Kiss syndrome. Radiologically isolated syndrome. Diseases of the hypothalamic-pituitary system

Modern drugs can change the course of this serious disease

It took Michelle Maglioni three years to clarify the diagnosis of multiple sclerosis.

She had her first flare-up in 1988, when she experienced a frightening bout of numbness in her lower body, starting from her lower back. Then she decided that she had a displacement of a vertebra or a pinched nerve from some sudden movement. She was referred to a neurologist, who confirmed that she had a herniated disc and prescribed physical therapy. A few months later, the numbness was gone. Maglioni was then 30 years old, she actively worked in one of the New York public organizations. She tried to put the incident out of her mind.

But the disease avenged her neglect, again making itself felt when Michelle was visiting friends in Europe. “This time, my right arm and left leg failed,” she recalls. Returning home, she turned to another neurologist, who in June 2001 officially diagnosed her with multiple sclerosis. A month later, she began regular intake of a new basic drug with a proven ability to slow the progression of multiple sclerosis.

Lucky with the diagnosis

Surprisingly, Maglioni considers herself lucky. “In the time between diagnosis and treatment, I began to lose my peripheral vision,” she says. “For me, it was even worse than all the physical symptoms that I had.” After two months of treatment, peripheral vision was restored, and some other symptoms disappeared. Some signs of the disease still remained - for example, tingling in the left palm - but Michelle knew that things could be much worse if her diagnosis remained unexplained for a long time.

Until relatively recently, it would not have mattered whether Maglioni was diagnosed at an early or late stage of the disease. “We had no treatments, and all she could theoretically expect was some insurance and employment benefits,” recalls Dr. Patricia Coyle, professor of neurology at the State University of New York at Stony Brook, director of the Multiple Disorders Comprehensive Treatment Center. sclerosis at Stony Brook.

Everything has changed today. Experts are now unanimous that the use of basic drugs for the treatment of multiple sclerosis (including Avonex, Betaseron, Copaxone, Novantron and Rebif) gives the best chance to delay the development of the disease, provided that treatment is started early. The results of recent scientific studies suggest that the best protective effect could be achieved with the immediate administration of these drugs after the first clinical episode (clinically isolated syndrome), despite the fact that the official diagnosis of multiple sclerosis cannot be made until the patient has undergone at least two bouts of illness.

What is a "clinically isolated syndrome"?

Clinically isolated syndrome (CIS) can be thought of as the "first bout" of multiple sclerosis, explains Dr. Coyle. This is a single clinical exacerbation, indicating the presence of demyelinating changes (destruction of the protective substance that covers the nerve endings in the brain and spinal cord). For example, unilateral optic neuritis or numbness on one side of the body may be considered CIS. The clinically isolated syndrome is usually not accompanied by any other clinical signs or symptoms, and (as was the case with Maglioni) many other explanations for sudden numbness in one hand or visual impairment can be devised. However, according to Dr. Coyle, if your doctor has ruled out other possible causes, and the MRI study showed the presence of characteristic changes, an episode of CIS should be a reason to discuss with your doctor about the possible appointment of basic therapy for multiple sclerosis.

Benefits of Early Treatment for Multiple Sclerosis

According to Dr. Coyle, the results of the studies suggest that young people who have only a clinically isolated syndrome, but have certain changes on MRI of the brain, have a very high risk of developing multiple sclerosis. “There have been three large independent studies at the level of the third stage of clinical trials, and all three showed a better prognosis for patients in this group in the use of basic drugs for the treatment of multiple sclerosis compared with placebo,” she says. As a result of these studies on the effects of the drugs Avonex, Betaseron and Rebif, it was found that the use of any of them in patients who underwent a single clinical episode helped to delay the onset of overt multiple sclerosis. How long this protective effect can last remains to be seen through ongoing research.

When a patient with multiple sclerosis develops a "clinically isolated syndrome" (an example is the numbness of the lower body in Michelle Maglioni in 2001), this means that the disease has been developing in the brain for some time. Dr. John Rishert, the American Multiple Sclerosis Society's Vice President for Research and Targeted Programs, likens the process to the movement of a locomotive rolling downhill. “Having started, the autoimmune reaction develops further like a train running over a mountain range. It's much easier to brake it at the very beginning of the descent than later, when it picks up unstoppable acceleration,” he says.

Slow down multiple sclerosis

Despite the fact that treatment was not started after the first attack in 2001, Maglioni believes that the start of basic therapy for multiple sclerosis, even at the stage at which it was done, made it possible to “slow down” the “locomotive” of her disease that had begun to accelerate - according to at least for the time being. “Since the beginning of the drug, I have not had a single obvious exacerbation. And there were no new plaques on the MRI for the past two years, she says. “This is the best I can hope for: the medicine works as it should - slows down the development of the disease and does not allow exacerbations to develop.”

But multiple sclerosis failed to "slow down" Maglioni's vital activity. Today she is Vice President of Communications for the New York Chapter of the Multiple Sclerosis Society of America. She actively participates in fundraising events, organizes teams to participate in marches against multiple sclerosis, and even swims a three-mile distance on the Hudson as part of a campaign to raise funds for research and other programs on multiple sclerosis.

“I remember what I felt when I first heard my diagnosis - I was literally crushed by it. But if it was ever lucky that you were diagnosed with multiple sclerosis, it is only in our time, when so many basic drugs have been created that change the course of the disease. And new drugs are on the way, and there is much more knowledge about this disease now than just 10 years ago, she says. “Physicians can do a lot right now to keep our disease under control, but we, who live with this disease, must act with them.”

Currently, the concepts of radiologically isolated syndrome [RIS] and clinically isolated syndrome [CIS] have been introduced into clinical practice (you can read about RIS).

The improvement of existing and the introduction of new methods of neuroimaging, as well as the development of new diagnostic criteria for multiple sclerosis (MS) made it possible to detect it early enough. The clinical manifestation of MS does not always coincide with the real time of its onset. In approximately 90% of cases of MS, the first episode of demyelination proceeds in the form of the so-called "clinically isolated syndrome", when there are no signs of "dissemination in time" yet, and signs of "dissemination in space" are either present or absent.

Clinically isolated syndrome ( CIS) [currently defined as] is a monophasic (i.e., for the first time with a relatively rapid onset) frolicking symptomatology, or rather, a frolicking single clinical episode, which is caused by a presumably inflammatory demyelinating disease. "CIS" has a synonym - "the first demyelinating episode" (or "the first episode of demyelination").

Remember! CIS is characterized by the formation of neurological symptoms within 2 to 3 weeks without any apparent cause and in the absence of fever. A characteristic feature of CIS is the regression of symptoms.

Most often, CIS is manifested by unilateral retrobulbar neuritis, trigeminal neuralgia, transverse myelitis, Lhermitte's symptom, bilateral internuclear ophthalmoplegia, paroxysmal dysarthria/ataxia, paroxysmal tonic spasms, or impaired sensitivity.

(! ) It should not be forgotten that CIS is not always the first manifestation of MS, but may be a manifestation of such diseases as a tumor of the brain or spinal cord, cervical spondylosis, cerebral vasculitis, sarcoidosis, mitochondrial encephalopathy, etc.

The symptoms detected in CIS serve as objective [clinical] signs of one or more foci of demyelination in the brain or spinal cord (in 50-70% of cases of CIS, multiple subclinical foci of demyelination are detected already at the first MRI); sometimes, with monosymptomatic CIS, clinically “silent” foci of demyelination can also be detected (i.e., signs of multiple CNS lesions are additionally detected, which confirms dissemination in space). Thus, patients with CIS may present with various combinations of neurological symptoms and MRI findings; at the same time, despite the fact that simultaneous detection of multiple clinical / paraclinical manifestations [CIS] is possible, however, dissemination over time should not be obvious. In this regard, in the modern classification of CIS, the following types (options) are distinguished:

type of 1 - clinically monofocal; at least 1 asymptomatic MRI lesion;
type of 2 - clinically multifocal; at least 1 asymptomatic MRI lesion;
type of 3 - clinically monofocal; MRI can be without pathology; no asymptomatic MRI lesions;
type of 4 - clinically multifocal; MRI can be without pathology; no asymptomatic MRI lesions;
type of 5 - no clinical features suggestive of demyelinating disease, but suggestive MRI findings.

In this way, the criterion of "CIS" is not the semiotic-topic (syndromic) isolation of clinical neurological symptoms, but its (i.e. symptoms) "temporal a I am limited” - monophasic (i.e., the absence of signs of dissemination in time); CIS can be monofocal or multifocal, but always without signs of dissemination over time, i.e. always limited in time - monophasic.

It is difficult to predict whether MS will develop after the first episode, but the currently used McDonald criteria (due to the widespread use of MRI and its increasing role in the diagnosis of MS) ​​allow in a certain percentage of cases of CIS to establish the diagnosis of definite MS before the development of the second clinical attack. C. Dalton et al. (2003) found that the application of the McDonald criteria allows diagnosing MS more than twice as often during the first year after the detection of CIS, without waiting for the second episode of demyelination. Detection of 9 (nine) or more lesions on a tomogram that do not accumulate a contrast agent is an important prognostic sign of MS.

Note! Increasingly, in routine clinical practice, patients undergoing magnetic resonance imaging (MRI) for examination for indications such as traumatic brain injury or migraine are additionally diagnosed with white matter pathology in the central nervous system (CNS). These changes can be either non-specific (described by radiologists as “unidentified light objects”) or highly characteristic of demyelinating pathology, taking into account their morphology and localization in the CNS. The latter were proposed to be singled out in " radiologically isolated syndrome» (RIS), preceding the clinically isolated syndrome (CIS) and being the first clinical manifestation of multiple sclerosis.

note .

The clinical picture of multiple sclerosis (MS) is very diverse, while there is not a single specific symptom characteristic of this nosological unit, which explains the high frequency of diagnostic errors. It has been established that even at present, 5-10% of patients who are diagnosed with multiple sclerosis do not actually have this disease.

The most difficult is the diagnosis at the debut of multiple sclerosis. The true onset of the disease often escapes the researcher's field of vision, which is facilitated by a significant period of time between the clinical debut of the pathological process and the further course. Anamnestic data are important, which almost always contain an indication of the polysymptomatic nature of the disease, the instability of symptoms, as well as a progressive or relapsing course. It is especially important to identify the most initial, albeit very distant symptoms of the disease. You should always keep in mind the possibility of misinterpretation of previous exacerbations (when collecting anamnesis) - the presence of unilateral loss of vision, Bell's palsy, trigeminal neuralgia, episodic systemic vertigo or "carpal tunnel syndrome" with sensory disturbances that do not correspond to the region of innervation of the median nerve.

The period during which patients consider themselves healthy, forgetting about the episode that has occurred, can be several years. Thus, the very initial signs of the disease are often not fixed, and sometimes a long remission makes the initial symptoms that took place many years ago be regarded as having nothing to do with the underlying disease. Often, patients come to the doctor after the second and subsequent exacerbations, as a rule, manifested by a large number of symptoms that are more persistent than during the first attack. The first manifestations of the disease are often monosymptomatic, unstable, distant from the second exacerbation by a longer remission and are often not taken into account.

Clinical syndromes at the onset of multiple sclerosis

Theoretically, in the debut of multiple sclerosis, the development of almost any neurological symptomatology is possible. However, certain areas of the CNS are more commonly affected in multiple sclerosis than others (see figure). For example, despite the relatively small amount of myelin in the optic nerves, its damage in the form of optic (retrobulbar) neuritis at the onset of the disease is observed in 15–20% of cases. Other frequent first clinical manifestations of multiple sclerosis include transverse (usually incomplete) myelopathy syndrome (10-15%), oculomotor disorders, more often in the form of incomplete internuclear ophthalmoplegia (7-10%), symptoms of damage to the pyramidal tract at different levels (10 %), disorders of deep and superficial sensitivity (33%), as well as dysfunctions of the cerebellum and its pathways.

Retrobulbar (optical) neuritis(RBN) is manifested by dull or blurred vision, pain when moving the eyeballs, and sometimes photophobia. One-sidedness of the lesion, acute or subacute development, as well as reversibility of visual impairment are characteristic. Objectively, a decrease in visual acuity, an afferent pupillary defect, color desaturation (especially in red), and a central scotoma are detected. For the detection of a mild lesion, a very sensitive method is the study of low-contrast vision, which reveals anomalies even with completely normal visual acuity; in the acute stage, with sometimes developing papillitis in the fundus, edema of the optic nerve head is detected, but with “pure” retrobulbar neuritis, there are no changes in the acute period (paleness of the nerve disk usually develops later). Symptoms that are not typical for optic neuritis in multiple sclerosis include the following symptoms: complete absence of pain, complete loss of vision, superacute onset (typical of vascular etiology of neuropathy), bilateral involvement (typical of optomyelitis, Leber's neuropathy), the presence of neuroretinitis in the fundus, retinal hemorrhages , the presence of fever, or poor clinical recovery for one month or more after the onset of symptoms.

Myelitis(incomplete transverse myelitis)

Myelitis usually incomplete transverse (violation of not all three main functional tracts of the spinal cord - sensory, motor and regulating pelvic functions). Girdle-like tingling sensations in the chest or abdomen are typical, reflecting damage to the posterior columns and often associated with a horizontal level of sensory disturbances. Symptoms atypical for myelitis in multiple sclerosis include a hyperacute onset, the presence of longitudinal or complete transverse myelitis, severe radicular pain, and the development of spinal shock.

stem syndrome

stem syndromes usually presents with incomplete internuclear ophthalmoplegia, but facial myokymia or weakness, systemic dizziness, sensory disturbances on the face (may also reflect lesions in the upper cervical spinal cord or subcortically) and other syndromes are also possible.

Movement disorders

Movement disorders represented by pyramidal paresis, more often unilateral and more often affecting the lower extremities, may be associated with spasticity, stiffness, spasms, cramps and gait disturbance (these symptoms sometimes develop in the absence of formal paresis).

Sensory disturbances

Sensory disturbances in the debut, for the most part, they reflect foci in the posterior columns, and not in the spinothalamic pathways, and a decrease in vibration sensitivity usually develops in the early stages, and always before the violation of the muscular-articular feeling; sensory disturbances can be negative or positive - tingling, burning, itching, paresthesias, hyperpathy, allodynia, dysesthesias, sometimes difficult to describe (for example, a feeling of swelling of a limb, or a feeling that the skin is surrounded by clothing fabric.

Cerebellar disorders

Cerebellar disorders with multiple sclerosis, they are manifested by systemic dizziness, instability (the latter, however, may reflect a disorder of deep sensitivity, the vestibular system, spasticity or general weakness), clumsiness, loss of balance, tremor. Scanned speech, rebound phenomenon, ataxia of limbs or gait, dysmetria and intentional tremor are detected objectively; Romberg's symptom is often reported, but usually postural disturbances are present both with open and closed eyes [Khabirov F.A., Averyanova L.A., Babicheva N.N., Granatov E.V., Khaibullin T.I., 2015].

Other symptoms

For multiple sclerosis, especially in the debut, paroxysmal syndromes are characteristic. Of the latter, tonic convulsions and paroxysmal ataxia and dysarthria are well characterized, in both cases the attacks are very short - from 10 seconds to 2 minutes, with a frequency of up to 10–40 per day, provoked by hyperventilation movements; tonic convulsions of spinal origin (flexion of the hand and arm) are often preceded by sensory disturbances (heat, pain) in the opposite limb; if the spasm also captures the face, then sensory disturbances are usually absent, and the focus is located in the trunk; the same applies to very brief episodes of dysarthria and ataxia. Isolated cases of these syndromes are described with CNS lesions in SLE, but in general they are so specific for multiple sclerosis that they are considered almost pathognomonic. Other paroxysmal symptoms are less specific - glossopharyngeal neuralgia, paroxysmal itching, sudden loss of tone, kinesiogenic athetosis, hiccups, segmental myoclonus, Lermitte's phenomenon and trigeminal neuralgia also belong to paroxysmal ones; the latter develops in multiple sclerosis at a younger age and is often bilateral, but in general, unlike many other paroxysmal symptoms, multiple sclerosis causes a very small proportion of cases of trigeminal neuralgia observed in routine practice. In addition to non-epileptic ones, true epileptic seizures are also described in the debut of multiple sclerosis, as a rule, within the framework of the encephalopathy syndrome in ADEM-like debut of multiple sclerosis.

According to our own data, the most common syndromes in the onset of multiple sclerosis (figure) from a topical point of view were optic neuritis (16%) and myelopathy syndrome (20%), stem disorders and cerebellar disorders were less common (13 and 7%, respectively). Hemispheric sensory and motor disorders were detected in 11% and 8% of patients, and various variants of polyfocal debut - in 14%. We observed other variants of the onset of the disease in less than 6% of cases (mainly paroxysmal non-pileptic symptoms, epileptic seizures and encephalopathy syndrome as part of the ADEM-like onset of multiple sclerosis) [Khabirov F.A., Khaibullin T.I., Granatov E. V., Averyanova L.A., Babicheva N.N., Shakirzyanova S.R., 2015].

Picture. The structures of the central nervous system that are most often affected in the debut of multiple sclerosis. Polyfocal onset variants account for approximately 14% of cases (the analysis was conducted on more than 800 newly diagnosed cases of multiple sclerosis from 2010 to 2016).

Clinical syndromes in the advanced stage of multiple sclerosis

As in the debut of the disease, a characteristic feature of multiple sclerosis is the variety of its clinical manifestations. The disease is characterized by the formation of scattered foci of inflammation in the central nervous system, therefore, it usually manifests itself as a set of symptoms associated with damage to various conduction systems.

Multiple sclerosis is characterized by the syndrome of "clinical dissociation" ("splitting"), which reflects the discrepancy between the symptoms of damage to one or more functional systems. For example, with central paresis with an increase in proprioreflexes and the presence of pathological pyramidal signs, instead of the expected spasticity, hypotension is detected. Another symptom typical of multiple sclerosis is the “hot bath” phenomenon (Uhthoff phenomenon), which is characterized by a temporary increase or the appearance of symptoms when the ambient temperature rises (hot bath, bath, hot food, hyperinsolation) or the patient’s body temperature rises (exercise, fever).

A qualitative assessment of neurological disorders in multiple sclerosis in accordance with international standards is carried out using the expanded disability scale (EDSS), which includes a systematic assessment of the neurological status according to 7 Kurtzke functional systems, as well as the patient's ability to walk and self-care (see figure).

Picture. A sample interface of an online EDSS calculator in Russian that allows you to automatically calculate the EDSS score (screenshot from the website http://edss.ru).

The application as an expert tool and reference is useful for neurologists who specialize in the diagnosis and treatment of multiple sclerosis and other demyelinating diseases and who use the EDSS on a daily basis. To expand the circle of users, the program is available in 3 languages ​​(English, Russian, German), and the interface is equally easy to use, both on the screen of computers and smartphones. The EDSS calculator received the Certificate of state registration of the computer program No. 2016610500 dated January 13, 2016.

According to the pathogenesis of multiple sclerosis, the full clinical picture is dominated by polymorphic symptoms of CNS damage due to inflammatory and neurodegenerative lesions of the pathways, especially with a developed fast-conducting myelin sheath: optic pathways, pyramidal tracts, cerebellar tracts, posterior longitudinal bundle, associative fibers of the cerebral hemispheres, posterior columns of the spinal cord. brain, etc. Thus, in the neurological status, various combinations of asymmetric lesions of the optic nerves (optic neuritis with possible subsequent partial atrophy), dysfunction of the oculomotor nerves (various types of concordance, double vision, pathological reflex ocular movements in the form of nystagmus), pseudobulbar syndrome, central paresis and paralysis with spasticity, cerebellar symptoms (unsteadiness in standing position and when walking, trembling in the limbs, slowness and scantiness of speech, decreased muscle tone), various types of tremulous hyperkinesis (trembling of the head, trunk, limbs), sensory disturbances, dysfunctions of the pelvic organs ( urinary retention, imperative urge, constipation, incontinence), a cognitive-emotional symptom complex (disorders of abstract thinking, attention, increased mood, reduced criticism and self-criticism).

Damage to cranial nerves

Optic neuritis often develops as the only or one of the manifestations of the next exacerbation of multiple sclerosis and is typically manifested by a unilateral decrease in visual acuity. Vision is usually partially or completely restored in various periods - from several days to several months, but with frequent repeated neuritis, partial atrophy of the optic nerves eventually develops with a more or less pronounced permanent visual defect (which, however, usually does not reach complete blindness)

Of the other cranial nerves, the oculomotor nerves are most commonly affected. In addition to direct damage to the intrastem sections of the nerves themselves by the demyelinating process, oculomotor disorders are often caused by damage to the posterior longitudinal bundle in the brain stem with the development of unilateral or bilateral internuclear ophthalmoplegia (diplopia in lateral gaze, while observing the impossibility of adducting the eyeball on the side of the focus, and horizontal nystagmus in the retracted eye). A very common symptom of multiple sclerosis is nystagmus, which can be represented by almost all variants, depending on the localization of the focus of demyelination. For example, horizontal nystagmus, often with a rotator component, is associated with lesions of the brainstem, monocular - with involvement of the cerebellum, and vertical - with damage to the oral parts of the brainstem. In the presence of nystagmus, patients often complain of blurred vision or the illusion of objects trembling (oscillopsia).

There are also frequent symptoms from the V and VII pairs of cranial nerves associated with damage to the fibers that form them in the brain stem. Thus, damage to the intratruncal portion of the facial nerve is manifested by peripheral paresis of the facial muscles, which in some cases is part of the alternating hemiplegic syndrome. Characteristic of the defeat of the facial nerve in multiple sclerosis is the absence of signs of a gross lesion, the instability of symptoms, as well as the frequent combination with lesions of other CNs. With the predominance of irritation of the fibers of the facial nerve, the appearance of facial myokymia or facial hemispasm is possible. The defeat of the trigeminal nerve can be manifested by neuralgia or impaired sensitivity on the face and paresis of the masticatory muscles.

Damage to the connections of the vestibular nuclei with other stem structures and the cerebellum is manifested by systemic dizziness, accompanied by nausea and vomiting; with simultaneous damage to the fibers belonging to the auditory portion of the VIII pair of CNs, tinnitus and / or hearing loss are possible (the latter symptoms do not belong to frequent manifestations of multiple sclerosis).

The defeat of the intrastem portions of the nerves of the bulbar group leads to the development of paralysis of the muscles of the soft palate, pharynx, larynx and tongue, which is manifested by dysarthria, dysphagia and dysphonia, which, however, are more often the result of supranuclear lesions, i.e. occur within the framework of pseudobulbar palsy, accompanied by violent laughter or crying.

Pyramidal syndrome (ndestruction of the pyramidal tracts)

Symptoms of lesions of the pyramidal tract are the most common manifestation of multiple sclerosis and the main cause of disability in patients. Depending on the location of the focus, patients may have central mono-, hemi-, tri-, and tetraparesis, but lower paraparesis is most characteristic of MS. Paresis, as a rule, is accompanied by spasticity, increased proprioreflexes, clonus of the feet and kneecaps, pathological foot signs (often extensor type) and a decrease in skin reflexes, primarily abdominal ones. However, a combination of central paresis with severe muscular hypotension (due to damage to the cerebellum and / or conductors of deep sensitivity) or with dystonia is often observed, in such cases proprioreflexes may be reduced or even absent.

Sensory pathway damage

Sensitivity disorders are observed in more than 80% of patients with multiple sclerosis. The most common symptoms that patients with multiple sclerosis present during the examination are a feeling of numbness, burning, a feeling of "crawling". These disorders are often unstable, often accompanied by pain. Sensory disturbances may be conductive or, less commonly, segmental. Mosaic sensitivity disorders are often observed. For multiple sclerosis, violations of deep sensitivity, in particular vibration, and muscular-articular feeling are typical, which is accompanied by the development of sensitive ataxia and sensitive paresis. With the localization of foci of demyelination in the spinal cord, especially within the posterior columns, Lermitte's symptom is possible - the occurrence, when the head is tilted, of a paroxysmal sensation of the passage of an electric current along the spine, sometimes radiating to the limbs.

Cerebellar disorders

Cerebellar disorders in multiple sclerosis can be represented by static and dynamic ataxia, dys- and hypermetry, asynergy, misses in coordination tests, scanned speech and megalography, decreased muscle tone, and atactic gait. Intentional tremor is often observed; in case of damage to the fibers that connect the dentate and red nuclei, Holmes's tremor develops (rest tremor, which increases in postural conditions and, when purposeful movements are attempted, it transforms into large-scale involuntary movements that can spread to the head and trunk. In case of damage to the cerebellar vermis, in addition to severe static Ataxia, axial tremor of the head and/or trunk (titubation) is possible [Averyanova L.A., 2014].

Pelvic disorders

In the vast majority of patients with multiple sclerosis, especially with lesions of the spinal cord, at a certain stage of the disease, disorders of the functions of the pelvic organs occur. As a result, the synchronous work of the detrusor and sphincters of the bladder is disrupted: hyper- or areflexia of the detrusor, detrusor-sphincter dyssynergia.

Symptoms of detrusor hyperreflexia are frequent urination, urgency, and urinary incontinence. Detrusor areflexia - lack of urge to urinate, overflow of the bladder and urinary incontinence, difficulty urinating with a sluggish stream, a feeling of incomplete emptying of the bladder. Detrusor-sphincter dyssynergy is characterized by incomplete emptying of the bladder with residual urine (possibility of developing inflammatory complications), intermittency of the urine stream, urinary retention, accompanied by pain in the lower abdomen and perineum.

Violations of the function of the rectum are observed somewhat less frequently than the pathology of urination. They are usually represented by constipation, more or less persistent, less often by imperative urge to empty the intestines and fecal incontinence (with localization of demyelination foci in the lumbosacral part of the spinal cord).

Dysfunction of the pelvic organs in men is usually combined with sexual dysfunction (erection and ejaculation disorders).

Cognitive and psycho-emotional disorders

Disorders of mental and intellectual-mnestic functions as a consequence of multiple sclerosis itself or as a psychological reaction to the disease are often noted. They can be represented by emotional-affective disorders: depression, euphoria, neurosis-like states, less often - psychoses. Some patients with multiple sclerosis experience panic attacks. With milder variants of the course of the disease, mood lability, accentuation of innate personality traits, apathetic or anxious states are noted. Along with this, cognitive disorders can develop: impaired memory, attention, abstract thinking, reduced speed of thinking, speed of information evaluation. As the disease progresses, mild or even moderate dementia may develop.

For multiple sclerosis, chronic fatigue syndrome is very characteristic - rapid physical fatigue with the need for frequent rest, emotional exhaustion, inability to wait long, limited motivation, drowsiness. A feature of this syndrome in multiple sclerosis is that the fatigue of patients is not adequate to physical or any other load.

It is customary to distinguish four main types of MS flow.

Relapsing-remitting type of course

Relapsing-remitting multiple sclerosis characterized by the presence of clearly defined exacerbations with complete recovery or with consequences and residual deficits, the periods between exacerbations are characterized by the absence of disease progression. It is the most common variant of multiple sclerosis, accounting for 80 to 90% of all cases of the disease.

secondary progressiveflow type

Secondary progressive multiple sclerosis characterized by the onset after an initial relapsing-remitting course by progression, accompanied or not accompanied by occasional exacerbations, minor remissions, or plateau periods. The period from the onset of the disease to the onset of the progression stage varies and can average from 9 to 20 years or more.

Primary progressiveflow type

Primary progressive multiple sclerosis characterized by progression from the onset of the disease, occasional plateaus or temporary minor improvements are possible. This rarer form accounts for up to 10% of all cases.

Progressive-recurrent type of course

Progressive-relapsing multiple sclerosis characterized by progression from the onset of the disease, with clear acute exacerbations, with or without complete recovery, the periods between exacerbations are characterized by ongoing progression. This course is noted in a small proportion of patients with primary progressive disease.

At the same time, an exacerbation of multiple sclerosis means the development of a new or an increase in already existing neurological symptoms, typical of an acute inflammatory demyelinating lesion of the central nervous system, lasting at least 24 hours, in the absence of fever or an infectious process. Symptoms of an exacerbation of multiple sclerosis can be both permanent and paroxysmal (many episodes of paroxysmal disorders within at least 24 hours). Criteria for exacerbation of multiple sclerosis on the EDSS scale usually include an increase of 1 point in at least 2 functional systems or 2 points in 1 functional system, or an increase in the EDSS score of at least 0.5 points. Two exacerbations of multiple sclerosis are considered separate if the time interval between the completion of the first and the development of the second exacerbation is at least 30 days. The progression of the disease is usually understood as a gradual increase in the degree of neurological disorders for 1 year or more.

Along with the listed variants of the flow recognized by the majority of researchers, several additional ones are sometimes distinguished. For example, a benign course of multiple sclerosis with the development of minimal neurological symptoms for 10 years or more, a transient progressive course (figure).

Picture. Types of course of multiple sclerosis (MS). "Classic": RR MS - relapsing-remitting course of multiple sclerosis; VPT MS - secondary progressive course of multiple sclerosis; PPT MS - primary progressive course of multiple sclerosis; PRT MS is a progressive-relapsing course of multiple sclerosis. Additional: DT MS - benign course of multiple sclerosis; TPT MS is a transient progressive course of multiple sclerosis. Adapted from .

In recent years, due to the need to more adequately reflect the modern understanding of the pathogenesis of multiple sclerosis, as well as with the aim of wide dissemination of the term CIS and the need to take into account not only clinical, but also MRI disease activity, the classical types of the course were revised in 2013. Definition of new phenotypes currents and their relationship with traditional ones is shown in the figure.

Picture. New definitions of the types of course of multiple sclerosis. The division of the type of flow into relapsing-remitting and progressive is preserved. The definitions of recurrence and progression have not changed, however, the phenotype of CIS and the descriptor of “activity” have been added, which means the presence of either clinical exacerbations or contrasted, new or clearly increased T2 lesions on MRI, which is performed at least once a year. (it is obvious that active CIS turns into the phenotype of the relapsing-remitting course of MS). Adapted from Lublin F.D., Reingold S.C., Cohen J.A. et al., 2014.

Time stages of development

The widespread use of the term " clinically isolated multiple sclerosis syndrome"(KIS RS), and then the term" Radiologically isolated multiple sclerosis syndrome» (RIS RS) served as the basis for the development of the concept of the time stages of the development of multiple sclerosis. CIS is understood as the first episode of neurological disorders caused by an inflammatory demyelinating lesion of the CNS, which, however, does not meet the formal diagnostic criteria for relapsing-remitting multiple sclerosis, usually due to the lack of a criterion for dissemination over time. Naturally, it is extremely important to conduct a thorough differential diagnosis and exclude other causes of such damage to the central nervous system. CIS can be mono- or multifocal, mono- or polysymptomatic. The most common monofocal variants of CIS are optic neuritis, incomplete transverse myelopathy, various stem syndromes, hemispheric focal lesions. To date, there is no reliable way to determine if (and when) CIS can progress to multiple sclerosis, although many different biomarkers and prognostic factors have been proposed.

As for the term "radiologically isolated syndrome" (RIS), then it means changes that are accidentally detected during MRI, typical of multiple sclerosis, but in the absence of any clinical manifestations. To state that a subject has RIS, the following criteria must be met.

• A. Characteristic focal changes in the white matter of the brain according to MRI:

• ovoid, well-circumscribed, homogeneous lesions with or without involvement of the corpus callosum;
• the size of T2 hyperintense foci is more than 3 mm and they meet the Barkov criteria (at least 3 out of 4) in terms of dissemination in space;
• white matter abnormalities do not match the vascular pattern;

• B. There is no history of remitting clinical symptoms of neurological dysfunction;
• C. MRI abnormalities are not associated with clinically obvious impairments in social, occupational, or general function;
• D. Anomalies on MRI are not directly related to exposure to substances (drugs, household toxins) or medical conditions;
• E. MRI phenotype does not correspond to leukoaraiosis or widespread white matter abnormalities without involvement of the corpus callosum;
• E. Cannot be explained by other pathological processes.

The risk of transformation of RIS into CIS is not exactly known, but it is increased in the presence of spinal lesions. Thus, de facto RIS is a subclinical form of multiple sclerosis, based on this, the time stages of the disease can be represented as the following sequence: RIS → CIS → relapsing-remitting multiple sclerosis → secondary progressive multiple sclerosis.

Specific phenotypes of multiple sclerosis

There are several variants of multiple sclerosis, which differ from the usual cases either by the features of the course, or by MRI (or pathomorphological picture).

Marburg disease

Marburg disease- a malignant variant of multiple sclerosis. It is characterized by an acute onset with a predominant lesion of the brain stem, rapid progression of the disease, and the absence of remissions. Irreversible neurological disorders increase very quickly, and after a short time the patient already experiences difficulties associated with movement and self-care (score of 6 points or more on the EDSS scale after 3 years and earlier from the onset of the disease). Thus, the disease is characterized by an acute onset, a severe course with a rapid onset of pronounced functional disorders, up to a lethal outcome. MRI reveals multiple foci of demyelination of various sizes, including large ones, with overlapping zones of perifocal edema. Characterized by contrast enhancement of foci, their localization in the brain stem.

Balo's concentric sclerosis

Balo's concentric sclerosis- a relatively rare, rapidly progressive variant of multiple sclerosis in young people, in which there is the formation of large foci of demyelination in the white matter of the hemispheres, sometimes with the involvement of the gray matter. The foci consist of alternating areas of complete and partial demyelination, located concentrically or chaotically, which creates a typical pathomorphological picture, in most cases it is visualized on MRI (plaques are represented by alternating concentric areas). In some cases, the disease may have a relatively benign course, especially with timely pulse therapy with glucocorticoids.

Pseudotumorous multiple sclerosis characterized by a clinical picture of a subacutely developing volumetric process, as a rule - cerebral localization; noted in patients with significant multiple sclerosis. Sometimes such a course is also possible in the debut of the demyelinating process. In some cases, pseudotumor syndrome may recur. A number of features (for example, the nature of the accumulation of contrast in the form of an open ring) make it possible to differentiate this variant from a tumor-like lesion of the central nervous system, however, in many cases, PET, special MRI methods, or a biopsy study are necessary.

Clinically isolated syndrome (CIS) is the result of a single episode of demyelination in one (monofocal episode) or several parts of the central nervous system (multifocal episode). In 85% of patients who are eventually diagnosed with multiple sclerosis, the first manifestation of symptoms of the disease or the first relapse (attack, exacerbation) is called a clinically isolated syndrome (CIS).

If, along with clinical manifestations, MRI of the brain and spinal cord reveals lesions characteristic of MS, then, in some cases, a clinically isolated syndrome can be considered as the onset of multiple sclerosis. If over time, after CIS, a clinical picture of the second episode of exacerbation of the disease develops, or new foci of demyelination are detected on subsequent MRI, then reliable multiple sclerosis is diagnosed.

However, not all patients who experience a clinically isolated syndrome develop multiple sclerosis later on. Many do not show the characteristic MRI picture of demyelination and subsequently do not develop new symptoms.

Diagnosis of clinically isolated syndrome

In diagnosing a clinically isolated syndrome, it is important to rule out other possible causes of symptoms. The medical history, neurological examination, and a range of clinical tests combine to help identify or rule out any other potential causes of the symptom(s). However, MRI is the most informative diagnostic method that allows visualizing possible foci of demyelination in the central nervous system.

The symptoms detected in CIS often indicate the localization of the focus of demyelination. Most often, foci are found in the following parts of the central nervous system:

• spinal cord - in this case, we are talking about transverse myelitis;
• optic nerves - in this case, we are talking about optic neuritis (retrobulbar neuritis);
• brain stem

If the damage is clinically manifested in any one department of the CNS, then it is called "monofocal", if at once in several, then we are talking about a "multifocal" disorder.

The most common manifestations of CIS

Transverse myelitis

Transverse myelitis occurs when the myelin sheaths covering the nerve fibers of the spinal cord are destroyed.

Depending on in which part of the spinal cord the focus of demyelination is located (cervical, thoracic, lumbar, sacral), disturbances occur in the work of the corresponding organs, upper or lower extremities.

There are four main symptoms of transverse myelitis:

• Weakness in arms and/or legs
• Sensory disturbance
• Bladder and colon dysfunction

Optic neuritis (retrobulbar neuritis)

Optic neuritis (retrobulbar neuritis) is caused by demyelination of the optic nerve, which transmits images from the retina to the back of the cerebral cortex. Acute attack of optic neuritis is characterized by

• sudden loss of visual acuity,
• pain when moving the eyeballs,
• color vision disorder (dyschromatopsia)

Pathological processes in the brain stem

Sometimes pathological processes of demyelination affect the brainstem - part of the base of the brain, in which the nuclei of cranial nerves and vital centers (respiratory, vasomotor and a number of others) are located. Symptoms of brainstem damage are varied and may include:

• various oculomotor disorders, nystagmus
• dysarthria, swallowing disorders
• violation of statics, coordination, etc.

Treatment of clinically isolated syndrome

Depending on the nature and severity of symptoms observed in clinically isolated syndrome, corticosteroid therapy may be recommended to reduce the severity and duration of symptoms. If necessary, symptomatic therapy can be prescribed to reduce the severity or completely compensate for symptoms.

Probability of developing MS

The results of some long-term clinical studies indicate that 50% of people who have had CIS develop multiple sclerosis within five years. To date, there is no method that would allow to determine the individual risk of developing multiple sclerosis after suffering a clinically isolated syndrome.

However, researchers have attempted to identify factors that may influence the likelihood of developing MS. The presence or absence of these factors cannot determine the absolute risk of developing MS, however, in some cases, they may be useful in making decisions about further treatment.

• Optic neuritis is associated with a lower risk of developing definite MS, and better prognostic data in the event of the disease, than other types of clinically isolated syndrome.
• Isolated sensory symptoms, which may include numbness, tingling, or visual disturbances, are thought to be associated with a lower risk of developing MS compared with symptoms suggestive of musculoskeletal involvement. In CIS associated with movement disorders, the risk of developing MS is increased.
• Absence of lesions on MRI is associated with a lower risk of developing MS, while scans showing a large number or volume of lesions are associated with a high risk of definitive multiple sclerosis.

Sometimes, in order to confirm or exclude the diagnosis of multiple sclerosis, a laboratory analysis of cerebrospinal fluid (CSF) is necessary - the fluid that bathes the brain and spinal cord. The presence of specific markers in CSF may indicate MS.

INTERNATIONAL NEUROLOGICAL JOURNAL

INTERNATIONAL NEUROLOGICAL JOURNAL 1

INTERNATIONAL NEUROLOGICAL JOURNAL

UDC 616-071+616.832-004.2+616-08+613.95

EVTUSHENKO S.K.1, MOSKALENKO JR.2, EVTUSHENKO I.S.3

1 Kharkiv Medical Academy of Postgraduate Education

2 Regional Center for Demyelinating Diseases, Donetsk

3 DonNMU im. M. Gorky

FROM A CLINICALLY ISOLATED SYNDROME TO RELIABLE DIAGNOSIS OF MULTIPLE SCLEROSIS AND ITS EFFECTIVE THERAPY IN CHILDREN

Summary. The article presents the results of 30 years of experience in the early diagnosis of multiple sclerosis in children using magnetic resonance imaging, visual and cognitive evoked potentials, biochemical and immunological studies of blood and cerebrospinal fluid. The authors describe the options for the debut of this difficult-to-treat disabling disease in children. Therapy regimens are presented, including pulse therapy with solu-medrol, plasmapheresis and intravenous immunoglobulin, as well as experience with the use of immunomodulators in children.

Key words: multiple sclerosis, children, diagnosis, treatment.

Multiple sclerosis (MS) is a chronic progressive demyelinating disease of the nervous system that begins predominantly at a young (including childhood) age, is characterized by multi-focal lesions of the white matter of the central nervous system, a relapsing-progressive course, variability of neurological symptoms and leads to early disability and impaired quality of life. This is what makes the problem of MS socially significant. It is especially important to be vigilant about MS in neurological pediatric practice, since in recent years there has been a tendency towards an increase in the incidence of MS in children. From 1978 to 2005, 53 children aged 7 to 18 years were under our supervision (personal archive), and from 2006 to 2014, reliable MS was diagnosed in our clinic in 63 children. The increase in the number of children with MS is associated

both with an increase in morbidity and with an improvement in diagnostic capabilities. There are features of the course of the disease, there is a high risk of developing a persistent irreversible neurological deficit and disability already in childhood.

Unfortunately, even today there are many debatable, unclear and unresolved issues in the concept of the origin of multiple sclerosis. Nevertheless, a giant breakthrough has been made in the discovery of the pathogenetic mechanisms of the development of the inflammatory-destructive process in this insidious disease. RS in on-

Evtushenko Stanislav Konstantinovich E-mail: [email protected]

© Evtushenko S.K., Moskalenko M.A., Evtushenko I.S., 2015 © International Neurological Journal, 2015 © Zaslavsky A.Yu., 2015

Currently, it is considered as a multifactorial disease with a hereditary predisposition realized through a polygenic system responsible for the immune response and type of metabolism (HLA-BCI). The “trigger link” of the pathological process often includes infectious agents, primarily viruses (EVU, HNU type VI, JC viruses, retroviruses, measles, rubella, etc.). In table. 1 shows the homology 114-120 of the 08P peptide with the peptides of some viruses related to the etiology of multiple sclerosis.

Table 1. Homology 114-120 of the OBR peptide with the peptides of some viruses (Bronstein IM et al., 1999) related to the etiology of multiple sclerosis

Viruses/peptides Amino acid sequence

OSP 114-120 GVAKYRR

Epstein-Barr virus PVAKRRR

Coxsackie In GVPKNRR

Human immunodeficiency virus I GVAKKLR

Human immunodeficiency virus II GLAKKRR

Herpes simplex virus II GSAKRRR

Geographical and environmental factors that have a long-term impact and shape the characteristics of immunoregulation and metabolism are important. MS is more common in regions with humid cool climates compared to regions with humid dry or cold dry climates. There is a so-called latitude gradient - an increase in the incidence from north to south and from west to east. It is known that the risk of development is associated not only with the place of residence, but also with belonging to a particular race, ethnic group. To a greater extent, the disease is common among the white population of the Earth. It has been proven that with an increase in the level of vitamin D in the body, the risk of developing MS decreases (perhaps in connection with this, the frequency of the disease increases with distance from the equator and less exposure to sunlight). Vitamin B is a powerful regulatory factor that suppresses immunopathological reactions (excessive activity of CB3 + -T cells, leading to damage to the myelin sheath of neurons).

The factor in the implementation of the pathological process (myelin and axonopathy, neurodegeneration) are immunopathological and inflammatory mechanisms involving activated T cells, CD25, CD95, cytokines, autoidiotypic antibodies. The basis of the disease is progressive demyelination of the pathways, referred to as "naked nerve disease", with a clinical picture of multifocal damage to the brain and spinal cord. There are 5 main stages

MS immunopathogenesis: activation of T cells and their differentiation into CD4 T cells; proliferation of activated T cells; involvement of B-cells and monocytes in the pathological process; migration of T cells across the blood-brain barrier; reactivation of T cells in the CNS and induction of demyelination.

At the same time, axonal damage is the basis for the formation of neurological deficit at an early stage of MS. That is why the pathogenesis of primary and secondary progressive MS is the progressive loss of axons and their receptors, while the production of cerebral trophic factor is impaired. Unfortunately, we rarely “catch” the first progressive inflammatory reaction that has begun, because it first diffusely damages the brain, but manifests itself locally. But already at stage II of the progressive inflammatory-degenerative process, bare axons become a target for glutamate-mediated cytotoxicity, which leads to axonal degeneration. Determining the level of excitotoxicity is today a marker of prognosis and choice of therapy in MS. Evidence of axonal degeneration are: atrophy of the brain and spinal cord (correlating with neurological deficit according to morphology and magnetic resonance imaging (MRI)), a decrease in the level of the neuronal marker K-acetylaspartate according to MR spectroscopy.

The most important clinical criteria for diagnosing MS in the age aspect are: the onset of the disease in childhood and young age, the polymorphism of clinical manifestations, the “flickering” of symptoms even throughout the day, the undulating course of the disease, the presence of clinical dissociations. The main (initial), unfortunately, clinical symptoms of MS that are not claimed by young neurologists have not lost their significance: Charcot's tetrad (not a triad) - nystagmus, intentional tremor, scanned speech, lower paraparesis; Marburg pentad - nystagmus, intentional tremor, absence or lethargy of abdominal reflexes, blanching of the temporal halves of the nipples of the optic nerves, spastic paresis of the legs; Markov's sextad - visual disturbances with narrowing of the visual fields for colors, vestibulopathy, oculomotor disorders (transient double vision), damage to the pyramidal system, an isolated decrease in vibrational sensitivity.

When a patient is suspected to have MS, we insist on examining the classic clinical symptoms and reflexes with well-defined reflex arcs, as this allows a clear detection of diffuse organic damage to the nervous system. That is why all children need to undergo a thorough in-depth neurological examination with a study of cranial innervation, including an assessment of the symptoms of posterior and anterior internuclear ophthalmoparesis, supranuclear lesions of the cranial nerves (symptoms of oral automatism: Bekhterev's proboscis reflex,

Oppenheim's labial reflex, Karchikyan's distance-oral reflex, Toulouse-Wurp reflex, Marinescu-Radovici palmar-under-chin reflex). In addition to the study of tendon, periosteal and abdominal reflexes, an assessment of surface and vibration sensitivity, muscle-articular feeling, a mandatory check of the symptom of Tom - Jumenti, Lermitte, hand reflexes (Jacobson - Lask, Bekhterev, Zhukovsky, Rossolimo, Venderovich, Wartenberg), pathological foot signs (Babinsky, Oppenheim, Chaddock, Puusep, Rossolimo), automatism reflexes (Chlenov - McCarthy, Astvatsaturov, Razdolsky), tests for ataxia and asynergy (simple

and sensitized Romberg test, knee-calcaneal test, Stuart-Holmes test, Babinsky's asynergy test).

All patients were diagnosed according to the criteria of C.M. Poser, 1983, W.J. McDonald, 2001, 2005, 2010 (Tables 2, 3).

One of the most important signs of multiple sclerosis is clinical dissociation. The main clinical dissociations in MS in children have been identified:

1. High, with clonus reflexes with mild or moderate impairment of range of motion.

2. Violation of vibration sensitivity in the arms and legs with discoordination of the performance of dynamic

Table 2 Criteria for the diagnosis of multiple sclerosis (C.M. Poser et al., 1983)

Clinically significant 2 exacerbations + 2 clinical lesions; 2 exacerbations + 1 clinical lesion + 1 paraclinical lesion (registered by MRI or evoked potential method)

Reliable, laboratory-confirmed 2 exacerbations + 1 clinical lesion or paraclinical lesion + oligoclonal bands or increased synthesis of 1gO in CSF; 1 exacerbation + 2 clinical lesions + oligoclonal bands or increased synthesis of 1dO in CSF; 1 exacerbation + 1 clinical lesion + 1 paraclinical lesion + oligoclonal bands or increased CSF 1gO synthesis

Clinically probable 2 exacerbations + 1 clinical focus; 1 exacerbation + 2 clinical foci; 1 exacerbation + 1 clinical focus + 1 paraclinical focus

Probable, laboratory confirmed 2 exacerbations + oligoclonal bands or increased synthesis of 1gO in CSF

Clinical picture Additional data

> 2 exacerbations, objective clinical evidence of > 2 lesions Not required

> 2 exacerbations, objective clinical evidence of 1 lesion, and reasonable clinical evidence of a previous exacerbation history Not required

> 2 exacerbations, objective clinical evidence of the presence of 1 lesion Dissemination in space, which can be confirmed by: - ​​the presence of > 1 m2-hyperintense lesion located in at least 2 of the 4 zones characteristic of MS (juxtacortical, periventricular, infratentorial, infratentorial, in spinal cord) or - waiting for the next clinical exacerbation

1 exacerbation, objective clinical evidence of > 2 lesions Dissemination over time, which can be confirmed by: - ​​the presence of a new T2-hyperintense and/or contrast-accumulating lesion on subsequent MRI compared to the previous MRI, regardless of the time of the baseline scan or - the presence on MRI of an asymptomatic lesion(s) that accumulates contrast and a lesion that does not accumulate contrast, or - the expectation of the next clinical exacerbation

Table 3. Criteria for establishing the diagnosis of definite multiple sclerosis

(W.J. McDonald, 2010)

The end of the table. 3

1 exacerbation, objective clinical data on the presence of 1 lesion (clinically isolated syndrome - CIS) Dissemination in time and space: -> 1 T2-hyperintense lesion located in at least 2 of the 4 zones characteristic of MS (juxtacortical, periventricular, infratentorial , in the spinal cord) or - waiting for the next clinical exacerbation and - the presence of a new T2-hyperintense and/or contrast-accumulating lesion on subsequent MRI compared to the previous MRI, regardless of the time of the baseline scan, or - the presence of an asymptomatic lesion on MRI ( s), accumulating contrast, and a focus that does not accumulate contrast or - waiting for the next clinical exacerbation

No exacerbations with gradual progression of neurological symptoms Disease progression within 1 year (retrospectively or prospectively) and the presence of at least 2 of 3 criteria: - 1 T2 hyperintense lesion located juxtacortically or periventricularly or infratentorially; - > 2 T2-hyperintense foci in the spinal cord; - characteristic changes in CSF (presence of oligoclonal IgG groups in CSF or elevated IgG index)

mic tests with the preservation of the articular-muscular feeling (tuning fork 128 Hz).

3. Pathological reflexes with reduced knee and carporadial reflexes.

4. Severe pyramidal symptoms in the form of lower paraparesis with a decrease in muscle tone.

5. Different severity of hyperreflexia in the upper and lower extremities.

6. Dissociation between superficial and deep abdominal reflexes.

7. Paleness of the temporal half of the optic discs, atrophy with normal visual acuity or a drop in visual acuity with a normal fundus.

8. Presence of pelvic disorders with mild pyramidal syndrome.

9. Diffuse decrease in muscle tone and identification of the "jackknife" symptom.

10. MRI-negative debut of MS (no changes on MRI with clear clinical manifestations of multifocal brain damage).

11. The presence of multiple foci on MRI with a monosymptomatic debut.

12. The appearance of foci on MRI and their regression do not coincide in time with the clinical stages of exacerbation and remission (discrepancy between the clinical severity and detected foci of brain damage).

13. Discrepancy between the clinical and neurological picture and the localization of the identified foci of demyelination in the brain according to MRI data.

Typical clinical manifestations of MS in children are: motor and atactic disorders, vibration sensitivity disorders, brainstem, visual and cortical symptoms, psychoneuro-

hygienic disorders and progressive cerebral and peripheral autonomic failure.

Based on 30 years of experience in monitoring children with multiple sclerosis, we have identified 4 options for his debut. These provisions, to a certain extent, distinguish MS in children from MS in adults.

Clinically isolated syndrome as the debut of multiple sclerosis in children with its monosymptomatic onset (according to our data, up to 50% of patients)

1. Retrobulbar optic neuritis (about 35%, according to our data).

2. Sensory disturbances in the form of a feeling of numbness of the trunk, limbs and / or face (about 25%).

3. Paresis of the upper or lower limb, including afferent paresis with the appearance of a feeling of awkwardness in the limb (about 15%).

4. Oculomotor disorders with diplopia (about 8%).

5. Ataxia (about 3%).

6. Neuropathy of the facial nerve (about 3%).

7. Cephalgia with CSF hypertension syndrome (about 3%).

8. Violation of the function of the pelvic organs in the form of urinary retention (about 3%).

9. Dizziness (up to 2%).

10. Epileptic syndrome (up to 1%).

11. Psychoneurological disorders (acute psychotic states, aphasia, cognitive impairment) (up to 1%).

12. Dysarthria (as a manifestation of pseudobulbar syndrome) (up to 1%).

MRI can reveal both single and multiple foci of demyelination in the brain and/or spinal cord. According to our data, cerebral

Figure 1. Foci of demyelination in the brain and spinal cord

the form of MS with a monosymptomatic onset is observed in 33% of children, and cerebrospinal - in 67% of patients.

Initial symptoms of a polysymptomatic debut of multiple sclerosis in children (according to our data, up to 44% of patients)

We observed in our patients a combination of ataxia, paresis in the extremities, sensory disorders, retrobulbar neuritis, oculomotor disorders, dizziness, dysarthria, dysfunction of the pelvic organs and cognitive impairment.

1. Opticomyelitis (optic neuropathy + lower paraparesis + dysfunction of the pelvic organs).

2. Retrobulbar optic neuritis + paraparesis.

3. Ataxia + retrobulbar optic neuritis + paraparesis.

4. Ataxia + lower paraparesis.

5. Ataxia + paraparesis + dysfunction of the pelvic organs.

6. Ataxia + paraparesis + cognitive impairment.

7. Ataxia + oculomotor disorders (often in the form of abducens neuropathy) + hemiparesis.

8. Ataxia + sensitive disorders (in the form of numbness of the trunk, limbs and / or face).

9. Ataxia + paraparesis + epileptic syndrome.

MRI can reveal both solitary and

multiple foci of demyelination in the brain and / or spinal cord. According to our data, the cerebral form of MS with a polysymptomatic onset is observed in 17% of children, and cerebrospinal - in 83% of patients.

Erased initial symptoms without a significant neurological picture and complaints, but with gross incidentally detected demyelinating lesions of the brain on MRI (according to our data, up to 2% of patients)

At the time of the examination, the patients did not present any special complaints!

Examples of situations in which we diagnosed MS in children who did not present complaints at the time of examination:

a) during a professional examination, a pediatric neurologist revealed high reflexes (no complaints!) and sent the child for a consultation to the clinic. On MRI - periventricular confluent foci of demyelination;

b) the boy accidentally received a light blow on the head with a book. There were moderate headaches, which disappeared in a day. 20 days after that, he accidentally hit his head again. The headaches reappeared. In status: posterior nuclear ophthalmoparesis, Marinesko-Radovichi symptom ++,

increased reflexes. MRI shows 4 foci of demyelination. MRI revealed active foci after Magnevist injection (Fig. 1);

c) a 12-year-old girl lost consciousness in a stuffy room. There were no further complaints. In the neurological status, latent posterior nuclear ophthalmoparesis. Increased reflex, decreased vibration sensitivity up to 12 seconds. Studies were carried out: examination of the fundus, EEG, ECG, ultrasound of the vessels of the neck and head - no pathology was detected. MRI revealed foci of demyelination in both hemispheres of the brain and spinal cord (Fig. 1).

MRI-negative debut of MS (typical symptoms of MS, but no pathology was detected on MRI at the time of examination) (according to our data, up to 4% of patients)

In such cases, it is necessary to study cerebrospinal fluid with a polymerase chain reaction to detect DNA of herpes group viruses, to determine the intrathecal synthesis of immunoglobulin O. It is necessary to study visual evoked potentials and long-latency cognitive potentials to detect hidden foci. This form must be attributed to probable multiple sclerosis. In case of symptoms of manifest pyramidal and atactic syndrome (or other manifestations), recommend treatment (corticosteroids, intravenous immunoglobulins, acelysin, milgamma).

There are 4 types of MS course, characteristic for both adults and children:

1. Relapsing-remitting. It is characterized by an undulating course with clearly defined exacerbations and subsequent full or partial recovery of the impaired function without signs of progression during the period of remission. This type of course is observed in 90% of children with MS in the early stages of the disease.

2. Primary progressive (from the very beginning of the disease there is a steady progression, without clear periods of exacerbation and remission).

3. Secondary progressive (after the stage of exacerbations and remissions, the stage of a chronic increase in neurological symptoms begins).

4. Progressive with exacerbations (against the background of constant progression, there are clear periods of exacerbation, after the relief of which there is a gradual increase in the symptoms of the disease).

We observed malignant forms of MS in children (in one case with a fatal outcome).

Clinical example.

Patient A., aged 11, first came to our clinic with complaints of strabismus, double vision, which appeared about 3 weeks ago. Upon admission, the neurological status revealed posterior internuclear ophthalmoparesis, monocular nystagmus of the left eye, convergent strabismus due to the right eye, horizontal diplopia; decrease in abdominal reflexes, knee, high Achilles reflexes, S D, slight paresis of the left limbs. There were no pathological changes in the fundus of the eye. A narrowing of the visual fields for colors was revealed. An MRI of the brain revealed no pathology. On the background of therapy, diplopia stopped. The girl was discharged with a diagnosis of stem demyelinating encephalitis. A monosymptomatic debut of multiple sclerosis was suspected in the absence of changes on MRI of the brain.

Subsequently, the child begins frequent (every 2-5 months) exacerbations of the disease in the form of retrobulbar neuritis (unilateral and bilateral), dysfunction of the pelvic organs, lower paraparesis and tetraparesis, ataxia; atrophy of the optic nerves develops. Dynamics of the MRI picture: a single small focus of demyelination appears on the right in the projection of the pons, then foci of demyelination are determined in the area of ​​the bridge on the right up to 0.5 cm, in the area of ​​the corpus callosum up to 0.3 cm and periventricular zones of demyelination up to 0.45 cm wide. MRI of the cervical spinal cord revealed foci of demyelination 0.3 cm to 0.4 cm wide from the level of the C2 body to the upper edge of the C5 vertebral body. Subsequent MRI of the spinal cord revealed multiple confluent foci up to 1.0 cm throughout the cervical region, as well as multiple zones of demyelination in the thoracic and lumbar regions. At the initial stages, the treatment resulted in an effect in the form of a significant reduction in neurological symptoms, however, the duration of remissions decreased, exacerbations were polysymptomatic, and after 4 years of illness, the child died with a clinical picture of cerebral edema. Autopsy revealed foci of demyelination. The main changes were noted in the cervical and upper thoracic spinal cord.

It should be noted that children more often (up to 75% of cases) have a benign form of MS.

The most typical features of the course of MS in children are as follows:

1. In children, monosymptomatic initial manifestations of MS are more common (up to 65%).

2. The most vulnerable age is 11-14 years old, more often in girls (m/d = 1: 3).

3. In children at the onset of the disease, even with severe polysymptomatic manifestations, a complete recovery of the neurological deficit is more often noted.

4. At the initial stage, a relapsing course prevails with frequent exacerbations and short remissions (2-4 months).

5. During the period of exacerbation, weakness in the lower extremities (pyramidal syndrome), ataxia, and headache are noted.

6. Only 20% of patients complain of dysfunction of the pelvic organs.

7. Almost all patients have a positive reaction to the introduction of corticosteroids.

8. The prognosis (up to 75% of cases) can be favorable, without severe exacerbations for 5-10 years with proper therapy.

9. In 20% of the entire population of children with MS, there are primary progressive forms that are difficult to treat.

Three degrees of PC recognition reliability according to McAlpin (2000):

Reliable MS - progressive lower paraplegia, a combination of pyramidal and cerebellar disorders, damage to the optic nerve, the presence of remissions;

Probable MS - multifocal onset with good remission and "flickering" of the same symptoms without signs of relapse and progression for a year or more;

Doubtful MS - progressive lower paraplegia, no clear remissions.

There are the following stages of MS: exacerbation (exacerbation), remission, chronic progression, stabilization, debut of MS, pseudo-exacerbation (decompensation).

The scoring of functional systems is carried out according to the Kurtsk scale (Expanded Disebility Status Scale, EDSS, 1983).

Diagnosis example: multiple sclerosis, cerebrospinal form, relapsing course, exacerbation stage with lower paraparesis, ataxia, partial atrophy of the optic nerves, reduced vibrational sensitivity, with multiple foci of demyelination in both hemispheres of the brain according to MRI, severity according to EDSS 3.5 points (pyramidal system - 3 points, cerebellar functions - 3 points, stem - 2 points, sensory - 2 points, visual functions - 1 point, functions of the pelvic organs - 0 points, cerebral functions - 1 point).

The diagnosis of MS in children is more clinical than instrumental and should be made by a panel of competent physicians and researchers involved in this issue. Often, at the debut of MS, children are sent to us for examination with other diagnoses (retrobulbar neuritis, encephalitis, transient cerebrovascular accident, etc.).

It is always necessary to make a differential diagnosis of MS with other diseases of the nervous system. We diagnosed 87 (out of 203 referred to the clinic with suspected MS) children aged 7 to 17 years with the following diseases:

Disseminated encephalomyelitis - 33;

Brain tumors - 10;

Tumors of the spinal cord - 3;

Tuberous sclerosis - 4;

Neurofibromatosis type 1 with compression of the spinal cord - 2;

Paraplegia plus:

Strumpel's disease - 4;

Charleois - Sazheno - 2;

Vascular malformation of the spinal cord/brain - 3;

Dandy-Walker syndrome - 2;

Olivopontocerebellar degeneration - 4;

Adrenoleukodystrophy - 3;

Neuroborreliosis - 2;

Leber's disease - 2;

Hepatolenticular degeneration - 5;

HIV-associated leukoencephalopathy - 2;

Cerebral vasculitis - 3;

Mitochondrial encephalomyopathy (Ley's disease) - 2;

Hereditary leukoencephalopathy with hyperkeratosis - 1.

Particularly difficult is the differential MRI diagnosis of foci of demyelination, dysmyelination and metabolic disorders in children with such diseases:

Subacute sclerosing panencephalitis Van Bogart;

Acute disseminated encephalomyelitis;

Neuroborreliosis;

Adrenoleukodystrophy;

Optoencephalitis Leber;

Multifocal leukoencephalopathy;

Optocomyelitis Devik;

Schilder's leukoencephalitis.

Diagnostic value of clinical and instrumental

tal indicators in multiple sclerosis:

1. Clinical manifestations - 75%.

2. Magnetic resonance imaging of the brain and spinal cord - 85% (Fig. 2).

The most common localization of demyelination foci in the brain in children observed in the clinic, according to MRI:

Periventricular - 100% of cases;

Subcortically in the hemispheres of the brain - 83%;

In the cerebellum - 42%;

In the corpus callosum - 24%;

In the legs of the brain - 22%;

In the trunk - 20%.

When only periventricular foci are detected on MRI (especially in the absence of clinical manifestations of multifocal brain damage), an assumption about the perinatal genesis of foci is often heard. This requires a repeat MRI study with intravenous contrast (Gadovist, Magnevist) and mandatory MRI control after 6 months.

Depending on the time of onset of the disease in the same patient, it is possible to distinguish three types of plaques according to MRI data:

Acute (active, new foci of demyelination), old (permanent, chronic, inactive foci);

Old chronic lesions with signs of temporary (immanent) activation along the periphery of the plaque, which can be regarded as a continuation of plaque growth;

Shadows of plaques (like a penumbra in ischemic stroke) are a zone of thinning of myelin.

Figure 2. Foci of demyelination in the brain and spinal cord

Figure 3. Study of visual evoked potentials for reversal of the checkerboard pattern

MRI studies show that the pathological process in MS exhibits a slow but almost constant activity. According to MRI monitoring, it is possible to register new lesions or an increase in old ones up to 10 times a year. That is why the factor of constant activity of the demyelinating process determines the need for continuous treatment of MS. The absence of new symptoms during the period of clinical remission of MS does not reflect the stabilization of the pathological process, but, more likely, is due to the absence of gross violations of impulse conduction in the foci or the localization of foci in functionally insignificant areas of the brain. In this regard, it is mandatory to conduct MRI with intravenous contrast and study evoked potentials, which will determine the degree of activity of the process.

At the same time, according to MRI data, the correspondence between the severity of MS and the intensity of damage by the demyelinating process of the brain and spinal cord is observed only in 65-70% of cases.

3. Visual evoked potentials and long-latency evoked cognitive potentials to a significant stimulus - 80%.

The study of visual evoked potentials for the reversal of the checkerboard pattern makes it possible to identify clinically silent lesions in patients with a presumed demyelinating process (Fig. 3).

The study of long-latency cognitive potentials to a significant stimulus makes it possible to objectively quantify the perception and processing of information by the brain (Fig. 4).

4. Decreased vibration sensitivity (tuning fork 128 Hz) - 80%.

5. Transcranial magnetic stimulation makes it possible to determine not only the levels of damage to the pyramidal tract, but also the severity of the lesion (Fig. 5).

7. Laboratory study: oligoclonal IgO - 90%, FLC-c content - 95%, FLC-c index - 97%.

15-1-1-1-1-1-1-1-1-1-1

O 100 200 300 400 500 600 700 S00 900 1000

Figure 4. Study of long-latency cognitive potentials in response to a significant stimulus

Figure 5. Transcranial magnetic stimulation

Unfortunately, these studies are not readily available in medical practice. We consider the determination of the permeability of the blood-brain barrier and intrathecal synthesis of IgO as an alternative. We have introduced a method for determining albumin and immunoglobulin O, their ratio in blood and cerebrospinal fluid, which is a certain neurogenic marker, and in some cases confirms the specificity of lesions of the nervous system, especially if autoimmune diseases are suspected. An increase in the IgO/albumin ratio is observed in 80% of cases of multiple sclerosis.

To a certain extent, the level of intrathecal synthesis of ]eO can be considered equivalent to oligoclonal IgO. An increase in intrathecal

IgG synthesis indicates an inflammatory, predominantly autoimmune lesion of the central nervous system.

An obligatory examination pattern is to determine the degree of immunity tension, as well as the severity of the autoimmune inflammatory process and demyelination. The most significant CD cell populations in the study of cellular immunity in children with suspected MS:

CD3 (T-lymphocytes) - mature T-lymphocytes, total;

CD4 (T-helpers) - responsible for the maturation of T-killers, the activation of the cytotoxic function of macrophages, the secretion of interleukins and other cytokines;

CD8 (T-suppressors) - inducers that inhibit the immune response (inhibit the production of antibodies due to a delay in the proliferation and differentiation of B-lymphocytes);

CD4/CD8 - immunoregulatory index;

CD20 (B-lymphocytes) - participation in humoral immune reactions, antibody production;

CD16CD56+ (NK-cells - natural killers) - destruction of cells lacking molecules of the major histocompatibility complex on the surface of malignant-quality cells and cells modified by the virus;

CD3 + CD25 + (activated T-lymphocytes) - stimulation of antibody production and cytotoxicity;

CD22+CD25+ (activated B-lymphocytes) - an indicator of the activity of the immune response in autoimmune and atopic inflammation;

CD14 (monocytes, macrophages) - binding of macromolecules in the early stages of inflammation;

CD95 (apoptosis factor) - activity of the apoptotic process;

HLA-DR (activated lymphocytes) - mature T-lymphocytes.

The most frequently noted decrease in the level of CD4 and CD8, an increase in the level and CD95-lymphocytes. Increased suppressor activity of lymphocytes (equivalent to T-autoreactivity of cells), activation of T-killer cells, depression of immunoglobulins G in the blood, but with an increase in intrathecal IgG synthesis and a decrease in the IgG/albumin index quite reliably indicate the activation of the inflammatory process. These indicators form the basis for the choice of treatment regimens for MS in children.

7. Examination of the cerebrospinal fluid with a polymerase chain reaction to detect the DNA of herpes viruses (HSV type 1-2, HHV type 6, CMV, EBV) is necessary not from the point of view of clarifying the etiology of MS, but to determine the correct treatment tactics . According to our data, in 5-7% of cases in children with MS, there is an association with viruses, which requires specific antiviral therapy. A technique for determining the DNA of human polyomavirus 2 (JC virus, JCV) in blood and cerebrospinal fluid has been mastered. This is of great importance for the correct choice of immunomodulatory therapy, given the

the possibility of JCV activation with the development of progressive multifocal leukoencephalopathy.

The treatment of MS is a complex and sequential process, the stages of which are:

1) timely detection of the disease in the early stages and the establishment of a reliable diagnosis of MS;

2) relief of exacerbations with corticosteroids;

3) prevention of exacerbations with the help of modern immunomodulators (prolonged modified therapy);

4) conducting symptomatic therapy and rehabilitation.

Therapy for the debut and exacerbation of MS in children

When DNA of herpes viruses is detected in the cerebrospinal fluid and/or blood by polymerase chain reaction (HSV type 1-2, HHV type 6, CMV, EBV) at the stage of MS diagnosis, it is advisable to conduct an intravenous course of acyclovir in a single dose of 10 mg / kg (no more than 250 mg) 3 times a day for 5-7 days.

At the onset of MS or an exacerbation of the disease, solu-medrol (methylprednisolone) 10–20 mg/kg (not more than 1000 mg) is administered intravenously every other day No. 3–5 in combination with plasmapheresis (2–3 procedures), especially when a high level of circulating immune complexes in the blood and increased BBB permeability. In case of incomplete restoration of functions, a transition to oral administration of corticosteroids (metipred, medrol) 16-24 mg with a gradual decrease in dose or a course of synactena-depot (0.5-1.0 mg intramuscularly 1 time per week No. 8, then 1 once every 2 weeks No. 4).

Acelizin is used at 0.5-1.0 g intramuscularly 1 time per day No. 5-7 (it reduces the production of prostaglandins and stimulates the synthesis of anti-inflammatory interleukins).

Intravenous immunoglobulins (IVIG) are used to treat MS patients. IVIG is a 100% biological blood product and is a fairly safe therapy approved for use in children.

Several mechanisms of IVIG action in autoimmune diseases have been described: suppression of the complement system; inhibition of the production of pro-inflammatory cytokines by monocytes; stimulation of the production of anti-inflammatory cytokines by monocytes and macrophages; binding to antibodies to self-antigens and their blocking; a decrease in the production of autoantibodies (as a result of the binding of anti-idiotypic antibodies contained in IVIG to antigenic determinants and immunoglobulins G and M on B-lymphocytes); induction of apoptosis in B and T cell lines; inhibition of superantigen-mediated activation of T-cells. IVIG also contains antibodies to variable and stable regions.

CD4, which determines the immunoregulatory effect of the drug. IVIG suppresses the autoimmune process in MS by inhibiting overactivated complement, stimulates anti-inflammatory interleukins, suppresses antibodies to AMDA receptors, reduces the activity of the cytokine TNF, and stimulates the proliferation of oligodendrocytes that enhance myelin production. To date, several randomized placebo-controlled studies have been conducted to evaluate the ability of IVIG to prevent exacerbations, disease progression, reduce MRI activity in various types of MS, as well as the ability of IVIG to stimulate remyelination in the CNS and restore lost functions in multiple sclerosis. It was shown that the frequency of exacerbations of MS with IVIG was reduced by 48-63% compared with placebo. Patients with a clinically isolated syndrome at high risk of developing MS who received IVIG for a year had a 64% reduction in the likelihood of developing significant MS. IVIG has been shown to be effective in relapsing-remitting MS (class I evidence).

Studies have been conducted on MRI changes in patients treated with IVIG. It has been shown to reduce the number of new and active lesions, slow the increase in the volume of lesions, slow the atrophy of the medulla in patients treated with IVIG, compared with placebo.

According to the guidelines of the European Federation of Neurological Sciences, IVIG is recommended as 2nd or 3rd line of therapy in patients with relapsing-remitting MS who are intolerant to other therapy, as well as during pregnancy and lactation, when no other approved therapy exists. IVIG remains the only approved drug for the treatment of MS during pregnancy and lactation. The protocol of standards of care for patients with MS in Russia includes the course use of IVIG (class II evidence). It is recommended to administer the drug once a month (dose 0.15-0.4 g/kg) for 2 or more years.

For the treatment of our patients, we use Ukrainian-made immunoglobulin for intravenous administration (manufactured by Biopharma, Kyiv) - bioven-mono (5% solution) or bioven (10% solution). The drug is administered at a dose of 0.4 g/kg every other day No. 3-5 (depending on the severity of MS), followed by a repetition of the course after 3-6 months.

The use of IVIG is an alternative to long-term immunomodulatory therapy with interferon-beta and glatiramer acetate.

Treatment regimens for children with MS at the onset of the disease and during exacerbations:

1. With moderate severity of exacerbation:

Pulse therapy (solu-medrol or methylprednisolone 500-1000 mg intravenously every other day No. 3-5).

2. In severe exacerbation with pronounced changes in the immunogram in combination with a high level of CEC:

Pulse therapy + plasmapheresis (2-3 procedures every other day)

Pulse therapy + plasmapheresis + intravenous administration of immunoglobulin 0.4 g/kg every other day No. 3-5.

3. In severe exacerbation with changes in the immunogram and an unexpressed increase in the CEC level):

Pulse therapy + intravenous immunoglobulin.

In the initial stages of MS, the next exacerbation of the disease is especially difficult to predict, especially in childhood. It is for this reason that the immediate and long-term prognosis of the disease is difficult. The most informative indicator of the prognosis of MS are the features of the course of the disease in the first 3-5 years, as well as the effectiveness of the treatment. According to the literature, among adults, a benign course of the disease with rare exacerbations is observed in 20% of patients, a relapsing course with frequent exacerbations - in 30%, a progressive course - in 50%. Mortality 25 years after the onset of the disease ranges from 15 to 26%. Information on the incidence of mild and severe MS in children is extremely controversial. But at the same time, severe MS in children is becoming more common. According to our data, a severe course of MS with frequent exacerbations and the rapid formation of a persistent neurological deficit in children is observed in 25% of cases, and the transformation of a remitting into a secondary progressive course in the first 2 years of the disease is observed in 13% of patients.

Today, a neurologist has a number of modern immunomodulatory drugs that can change the course of MS: reduce the frequency of exacerbations, slow down the growth of disability and prevent premature death. However, it has not yet been possible to radically solve the problem of treating this serious disease. Unfortunately, this is hindered by the insufficiently studied issue of early establishment of a reliable diagnosis and treatment of children with MS. Currently registered drugs for the treatment of patients with MS are not always effective and are not without side effects.

The main principle of therapy for patients with MS today is considered to be the early appointment of immunomodulators to prevent exacerbations, stabilize the condition, prevent transformation into a progressive course and slow down the increase in disability. To this end, it is currently generally accepted for the treatment of both adult patients and children is the appointment of interferons-beta-1b (Betaferon, Betfer-1b), interferons-beta-1a (Rebif, Avonex, Betfer-1a) and glatiramer acetate (Copaxone , glatimer) (Table 4).

Table 4. Drugs for immunomodulating therapy in patients with MS

IFN-ßnb (betaferon) 8 million IU 16 ml IU Every other day, subcutaneously

IFN-|-1a (rebif) 22 mcg (6 million IU) 44 mcg (12 million IU) 3 times a week, subcutaneously

IFN-|-1a (avonex) 6 million IU once a week, intramuscularly

Glatiramer acetate (Copaxone) 20 mg daily, subcutaneously

The main mechanisms of action of P-interferons (Betaferon, Rebif, Avonex):

Inhibition and modulation of the activity of the cytokine gamma-interferon (the main pro-inflammatory cytokine that contributes to the occurrence of exacerbations of MS);

Inhibition of co-stimulation molecules required to activate T-lymphocytes and enhance apoptosis of autoreactive T-lymphocytes;

Increased suppressor activity of T-lymphocytes;

Decreased expression of major histocompatibility complex molecules on antigen-presenting cells;

Blockade of matrix metalloprotease and adhesion molecules, which prevents the penetration of activated cells into the brain tissue through the blood-brain barrier.

Such an immunomodulatory effect makes it possible to weaken the action of antibodies to the main components of myelin, which ultimately reduces the activity of the inflammatory process in MS.

The main mechanisms of action of glatiramer acetate (a standardized mixture of synthetic peptides of four amino acids: L-alanine, L-glutamine, L-lysine, L-tyrosine):

Formation of a close connection with the trimolecular complex of membranes of antigen-presenting cells with the formation of a false target for T-lymphocytes;

Proliferation of specific T cells that suppress the activity of other autoaggressive cell lines and are able to penetrate the blood-brain barrier and create background suppression;

Apoptosis of activated T1 lymphocytes;

Suppression of the pro-inflammatory effect of y-IFN and IL-2;

Stimulation of the production of neurotrophic factors (neuroprotective effect).

A number of randomized multicenter studies have been conducted to study the efficacy and safety of immunomodulatory drugs in adults: BEYOND, BENEFIT, BECOME, EVIDENCE, INCOMIN, OVIMS, REGARD, BICC. In the clinic of nervous diseases DonNMU in 2001-2003. Betaferon was clinically tested in young people, including children. The results were obtained, indicating a good tolerability of the drug.

Over the past 6 years, 24 children under our supervision received immunomodulatory therapy:

Interferon-beta-1b (betaferon) - 10 patients;

Interferon-beta-1a (rebif, avonex) - 6 children;

Glatiramer acetate (Copaxone) - 8 patients.

A positive effect was noted in the form of lengthening

remissions, satisfactory tolerability of therapy. Only in 1 patient out of 10 treated with betaferon, it became necessary to discontinue the drug due to an adverse reaction (cardiopathy). Due to an allergic reaction to Copaxone, immunomodulatory therapy was canceled in 2 children. In 6 patients (25%), despite the use of immunomodulators, the disease acquired a secondary progressive character. For the rest of the patients, immunomodulatory therapy was continued even after their transition to the adult category of patients.

Two children in whom immunomodulators were canceled due to the transformation of the course of MS from relapsing to secondary progressive, received courses of immunostatic therapy with mitoxantrone (12 mg/m2 body intravenously):

In 1 child (girl 17 years old) there was a temporary deterioration in the condition (up to 2 months) with subsequent stabilization;

The second patient (a 16-year-old girl) is in stable remission with a decrease in neurological deficit.

Based on literature data and our own experience, we consider it expedient to prescribe immunomodulatory therapy in childhood only after a reliable diagnosis of MS has been established and a preliminary thorough physical examination has been made. We have found that starting therapy with minimal doses and slower (than in adults) dose titration provide better tolerability of immunomodulatory drugs.

Recently, a number of new drugs have appeared for the treatment of patients with MS: tysabri (natalizumab), rituximab, alemtuzumab, teriflunomide, fingolimod (Gilenia), laquinimod, BG12. Testing of these drugs in children with MS is just beginning. And in adults, when using these drugs, not only side effects were recorded, but also a serious deterioration in health. In particular, the development of progressive multifocal leukoencephalopathy due to the activation of human polyomavirus 2 (JC virus) against the background of a decrease in immunity has been described during treatment with natalizumab.

Table 5. Symptomatic therapy in MS

Clinical symptoms Therapy

Spasticity (Rdalud, baclofen, valproates (depakin, convulsofin, convulex), glycine Dysport (with severe spasticity) Therapeutic exercises

Urgency, Urinary Incontinence and Urinary Incontinence Oxybutin (driptan, sibutin) Adiuretin SD Pelvic floor muscle training

Difficulty urinating Galantamine, Neuromidin Magnetic and electrical stimulation of the bladder

Ataxia and tremor Milgamma, magne-B6, glycine, tenoten, cognum Carbamazepine Therapeutic gymnastics

Dizziness Betaserc, Phezam, Thiocetam

Syndrome of intracranial hypertension Diacarb, glycerin, L-lysine aescinate

Chronic fatigue syndrome, neurosis-like conditions, cognitive impairment Semax, adaptol, noofen, glycine, stimol, gamalate-B6 Kognum

The registration of movectro (cladibrine) was canceled due to cases of cancer in patients receiving this drug.

After stopping the exacerbation, neuroprotective therapy (semax, thiocetam, cerebrolysine), essentiale, nucleo CMF forte (keltikan), treatment with nicotinamide, lipoic acid, cytoflavin, carnitine chloride (carniel, agvantar, elcar) is carried out. Taking into account the emotional and cognitive impairments typical for children with MS, the need for injecting drugs (which creates an additional stressful situation for the child), drugs that combine nootropic and sedative effects, hopantenic acid preparations (kognum), have recently been widely used. They have a nootropic and anticonvulsant effect, increase the brain's resistance to hypoxia and the effects of toxic substances, stimulate anabolic processes in neurons, combine a sedative effect with a mild stimulating effect, reduce the manifestations of extrapyramidal disorders and neurogenic urinary disorders.

Symptomatic therapy is presented in table. 5.

The accumulated long-term experience of the employees of the Donetsk National Medical University named after I.I. M. Gorky for the diagnosis and treatment of children with MS and other demyelinating diseases made it possible to organize in 2011 on the basis of the neurological department of the regional children's clinical hospital the Center for Demyelinating and Degenerative Diseases of the Nervous System in Children. The goal of the center is to provide timely diagnosis and improve the quality of treatment for children with demyelinating and degenerative diseases of the nervous system.

The center provides specialized assistance to children with multiple sclerosis, multiple

encephalomyelitis and other forms of acute, subacute and chronic disseminated demyelination; demyelinating polyradiculoneuropathy; hereditary neuropathies; myasthenia gravis; hereditary ataxias; degenerative diseases with extrapyramidal disorders (including the juvenile form of Parkinson's disease, dystonia), spinal cerebellar degeneration and other degenerative diseases of the nervous system.

For the diagnosis of these diseases in the Center, in addition to clinical, instrumental and laboratory examination methods are used:

MRI of the brain and spinal cord with intravenous contrast (Gyroscan Intera T10, Holland);

Study of visual evoked potentials for reversal of the chess pattern (computer diagnostic complex "Expert", Tredex, Ukraine);

Study of long-latency cognitive potentials to a significant stimulus (computer diagnostic complex "Expert", Tredex, Ukraine);

Electroencephalography (Tredex device, Ukraine) and electroencephalographic monitoring during wakefulness and sleep (Axon M device, Ukraine);

Electroneuromyography (device "Neuro-MVP-micro", Russia);

Transcranial magnetic stimulation;

Studies of cellular and humoral immunity (CSTO laboratories, New Diagnostics, Diagnostic Pasteur);

Examination of cerebrospinal fluid with a polymerase chain reaction to detect DNA of cytomegalovirus, Epstein-Barr virus, herpesvirus types 1-2 and 6, JC virus (JCV, human polyomavirus type 2) and Rubella virus RNA (laboratory "New diagnostics”, “Diagnostic Pa-

erased"). In 2013, for the first time in Ukraine, the methodology for determining JCV was mastered;

The study of the permeability of the blood-brain barrier: the level of albumin, immunoglobulin G, intrathecal IgG synthesis index (Laboratory "New Diagnostics").

A register of children in the Donetsk region with reliable MS, as well as children being observed for probable MS, has been created. Since its foundation, 33 children with reliable MS have been under observation in the center.

In the treatment of demyelinating diseases, in addition to pulse therapy, plasmapheresis and intravenous immunoglobulin (bioven mono, bioven) are widely used. Treatment regimens with intravenous immunoglobulin have been developed with a course repeated after 3-6 months. The technique of immunomodulating therapy in the treatment of children with MS has been mastered using all groups of immunomodulators: interferons-beta-1a (rebif, betabioferon-1a, betfer-1a, Avonex), interferons-beta-1b (betaferon, betabioferon-1c, betferon 1c, P-interferon-1c), glatiramer acetate (copaxone, glatimer), including titration of drug doses and relief of exacerbations against the background of ongoing continuous immunomodulatory therapy.

The work of the center makes it possible to carry out early diagnosis of demyelinating and degenerative diseases of the nervous system in children, to introduce new modern methods of treatment, which makes it possible to achieve a better effect of the therapy, longer remissions, delay and sometimes prevent disability in children with this severe neurological pathology.

We consider it necessary to introduce educational programs to train pediatric neurologists in the diagnosis of reliable multiple sclerosis and methods of treatment of children with MS. Such training is carried out at the thematic advanced training courses for doctors, seminars are held for general practitioners and pediatric neurologists at the Center for Demyelinating Diseases. We also consider it extremely important to allocate state budget funds for examination (magnetic resonance imaging with the use of contrast agents, immunological studies, detection of virus DNA in the blood and cerebrospinal fluid) and treatment of these patients, including not only interferons-beta and glatiramer acetate, but and intravenous immunoglobulin.

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Received 01/04/15 ■

Svtushenko S.K.1, Moskalenko M.A.2, Svtushenko 1.S.3

1 Kharkov medical academy!

2 Regional center for dem1el!

3 DonNMU 1m. M. Gorky

VGD CL|N|CHNO ¡ZOLOVANOY SYNDROME TO V|ROG1DNOT DIAGNOSIS OF ROS1YAN SCLEROSIS AND YOGO EFFECTIVENESS OF THERAPYT IN CHILDREN

Summary. At the stats, the results of the 30th anniversary of the early diagnosis of pink sclerosis in the second half of the century were recorded, magnetically resonant! tomografp, zorovih i kogshtivnyh vy-klikanyh potenschalsh, biochemical and immunological effects of blood and spinal cord! crack. The authors described a variant of the debut of this important curable roiling sickness in children. A therapy scheme has been devised to include pulse therapy with solu-medrol, plasmapheresis and intravenous 1-munoglobulin, as well as additional immunomodulator stagnation in days.

Key words: research sclerosis, children, diagnostics, l1ku-bath.

Yevtushenko S.K.1, Moskalenko M.A.2, Yevtushenko I.S.3

1 Kharkiv Medical Academy of Postgraduate Education, Kharkiv

2 Regional Center of Demyelinating Diseases, Donetsk, Ukraine

3 Donetsk National Medical University named after M. Horkyi, Donetsk

FROM CLINICALLY ISOLATED SYNDROME TO ACCURATE DIAGNOSIS OF MULTIPLE SCLEROSIS AND ITS EFFECTIVE THERAPY IN CHILDREN

summary. The results of 30-year experience in the early diagnosis of multiple sclerosis in children using magnetic resonance imaging, visual and cognitive evoked potentials, biochemical and immunological studies of the blood and cerebrospinal fluid are described in the article. Different variants of the onset of this hard to treat, disabling disease in children are described by the authors. The schemes of therapy, including solu-medrol pulse therapy, plasmapheresis and intravenous immunoglobulin, as well as the experience ofusing immunomodulators in children, were specified.

Key words: multiple sclerosis, children, diagnosis, treatment.