Clinical conundrum of neuroleptic malignant syndrome

Clinical conundrum of Neuroleptic malignant syndrome

Clinical conundrum of Neuroleptic malignant syndrome

Dr. A.V. SRINIVASANDr. A.V. SRINIVASAN

9/9/03Madras Medical College

9/9/03Madras Medical College

INTRODUCTIONINTRODUCTION

IN ANY FIELD,

FIND THE STRANGEST THING

AND EXPLORE IT

John Archibald Wheeler

IN ANY FIELD,

FIND THE STRANGEST THING

AND EXPLORE IT

John Archibald Wheeler

Clinical Knowledge – Trinity principles

Clinical Knowledge – Trinity principles

Observation

Recording

Thinking

Observation

Recording

Thinking

ThinkingThinking

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

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

REVIEW OF LITERATUREREVIEW OF LITERATURE

“THE WORLD IS NOT ONLY QUEERER THAN

WE IMAGINE; IT IS QUEERER THAN WE CAN

IMAGINE”

- J B S Haldane

“THE WORLD IS NOT ONLY QUEERER THAN

WE IMAGINE; IT IS QUEERER THAN WE CAN

IMAGINE”

- J B S Haldane

CLINICAL FEATURESCLINICAL FEATURES1968 - 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

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

POPE et al (1986) modified by KECK 1989POPE 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

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

INCIDENCEINCIDENCE POPE 1.4% (12 MONTHS)

(1986)

SHALIV 0.4% (13 YRS)

(1986)

KECK 0.9% (12 YRS

(1989)

PROSPECTIVE STUDY

0.2%; 0.7%; 0.9%

(6M) (12M) (18M)

POPE 1.4% (12 MONTHS)

(1986)

SHALIV 0.4% (13 YRS)

(1986)

KECK 0.9% (12 YRS

(1989)

PROSPECTIVE STUDY

0.2%; 0.7%; 0.9%

(6M) (12M) (18M)

G-ADDONIZO et al 1987G-ADDONIZO et al 1987

AGE 12-79 Yrs Mean 40 yrs

10-19 11

20-29 21

30-39 27

40-49 20

50-59 18

60-69 15

70-79 3

SEX 63% MEN 37% WOMEN

AGE 12-79 Yrs Mean 40 yrs

10-19 11

20-29 21

30-39 27

40-49 20

50-59 18

60-69 15

70-79 3

SEX 63% MEN 37% WOMEN

PRIMARY PSYCHIATRIC DISORDERPRIMARY PSYCHIATRIC DISORDER SCHIZOPHRENIA 38 44% BIPOLAR (MANIA) 22 26%

MAJOR DEPRESSION 9 10%

Other Include: Schizo Affective

Atypical Psychosis

Alcohol Abuse 20%

Bipolar Depression

Mental Retardation

Organic Mental Syndrome

Dementia

SCHIZOPHRENIA 38 44% BIPOLAR (MANIA) 22 26%

MAJOR DEPRESSION 9 10%

Other Include: Schizo Affective

Atypical Psychosis

Alcohol Abuse 20%

Bipolar Depression

Mental Retardation

Organic Mental Syndrome

Dementia

PATIENTS AT RISK OF NMSPATIENTS AT RISK OF NMS 2 : 1

Occasionally in Children

Agitated Patients in ICU; Aids, Multiple Injuries, Infection

Physical Exhaustion & Dehydration

Preceding Psychomotor Agitation

Organic Brain Syndrome / MR

PD ; Hyponatremia

2 : 1

Occasionally in Children

Agitated Patients in ICU; Aids, Multiple Injuries, Infection

Physical Exhaustion & Dehydration

Preceding Psychomotor Agitation

Organic Brain Syndrome / MR

PD ; Hyponatremia

DRUGSDRUGS HALOPERIDOL 61 57%

CHLORPROMAZINE 28 24%

FLUPHENAZINE DECONATE 17 10%

LEVOPROMETHAZINE 10 9%

• > 1 NEUROLEPTIC 31 29%

DEPOT NEUROLEPTIC 18 17%

• IM NEUROLEPTIC 28 26%

• IV NEUROLEPTIC 3 3%

HALOPERIDOL 61 57%

CHLORPROMAZINE 28 24%

FLUPHENAZINE DECONATE 17 10%

LEVOPROMETHAZINE 10 9%

• > 1 NEUROLEPTIC 31 29%

DEPOT NEUROLEPTIC 18 17%

• IM NEUROLEPTIC 28 26%

• IV NEUROLEPTIC 3 3%

PRESENTATIONSPRESENTATIONS

COMPLETE PICTURE - 72 hrs

LOW GRADE PYREXIA - May precede NMS

MILD INCREASE OF DIASTOLIC BP

45 minutes - 65 days (5 days)

10 days - 89% cases

14 months - chlorpromazine fixed dose

COMPLETE PICTURE - 72 hrs

LOW GRADE PYREXIA - May precede NMS

MILD INCREASE OF DIASTOLIC BP

45 minutes - 65 days (5 days)

10 days - 89% cases

14 months - chlorpromazine fixed dose

COMPLICATIONS AND CAUSE OF DEATHCOMPLICATIONS AND CAUSE OF DEATH

• PNEUMONIA - 15

• RENAL FAILURE - 9

• CARDIAC ARREST - 7

• SEIZURES - 4

• SEPSIS - 3

• PULMONARY EMBOLISM - 3

CAUSES OF DEATH• CARDIO PULMONARY ARREST - 7

• PNEUMONIA - 5


• SEPSIS - 2

• HEPATO RENAL FAILURE - 2

• PNEUMONIA - 15

• RENAL FAILURE - 9

• CARDIAC ARREST - 7

• SEIZURES - 4

• SEPSIS - 3


CAUSES OF DEATH• CARDIO PULMONARY ARREST - 7

• PNEUMONIA - 5


• SEPSIS - 2

• HEPATO RENAL FAILURE - 2

DIFFERENTIAL DIAGNOSISDIFFERENTIAL DIAGNOSIS

Malignant Hyperthermia

Lethal Catatonia

Neuroleptic Induced Catatonia

Neuroleptic Induced Anti-Cholinergic Syndrome

Neuroleptic Induced Heat Stroke

The Serotonin Syndrome

Malignant Hyperthermia

Lethal Catatonia

Neuroleptic Induced Catatonia

Neuroleptic Induced Anti-Cholinergic Syndrome

Neuroleptic Induced Heat Stroke

The Serotonin Syndrome

TREATMENTTREATMENT

SUPPORTIVE MEASURES

• Dantrolene and Dopamine Agonists

• Other Drugs Therapy

• ECT

RE-USE OF NEUROLEPTICS

• Early Challenge

• Long Term Challenge

SUPPORTIVE MEASURES

• Dantrolene and Dopamine Agonists

• Other Drugs Therapy

• ECT

RE-USE OF NEUROLEPTICS

• Early Challenge

• Long Term Challenge

PATHOGENESISPATHOGENESIS

Abnormality of skeletal muscle

Abnormality of dopamine within the CNS

Autopsy findings

Abnormality of skeletal muscle

Abnormality of dopamine within the CNS

Autopsy findings

NMS Develops Earlier and Takes Longer

Time to Resolve in Schizophrenic Patients

Compared to Affective disorders

Mortality is Higher in Schizophrenics

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)SRINIVASAN et al (1990)

Clinical Knowledge

Observations – First Trinity Principle

Clinical Knowledge

Observations – First Trinity Principle

The understanding of Clinical Conundrum of

Neuroleptic Malignant Syndrome would become

clearer when Schizophrenia and Affective disorders

are studied separately.

The understanding of Clinical Conundrum of

Neuroleptic Malignant Syndrome would become

clearer when Schizophrenia and Affective disorders

are studied separately.

Clinical Knowledge

Second Trinity Principle

Clinical Knowledge

Second Trinity Principle

Aims and ObjectivesAims and Objectives1. 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

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

Aims and ObjectivesAims 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

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

Inclusion criteriaInclusion 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

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

1. Absence of primary psychiatric diagnosis

2. Due to other drug induced, systemic or

neuropsychiatric illness

Exclusion criteriaExclusion criteria

MethodologyMethodology

1. Data Collection

2. Data Presentation

3. Data Analysis

4. Data interpretation

1. Data Collection

2. Data Presentation

3. Data Analysis

4. Data interpretation

Data CollectionData Collection

1. Computer coded case sheet

2. Excel spread sheet

1. Computer coded case sheet

2. Excel spread sheet

Data PresentationData Presentation

Graphs

Dendrograms

Graphs

Dendrograms

Data Analysis Data Analysis

Tabulation

Statistical test of hypothesis

Correlation analysis

Factor Analysis

Cluster Analysis

Discriminant Analysis

Tabulation

Statistical test of hypothesis

Correlation analysis

Factor Analysis

Cluster Analysis

Discriminant Analysis

Summary statistics of Schizophrenia, Affective disorder, and NMS patients

Summary statistics of Schizophrenia, Affective disorder, and NMS patients

Schizophrenia Affective

Disorder

Age 32 43

Duration of illness 5 yrs 3 yrs

Onset 9 hrs 17 hrs

Schizophrenia Affective

Disorder

Age 32 43

Duration of illness 5 yrs 3 yrs

Onset 9 hrs 17 hrs

Important Observations Important Observations

Analysis of Variance indicate :

Schizophrenia and Affective disorder patients

differ significantly.

Analysis of Variance indicate :

Schizophrenia and Affective disorder patients

differ significantly.


1. Age

2. Onset

3. Evolution

4. Resolution

5. EPS

6. ANS

7. Fever

8. Altered sensorium

Pre NMS Drug Pre NMS Drug

11 14

36 43

15 16

60 68

77 85

17 15

15 20

Onset (in hrs)

Evolution (in hrs)

Resolution (in days)

Extra PyramidalSymptoms (in hours)

AutonomicSymptoms (in hours)

Fever (in hrs)

Altered Sensorium(in hrs)

C H

Pre-NMS Drug

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

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


The chi-square statistic indicates the rejection

of the hypothesis that there is uniformity in

giving bromocriptine to both the groups

The chi-square statistic indicates the rejection

of the hypothesis that there is uniformity in

giving bromocriptine to both the groups


Factor Analysis of Parameters responsible for NMS Factor Analysis of Parameters responsible for NMS

Component Matrix

.906

.885

.805

.769




Fever (in hrs)

1

Component

Factor analysis of parameters for Schizophrenia Factor analysis of parameters for Schizophrenia

Component Matrix

.913

.888

.779

.497



Fever (in hrs)


1

Component

Factor Analysis of Parameters of Affective Disorder. Factor Analysis of Parameters of Affective Disorder.

Rotated Component Matrix

.955 .154

.931 .251

.181 .906

.200 .898




Fever (in hrs)

1 2

Component

Structure of Parameters – According to their importance

Structure of Parameters – According to their importance

Structure of Parameters - Rankwise

.898

.700

.597

.287




Fever (in hrs)

1

Function

Dendrogram showing the relationship between the parameters of NMS

Dendrogram showing the relationship between the parameters of NMS

Rescaled distance cluster combineRescaled distance cluster combine

0 5 10 15 20 25Variable num

Ext. Pyr

Aut. sym

Evolution

Onset

Fever

Alt. sen.

Resolution

Dendrogram showing the relationship between parameters of Schizophrenia patients

Dendrogram showing the relationship between parameters of Schizophrenia patients



Ext. Pyr

Aut. sym

Fever

Onset

Alt. Sen.

Evolution

Resolution

Dendrogram showing the relationship of parameters affective disorders

Dendrogram showing the relationship of parameters affective disorders



Onset

Fever

Alt. Sen.

Ext. Pyr.

Aut. Sym.

Evolution

Resolution

The Classification Function coefficients and the Group Centroids

The Classification Function coefficients and the Group Centroids

Classification Function Coefficients

-2.55E-02 -3.48E-02

6.294E-02 .133

.165 7.480E-02

-2.30E-02 6.808E-02

-2.837 -7.686



Fever (in hrs)


(Constant)

Schizophrenia

AffectiveDisorder

Type of patients

Fisher's linear discriminant functions

Functions at Group Centroids

-1.296

.864

Type of patientsSchizophrenia

Affective Disorder

1

Function

Classification of Schizophrenia and Affective Disorder Patients

Classification of Schizophrenia and Affective Disorder Patients

Classification Resultsa

17 3 20

2 28 30

85.0 15.0 100.0

6.7 93.3 100.0

Type of patientsSchizophrenia

Affective Disorder

Schizophrenia

Affective Disorder

Count

%

Original

Schizophrenia

AffectiveDisorder

Predicted GroupMembership

Total

90.0% of original grouped cases correctly classified.a.

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

AVS-CUV CriterionAVS-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

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

Validation of HypothesisValidation of Hypothesis

NilUnlikely3 patients LikelyMortality

11 days15 days23 days30 daysResolution

52 hours72 hours27 hours24 hoursEvolution

107 hours96 hours50 hours48 hoursAutonomic symptoms

85 hours96 hours40 hours48 hoursExtra pyramidal symptoms

26 hours24 hours10 hours12 hoursAltered sensorium

ValidatedHypothesisValidatedHypothesis

Affective disorderSchizophrenia

DISCUSSION Distribution of cases by Age

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

DISCUSSION (Contd...)

Distribution of cases by diagnosisDISCUSSION (Contd...)

Distribution of cases by diagnosis





Schizophrenia 38 55 20 40

Affective Disorder 31 45 30 60

Total 69 100 50 100

DISCUSSION (Contd...) Distribution of cases by Age

DISCUSSION (Contd...) Distribution of cases by Age





Below 40 11 34 5 29

Above 40 21 66 12 71

Total 32 100 17 100

DISCUSSION (Contd...) Mean age of OnsetDISCUSSION (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

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

DISCUSSION (Contd...) NMS Evolution daysDISCUSSION (Contd...) NMS Evolution days

Study DaysStudy Days

Srinivasan (2002) 1.7

Shaliv (1986) 4.8

Addonizio (1987) 14.0

Caroff – Wt. Avg. 7.5

DISCUSSION (Contd...) NMS Evolution days by diagnosis

(Srinivasan – 2002)

DISCUSSION (Contd...) NMS Evolution days by diagnosis



Schizophrenia 1.1

Affective Disorder 2.2

All Cases 1.7

DISCUSSION (Contd...) Resolution time - DaysDISCUSSION (Contd...)

Resolution time - Days


Srinivasan (2002) 15.9

Shaliv (1986) NA

Addonizio (1987) 13.0

Caroff – Wt. Avg. NA

DISCUSSION (Contd...) NMS Resolution days by diagnosis


DISCUSSION (Contd...) NMS Resolution days by diagnosis



Schizophrenia 20.3

Affective Disorder 11

All Cases 15.9

DISCUSSION (Contd...)DISCUSSION (Contd...)

Grace : Dopamine Release

Phasic (Behavioural Stimuli)

Tonic (Regulated by Prefrontal

Cortical Afferents)

Grace : Dopamine Release

Phasic (Behavioural Stimuli)

Tonic (Regulated by Prefrontal

Cortical Afferents)

DISCUSSION (Contd...) DOPAMINE - HYPOTHESIS

DISCUSSION (Contd...) DOPAMINE - HYPOTHESIS

Schizophrenia

• Hyper dopaminergic – Positive Symptom

• Hypo dopaminergic – Negative Symptom

Affective Disorder

• Hyper - Mania

• Hypo - Depression

Schizophrenia

• Hyper dopaminergic – Positive Symptom

• Hypo dopaminergic – Negative Symptom

Affective Disorder

• Hyper - Mania

• Hypo - Depression

DISCUSSION (Contd...) PET/ SPECT STUDIES

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

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

Answer to clinical Conundrum (Puzzling problem for experts)

of NMS

Answer to clinical Conundrum (Puzzling problem for experts)

of NMSTonic Phasic = Normal

Cortex Basal Ganglia

D1 Receptor D2 Receptor

NEUROLEPTICS BLOCK

NORMAL BLOCKED Duration of NMS IS

Less Resolves Faster

BLOCKEDBLOCKED Duration is Longer

& Mortality is more

Tonic Phasic = Normal

Cortex Basal Ganglia

D1 Receptor D2 Receptor

NEUROLEPTICS BLOCK

NORMAL BLOCKED Duration of NMS IS

Less Resolves Faster

BLOCKEDBLOCKED Duration is Longer

& Mortality is more

ConclusionConclusionSchizophrenia

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

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

Conclusion (Contd…)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

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


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

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


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

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

ObservationPractical Neurology

ObservationPractical 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

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

Prospective study of fifty

patients

Prospective study of fifty

patients

Clinical Knowledge

Recording - Second Trinity Principle

Clinical Knowledge

Recording - Second Trinity Principle

Proposed new dopamine hypothesisProposed new dopamine hypothesis

Tonic Phasic Normal

Cortex Basal GangliaPredominantly Predominantly D2D1 receptor Receptor

Neuroleptics Block

Normal Blocked Duration of NMSis less resolvesfaster

Blocked Blocked Duration is longer &mortality is more

Clinical KnowledgeThinking - Third Trinity Principle

Clinical KnowledgeThinking - Third Trinity Principle

This thesis is dedicated to

the memory of my

Professor C.D. MARSDEN

for his helpful

comments and encouragement

This thesis is dedicated to

the memory of my

Professor C.D. MARSDEN

for his helpful

comments and encouragement

My sincere

Gratitude

and

Thanks

My sincere

Gratitude

and

Thanks

Dedicated to my family for making everything worthwhile

Dedicated to my family for making everything worthwhile

Health & Medicine

Clinical conundrum of neuroleptic malignant syndrome