Neuroleptic Malignant Syndrome

12/20/2010
Neuroleptic Malignant
Syndrome
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AUTHORS ASSUME ANY LIABILITY FOR
Anoop Bhagat
ANY INJURY AND OR DAMAGE TO
Medicine/Psychiatry
PERSONS OR PROPERTY ARISING FROM
Resident
Objectives
THIS WEBSITE AND ITS CONTENT.
Introduction
 Life threatening and potentially fatal.
 Identifying Neuroleptic Malignant Syndrome
 Pathophysiology of Neuroleptic Malignant Syndrome
 Treatment of Neuroleptic Malignant Syndrome
 Legal aspects
 Idiosyncratic reaction to a neuroleptic medication.
 Delay and Colleagues
 ‘akinetic hypertonic syndrome’
 After introduction of neuroleptics in 1960
 Typical and Atypical Antipsychotics
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Associated Medications
 Most often seen with the typical high potency
neuroleptic agents
 Reported also with :
- low potency neuroleptic agents
- atypical antipsychotic agents
- antiemetic agents
 Antiparkinson medication withdrawal
Epidemiology
Epidemiology
 Incidence
Agency for Healthcare Research and Quality
- 2000 – 2075 cases
- 2001 – 2444 cases
- 2002 – 1835 cases
Risk factors
 Most frequently older antipsychotics
 Duration of treatment
 Keck and associates
 No geographic variation
 Pre-morbid Psychomotor agitation
 No racial variation
 Higher in males
 Higher doses of neuroleptics with greater rates of dose
increase
 Less than 40 years of age
 Higher number of intramuscular injections
 Elderly and children
 Concurrent use of lithium
 0.02 to 2.4 percent
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Risk Factors
Mortality
 Simultaneous use of 2 or more neuroleptics
 10 – 20 %
 Encephalitis,
Encephalitis AIDS increase susceptibility
 Decreased over the past 2 decades
 Dehydration
 Maybe due to the awareness of the syndrome
 High serum creatinine kinase
 Higher mortality with medical complications
 Iron defeciency
and substance abuse
Neuroleptic Malignant Syndrome
Pathogenesis
 Detection of Suspected Neuroleptic Malignant
Syndrome DVD/VHS Trailer
 Central dopamine blockade theory.
 2 Major Theories.
Theories
 Neuroleptic induced muscle toxicity.
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Central Dopamine Blockade
Theory
Dopamine Activity
 Thermoregulation
 Suggested by Henderson and Wooten
 Hypothalamus
Impaired heat dissipation
 Corpus Striatum
Muscle rigidity
 Spinal cord
Autonomic disturbances
 Low CSF dopamine metabolite
Pathophysiology
Neuroleptic Induced Muscle Toxicity
 Calcium ion transport
 Increased contractility
 Hyperthermia
 Muscle cell breakdown
 Dantrolene
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Genetics
Clinical Manifestations
 Mental status change
- 82 % of patients
 Familial clusters
 D2 receptor gene
 Reduced function of dopamine receptors
 Inherited changes
 Muscular rigidity
- lead pipe rigidity
 Hyperthermia
- 87 % of patients
 Autonomic instability
- 88% of patients
Atypical Manifestations
 Atypical antipsychotics
 Conventional antipsychotics
 Varied presentation
Criteria A
 Development of severe muscle rigidity
 Development of elevated temperature
 Associated with neuroleptic medication use
 DSM V
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Criteria B
Criteria C
 Two or more of the following:
1. diaphoresis
2. dysphagia
3. tremor
4. incontinence
5. changes in the level of conciousness ranging from
confusion to coma
 The symptoms in Criteria A and B are not due to another
substance (eg. Phencyclidine) or a neurological or other
general medical condition (eg. Viral encephalitis).
6. mutism
7. tachycardia
8. elevated or labile blood pressure
9. leukocytosis
10. Laboratory evidence of muscle injury (eg. Elevated CPK)
Criteria D
Dysautonomic syndromes
 Serotonin syndrome
 The symptoms in Criteria A and B are not better
accounted for by a mental disorder (eg. Mood disorder
with catatonic features).
M li
th
th
i
 Malignant
hyperthermia
 Malignant catatonia
 Central anticholinergic syndrome and other drug related
syndromes
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Serotonin Syndrome
NMS vs. Serotonin Syndrome
 Detailed history of medication use
 Use of Serotonin Specific Reuptake Inhibitors
 Medication dose adjustment
 Shivering
 Symptom onset
 Hyperreflexia
 Neuromuscular
 Myoclonus
 Rhabdomyolysis
 Ataxia
 Metabolic Acidosis
 GI effects
Malignant Hyperthermia
 Rare genetic disorder
 Associated with anesthetic agents
 Hyperthermia
 Muscle rigidity
 Dysautonomia
 Muscle contracture testing
Malignant Catatonia
 Behavioral prodrome
 Psychosis, agitation, catatonic excitement
 Dystonic posturing, waxy flexibility, stereotyped
repetitive movements
 Impossible to differentiate in 22% of patients
 Laboratory values are typically normal
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Catatonia
Anticholinergic Syndrome
 Dry skin, decreased sweating, mydriasis, dry mouth
 http://www.youtube.com/watch?v=zAEJ-Jvndms
 Less severe elevated body temperature and
encephalopathy
 Creatinine kinase levels not elevated
 Diaphoresis and rigidity are absent
Other Drugs
Differential Diagnosis
 Cocaine and ecstasy
 Increased physical exertion
 Rigidity is not common
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Investigations
Imaging
 Complete blood count (CBC)
 Blood cultures
 Comprehensive metabolic profile
 Creatinine kinase level
 Urine myoglobin level
 CXR
 CT Head
 Lumbar Puncture
 Arterial blood gas (ABG) level
 INR
 Serum and urine drug screening (eg, salicylates,
cocaine, amphetamines)
Laboratory Abnormalities
 Elevated serum CK
 Leukocytosis
 Liver transaminases
 Acute renal failure
Histology
 Muscle Biopsy
- Controversial
- Grossly swollen
- Edematous
- Necrosis
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Histology
NMS Complications
 Rhabdomyolysis
 Acute renal failure
 Thromboembolism
 Acute respiratory failure
 Seizures
 DIC
 Hepatic failure
 Sepsis
Prognosis
Management
 Resolution in 2 weeks
 Prolonged course
 Prompt recognition
- Depot antipsychotics
 Immediate discontinuation of the neuroleptic
- Structural brain disease
 Intensive supportive care and medical monitoring
 Sequelae
 Treatment of comorbid medical illness
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Supportive Measures
Pharmacotherapy
 Reduce body temperature.
 Treat suspected or secondary infections with empiric
antibiotics.
 Consider intubation for patients with excessive salivation,
swallowing dysfunction, coma, hypoxemia, acidosis, and
severe rigidity with hyperthermia.
 Rapid peripheral muscle relaxation
 Dantrolene
 Dopamine agonists
 Combined therapy
 Aggressive hydration
 Hemodynamic monitoring.
 Sedate the patient.
Dantrolene
Dopamine Agonists
 Muscle relaxant
 Inhibits calcium ion release
 Recommended
R
d d ffor severe hyperthermia
h
th
i
 Bromocriptine
 25 mg/d PO initially
 Amantadine
 gradually increase to tid/qid
 Levodopa and carbidopa
 not to exceed 400 mg/d
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ECT and NMS
Post NMS Neuroleptic Use
 Wait at least 2 weeks
 Alternative to oral treatment
 Reasonable treatment option
 6-10 treatments
 Hydration
NMS Sequelae
 Cerebellar neuronal degeneration
 Lithium
 Dysarthria
 Difficulties comprehending commands
 Attention problems
 Abnormalities in her muscle tone, power, reflexes, gait,
co-ordination and sensory function
 Cerebellar gait ataxia
 Use lower potency antipsychotics
 Start low and go slow with titration
 Avoid concomitant lithium use
 Avoid dehydration
 Monitor for NMS
NMS in Children and Adolescents
 Dr. Neuhut et al
 Published cases over an 18 year period
 Increased creatinine kinase, fever, tachycardia, rigidity,
altered mental state
 Prompt management
 NMS symptoms resolved
 No reported deaths
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Legal Aspects
Legal Aspects
 Discontinue neuroleptic promptly.
 Use of dantrolene or bromocriptine
 Seek appropriate consultation.
 Risk factors
 Transfer to higher level of care.
 Informed consent
 Document differential diagnosis.
 Psychoeducation
 Document treatment plan.
 Inform the family.
Resources
Resources
 National Organization for Rare Disorders
 Neuroleptic Malignant Syndrome Information Services
 (NORD)
 NMSIS
 orphan@rarediseases.org
 888-667-8367
 www.rarediseases.org
 www.nmsis.org
 Tel: 203-744-0100
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References
References

Heiman-Patterson TD. Neuroleptic malignant syndrome and malignant hyperthermia.
Important issues for the medical consultant. Med Clin North Am. Mar 1993;77(2):477-92.


Lazarus A, Mann SC, Caroff SN. The Neuroleptic Malignant Syndrome and Related
Conditions. Washington, DC: American Psychiatric Press; 1989.
Castillo E, Rubin RT, Holsboer-Trachsler E: Clinical differentiation between lethal catatonia
and neuroleptic malignant syndrome. American Journal of Psychiatry 146:324-328, 1989

Nierenberg D, Disch M, Manheimer E, Patterson J, Ross J, Silvestri G, et al. Facilitating
prompt diagnosis and treatment of the neuroleptic malignant syndrome. Clin Pharmacol
Ther. Nov 1991;50(5 Pt 1):580-6.
Levenson JL: Clinical differentiation between lethal catatonia and neuroleptic malignant
syndrome (ltr). American Journal of Psychiatry 146:1241, 1989

Shalev A, Hermesh H, Munitz H: The role of external heat load in triggering the neuroleptic
malignant syndrome. American Journal of Psychiatry 145:110-111, 1988

Reulbach U, Dütsch C, Biermann T, Sperling W, Thuerauf N, Kornhuber J, et al. Managing an
effective treatment for neuroleptic malignant syndrome.
syndrome Crit Care.
Care 2007;11(1):R4.
2007;11(1):R4


Sachdev P, Mason C, Hadzi-Pavlovic D. Case-control study of neuroleptic malignant
syndrome. Am J Psychiatry. Aug 1997;154(8):1156-8.
Stoudemire A, Luther JS: Neuroleptic malignant syndrome and neuroleptic-induced
neuroleptic induced
catatonia: differential diagnosis and treatment. International Journal of Psychiatry in
Medicine 14:57-63, 1984


Shiloh R, Valevski A, Bodinger L, Misgav S, Aizenberg D, Dorfman-Etrog P, et
al. Precautionary measures reduce risk of definite neuroleptic malignant syndrome in newly
typical neuroleptic-treated schizophrenia inpatients. Int Clin
Psychopharmacol. May 2003;18(3):147-9.
Scheftner WA, Shulman RB: Treatment choice in neuroleptic malignant syndrome.
Convulsive Therapy 8:267-279, 1992

Davis JM, Janicak PG, Sakkas P, et al: Electroconvulsive therapy in the treatment of the
neuroleptic malignant syndrome. Convulsive Therapy 7:111-120, 1991

Gold R, Lenox RH: Is there a rationale for iron supplementation in the treatment of
akathisia? A review of the evidence. Journal of Clinical Psychiatry 56:476-483, 1995

Pelonero AL, Levenson JL, Silverman JJ: Neuroleptic therapy following neuroleptic malignant
syndrome. Psychosomatics 26:946-948, 1985


Delay J, Pichot P, Lemperiere T, et al: Un neuroleptique majeur non phenothiazine et non
reserpine, l'haloperidol, dans le traitement des psychoses [Haloperidol, a nonphenothiazine,
nonreserpine neuroleptic for the treatment of psychosis]. Annales Medico-Psychologiques
118:145-152, 1960
References

Croarkin PE, Emslie GJ, Mayes TL. Neuroleptic malignant syndrome associated with atypical
antipsychotics in pediatric patients: a review of published cases. J Clin
Psychiatry. Jul 2008;69(7):1157-65.

Deuschl G, Oepen G, Hermle L. Neuroleptic malignant syndrome: observations on altered
consciousness. Pharmacopsychiatry. Jul 1987;20(4):168-70.

Dickey W. The neuroleptic malignant syndrome. Prog Neurobiol. 1991;36(5):425-36.

Gurrera RJ, Chang SS, Romero JA. A comparison of diagnostic criteria for neuroleptic
malignant syndrome. J Clin Psychiatry. Feb 1992;53(2):56-62.

Hammerman S,
S Lam C
C, Caroff SN.
SN Neuroleptic malignant syndrome and aripiprazole.
aripiprazole Journal
of the American Academy of Child and Adolescent Psychiatry. June 2006;45 (6):639-41.

Kaplan HI, Sadock BJ, Grebb JA. Kaplan and Sadock's Synopsis of Psychiatry. Philadelphia,
Pa: Lippincott, Williams, & Wilkins; 1994:1913, 2004-2005.

Kaufman KR, Levitt MJ, Schiltz JF, Sunderram J. Neuroleptic malignant syndrome and
serotonin syndrome in the critical care setting: case analysis. Ann Clin Psychiatry. JulSep 2006;18(3):201-4.

Keck PE Jr, Caroff SN, McElroy SL. Neuroleptic malignant syndrome and malignant
hyperthermia: end of a controversy?. J Neuropsychiatry Clin
Neurosci. Spring 1995;7(2):135-44.

Keck PE Jr, Pope HG Jr, McElroy SL. Declining frequency of neuroleptic malignant syndrome
in a hospital population. Am J Psychiatry. Jul 1991;148(7):880-2.

Klein JP, Fiedler U, Appel H. Massive creatine kinase elevations with quetiapine: report of two
cases. Pharmacopsychiatry. 2006;39(1):39-40.
 bhagat@etsu.edu
bh
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Thank You
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