A case report of neuroleptic malignant syndrome

Abstract

A 32-year-old male patient with a history of treatment resistant paranoid schizophrenia developed neuroleptic malignant syndrome (NMS) during changeover of his antipsychotic medication from zuclopenthixol depot to clozapine. This case highlights the difficulties of cross-tapering two antipsychotics—that is, converting from a typical depot medication to an oral atypical antipsychotic.

BACKGROUND

This case involves a 32-year-old male patient who has been known to the psychiatric services since he was 5 years old with a diagnosis of hyperkinetic syndrome (hyperkinetic disorder unspecified F90.9). He is also known to have a mild learning disability.

The patient was first diagnosed with probable psychosis in 1993 and subsequently given a diagnosis of paranoid schizophrenia in 1996. At this point he was started on haloperidol depot, 300 mg intramuscularly every 2 weeks, with limited success. This was changed to zuclopenthixol decanoate depot in 2001 after a brief admission to a psychiatric inpatient unit for a relapse in his psychotic illness.

The patient’s medical history is unremarkable and there is no recent medical illness requiring medication. There is a family history of mental illness, with a maternal grandfather, uncles and an aunt described as having had “nervous breakdowns”. His parents are divorced and he has two brothers, aged 30 years and 25 years old.

Unemployed most of his adult life, he lives on his own and is supported by the community mental health team with a community psychiatric nurse and regular day activities in a day centre.

He is known to have used amphetamines in his adolescence; however, there is no recent history of illegal substance or alcohol misuse.

PRESENTATION

In January 2008 concerns were raised regarding the patient’s mental state, as there were symptoms suggestive of a relapse in his illness. He presented with symptoms of persecutory beliefs and ideas of reference. He was convinced that people were talking about him and laughing at him. He started to become increasingly concerned that people were going to attack him.

It was apparent that he had a relapse in his illness and was considered to have treatment resistant schizophrenia. Response to either of the two antipsychotic medications was poor despite adequate treatment over a sufficient period of time. His medications were haloperidol depot, 300 mg every 2 weeks, and zuclopenthixol decanoate depot, 200 mg every 2 weeks.

The plan was to stop zuclopenthixol and start him on clozapine. Before the switchover of the medication, a full physical examination was performed which was normal. Routine tests such as full blood count, urea and electrolytes, liver function tests, thyroid function tests and electrocardiogram (ECG) were all unremarkable.

The zuclopenthixol decanoate depot was stopped and the patient was started on clozapine, according to the Maudsley prescription guidelines¹ and advice from the clozapine patient monitoring service. The titration of medication was done in a day hospital setting to monitor his progress and vital signs.

Clozapine was started at 12.5 mg oral once a day, with increments of 12.5 mg a day for the next 2 days and increments of 25 mg a day subsequently. By day 13 the clozapine dose was at 50 mg in the morning and 100 mg at night.

On day 13 of clozapine treatment, the patient started feeling unwell: dizziness upon standing, complaining of sweats, palpitations and facial flushing. His vitals signs were closely monitored and he was also reviewed by the on call doctor.

The patient denied using any illicit substances. He had been physically well until this point and had not been prescribed any other medication. He had been attending the day hospital on a daily basis for the previous 2 weeks. Accidental overdose of medication was ruled out as his medication was supervised by the nursing staff in the day hospital. Similarly there was no evidence of using over the counter medication or any recent travel that could cause his current symptoms.

Examination revealed blood pressure fluctuating between 69/59 mm Hg and 144/93 mm Hg, tachycardia of 120 beats/min, and body temperatures (ear canal measurement) of 37.9°C and 38.5°C on two consecutive days.

INVESTIGATIONS

Blood tests showed a creatinine kinase (CK) concentration of 216 IU/l. Subsequent CK values remained high, at 521 IU/l 2 days later. An ECG showed sinus tachycardia. Other routine investigations such complete blood count, liver function test, and urea and electrolytes were normal. The cardiac enzyme troponin I was normal.

DIAGNOSIS

The patients was diagnosed with neuroleptic malignant syndrome (NMS).

DIFFERENTIAL DIAGNOSES

• Encephalitis

• Meningitis

• Heat exhaustion

• Parkinsonism

• Acute dystonia

• Serotonergic syndrome

• Drug toxicity

MANAGEMENT

The patient was admitted to the psychiatric inpatient unit immediately. Emergency medical and cardiology opinions were sought. Clozapine, which was considered the offending agent, was stopped immediately.

Over the next 4 days his vital signs normalised. CK concentrations gradually dropped and were normal at 152 IU/l within 10 days’ time.

He was restarted on zuclopenthixol depot after an initial test dose of 100 mg intramuscularly with no concerns. Precautions were taken for the symptoms to resolve completely.

No further treatment was required in the above case; however, in severe cases of NMS, admission to an intensive care unit for artificial ventilation may be necessary. Adequate rehydration is essential to prevent renal failure, as mortality can be as high as 50% in patients who develop renal failure.²

Dantrolene sodium, a muscle relaxant, is used to treat hyperthermia and rigidity. Bromocriptine, a dopamine agonist, is used in combination with dantrolene to overcome antipsychotic induced dopamine blockade.

Benzodiazepines are effective in managing and treating psychotic symptoms, and electroconvulsive therapy (ECT) for severe psychosis has been utilised.

OUTCOME AND FOLLOW-UP

The patient was stabilised on depot medication and discharged to the day hospital, where his symptoms and vital signs were monitored. He is currently being reviewed in an outpatient clinic and is on zuclopenthixol decanoate depot, 200 mg intramuscularly weekly.

DISCUSSION

NMS is a rare, life threatening side effect of antipsychotic medication characterised by hyperthermia, muscular rigidity, altered mental state and autonomic dysfunction. Other symptoms include tachycardia, tachypnoea, diaphoresis, sialorrhea, tremor, urinary incontinence and retention.

The incidence is about 1% in patients treated with antipsychotic medication. Mortality is about 5–11.6%. Death usually occurs as a result of respiratory failure, disseminated intravascular coagulation, renal failure and/or cardiovascular collapse.²

NMS may last 7–10 days after stopping oral antipsychotic medication and up to 21 days after stopping depot antipsychotic. According to the manufacturers of zuclopenthixol decanoate (Lundbeck) the depot has a half life of 19 days. Maximum serum concentrations of zuclopenthixol are reached in 3–7 days following intramuscular injection.

The manufacturers report that the therapeutic index of zuclopenthixol is narrow but were unable to give an exact figure. Their advice is to aim for a serum concentration of 3–4 μg/l for a moderately psychotic patient and 5–8 μg/l for a severely psychotic patient.

Clozapine, like any other antipsychotic medication, is implicated in NMS. The most common side effects with the drug are sedation, hypersalivation, constipation, hypotension, hypertension, tachycardia, myocarditis, weight gain, fever, seizures, nausea, nocturnal enuresis, neutropenia, and agranulocytosis.

The uncommon adverse effects are delayed agranulocytosis, delirium, eosinophilia, hepatic failure, pneumonia, pancreatitis, thrombocytopenia, NMS, and heat stroke occasionally mistaken for NMS.

Clozapine interacts with many medications. Certain drugs are known to reduce plasma concentrations of clozapine by induction of cytochrome P450 enzymes. These include drugs such as phenytoin, nicotine, and rifampicin.

Some drugs such as cimetidine, caffeine, citalopram, ciprofloxacin, and erythromycin may increase plasma concentrations of clozapine by inhibiting the enzymes and potentially causing adverse effects.

The plasma concentration threshold of clozapine varies from one patient to another. The general recommendation is to aim for >0.35 μg/l for a good response. An upper limit has not been defined, although values above 100 μg/l are associated with toxicity and serious side effects. Measuring plasma clozapine concentrations is not only useful in optimising treatment but also for preventing dangerous side effects.¹

NMS is an idiosyncratic reaction. There is no evidence whether it is dose dependent, as many argue NMS can occur at any dose. However, higher doses, parental administration and rapid increase in dosage are implicated according to a case study. One paper reports occurrence of NMS after an increase in the dose of antipsychotic medication.³

Pathophysiology

Neuroleptic medication causes dopamine blockage in the central nervous system, leading to dopamine deficiency. Dopamine deficiency in substantia niagra or striatum causes rigidity, and in the hypothalamus it impairs thermoregulation.

Acetylcholine is also implicated in NMS upon initiation of donepezil, an acetylcholinesterase inhibitor, in one study.⁴

Risk factors for NMS⁵

• Increased temperature

• Dehydration or depleted volume state

• Agitation

• Catatonia

• Rapid antipsychotic initiation

• Dose escalation

• Withdrawal of anti-parkinsonian medication

• Depot intramuscular preparations

• Organic brain disease

• Affective disorder

• A previous NMS

Drugs implicated in NMS

• Phenothiazines

• Butyrophenones

• Thioxanthenes

• Tricyclic antidepressants

• Monoamine oxidase inhibitors

• Phenytoin

• Carbamazepine

• Metoclopramide

• Hydroxyzine

Diagnostic criteria

We noticed much variation in diagnostic criteria for NMS. Benzer (2007)² reports that Diagnosis of NMS can be confirmed but not excluded based on the following criteria:

• Recent treatment with a neuroleptic in the last 1–4 weeks

• Hyperthermia of >38°C

• Muscular rigidity

And evidence of at least five of the following symptoms:

• Tachycardia

• Change in mental state

• Hypertension or hypotension

• Diaphoresis or sialorrhea

• Tremor

• Incontinence

• Increased creatinine phosphokinase (CPK) or urinary myoglobin

• Leucocytosis

• Metabolic acidosis

• Exclusion of other drug induced, systemic, or neuropsychiatric illness

Other articles

A review of similar published cases in a Medline search showed about 500 case reports related to NMS due to various aetiologies.

Caroff and Mann’s (1993) study⁶ highlights the importance of early recognition and discontinuation of the triggering drugs and management.

According to Karagianis et al (1999),³ Clozapine was deemed a highly probable cause of NMS in 14 cases, a medium probability cause in five cases, and a low probability cause in eight cases in their study of all cases reported in Medline between 1966–1999.

LEARNING POINTS

• Neuroleptic malignant syndrome (NMS) is potentially fatal.

• Caution needs to be exercised when switching depot typical antipsychotic to oral atypical antipsychotic, which may induce NMS. This is partially due to the prolonged action of the depot preparations.

• Cross-taper cautiously, and benzodiazepines can be used to monitor any worsening of symptoms during the switchover.

• Remember to request routine investigations and ECG before switching over, and to monitor vital signs and check creatinine kinase values and complete blood counts if the clinical picture suggests NMS.