1. Introduction

Damage to the nervous system in children is observed in various diseases, including neurological syndromes involving the central nervous system (CNS), peripheral nervous system, autonomic nervous system and the development of mental disorders. In many diseases in children, against the background of the clinical symptoms of the underlying disease, symptoms of damage to the nervous system are observed, which decrease and disappear during the treatment, but in some cases neurological symptoms persist or recur, which requires a complete clinical and laboratory examination, differential diagnosis of diseases with manifestations neurological and mental symptoms, consultations of rheumatologists, neurologists.

2. Etiology

A large number of studies point to the relationship of streptococcal infection with the development of lesions of the nervous system.

Group A beta-hemolytic streptococcus (GABHS, Streptococcus pyogenes) causes a variety of bacterial infections in humans [1,2]. The clinical forms of streptococcal (group A) infection are diverse with the development of superficial lesions (tonsillopharyngitis, otitis, sinusitis, erysipelas) and invasive forms of diseases (cellulitis, myositis, meningitis, pneumonia, peritonitis, endocarditis, arthritis, scarlet fever, sepsis), and also contributes to the development immunopathological diseases (acute rheumatic fever, poststreptococcal glomerulonephritis, poststreptococcal autoimmune diseases of the central nervous system.

GABHS has a pathogenic effect, can persist in infected tissues due to the surface M-protein, which allows the microorganism to escape phagocytosis by polymorphonuclear leukocytes in the absence of antibodies specific to this type of protein, providing colonization on the mucosa [1,3]. GABHS contributes to the development of autoimmune complications [4]. Streptococcal infection plays a significant role in the pathogenesis of various lesions of the central nervous system, including Sydenham's chorea (chorea minor), neuropsychiatric disorders (PANDAS), and possibly tics, impulsive-compulsive disorders) [2,5,6].

The literature describes cases of acute onset tics and obsessive-compulsive disorders without prior GABHS infection. Children have also been described in whom acute onset or exacerbation of tics and OCD occurred after an infection (viral and/or bacterial).

Timely study of anamnesis, identification of genetic predisposition, clinical examination and laboratory and instrumental studies play an important role in making a diagnosis and conducting appropriate therapy. Symptoms of CNS damage depend on the etiology of the disease and the nature of the damage.

3. Clinical Manifestations

Rheumatism is an infection caused by group A β-hemolytic streptococcus. In recent years, there has been a tendency towards an increase in the incidence of rheumatism in all age groups, and more intensively in children. This trend is also due to the presence of secular rhythms characteristic of aggressive streptococcal infection and a decrease in the sensitivity of streptococci to penicillins. For childhood rheumatism, chorea is characteristic, occurring in 12-17% of cases, mainly in early puberty and in girls.

Rheumatic chorea (small chorea or Sydenham's chorea) - due to the involvement in the pathological process of various brain structures (striated body, subthalamic nuclei, cerebellum). The latent period can last up to several months from a previous streptococcal infection. In some cases, after a streptococcal infection, signs of rheumatic brain damage begin gradually, when health worsens, school performance decreases, sleep is disturbed, the child becomes irritable, sometimes signs of heart damage are detected later. Chorea minor is often associated with carditis, the symptoms of which come to light later.

Rheumatic chorea is characterized by a pentad of symptoms:

- distal hyperkinesis

- muscle hypotension (up to muscle flabbiness with imitation of paralysis)

- disorders of statics and coordination

- vegetative-vascular dysfunction

- psycho-emotional disorders (mood instability, irritability, tearfulness, etc.).

Hyperkinesias increase with excitement, disappear during sleep, are more often bilateral, less often unilateral. There is a violation of handwriting, slurred speech, it is difficult for the child to eat and drink on his own. Against the background of adequate therapy, the manifestations disappear after 1-2 months. It is necessary to differentiate with other diseases, in the clinical picture of which there are signs of damage to the nervous system [7-9].

At the end of the last century, in 1998 Swedo S.E. and a group of scientists from the National Institute of Mental Health (USA) for the first time described a new disease characterized by an undulating course with obsessive-compulsive disorders and/or tics in children over 5 years of age with a history of streptococcal infection [10–12]. The disease has been named.

The disease was called "pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection", or PANDAS syndrome.

Subsequently, the researchers drew attention to the clinical heterogeneity of PANDAS (different severity and polymorphism of clinical manifestations), the difficulties in establishing the relationship between streptococcal infection and acute tics and obsessive-compulsive disorders without previous GABHS infection, the lack of association between the clinical exacerbation of PANDAS and changes in autoantibody titer and the lack of reliable diagnostic markers [13-18], which led to the introduction of a new name for the disease - "pediatric acute neuropsychiatric syndrome" (English Pediatric Acute Neuropsichiatric Syndrome, PANS), the key phenomenon of which is the acute onset of symptoms, the presence in the clinic of recurrence of symptoms with tics and obsessive-compulsive syndrome, the pathogenesis of PANS is not always associated with infectious factors [19,20]. PANS can have a variety of etiologies, including genetic and immunological, with or without prior infection [21]. It was noted that all cases of PANDAS are associated with streptococcus and are a subtype of PANS [22].

Diagnostic criteria for PANDAS syndrome [11]:

1) the presence of obsessive-compulsive disorders and / or tics;

2) debut in childhood: symptoms appear between 3 years of age and puberty;

3) paroxysmal type of the course of the disease, characterized by a sudden onset or a sharp increase in symptoms. Often the onset of symptoms or their aggravation can be associated with a specific day or week. Symptoms usually decrease significantly, and sometimes completely disappear between episodes of exacerbation;

4) connection with streptococcal infection - exacerbation should be associated with the detection of streptococcus in the nasopharynx and / or with an increase in the titer of antibodies to streptococcus;

5) connection with neurological disorders.

During an exacerbation, patients find changes in neurological status. Hyperactivity and hyperkinesias (including choreiform) are most often observed. The PANDAS syndrome is characterized by the severity of psychiatric aspects, as well as a much faster and complete regression of neuropsychiatric symptoms only with adequate antistreptococcal therapy.

Diagnostic criteria for PANS [6]:

1) a sharp, dramatic onset of obsessive-compulsive syndrome or a sharp restriction in food intake;

2) the presence of neuropsychic symptoms (≥2 simultaneously) with an acute onset:

• anxiety;

• emotional lability and/or depression;

• irritability, aggression and/or oppositional behavior;

• behavioral regression;

• decreased school performance (associated with attention deficit/hyperactivity disorder);

• sensory or motor abnormalities;

• somatic symptoms, including sleep disturbance, enuresis, frequent urination;

3) the symptoms are not explained by other known diseases.

Thus, the clinical symptoms of chorea minor (one of the manifestations of acute rheumatic fever) and PANDAS syndrome are similar (beginning after a streptococcal infection, clinical manifestations). The development of PANDAS syndrome is typical for children of prepubertal age (in contrast to chorea, for which the typical age group is children 5–8 years old). Chorea minor is combined with other clinical criteria for acute rheumatic fever (carditis, polyarthritis, rarely erythema annulare, rheumatic nodules) [23]. Chorea minor is characterized by a subacute onset of the disease, fever, and carditis, while PANDAS has an acute onset of the disease without systemic manifestations [24-27].

Despite the variability of the clinical symptom complex, the presence of obsessive-compulsive disorders (OCD) is common for both chorea and PANDAS syndrome. Tics and OCD are often observed in the prodromal period of chorea, and hyperkinesias join later [28-32]. Handwriting impairment and irritability are also seen in these conditions. Chorea often has a monophasic course.

PANDAS syndrome is characterized by the severity of psychiatric aspects, a much faster and complete regression of neuropsychiatric symptoms only with adequate antistreptococcal therapy. Such conditions occur with a certain frequency (the average duration of an attack is 12-15 weeks on average) and significantly reduce the patient's quality of life. For RANDAS, cardiac disorders are uncharacteristic [30].

It should be noted that there is a return of symptoms after streptococcal or other infection, which is an important criterion for PANDAS.

In PANDAS syndrome, unlike rheumatism, there are no classic symptoms of ARF (rheumatic nodules, annular erythema, arthritis, carditis), an older age of the onset of the disease, an undulating course, the occurrence of exacerbations of the disease often after a psycho-emotional event, the mandatory presence of neurological symptoms in the acute period, favorable forecast. In acute rheumatic fever, in most cases, the symptoms of minor chorea are often combined with symptoms of carditis, changes in the heart valves are observed, which is confirmed by electrocardiogram and echocardiogram [27].

Some authors express the opinion that the development of PANDAS may be associated not only with streptococcus, but also with other infections [20,33–37].

Conducted observations and studies indicate that patients with RANS syndrome have a genetic predisposition to certain infections and are prone to a pathological immune response with the production of cross-antibodies to microbial and brain antigens [37,38]. The clinical picture of PANS is characterized by the presence of an obsessive-compulsive syndrome with or without tics, emotional lability, anxiety, behavioral changes, etc. One of the manifestations of PANS is Tourret's syndrome, the prevalence of which is 5–7 cases per 100,00 children [38,39]. This pathology is characterized by transient tic disorders in the form of motor tics and auditory tics: echolalia (repetition of other people's words) and palilalia (repetition of one's own word), sometimes coprolalia (spontaneous utterance of socially undesirable or forbidden words or phrases) [40]. Tics in Tourette's syndrome are of a monotonous nature, temporarily suppressed, non-rhythmic, aggravated by emotional arousal, often they are preceded by an irresistible impulse, when the child experiences a feeling of tension and the need to perform certain movements, after which he feels better.

Recently, a large number of studies have been carried out on the pathophysiology of tics, Tourette's syndrome and ACS. A theory has been proposed to increase the activity of the supplementary motor area before the onset of tics, which plays an important role in the formation of sensory phenomena preceding the execution of tics (prodromal urges) [41]. Magnetic resonance imaging of the brain showed a decrease in the size of the caudate nucleus in children and adults with Tourette's syndrome [42], with a negative correlation between the size of the caudate nucleus in childhood and the severity of symptoms in older age [43]. In a study by E. Sowell et al. a decrease in the size of the cortex in the sensorimotor region, as well as in other regions (ventral frontal cortex, dorsal parietal cortex) was found in children with Tourette's syndrome [44].

4. Diagnostics

A sudden change in the child's behavior, the appearance of stereotyped actions and movements (obsessions, tics, hyperkinesis) indicates a specific lesion of the nervous system, which can be observed in ARF and various variants of the PANS syndrome, which requires consultation with a neurologist, rheumatologist.

When studying a family history, take into account the presence of neurological, mental disorders, autoimmune and autoinflammatory diseases in the patient's relatives, as well as frequent past infections, including streptococcal etiology in a child.

All children need a microbiological examination of the pharynx to confirm a previous nasopharyngeal infection. It is recommended to make a throat swab, regardless of the presence or absence of clinical pharyngitis, in case of exacerbation of neuropsychiatric symptoms [32,45]. For the diagnosis of infection, the determination of the level of antibody titer is used: antistreptolysin O (ASLO) and antideoxyribonuclease B (aDNase B) in the dynamics of observation, as well as other biochemical blood parameters indicating the presence of an inflammatory process. An electro- and echocardiogram will confirm the development of ARF, encephalography, and magnetic resonance imaging will reveal changes in the brain.

5. Conclusions

Features of the nervous system damage in ARF and PANS / PANDAS syndrome, the presence of neuropsychiatric symptoms require differential diagnosis, laboratory and instrumental studies to diagnose the nature of the CNS lesion and appropriate treatment and observation by a rheumatologist and neurologist depends on the established diagnosis. Timely diagnosis of the nature of the damage to the nervous system will allow for adequate therapy, preventive measures and monitoring of the identified pathology, respectively, which is of decisive importance in the prevention of persistent and severe lesions of the nervous system.