Malignant neuroleptic syndrome: emergency care, prevention

People who are treated with neuroleptic, anticonvulsant or antidepressant drugs have a high risk of developing a dangerous condition called neuroleptic syndrome. The syndrome can occur during the course of treatment - for example, when the dosage of the drug is increased, or when the treatment is suddenly stopped - after a certain period of time.

The onset of neuroleptic syndrome is difficult to predict. Its treatment requires urgent medical intervention, since a fatal outcome with the syndrome is not uncommon.

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Epidemiology

The first mentions of neuroleptic syndrome date back to the 60s of the last century. Today, doctors have recognized this syndrome as one of the most unfavorable possible consequences of taking neuroleptics. The mortality rate of patients with the syndrome, according to various sources, can be 3-38%, and in recent years this percentage has been significantly reduced.

The incidence of neuroleptic syndrome, according to foreign medical periodicals, is up to 3.23% of the total number of patients who were treated with neuroleptics. Over the past few years, the incidence of the syndrome has significantly decreased.

Neuroleptic syndrome is most often diagnosed in middle-aged patients. Men have a higher chance of developing the syndrome, by about 50%.

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Causes neuroleptic syndrome

Most often, the development of neuroleptic syndrome is observed when taking excessive doses of strong neuroleptic drugs (for example, fluorophenazine), and especially medications with an extended (prolonged) effect.

However, this does not always happen: neuroleptic syndrome can develop with the use of any neuroleptic drug, although somewhat less frequently.

The syndrome can be detected after a sharp increase in dosage, when taking two or three neuroleptic drugs at the same time, or when combining neuroleptics with lithium-based medications.

There have been no recorded hereditary cases of neuroleptic syndrome, so this theory is not considered.

The syndrome most often occurs in patients with previously diagnosed mental disorders: schizophrenia, affects, neuroses, mental retardation, etc.

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Risk factors

The onset of neuroleptic syndrome can be accelerated by:

• organic brain damage;
• dehydration of the body;
• anorexia, severe exhaustion of the body;
• a prolonged period of fasting or malnutrition;
• anemia;
• postpartum period.

Even seemingly minor cerebral damage sustained several years ago may affect sensitivity to neuroleptic treatment. For this reason, patients with perinatal trauma, craniocerebral trauma, infectious diseases of the brain, degenerative brain lesions, and alcohol abusers may be included in the risk group.

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Pathogenesis

The pathogenetic features of neuroleptic syndrome have not been fully studied. Many specialists assume that the syndrome occurs as a result of blockade of dopaminergic structures in the hypothalamus and basal ganglia, and not as a result of intoxication with neuroleptics.

Some scientists explain that the increase in temperature – the main symptom of the syndrome – appears due to the resulting muscle rigidity and intramuscular hypermetabolism, which causes increased heat production.

Currently, there is a consensus among scientists that immune disorders with subsequent autoimmune failure in the central nervous system and visceral organs play an important role in the development of neuroleptic syndrome. Homeostatic disorders become the main causes of severe circulatory and consciousness disorders, which can lead to the death of the patient.

In addition, experts have discovered that the pathogenetic mechanism of the development of the syndrome is associated with sympathoadrenal and serotonin hyperactivity.

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Symptoms neuroleptic syndrome

Neuroleptic syndrome is characterized by the following symptoms, which are called the “tetrad” (four signs):

• increased temperature (more than 37°C);
• general muscle weakness;
• clouding of consciousness (possible development of a comatose state);
• disturbances in the functioning of the autonomic nervous system (profuse sweating, increased heart rate and arrhythmia, blood pressure surges, pale skin, increased salivation, respiratory and urinary disorders).

More than a quarter of patients have dystonic muscle contraction, and every second patient has tremors in the fingers and/or limbs. Additionally, symptoms such as a or hypokinesia, nystagmus, speech disorders, muteness, tonic spasm of the masticatory muscles, swallowing disorders, opisthotonus may be observed.

A smaller number of patients experience myoclonic seizures, hyperkinesis, and epileptic seizures.

The first signs can sometimes manifest themselves in the form of dehydration - decreased turgor, dry skin, dry oral mucosa.

The clinical picture increases, reaching its limit within 1-3 days, but in some cases the process occurs more intensively - over several hours.

Due to significant muscle weakness, including respiratory weakness, dyspnea develops. Severe skeletal muscle spasm can provoke rhabdomyolysis, which occurs with an increase in creatine phosphokinase levels in the bloodstream. Myoglobinuria, acute renal failure, metabolic acidosis, and tissue oxygen deficiency are then observed. Complications may include aspiration pneumonia, infarction, septicemia, thromboembolism, shock, pulmonary edema, intestinal necrosis, and paralysis.

Stages

Neuroleptic syndrome occurs in stages, which may be more or less pronounced in different patients:

1. The stage of neuroleptic parkinsonism is characterized by trembling of the limbs and head. The patient's movements are constrained, muscle tone increases: the muscles resist evenly at all stages of passive movement.
2. Acute dystonic stage is one of the extrapyramidal complications after taking antipsychotic drugs. The stage is manifested by involuntary movements in the form of contractile spasms of individual muscle groups throughout the body.
3. The akathisia stage is accompanied by a temporary or continuous internal sensation of motor tension: the patient feels the need to constantly make some movements or change the position of his body.
4. The stage of tardive dyskinesia is characterized by hyperkinesis, sometimes with the involvement of facial muscles in the process. Forced involuntary motor activity is observed (more often in elderly patients).
5. The stage of neuroleptic syndrome itself.

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Forms

• Neuroleptic malignant syndrome.

Most experts agree that neuroleptic malignant syndrome has a predominantly central etiology. This means that most disorders occur in the subcortex of the brain.

However, the effect of antipsychotic drugs on skeletal muscles also plays a significant role in the process, which can lead to the breakdown of myocytes (so-called rhabdomyolysis) and blocking of peripheral dopamine receptors.

Neuroleptics potentiate the blockade of central dopamine receptors, which leads to significant disorders of motor activity, with such an important symptom as muscle rigidity.

Changes in dopamine metabolism, in turn, are the trigger for disruption of the autonomic nervous system and cardiac activity.

At the same time, almost all metabolic processes are disrupted, the permeability of the blood-brain membrane changes. Intoxication reactions are triggered, cerebral edema begins. As a result, mental disorders and failures at the conscious level appear.

• Extrapyramidal neuroleptic syndrome.

Extrapyramidal neuroleptic syndrome is a combination of neurological symptoms that manifest themselves primarily as movement disorders due to the use of neuroleptic drugs. This term also includes disorders that are provoked by treatment with other drugs that interfere with dopaminergic activity processes: such drugs include antidepressants, antiarrhythmic drugs, cholinomimetics, lithium-based drugs, anticonvulsants and antiparkinsonian drugs.

The syndrome may be accompanied by all extrapyramidal disorders: parkinsonism, tremors of the limbs, dystonia, chorea, tics, myoclonic seizures, etc. Such symptoms are combined with some mental disorders.

• Neuroleptic deficit syndrome.

This syndrome has many other names - in particular, it is often called neuroleptic defect, or neuroleptic-induced deficit syndrome. The development of the syndrome is often mistaken for schizophrenia, due to similar symptoms:

• apathy;
• general lethargy;
• slow speech reproduction;
• weakness;
• abulic syndrome;
• lack of motivational and proactive factors;
• isolation, withdrawal into oneself;
• inattention and memory impairment;
• decreased emotionality;
• indifference, absolute cold-bloodedness.

Often this condition is complicated by psychotic reactions in the form of depersonalization and derealization. At the same time, extrapyramidal disorders, depressive state (oppression, bad mood), irritability, sleep disorders, phobias are present.

• Acute neuroleptic syndrome.

Neuroleptic syndrome is based on acute dopamine deficiency - the course of such a condition is always increasing and rapid. The clinical picture increases, reaching its limit within 1-3 days, but in some cases the process occurs more intensively - within several hours.

This is why assistance for neuroleptic syndrome should be provided as early and quickly as possible – after all, not only the health, but also the life of the patient depends on it.

The so-called chronic neuroleptic syndrome includes a period of late dyskinesias, which occurs in approximately 20% of patients who regularly undergo a course of treatment with neuroleptics, as well as in 5% of patients who take these drugs for a year. In other words, the chronic course of the syndrome includes those disorders that do not tend to regress within six months after the end of treatment with neuroleptics.

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Complications and consequences

Late signs of neuroleptic syndrome may make themselves known after a long period of time - such late manifestations usually "stick" to the patient for a long time, and sometimes for life.

Such manifestations are quite typical. Most often these are:

• slowing down of movements, gestures;
• inhibition of natural reactions;
• "robot" gait;
• uncertain, unsteady movements;
• slowing down of facial reactions;
• slowing down of mental processes;
• deterioration of cognitive processes.

The degree of human socialization decreases sharply. Hyperkinetic obsessive movements are often observed, which is explained by changes in muscle tone.

In the most unfavorable cases, neuroleptic syndrome is complicated by:

• cerebral edema;
• pulmonary edema;
• insufficient function of the cardiovascular system;
• acute dysfunction of the kidneys and liver.

The listed complications can lead to death.

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Diagnostics neuroleptic syndrome

Diagnosis is often late, since in many cases the possibility of developing neuroleptic syndrome is not taken into account. The correct diagnosis can be made based on the clinical signs of the disease, and additional laboratory tests will help to establish the severity of the condition and monitor the dynamics of the pathology.

Blood tests show an increased white blood cell count (10-40 t/mcl), in some cases – a shift in the white blood cell count to the left, increased activity of creatine phosphokinase, lactate dehydrogenase and other muscle enzymes. Signs of increased blood clotting and the presence of nitrogen in the blood are observed, less often – increased activity of liver enzymes, increased calcium content in the blood, symptoms of electrolyte metabolism disorders.

Cerebrospinal fluid analysis is not informative.

Urinalysis reveals myoglobinuria.

Instrumental diagnostics for neuroleptic syndrome is not performed in the vast majority of cases, as it is not clinically important. Only in extremely difficult situations, when diagnosis is difficult due to external reasons, as well as when brain damage is suspected, the doctor may resort to magnetic resonance imaging or computed tomography.

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Differential diagnosis

Differential diagnostics are carried out:

• with benign neuroleptic extrapyramidal syndrome (occurs without disturbance of consciousness, without an increase in temperature);
• with febrile catatonia (develops without prior treatment with neuroleptics);
• with meningitis, meningoencephalitis, hemorrhage into the subarachnoid space (changes in the analysis of cerebrospinal fluid are detected);
• with heat stroke (occurs without increased sweating and muscle hypertonicity);
• with malignant hyperthermia (pathology is preceded by anesthesia with a gaseous substance or an injection of succinylcholine);
• with a feverish condition due to infection or intoxication;
• with alcoholic delirium.

Treatment neuroleptic syndrome

Neuroleptic syndrome requires urgent treatment with placement of the patient in the intensive care unit of a hospital. Therapeutic actions consist of urgent withdrawal of the antipsychotic or other provoking agent, elimination of hypovolemia and dehydration, prevention of respiratory failure, prevention of acute renal failure, and immediate correction of body temperature.

To eliminate muscle weakness, Amantadine, Bromocriptine, and Levodopa-based medications are prescribed.

It is also appropriate to use benzodiazepine drugs, in particular, Relanium.

If a patient develops acute renal failure, hemodialysis may be indicated.

Electroconvulsive treatment is of great importance for the elimination of neuroleptic syndrome. The procedures are carried out using a gentle method, with the simultaneous use of muscle relaxant and sedative drugs. It is possible to use short-term anesthesia.

After the attack of the syndrome is completely stopped and the body's functions are fully restored, if necessary, treatment with neuroleptics can be resumed - with a mandatory revision of the dosage.

Urgent Care

At the first signs of neuroleptic syndrome development, gastric lavage is indicated as soon as possible - the sooner, the better. Lavage is used even in cases where the drug was taken several hours ago.

When washing the stomach, table salt or saline solution is added to the water. The patient is given a saline laxative and a sorbent to drink.

Oxygen therapy is mandatory.

In the development of a collapse state, measures are taken to hydrate the body: fluids and Norepinephrine are administered intravenously (drugs such as Adrenaline or Ephedrine are contraindicated in neuroleptic syndrome due to the risk of developing paradoxical vasodilation). To support cardiac activity and prevent arrhythmia, Lidocaine and Diphenin are administered, and Diazepam is indicated for convulsions.

In addition to intensive therapy, forced diuresis is performed without the use of blood alkalization.

Medicines used to treat neuroleptic syndrome

	Method of administration and dosage	Side effects	Special instructions
Midantan (Amantadine)	Take 0.1 g orally three times a day, or as an intravenous drip in an amount of 0.2 g up to three times a day.	Motor agitation, headache, decreased blood pressure, arrhythmia, dyspepsia, and urinary disorders are possible.	Treatment with the drug should not be stopped abruptly. Amantadine is incompatible with ethyl alcohol.
Bromocriptine	Take 2.5-10 mg three times a day.	Possible liver dysfunction, dyspepsia, dizziness, hallucinations, decreased blood pressure, skin rashes.	Treatment is carried out under regular monitoring of blood pressure and the general condition of the patient.
Nakom (Levodopa, Carbidopa)	Take ½-1 tablet three times a day.	Sometimes dyskinesia, blepharospasm, depression, chest pain, and blood pressure instability are observed.	It is not recommended to suddenly stop the drug, as a condition similar to NMS may develop.
Diazepam	Prescribed at 10 mg in the form of intravenous injections, after which they switch to oral administration in the amount of 5-10 mg three times a day.	Possible side effects include drowsiness, dry mouth, urinary incontinence, and decreased blood pressure.	The dose of the drug is reduced gradually. Diazepam cannot be combined with ethanol.

Prevention

It is very important to prevent the development of neuroleptic syndrome, since the treatment of this pathology is quite complex. It is recommended to resort to prescribing antipsychotic drugs only when it is truly justified. For example, people suffering from affective disorders or split personality should take neuroleptics only in extreme cases and for a short time. Also, people with mental retardation or organic pathologies, as well as elderly people, should not be treated with such drugs for a long time.

Before any case of taking neuroleptics, the patient must be carefully examined - at least once every six months, throughout the entire period of such therapy. If the therapeutic course a priori must be long-term (at least a year), then it is necessary to conduct trial reductions in the dosage of neuroleptics, or even their gradual withdrawal.

If the patient has suspicious symptoms indicating the likely rapid development of neuroleptic syndrome, it is necessary to inform his family about the possible consequences. This will allow a decision to be made on the advisability of further continuation of treatment.

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Forecast

Neuroleptic syndrome ends in death of the patient in approximately 15% of cases. Death is most often caused by pulmonary artery thrombosis, acute heart failure, insufficient renal function, complicated aspiration pneumonia, and respiratory distress syndrome.

Mortality rates have been reduced in recent years due to early diagnosis of the syndrome and improvements in emergency and intensive care treatment.

If a patient with neuroleptic syndrome remains alive, then the symptoms gradually fade away over 7-14 days. Cognitive disorders, balance and movement coordination disorders, Parkinsonism remain for another 1-2 months or more. A more severe rehabilitation period is observed after treatment with neuroleptic drugs that tend to accumulate, as well as in patients who were previously diagnosed with schizophrenia.

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