT ONLY QUEERER
THAN WE IMAGINE; IT IS QUEERER THAN
WE CAN IMAGINE”
- J B S Haldane
7. CLINICAL FEATURES
1968 - Delay – NMS was described with
Fever, Pallor, Movement Disorder & Signs in the Lungs
1985 - LEVENSON CRITERIA
MAJOR MINOR
FEVER TACHYCARDIA
RIGIDITY ABNORMAL BLOOD PRESSURE
ELEVATED CK TACHYPNOEA
ALT. LEVEL OF CONSCIOUSNESS
PROFUSE SWEATING
LEUKOCYTOSIS
3 MAJOR
2 MAJOR AND 4 MINOR
8. POPE et al (1986) modified by KECK 1989
1. Hyperthermia : > 380 C in absence of other Etiologies
2. At least two of the Extra Pyramidal signs
3. At least two of the Autonomic Dysfunction
4. Retrospective Diagnosis
If documentation of one of the above criteria is inadequate,
diagnosis of possible NMS is permissible if the remaining
two are met - plus one of the following:
a) Clouded consciousness; delirium, mutism, stupor or coma
b) Leukocytosis (WCC > 15 x 109/1)
c) Serum CK > 1000 U/1
17. TREATMENT
SUPPORTIVE MEASURES
• Dantrolene and Dopamine Agonists
• Other Drugs Therapy
• ECT
RE-USE OF NEUROLEPTICS
• Early Challenge
• Long Term Challenge
19. Clinical Knowledge
Observations – First Trinity Principle
NMS Develops Earlier and Takes Longer
Time to Resolve in Schizophrenic Patients
Compared to Affective disorders
Mortality is Higher in Schizophrenics
SRINIVASAN et al (1990)
20. Clinical Knowledge
Second Trinity Principle
The understanding of Clinical Conundrum of
Neuroleptic Malignant Syndrome would become
clearer when Schizophrenia and Affective disorders
are studied separately.
21. Aims and Objectives
1. To study the clinical conundrum of the following
symptoms of the Neuroleptic Malignant Syndrome in
Schizophrenia and Affective disorder separately
a. Fever b. Altered sensorium
c. Extra pyramidal symptoms
d. Autonomic symptoms
2. To study the evolution of this syndrome in
Schizophrenia and Affective disorder
3. To study the resolution of this syndrome in
Schizophrenia and Affective disorder
22. Aims and Objectives
4. To study the neuroleptic drug and the duration
of Neuroleptic Malignant Syndrome in
Schizophrenia and Affective disorder
5. To study the mode of administration of the drug
and the clinical conundrum in Schizophrenia
and Affective disorder
6. To study the mortality in Schizophrenia and
Affective disorder
23. Inclusion criteria
1. Only cases with
(a) fever
(b) altered sensorium
(c) extra pyramidal and
(d) autonomic symptoms which formed the
clinical tetrad for diagnosis of NMS are included
2. Progression of symptoms was analysed by the
method used by Velamoor
24. Exclusion criteria
1. Absence of primary psychiatric diagnosis
2. Due to other drug induced, systemic or
neuropsychiatric illness
30. Important Observations
Schizophrenia Affective
Disorder
Age 32 43
Duration of illness 5 yrs 3 yrs
Onset 9 hrs 17 hrs
31. Important Observations
Analysis of Variance indicate :
Schizophrenia and Affective disorder patients
differ significantly.
1. Age 5. EPS
2. Onset 6. ANS
3. Evolution 7. Fever
4. Resolution 8. Altered sensorium
32. Pre NMS Drug
Pre-NMS Drug
C H
Onset (in hrs) 11 14
Evolution (in hrs) 36 43
Resolution (in days) 15 16
Extra Pyramidal
60 68
Symptoms (in hours)
Autonomic
77 85
Symptoms (in hours)
Fever (in hrs) 17 15
Altered Sensorium
15 20
(in hrs)
33. Important Observations
1. Haloperidol was the commonest drug used
in both Schizophrenia and Affective disorder
- Statistically analysed
2. Other drugs - smaller number of patients -
not analysed
3. T-test for equality of Means did not show any
evidence for association between the
groups and medication
34. Important Observations
The chi-square statistic indicates the
rejection of the hypothesis that there is
uniformity in giving bromocriptine to both
the groups
35. Factor Analysis of Parameters responsible for NMS
Component Matrix
Component
1
Extra Pyramidal
.906
Symptoms (in hours)
Autonomic
.885
Symptoms (in hours)
Altered Sensorium
.805
(in hrs)
Fever (in hrs) .769
36. Factor analysis of parameters for Schizophrenia
Component Matrix
Component
1
Extra Pyramidal
.913
Symptoms (in hours)
Autonomic
.888
Symptoms (in hours)
Fever (in hrs) .779
Altered Sensorium
.497
(in hrs)
37. Factor Analysis of Parameters of Affective Disorder.
Rotated Component Matrix
Component
1 2
Autonomic
.955 .154
Symptoms (in hours)
Extra Pyramidal
.931 .251
Symptoms (in hours)
Altered Sensorium
.181 .906
(in hrs)
Fever (in hrs) .200 .898
38. Structure of Parameters –
According to their importance
Structure of Parameters - Rankwise
Function
1
Autonomic
.898
Symptoms (in hours)
Extra Pyramidal
.700
Symptoms (in hours)
Altered Sensorium
.597
(in hrs)
Fever (in hrs) .287
39. Dendrogram showing the relationship between
the parameters of NMS
Rescaled distance cluster combine
0 5 10 15 20 25
Variable num
Ext. Pyr
Aut. sym
Evolution
Onset
Fever
Alt. sen.
Resolution
40. Dendrogram showing the relationship between
parameters of Schizophrenia patients
Rescaled distance cluster combine
0 5 10 15 20 25
Variable num
Ext. Pyr
Aut. sym
Fever
Onset
Alt. Sen.
Evolution
Resolution
41. Dendrogram showing the relationship of
parameters affective disorders
Rescaled distance cluster combine
0 5 10 15 20 25
Variable num
Onset
Fever
Alt. Sen.
Ext. Pyr.
Aut. Sym.
Evolution
Resolution
42. The Classification Function coefficients and
the Group Centroids
Classification Function Coefficients
Type of patients
Schizophr Affective
Functions at Group Centroids
enia Disorder
Extra Pyramidal
-2.55E-02 -3.48E-02 Function
Symptoms (in hours)
Autonomic Type of patients 1
6.294E-02 .133
Symptoms (in hours) Schizophrenia -1.296
Fever (in hrs) .165 7.480E-02 Affective Disorder .864
Altered Sensorium
-2.30E-02 6.808E-02
(in hrs)
(Constant) -2.837 -7.686
Fisher's linear discriminant functions
43. Classification of Schizophrenia and
Affective Disorder Patients
Classification Resultsa
Predicted Group
Membership
Schizophr Affective
Type of patients enia Disorder Total
Original Count Schizophrenia 17 3 20
Affective Disorder 2 28 30
% Schizophrenia 85.0 15.0 100.0
Affective Disorder 6.7 93.3 100.0
a. 90.0% of original grouped cases correctly classified.
b. Misclassification rate in the case of schizophrenia as
affective disorder is near 15% and affective disorder wrongly
classified as Schizophrenia is only around 7 per cent
44. AVS-CUV Criterion
Clinically Definite : Autonomic symptoms and Signs,
Extra Pyramidal Symptoms,
Altered Sensorium and Fever
Clinically Probable : Autonomic Symptoms and Signs,
Extra Pyramidal Symptoms
Clinically Possible : Altered Sensorium with
Autonomic Symptoms or
Extra Pyramidal
46. DISCUSSION
Distribution of cases by Age
Age (Years) G. Addonizio (1987) Srinivasan (2002)
No. of Cases % No. of cases %
Below 30 11 10 5 10
30-39 21 18 12 24
40-49 27 23 12 24
50-59 20 17 9 18
60-69 18 16 6 12
70-79 15 13 3 6
Over 80 3 2 3 6
Total 115 100 50 10
47. DISCUSSION (Contd...)
Distribution of cases by diagnosis
Age (Years) G. Addonizio (1987) Srinivasan (2002)
No. of Cases % No. of cases %
Schizophrenia 38 55 20 40
Affective Disorder 31 45 30 60
Total 69 100 50 100
48. DISCUSSION (Contd...)
Distribution of cases by Age
Age (Years) G. Addonizio (1987) Srinivasan (2002)
No. of Cases % No. of cases %
Below 40 11 34 5 29
Above 40 21 66 12 71
Total 32 100 17 100
49. DISCUSSION (Contd...)
Mean age of Onset
Age (Years) G. Addonizio (1987) Srinivasan (2002)
Mean age No. of Mean age No. of
in Yrs. Cases in Yrs. Cases
All 40 115 39 50
50. DISCUSSION (Contd...)
NMS Evolution days
Study Days
Srinivasan (2002) 1.7
Shaliv (1986) 4.8
Addonizio (1987) 14.0
Caroff – Wt. Avg. 7.5
56. DISCUSSION (Contd...)
PET/ SPECT STUDIES
Chronic Schizophrenia / Major Depression
• Dorso Lateral Pre Frontal Cortex -
Hypometabolism Proven
NMS
• Longer time to Resolve
• Mortality is more
Functional dopamine Level plays a Crucial Role
57. Answer to clinical
Conundrum (Puzzling problem for experts)
of NMS
Tonic Phasic = Normal
Cortex Basal Ganglia
D1 Receptor D2 Receptor
NEUROLEPTICS BLOCK
NORMAL BLOCKED Duration of NMS IS
Less Resolves Faster
BLOCKED BLOCKED Duration is Longer
& Mortality is more
58. Conclusion
Schizophrenia
Average age at Schizophrenia occurs is 32 years;
and duration is nearly five years
Onset occurs at nine hours; evolution is nearly
27 hours; and resolution is 23 days
Altered sensorium is seen at 10 hours and fever
comes 12 hours after a person gets NMS
Extra pyramidal symptoms appears after 40 hours
and autonomic symptoms are seen at 50 hours
59. Conclusion (Contd…)
Altered sensorium heralds the onset of NMS
in Schizophrenia;
Fever, extra pyramidal, autonomic
signogether with altered sensorium form the
evolution of the clinical conundrum of NMS in
Schizophrenia
The disappearance of altered sensorium,
fever, extra pyramidal and autonomic signs
form the resolution of the syndrome
60. Conclusion (Contd…)
Affective Disorder
The average age at Affective disorder occurs is 43 years and
the average duration is nearly 3 years
Onset of NMS in Affective disorder occurs at 17 hours;
evolution time is nearly 52 hours; and the resolution occurs
after 11 days on the average
Fever occurs first, 17 hours after a person gets affected by
NMS in Affective disorder; Altered sensorium is seen nine
hours after the fever; extra pyramidal symptoms occur nearly
three and half days later; and autonomic symptoms are found
four and half days after the syndrome affect the patients
61. Conclusion (Contd…)
Fever heralds the onset and later results in altered
sensorium;
Extra pyramidal and autonomic symptoms are responsible
for completion in the clinical conundrum;
All the four, viz., fever, altered syndrome, extra pyramidal,
and autonomic symptoms form the clinical tetrad for
diagnosis of NMS; and
The disappearance of Fever, altered sensorium, extra
pyramidal, and autonomic form the resolution of the
syndrome
62. Observation
Practical Neurology
Jose Biller, MD
Professor and Chairman,
Department of Neurology
Indiana University Medical Center, Indianapolis
Recommended Readings
Dr. Srinivasan AV, et al. Neuroleptic malignant
syndrome. J Neurol Neurosurg Psychiat
53:514-516, 1990
64. Clinical Knowledge
Thinking - Third Trinity Principle
Tonic Phasic Normal
Cortex Basal Ganglia
Predominantly Predominantly D2
D1 receptor Receptor
Neuroleptics Block
Normal Blocked Duration of NMS
is less resolves
faster
Blocked Blocked Duration is
longer &
mortality is more
Proposed new dopamine hypothesis
65. This thesis is dedicated to
the memory of my
Professor C.D. MARSDEN
for his helpful
comments and
encouragement