NEUROLEPTIC MALIGNANT SYNDROME

Dr. Praveen GoonathilakeRegistrar in Psychiatry

Teaching Hospital- Jaffna

A severe disorder associated with

1. Introduction/Increase in dose of dopamine receptor antagonists. (mostly antipsychotics)

OR

2. Rapid withdrawal of dopaminergic agents.

Unpredictable Potentially life-threatening.

Introduction

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%.

• >38 C (100.4 F) Fever

• “Lead pipe” in most severe formMuscle rigidity

• Drowsiness, agitation, confusion, delirium, coma

Altered mental status

• Fluctuations in BP, tachypnoea, tachycardia, sialorrhoea, diaphoresis, flushing, skin pallor, incontinence

Autonomic instability

Clinical PresentationClassical tetrad of clinical features

In addition, Extrapyramidal motor signs – Tremour,

chorea, akinesia, dystonic movements.

Other symptoms – Dysphagia, dyspnoea, abnoramal reflexes, mutism, seizures.

◦ NMS associated with atypical antipsychotics – Core symptoms may be absent.

Clinical Presentation cont..

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%)

Development and Course

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

Development and Course cont..

Age, sex, time of year – not correlated with the risk.

Not specific to any neuropsychiatric diagnosis.

Catatonia – risk of progressing to NMS with antipsychotics.

Agitation Dehydration Restraint

Risk Factors

Preexisting abnormalities of CNS dopamine activity/ receptor function.

Iron deficiency.

Prior episode of NMS : reported in 15%-20% of cases.

Elevated environmental temperature - ? Contributing factor

Risk Factors cont..

High potency conventional antipsychotics – higher risk◦ Atypical antipsychotics: Less incidence.

Parental routes

Higher titration rates

Higher total doses

Antipsychotic-related Risk Factors

Precise mechanisms are unproven.

Antipsychotic-induced dopamine blockade

Sudden drop in CNS dopaminergic activity

Pathophysiology

Supportive evidence for this hypothesis:1) Withdrawal of dopaminergic drugs can precipitate an

NMS-like syndrome.2) All drugs associated are dopamine receptor blockers.3) Risk of NMS appears to be correlated with the

dopamine receptor binding affinity of drugs.4) Dopaminergic drugs are used in the treatment of

NMS.5) Patients with central dopamine tract lesions develop

similar syndromes.6) Low levels of homovanillic acid (dopamine

metabolite) detected in patients with acute NMS.

Pathophysiology

FBC – Leucocytosis (WBC 10000-40000)

CK – elevated (> 1000 IU/L)

Urine analysis – myoglobinuria indicate poor prognosis.

ABG – Metabolic acidosis

Serum iron – reduced ( ? An acute phase response)

Serum catecholamine - elevated

CSF – 95% normal.

Brain imaging – usually normal.

EEG – generalized slowing.(metabolic encephalopathy)

Investigations

Based on history, physical symptoms and laboratory findings.

Diagnosis by exclusion – Need to exclude other possible medical conditions.

Different sets of diagnostic criteria are used without satisfactory consensus.

2011 – diagnostic criteria by an International consensus study introduced.

Diagnosis

DSM-IV criteria for diagnosis

CNS infections (esp. viral encephalitis can be difficult to differentiate)

Malignant catatonia ( indistinguishable in >20% of cases)

Serotonin syndrome - Serotonergic drugs (eg: SSRI, TCA, MAOI)

Malignant hyperthermia ( intraoperatively, family Hx+)

Heatstroke (dry skin, muscle flaccidity)

Differential Diagnosis

Substances – Cocaine, amphetamine (esp. ecstasy) , hallucinogens (eg: Phencyclindine)

Alcohol/Hypnotic withdrawal

Nonconvulsive status epilepticus

Anatomic lesions in brainstem

Differential Diagnosis cont..

Immediate withdrawal of the offending agent. Reinstitution of abruptly withdrawn dopaminergic

agents. Supportive care – mainstay of management

Aggressive fluid resuscitation Monitoring and correction of electrolyte imbalances. Cooling measures (eg: cooling blankets, ice packs) – in

extreme hyperthermia. Monitoring for complications – cardioresp. failure, renal

failure, aspiration pneumonia, coagulopathies. Dialysis – renal failure Ventilator support – respiratory failure

Management

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.

Management cont..

Dopaminergic agents1. Bromocriptine

Starting dose - 2.5mg bd/tds oral/NG 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 and hypotension

2. Amantadine 200-400mg/day in divided doses oral/NG

Levadopa have been used in some cases. apomorphine

Management cont..

Dantrolene Muscle relaxant Started with 1-2.5mg/kg initial IV bolus 1mg/kg every 6hrly up to a max. dose of

10mg/kg/day. Tapering down or switching to oral form

after first few days. Discontinued once symptoms begins to

resolve. (Risk of hepatotoxicity)

Management cont..

Benzodiazepines May hasten the recovery in milder cases. May control agitation. Lorazepam

Starting dose 1-2mg IM/IV

CarbamazepineReported to have some effect.

Clonidine

Management cont..

ECT can be effective in,

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.

Management cont..

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.◦ Start with a low dose and titrate gradually.◦ Careful monitoring for early signs of NMS.

Antipsychotic use after NMS

Conservative use of antipsychotics.

Reduction of risk factors.

Early diagnosis.

Prompt discontinuation of offending agents.

Early supportive care and medical management.

Recommendations

1. Strawn JR, Keck Jr PE, Caroff SN: Neuroleptic Malignant Syndrome. Am J Psychiatry 2007, 164:870-876.

2. Berman BD: Neuroleptic Malignant Syndrome: A Review for Neurohospitalists. The Neurohospitalist 2011, 1:41-47.

3. Karagianis JL, Phillips LC, Hogan KP, LeDrew KK: Clozapine-Associated Neuroleptic Malignant Syndrome:Two New Cases and a Review of the Literature. The Annals of Pharmacotherapy 1999, 33: 623-630.

4. American Psychiatric Association: Diagnostic and statistical manual of mental disorders: DSM-V. Washington DC: American Psychiatric Association; 2013.

5. Sadock BJ, Sadock VA, Ruiz P: Kaplan & Sadock’s comprehensive textbook of psychiatry: 9th ed. Philadelphia: Lippincott Williams & Wilkins;2009.

THANK YOU!

References