Neuroleptic Malignant Syndrome (NMS) is a rare, but life-threatening, idiosyncratic reaction to neuroleptic medications. It refers to a combination of hyperthermia, muscular rigidity, altered mental status, and autonomic dysregulation. Contrary to earlier reports that typical or first-generation antipsychotics are mostly responsible for NMS, atypical antipsychotics have also been implicated. Thus, different classes of antipsychotics have been associated with NMS, including atypical antipsychotics. It often occurs shortly after the commencement of neuroleptics treatment, or after dose increases.

PATHOPHYSIOLOGY

Central dopamine D2 receptor blockade in the hypothalamus, nigrostriatal pathways and the spinal cord via the extrapyramidal pathways leading to rigidity and tremor. Also, hypothalamic D2 receptor blockade results in an elevated temperature set point and impairment of heat dissipating mechanisms. Peripherally, increased calcium release from the sarcoplasmic reticulum results in increased contractility, which results in hyperthermia, rigidity, and muscle cell breakdown. Furthermore, Autonomic dysfunction resulting from sympatho-adrenal hyperactivity and dysregulation may be due to the removal of tonic inhibition from the sympathetic nervous system because of D2 receptor blockade. Lastly, direct muscle toxicity may also be a mechanism of NMS.

1. Mental: Delirium, mutism progressing to lethargy, stupor and coma
2. Autonomic: Diaphoresis, Hyperthermia, Tachycardia, Incontinence, Labile blood pressure.
3. Neuromuscular: Psychomotor agitation, muscular rigidity, shuffling of gait and tremor.
4. Others: Dysphagia, Pallor, Dyspnoea

DIAGNOSIS

The diagnosis of NMS is mainly clinical. Laboratory findings are however vital in grading its severity or excluding other close differentials.

A. The cardinal features include:

1. Severe muscular rigidity
2. Hyperthermia (Temperature >300C)
3. Autonomic instability, 
4. Changes in the level of consciousness.

B. Presence of at least 2 other clinical features of NMS, including leucocytosis and laboratory evidence of muscle injury (e.g. elevated CPK).

C. Symptoms are not due to another substance (e.g. Phencyclidine), neurological, general medical condition or mental disorder (DSM).

1. Malignant hyperthermia
2. Medications such as metoclopramide, promethazine and droperidol that have decreased dopamine receptor activation may cause conditions indistinguishable from NMS
3. A rapid removal of medications with dopaminergic properties such as levodopa, bromocriptine and amantadine in patients treated for Parkinson’s disease is also associated with a similar syndrome
4. Lethal catatonia occurs in people with schizophrenia or during manic episodes. It has a prodromal period of excitement and agitation prior to the rigidity; whereas NMS tends to begin with rigidity.
5. Neuroleptic-induced EPSE: Neuroleptic-induced tardive dyskinesia, Neuroleptic-induced acute akathisia, Neuroleptic-induced acute dystonia, and Neuroleptic-induced parkinsonism.
6. CNS: Status epilepticus, stroke, brain trauma, neoplasms, acute intermittent porphyria, tetanus 
7. Serotonin syndrome occurs on exposure to serotonergic agents, particularly serotonin reuptake inhibitors (SSRIs). Consists of a triad of (1) altered mental state, (2) autonomic dysfunction, and (3) neuromuscular abnormalities. 

The following are noted due to muscle damage and necrosis.

1. Electrolytes: Elevated creatinine kinase, Increased aminotransferases (AST, ALT), Increased lactate dehydrogenase, Hyperkalaemia, Hyperphosphatemia, Hyperuricemia, Hypocalcaemia.
2. Urinalysis: Myoglobinuria, Proteinuria.
3. Full Blood count + Platelets: Leucocytosis, Thrombocytosis.
4. CSF analysis: Increased cerebrospinal fluid (CSF) protein

MANAGEMENT

The treatment is mainly supportive. The symptoms usually resolve in 1-2 weeks in most cases but can last as long as a month in NMS precipitated by long-acting depot injectable.

A.  ACUTE CARE

Supportive care is essential at this stage to prevent further complications and maintain organ function. This includes:

1. Discontinuation of all neuroleptics
2. Use of benzodiazepine for the purpose of restraint
3. Circulatory and ventilatory support as needed
4. Fluid resuscitation and alkalisation of urine to prevent acute renal failure and enhance excretion of muscle breakdown products
5. Antipyretics to control temperature in addition to other temperature lowering measures such as ice packs, cooling blankets etc.     B. PHARMACOTHERAPY

1. Dantrolene: dosage 100- 200mg/day. Stimulates muscle relaxation by modulating skeletal muscle contraction
2. Bromocriptine (5-10mg/day).  Strong dopamine D2 agonist and partial D1 receptor agonist.
3. Amantadine:  antiviral agent effective against influenza A. Proposed role in altering the release and reuptake of dopamine
4. Avoid the use of antimuscarinic agents as it may worsen the hyperthermia.  

C.  ELECTROCONVULSIVE THERAPY (ECT): proposed as a treatment for NMS based on its effectiveness in acute lethal catatonia. Suggested to be effective but cautious due to treatment-related complications.

D.  PREVENTION: This can be achieved through psychoeducation of the patient and their family members as to the risk and possible signs while commencing neuroleptics

COMPLICATIONS

• End-organ failure: Renal failure, Respiratory failure, Hepatic failure
• Neurovascular: Seizure, Cardiac arrest, Aspiration, Pulmonary embolism
• Others: Rhabdomyolysis, Infection, Uncontrolled psychosis.

1. David. S, Roger. S. Oxford Handbook of Psychiatry Fourth Edition, Oxford Press, 2019.
2. American Psychiatry Association. Diagnostic and Statistical Manual of Mental Disorders. (DSM V). 5th Edition. Washington DC: American Psychiatry Association; 2013.
3. https://epdf.pub/emergency-psychiatry-review-of-psychiatry1aa54702d5ad1bed4a46346762c4137c19398.html.
4. Neuroleptic malignant syndrome treatment and management. Available at https://emedicine.medscape.com/artcle/816018-treatment