Drug Induced Movement Disorders
NEUROLEPTIC MALIGNANT SYNDROME
Neuroleptic malignant syndrome is the rarest of the neuroleptic induced movement disorders. It is the most serious and represents a neurologic emergency in most cases. It has now been reported to occur with all drugs that effect the central dopaminergic system (including dopamine agonists and levodopa).
There's an isolated report of neuroleptic malignant syndrome in a patient on a trycyclic medication. It is likely an idiosyncratic reaction and patients can, if needed, be given the same agent again without recurrence.
It is estimated that 0.5-1% of patients exposed to neuroleptics will develop this syndrome. Most patients will develop it shortly after initial exposure and 90% within two weeks of starting the neuroleptic. It can occur with all the neuroleptics but haldol and trifluperazine are the most common. It has also been seen with clozapine and metoclopramide.
The classic triad involves the autonomic nervous system (fever in 100%), the extrapyramidal system (rigidity), and cognitive changes.
The two characteristic laboratory findings reported in 75% of cases are a high CPK and leukocytosis. 95% of patients are iron deficient. The CSF is usually normal. The EEG can show diffuse slowing. Other features include tachypnea (78%), diaphoresis (60%), and labile blood pressure (54%).
The temperature does not usually exceed 41°C and often peaks before the motor systems become prominent. The most frequent extrapyramidal findings include rigidity (90%) and tremor (56%).
Dystonia and chorea have also been reported. Mental status changes occur in 75% of patients. This starts as drowsiness and confusion but can progress to stupor and coma. Other symptoms can include seizures, pyramidal tract findings, ocular flutter, cardiac arrhythmias.
Physical exhaustion, dehydration, hyponatremia, young male gender, affective disorders, thyrotoxicosis, or prior brain pathology all increase the rate of this syndrome developing. An increased risk occurs in patients combining haldol with lithium.
Once symptoms develop progression is quite rapid and reaches peak intensity in about 72 hours. This can very from 45 minutes to as long as 65 days. Some cases remain mild and clear up without intervention.
The duration of the symptoms can last from 8 hours to 40 days (longer with parental medication). With early recognition and aggressive treatment there is only a 5% mortality rate (much improved in the last 20 years).
Most patients who survive make a full recovery. Some are left with permanent parkinsonism, ataxia, and dementia. Re-occurrences have been described following exposure to the same neuroleptic but this is not common.
The pathophysiology is not completely understood but is thought to involve 3 systems.
These include abnormalities in the:
- Central dopamine system.
- Muscle membrane dysfunction.
- Sympathetic nervous system. Evidence for the central dopamine mechanism comes from the fact that a similar syndrome is seen in Parkinson's disease with abrupt withdrawal of levodopa or anticholinergics. Additionally 95% of patients with this syndrome develop parkinsonian symptoms. Muscle abnormalities have been invoked because of the clinical similarity to malignant hyperthermia. Abnormalities in the sympathetic system are supported by changes in the urine and plasma catecholamine levels.
Early recognition is extremely important to reduce mortality. Without therapy this syndrome will resolve on its own over several weeks but with active treatment improvement will occur within 48-72 hours.
The first phase of treatment is supportive therapy with adequate hydration and metabolite (electrolyte) stabilization with cooling blankets to reduce hyperthermia. Ventilatory assistance may be required and occasionally dialysis is necessary for renal dysfunction.
Drug therapy starts with discontinuing the neuroleptic. There are a variety of other effective medications that can be used but the two most frequent ones include Dantrolene sodium and bromocriptine (individually or combined). These drugs reduce the mortality and shorten the course of the syndrome. Dantrolene can be given intravenously or orally starting with 2-3 mg per kg doses divided TID up to a total of 10 mg/kg/day. Bromocriptine can be given orally or by NG tube starting with 2.5 mg TID and increasing every 24 hours by 2.5 mg TID until a response is seen or until a maximum dose of 60 mg is achieved.
It is reasonable to start both drugs at the same time with intravenous Dantrolene and oral bromocriptine. Once symptoms start to resolve the Dantrolene can be discontinued and the bromocriptine can be maintained. The duration of treatment should be at least for ten days for oral neuroleptics, and two to three weeks for parental drugs. Other treatments that can be used include levodopa, pergolide, benzodiazepines, and rarely ECT.
If this syndrome occurs in the setting of Parkinson's disease the treatment is basically the same except the parkinsonian medication should be re-instituted as quickly as possible. Because of the risk of this syndrome drug holidays are no longer routinely recommended for Parkinson's disease.
If the neuroleptic is to be reintroduced a waiting period of two weeks should be used for oral medication at least six weeks for parental medication. It would be prudent to use a different neuroleptic than the one that originally caused the syndrome.
What Is Antipsychotic Medication?
Antipsychotic medication, otherwise known as neuroleptics, are mainly used in the treatment of disorders where there is an element of psychosis.
How Do They Work?
Antipsychotics can be split into two types; typical antipsychotics and atypical antipsychotics.
Both types work by altering the level of chemicals (called neurotransmitters) in the brain. These chemicals are the ones that are involved in transmitting impulses down the nerves in the brain. They tend to work at junctions between nerve fibres (called synapses). At these junctions the level of neurotransmitters is crucial in deciding whether an impulse carries on, or is stopped.
It is thought that in psychosis, the balance of neurotransmitters in the brain is wrong.
The particular name of the neurotransmitter that is affected by typical antipsychotics is dopamine. Atypical antipsychotics affect both dopamine and other neurotransmitters such as serotonin.
What Are The Possible Side-Effects?
Side-effects will be discussed as we consider each specific drug.
The Antipsychotics Available
Medicines tend to have more than one name. They have a general name (called the non-proprietary name), and a name given to them by the drug company that makes them (called the proprietary name). This can be very confusing, so we will list the antipsychotics by writing the non-proprietary name first, followed by the propriatary names in brackets. Just Click on the antipsychotic that interests you.