NEUROLEPTIC NEUROLEPTIC MALIGNANT MALIGNANT SYNDROMESYNDROME

Dr. Kaushik.P,Intern, Department of Psychiatry,M.S.Ramaiah Teaching Hospital

INTRODUCTION A severe disorder associated with

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

OR

2.Rapid withdrawal of dopaminergic agents.

Unpredictable Potentially life-threatening.

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%.

CLINICAL PRESENTATIONCLINICAL PRESENTATIONCLASSICAL TETRAD OF CLINICAL FEATURES

CLINICAL PRESENTATION CONT..In addition, Extrapyramidal motor signs – Tremor, chorea, akinesia, dystonic movements.

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

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

DSM-IV CRITERIA FOR DIAGNOSIS

DEVELOPMENT AND COURSE 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 CONT.. 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

RISK FACTORS Concurrent medical and neuropsychiatric

issues 1.Dehydration 2.Psychomotor agitation 3.Encephalitis and traumatic brain

injury 4.Mood disorders 5.Preexisting catatonia 6.History of NMS- in 15%-20% of cases. 7.Low serum iron Younger age Male gender

ANTIPSYCHOTIC-RELATED RISK FACTORS High potency conventional

antipsychotics – higher risk Atypical antipsychotics: Less incidence.

Parental routes

Higher titration rates

Higher total doses

PATHOPHYSIOLOGY

Precise mechanisms are unproven. Drug induced dopamine blockade,

followed by abrupt discontinuation of the drug

Sudden dopaminergic dysregulation

PATHOPHYSIOLOGY Supportive evidence for this hypothesis:

1) All drugs associated are dopamine receptor blockers.

2) Risk of NMS appears to be correlated with the dopamine receptor binding affinity of drugs.

3) Dopaminergic drugs are used in the treatment of NMS.

4) Patients with central dopamine tract lesions develop similar syndromes.

5) Low levels of homovanillic acid (dopamine metabolite) detected in patients with acute NMS.

PATHOPHYSIOLOGY CONT.. Also family clusters of NMS have found that

A1 allele of dopamine D2 receptor gene may be over expressed in these patients, this allele reduces the density and function of the dopamine receptor

INVESTIGATIONS CBC – Leucocytosis (Upto 40000)

CK – elevated (> 1000 IU/L)

Urine analysis – myoglobinuria (indicates poor prognosis)

ABG – Metabolic acidosis

Serum iron – reduced (probably an acute phase response)

Serum catecholamine - elevated

CSF – 95% normal.

Brain imaging – usually normal.

EEG – generalized slowing (metabolic encephalopathy)

DIFFERENTIAL DIAGNOSIS Primary CNS disorders- 1.CNS Vasculitis 2.Infarctions 3.Infection 4.Status Epilepticus 5.Trauma 6.Tumors 7.Acute Porphyria

Psychiatric disorders- Idiopathic Lethal Catatonia

DIFFERENTIAL DIAGNOSIS CONT..

Systemic Disorders- 1.Acute Porphyria 2.Autoimmune disorders 3.Dehydration 4.Heat stroke 5.Hyperthyroidism 6.Infections 7.Tetanus 8.Pheochromocytoma

DIFFERENTIAL DIAGNOSIS CONT.. Medication related disorders- 1.Anticholinergic syndrome 2.Levodopa syndrome 3.Malignant hyperthermia 4.Serotonin Syndrome

MANAGEMENT

Immediate withdrawal of the offending agent.

Supportive care – mainstay of management Aggressive fluid resuscitation Monitoring and correction of electrolyte

imbalances. Cooling measures (cooling blankets, ice packs,

ice water enema) Monitoring for complications –

cardiorespiratory failure, renal failure, aspiration pneumonia, coagulopathies.

Dialysis – renal failure Ventilator support – respiratory failure

MANAGEMENT CONT.. 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 agents

Bromocriptine Starting dose - 2.5mg bd/tds by

mouth 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,hypotension and induce emesis

MANAGEMENT CONT.. Amantadine- 200-400mg/day in divided doses

by mouth in divided doses

Levodopa- 50-100mg per day intravenous as

continous infusion

MANAGEMENT CONT.. Dantrolene Started with 1-2.5mg/kg initial IV bolus Then 1mg/kg every 6hrly up to a max. dose

of 10mg/kg/day for 8days Switching to oral form after first few days for

another 7days Discontinued once symptoms begins to

resolve. (Risk of hepatotoxicity)

MANAGEMENT CONT.. Benzodiazepines

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

Starting test dose 1-2mg IM/IV, if effective switch to mouth

Carbamazepine Reported to have some effect.

Clonidine

MANAGEMENT CONT.. ECT - good outcome with both unilateral

and bilateral treatments

can be effective when,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.

ANTIPSYCHOTIC USE AFTER NMS 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. Considering alternative therapies like ECT Start with a low dose and titrate gradually Careful monitoring for early signs of NMS.

RECOMMENDATIONS Conservative use of antipsychotics.

Cautious use of antipsychotics in patients with increased risk

Early diagnosis.

Prompt discontinuation of offending agents.

Early supportive care and medical management.

REFERENCES