Catatonic syndrome

Psychiatric phenomenon, a special form of insanity, first described as an independent disease K. Kolbaum at the end of the XIX century. He also owns the authorship of the name: catatonia, derived from the ancient Greek κατατείνω - to strain. The main manifestation of this condition is a violation of the tonus of the musculature of the body, its tension in conjunction with strong-willed disorders.

Later, the catatonic syndrome was attributed to schizophrenic psychosis. At present, it is known that catatonia can develop, in addition to schizophrenia, in many mental disorders, as well as neurological and general diseases and intoxications, neoplasms and brain traumas.

[1], [2], [3], [4]

Epidemiology

The prevalence of catatonia among the world's population is unknown, various studies report completely disparate data.

There is evidence that about 5-10% of schizophrenics develop symptoms of catatonia. Although catatonic manifestations are still considered in the context of schizophrenia, in some modern studies, among the sample of patients with catatonic syndrome, nine to ten individuals with affective disorders had only one schizophrenic.

It is assumed that among the young people with autistic disorders, the symptoms of catatonia are found in every sixth to eighth.

In the hospitals of psychiatric hospitals, according to different data, there are 10 to 17% of patients with catatonia. The role of ethnic factors in the development of this syndrome is unknown.

In female and male patients, the incidence of catatonia is almost the same, only idiopathic is more common in women.

Catatonic syndrome of individuals at risk can occur at any age, however, in children and the elderly is much less common than in the younger generation. Basically catatonia manifests in schizophrenics at the onset of manifestations of the underlying disease from 16 to 40 years.

[5], [6], [7], [8], [9], [10], [11], [12]

Causes of the catatonia

What exactly processes occurring in the brain cause a catatonic state at the present time is not exactly known. However, the intrauterine malformation of the cerebral cortex in the fetus can lead to schizophrenia, other mental disorders. Hereditary predisposition is not excluded.

Symptoms of catatonia are observed in people with functional disorders of cortical and subcortical glutamatergic interrelations, a balance between excitation and inhibition, functional deficiency of γ-aminobutyric acid, a blockade of postsynaptic dopamine receptors.

Also, in the autopsy of the deceased with catatonic syndrome, structural anomalies of the frontal elements of the brain (pits of the large brain, middle and lower frontal gyri) were revealed.

Catatonia is not an independent nosological unit. In addition to congenital anomalies and obstetric pathologies, among the causes that cause this syndrome are the acquired organic disorders as a result of diseases, injuries and intoxications.

[13], [14], [15], [16], [17]

Risk factors

The so-called catatonic spectrum of diseases in which the development of catatonia is most likely is singled out.

In the first place - it's mental disorders, and violations of the emotional state ( affect ) come to the fore, especially deep depression and mania, even ahead of even schizophrenia. This range of diseases includes post-traumatic and post-natal psychoses, hysterical neurosis, autistic disorders. The cathotonic syndrome is observed in mentally retarded patients and children with mental development disorders.

People who have suffered encephalitis, stroke and craniocerebral injuries, who suffer from epilepsy and neoplasms of the brain substance, as well as Tourette's disease, have a fairly high probability of developing a catatonic state.

As risk factors of this syndrome, some congenital and acquired metabolic disturbances that lead to sodium or cyanocobalamin deficiency, a copper surplus ( Wilson-Konovalov's disease ), and early childhood amavrotic idiocy are considered.

Chronic endocrine and autoimmune pathologies, oncological diseases, Verlhof disease, AIDS, typhoid fever can lead to the development of catatonia. Also, this condition can be a consequence of hypoxia, heat stroke, severe illnesses suffered in childhood, in particular, rheumatic attacks.

Catatonic syndrome develops in drug addicts, as a consequence of intoxication with carbon monoxide and exhaust gases, as a side effect of the therapeutic course of blockers of dopamine receptors (antipsychotics), anticonvulsants, glucocorticosteroids, ciprofloxacin antibiotic, disulfiram (a drug for treating alcoholics), muscle relaxants with the active ingredient of cyclobenzaprine. Sudden abolition of the antipsychotic clozapine, anticonvulsants and dopaminomimetics, benzodiazepine group preparations can cause this condition.

In some cases, it was not found out what triggered the development of catatonia - an idiopathic catatonic syndrome.

[18], [19], [20], [21]

Pathogenesis

The mechanism of development of this state also refers to the field of assumptions, but there are several.

Since the pronounced therapeutic effect in the treatment of catatonia is noted with the use of benzodiazepine group preparations, it is assumed that the basis for the disturbance of psychomotor functions is the deficiency of γ-aminobutyric acid (GABA), which is the main neurotransmitter of braking processes in the cerebral cortex. Benzodiazepines normalize the functions of the basal nuclei, affecting the GABA receptors, increasing the affinity of the acid to neurons of the brain. Another similar assumption concerns the increased activity of the exciting transmitter-glutamate.

When attempts to treat catatonia with neuroleptics, success was not achieved, even a deterioration in the condition of patients was observed. Proceeding from this, there is a hypothesis that catatonia arises from the instantaneous and massive blockade of dopaminergic receptors. Moreover, treatment with dopamine stimulants is usually successful, and also - electroconvulsive therapy (electric shock) also promotes the release of dopaminergic receptors.

Syndrome of abolition of atypical neuroleptic Clozapine is manifested as catatonia, its cause is associated with the release of choline and serotonergic receptors, and this increases the activity of these systems.

In patients with chronic catatonic syndrome accompanied by pronounced impairment of the speech function, bilateral imbalances in the upper part of the thalamic zone of the diencephalon and frontal lobes of the cortex of the cerebrum are detected on the tomograms using PET diagnostics.

Researchers distinguish a special type of autistic catatonia observed in persons with mental development disorders, in the pathogenesis of which γ-aminobutyric acid deficiency is considered, disorders in small cerebellar structures and a hereditary predisposition due to the presence of a gene on the long arm of the fifteenth chromosome.

Anecdotal epileptic seizure in the form of catatonic syndrome (ictal catatonia) is considered caused by a lesion of the visceral brain ( limbic system ).

These hypotheses are based on real observations of patients, their response to drugs and diagnostic studies. Another assumption is based on the fact that catatonic syndrome is currently observed in patients with mental and general diseases in a severe (dying) state. Catatonic stupor is seen as a reaction of horror, caused by a sense of imminent death. In such a state fall victim animals when meeting a predator.

[22], [23], [24], [25], [26], [27]

Symptoms of the catatonia

The first signs of impending catatonia create the impression of an anomalous increase in features characteristic of the individual. In the prodromal period, the patient more than usually closed, almost all the time spent alone, annoyed at trying to involve him in any general actions. He often complains about difficulties with falling asleep, headaches, weakness, impossibility of any purposeful actions.

Later, the mood changes significantly, anxiety arises, various delusions and visions, numbness of limbs and the whole body, the perception of reality is transformed, negativity grows, the patient can completely refuse to move and take food.

Many symptoms of catatonic syndrome are described, some of them are characteristic of different mental disorders, a complete complex of symptoms in one patient is not absolutely necessary. The features of clinical signs depend on the type of syndrome and age of the patient.

During the period of catatonic state, the following can be observed:

• stupor - a combination of full real estate and the absence of any kind of contact with the patient (mutism), while in principle the patient's ability to speak is preserved, sometimes there is one of the symptoms - real estate or mutism;
• negativism - the patient resists attempts to give his body a different position, while muscular resistance in force is equal to extraneous efforts;
• aversion to others, medical personnel (aversia) - the patient does not respond to treatment, turns away, all the way showing a reluctance to contact;
• catalepsy (wax flexibility) is an abnormally long retention of a pretentious, extremely inconvenient posture that a doctor can give to a sick person; in addition, the patient often takes strange uncomfortable positions himself and remains in them for a long time;
• submission, brought to automatism - the patient performs absolutely everything with extraordinary accuracy, the body submissively accepts any most uncomfortable pose without resistance, but again returns to the starting position when it is not touched (in contrast to catalepsy);
• the sign of the "air cushion" - the patient lies with his head elevated above the surface of the bed, as on an invisible cushion, long enough - a typical pose for catatonia;
• ambition - a demonstration of peculiar ambitions, the patient, agreeing, still does not want to obey, for example, hands the doctor out, but at the last moment pulls it away;
• verbigeration - the repetition of the same speech stereotypes: phrases or sentences, words (palalalia), individual syllables (logoclonia);
• logoreia - monotonous, continuous, incoherent muttering;
• echolalia - the patient echoes all the sounds pronounced by the doctor;
• echopraxia - repetition of someone's movements;
• blocking of thoughts and movements - sudden stopping of speech or movement;
• stereotypies and motor perseverations - a constant repetition of identical senseless movements.

The patients have wide open eyes, they grab the doctor's hand during the examination, the nurse or relatives, not allowing to touch. A characteristic feature is an instantaneous transition from a stuporous state to an excitable state and vice versa, while movements are impulsive, ridiculous and meaningless (jumping, rolling, attacking). Speech excitement is manifested by cursing, singing, indistinct mumbling. To excite both the motor and the speech are endless repetitions of grimaces, jumps, cries. Some patients are mannered - all the while greeting, bowing. Sometimes the transition from an excited state to a hindered one and vice versa occurs gradually.

In most cases, patients are satisfactorily oriented in time and space, but there is confusion, speech, hallucinations, very diverse, instantaneous or with gradual development.

Severe stages are characterized by such symptoms as mutism and real estate, sharp negativism, pretentious postures, unwillingness to eat, prolonged muscle rigidity, increasing speech disorders.

Often behind an excited state with delirium and hallucinations follows a brief normalization of the state, occasionally - so long that it borders on recovery.

Nevertheless, even more often catatonic stupor of different depth and duration develops. He can have a chronic course with frequent and sudden emotional outbursts, accompanied by meaningless escapades.

Sometimes the syndrome occurs in the form of catatonic seizures, expressed in the periodicity of stupor change and excitation.

The symptoms of a violation of the innervation of the vessels are striking: the pale face of the patient can instantly turn red, sometimes any part of the body blushes - the forehead, one cheek, ear, neck. Patients lose weight, they have persistent disturbances in sleep. Other somatic symptoms accompanying catatonia are arrhythmias, excessive sweating and salivation, eruptions resembling urticaria, fluctuations in body temperature (in the morning and in the evening), narrowing-the pupil increase and the variability of their reaction, shallow breathing.

Chronic catatonia in diseases of the psyche, in particular, in schizophrenics in general, leads to the progress of mental retardation. At the same time, with the catatonic form of schizophrenia, long-term remissions after the syndrome in 15% of patients are almost identical to their recovery.

Catatonia in a child often has the symptoms of rhythmic motor stereotypes - grimacing, running around in circles, the same type of movements with hands, legs, trunk, running or walking on tiptoes, on the outer or inner side of the foot, etc. Movements and actions are characterized by impulsivity, often there is mutism, echopraxia, echolalia and other speech disorders. Often a child may experience regressive catatonia - he begins to completely copy the behavior of animals (licking themselves and objects, eating without the help of cutlery, etc.).

It should be taken into account that the catatonic syndrome does not always go through all the stages of development described, and their arbitrary order is observed in different cases.

Psychomotor disorders in the catatonic syndrome are classified as agitation and stupor.

The excited state is characterized by psychomotor activity and is divided into such forms:

• pathetic excitation (with the preservation of consciousness) - is gradually increasing, in the highest phase - moderate manifestations; patients are mannered, pathos, an upbeat mood is observed, in the form of exaltation, and not hypertension; noteful poses and gestures are noted, perhaps echolalia; then the excitement grows, and the patient begins to frankly fool around, there are impulse actions reminiscent of gebefrenia;
• impulsive stimulation has an acute onset, develops suddenly and rapidly, in most cases the patient's actions are of a hard and destructive antisocial nature; verbal disturbances (verbigeration) are observed;
• the peak of the previous form, reaching the degree of frenzy, is singled out by some experts as a third option - mute excitement, when the patient, without uttering a sound, crushes everything around, splashing out aggression on others and even on himself.

With a stupor, almost always the muscles of the patient are tense and enslave, sometimes even passive movements are impossible. The patient, who is in the sub-stuporosis state, is inactive and slow, in the stuporous state, lies, sits or stands without movement. The patient is silent, the face is like a frozen mask, the facial expression is often absent, sometimes the movements of the muscles of the face correspond to the affective state - the patient wrinkles his forehead, squeezes his eyelids, strains the muscles of his jaws and neck, and extends his lips with a "pipe." In the catatonic stupor, patients can stay for a long time, which is calculated in weeks and months. Disorders of all functions, even instinctive ones, are observed, as well as symptomatic of disorders of the somatic sphere and the autonomic nervous system: cyanosis and edema of the extremities, hypersalivation, hyperhidrosis, seborrhea, hypotension. There are three stupor forms of catatonia:

• cataleptic - the individual holds a pose for a long period of time, often unnatural, which he took himself or gave to others (waxy flexibility), for example, lies on the "air cushion", covered with a blanket; normal and loud speech does not cause a reaction, but can respond to a whisper; under the influence of darkness and silence, the stupor sometimes weakens and contact for a while becomes possible (for this form there is the presence of delirium and hallucinations);
• negativistic - motor retardation is combined with opposition to any attempts to change the posture of the patient, resistance can be active and passive;
• numbness - the peak of inhibition and enslavement of the muscles, often in the embryo position or on the "air cushion", the lips are stretched out into the tube.

There were interconversion of one form of catatonic stupor or excitation into another, although such cases are rare. Most often there are transformations of the excited state to the stupor and vice versa, usually the corresponding type, for example, pathetic excitation → cataleptic stupor, impulsive → negativistic or stupor with a stupor.

By the presence or absence of a consciousness disorder, catatonia is classified into the following species: empty, lucid and onyroid.

Empty is characterized by symptoms typical of the syndrome without delirium and hallucinations, as well as affects: monotonous iterations of movements, postures, phrases and words, catalepsy, echosymptoms, negativism - inert (the patient sabotages requests), active (the patient commits actions, but not those that it is necessary), paradoxical (it performs the actions inverse to the required one). This type of syndrome is sometimes noted with organic lesions of brain tissue (neoplasms, the consequences of craniocerebral trauma, infections and intoxications).

Lucid (pure) catatonia is characterized by the presence of productive symptoms (delirium, hallucinations) without a consciousness disorder. The individual does not violate self-identification, he remembers and can reproduce the real events that occurred during the stupor period.

Onyroid catatonia - the course of this syndrome with delusional and manic episodes, hallucinations, moreover accompanied by confusion of consciousness. It begins suddenly with a marked increase in psychokinetic excitement. The individual quickly changes behavior, facial expressions and appear maniacal traits. Movements are active, natural, plastic, there is delirium, speech activity and lack of need for an interlocutor (schizophasia). The patient experiences bright and colorful events in an individual world, absolutely not corresponding to reality - a catatonic dream characterized by the presence of a plot and completion. The individual himself feels himself the main hero of the stories that occurred exclusively in his mind. They are accompanied by fantastic excitement, with intense emotional coloring, instantaneous changes from chaotic excitation to a stupor. The facial expression of the patient, reflecting the disturbances experienced by him in the catatonic sleep, is usually very expressive. Coming out of the syndrome, the patient does not remember any real events, but can describe his "dreams". Catatonic sleep lasts from several days to several weeks.

It is believed that lucid catatonia is characteristic only for schizophrenia, and onyroid - is more common in neoplasms of the basal parts of the brain, posttraumatic or acute epileptic psychoses, the consequences of severe infections and intoxications, progressive paralysis.

Febrile catatonia is an acute mental disorder and is observed in schizophrenics and persons with affective disorders. External manifestations resemble a oneiroid appearance, accompanied by a rapid development of not only psychopathological, but also somatic disorders. It can take a malignant course if therapeutic measures do not start immediately in the first hours of the development of the syndrome.

A specific symptom is a high body temperature, manifested as a fever, there may be temperature jumps. In addition, the patient's pulse and breathing quicken, an earthy-gray hue of the skin appears, facial features are sharpened, eye sockets fall, the forehead becomes covered with droplets of sweat, the eyes are not concentrated, the lips are dry, the tongue is white or brownish.

The cause of death of the patient is the development of cerebral edema.

Regressive catatonia is most often observed in children. It appears as a copying of behavioral stereotypes of animals.

[28], [29], [30]

Complications and consequences

The features of the catatonic syndrome are such that it can cause adverse effects for both the patient and the people around him. Ignore such a condition can not be done, it is necessary at the first signs of the syndrome to consult a doctor, and possibly hospitalize a patient.

For most patients in an excited state, antisocial behavior is characteristic, it can cause serious injuries to others and to oneself, including fatal injuries.

Failure to eat can lead to cachexia, dehydration of the body and starvation, if not fed and ill by the patient through a probe. Long-term nutrition in an unnatural way is complicated by disorders of the digestive system, disturbances of water-electrolyte balance, development of hypoglycemia and hypercapnia.

In patients with catatonic syndrome, due to prolonged lying in one (often unnatural) position, bedsores may appear, hypostatic pneumonia, venous thrombosis, pulmonary embolism, pneumothorax.

Failure to comply with basic hygiene rules can lead to infection of the oral cavity, genito-urinary organs.

Catatonia is often complicated by autonomic symptoms, hyperthermia, cardiac dysfunction, fluctuations in blood pressure, the appearance of muscle contractures, paresis and paralysis.

Malignant course of catatonic syndrome usually leads to a lethal outcome.

[31], [32], [33], [34]

Diagnostics of the catatonia

This condition is diagnosed by psychiatrists, based on the history of the disease and the results of objective examinations.

The basis for examining the patient is the presence of one or more symptoms of catatonic syndrome. Considered the presence of a long stay without movement in any one posture (stupor), anomalous excitation, mutism, negativism, resistance or automatic submission, fanciful postures (wax flexibility), echo phenomena, muscle rigidity, verbigeration and autism.

Laboratory tests are mandatory: blood - clinical, for glucose, creatine phosphokinase, thyroid hormones, hepatic assays, autoantibody content, heavy metals, HIV infection and Wasserman reaction; urine - common and for the presence of narcotic substances, specific tests for the study of kidney function. Bacteriological examinations of blood and urine can be prescribed.

Instrumental diagnostics is appointed based on the results of the examination and may include electrocardiography, ultrasound, electroencephalography, computer and magnetic resonance imaging. If necessary, the patient is prescribed a puncture of cerebrospinal fluid, other more specific studies may be prescribed.

Catatonia is a condition that occurs in a variety of diseases. First of all, the doctor needs to identify curable causes that play a decisive role in the choice of therapy tactics.

[35], [36], [37], [38], [39], [40], [41], [42]

Differential diagnosis

Catatonic syndrome can develop with various pathological conditions, and their differentiation is crucial in the appointment of drugs to normalize the patient's condition.

First of all, the patient is expected to have schizophrenia, since the catatonic syndrome is associated historically with this disease. Pathetic catatonia at the peak of the increase in symptoms should be differentiated from such a subtype of this disease as gebefrenia - those suffering precisely this form of disease behave childishly, grimace, crinkle, their emotional background is unstable. For the diagnosis of catatonic schizophrenia (according to the ICH-10), at least one of the main symptoms of catatonia (stupor / agitation, hardening in different poses / waxy flexibility / stiffness of muscles, negativism / command automatism) should be recorded in the patient continuing for at least two weeks.

For affective disorders, the diagnostic criterion is the most extreme manifestation - the catatonic stupor. Catatonia is recognized as an adjacent diagnosis for such affect disorders as obsessive-compulsive disorder, depression, mania, bipolar disorder.

Catalepsy (a condition in which a person keeps a long awkward any uncomfortable posture and this position can easily be changed) is one of the symptoms of catatonia, but not the only one. Cataleptic seizures are called sleep paralysis, in most patients they pass quickly enough.

Malignant neuroleptic syndrome caused by the use of antipsychotics, many experts consider as a kind of lethal catatonia. However, these two states have an important clinical difference - the beginning of the first is marked by extreme psychotic excitement, and the second begins with severe extrapyramidal rigidity of the musculature of the body. Their difference is of great importance, because in the first case, the measures taken can save a patient's life.

Encephalography helps to differentiate catatonia from an epileptic epistatus.

Differentiate catatonia from the syndrome of stiffness of the muscles, severe negative symptoms in mental pathologies, malignant hyperthermia, Parkinson's disease, dementia, organic catatonic disorders and other hyper- and hypokinetic syndromes.

A comprehensive examination of the patient helps to determine whether catatonia is functional or organic, and to establish which department it is necessary to hospitalize the patient to assist him - psychiatric or obscheomatic.

Treatment of the catatonia

Patients with catatonic syndrome almost always need hospitalization, in difficult cases - in the intensive care unit, because they require constant care of paramedical personnel and monitoring the functioning of vital organs.

Preference in the treatment of catatonia is given to drugs of benzodiazepine series, whose action is directed to stimulation of the inhibitory neurotransmitter γ-aminobutyric acid, whose reduced activity is considered one of the reasons for the onset of this condition. These substances have a calming and hypnotic effect, reduce mental agitation and have a relaxing effect on muscle tissue. They have a mild anti-seizure action.

There is an experience of treating patients with catatonia with the oral form of Lorazepam  medium-duration drug  and intramuscular injections of  diazepam  (prolonged action), with a rapid therapeutic effect (within two days) in most patients. Two of them reached a remission after a single dose. But half of the patients needed electro-shock therapy for further normalization of the condition.

Other researchers report an even more impressive effect of Lorazepam, 80% of the study group completely underwent catatonia signs within just two hours after taking the drug.

Preparations of benzodiazepine series in low dosages are effective in cases of catatonic stupor, as well as excitation. Catatonia of organic genesis is also well suited to therapy with these medicines.

Patients resistant to benzodiazepine therapy usually undergo electroconvulsive therapy. This method treats patients with mental illnesses, including schizophrenics. It is effective in depression, organic and hysterical, as well as idiopathic catatonia. The number of sessions of electroshock required by a particular patient does not depend on the causes that caused the catatonic syndrome. This radical method helps to increase the level of dopamine.

The treatment of catatonia with dopamine, especially its malignant forms, is also practiced in psychiatry. In addition to electroconvulsive therapy, which in this case is used as an emergency, the treatment regimens include benzodiazepines, Bromocriptine (dopamine receptor stimulant) and Dantrolene (muscle relaxant).

Also, the antiparkinsonian dopaminergic drug  Amantadine  was effective in the treatment of catatonia.

Neuroleptics try not to be used as a means of treating catatonia even in schizophrenics, the main disease of which is treated with these drugs.

Nevertheless, in cases of resistance to the action of benzodiazepines (resistant catatonia), the patient may undergo rapid and prolonged remission after treatment with an atypical neuroleptic  risperidone.

The cathotonic stupor, resistant to traditional treatment with benzodiazepines, succumbed to combined therapy with lithium preparations in combination with a neuroleptic.

Anticonvulsant medication for epileptics Finlepsin (Carbamazepine) has proven effective as an emergency aid and with maintenance therapy for catatonic syndrome.

Analogue of benzodiazepine Zolpidem quickly and beneficially affected the patient with catatonia, resistant to traditional drugs (benzodiazepines and electroconvulsive therapy). This drug selectively stimulates the benzodiazepine receptors of the subclass of omega-1.

It has no relaxing effect on the musculature and does not arrest seizures, however, has established itself as a good hypnotic, reducing the period of falling asleep and the latent phase of sleep, prolonging the total time and quality of sleep. In addition, the drug does not cause daytime sleepiness and addiction.

The described modern types of treatment have been investigated and have evidentiary power.

Prevention

Catatonia can arise from a variety of causes and all of them can not be prevented, however, it is quite possible to reduce the risk. We need to take responsibility for our health responsibly and teach our children about it, not to use psychoactive substances, to treat mental and neurological diseases in a timely manner, to increase stress resistance and strengthen immunity. As part of these activities, full-fledged nutrition, physical activity and a positive outlook on the world are expected.

If the family has a sick person at risk, then it must be protected from stress and traumatic situations, at the first signs of catatonia, one should seek medical help. Modern medicine has a good arsenal of funds for removing a person from this state.

[43], [44], [45], [46], [47], [48], [49], [50]

Forecast

Researchers of this phenomenon (mainly Western psychiatrists) report a favorable outcome of treatment of patients with catatonic syndrome, which has arisen for various reasons. Apparently, the forecast in most cases depends on the timely treatment, correctness and quality of treatment. Most patients responded quickly to treatment and withdrew from this condition.

Many researchers report that in patients with affective disorders (manias, depressions), the frequency of subsequent catatonic episodes was high. Periodically arising catatonia heavens the course of affective disorders, reduces the cognitive functions of patients, their activity in solving everyday life problems.

In schizophrenics, catatonic symptoms are also an unfavorable factor.

The development of catatonic syndrome in adolescents and in the elderly has more adverse consequences than in the young able-bodied population.

In general, the probability is high that the patient will be withdrawn from the acute catatonic stage, however, the long-term consequences and the frequency of relapses are determined by the basic diagnosis of the patient.

[51], [52], [53]