E.E. Edelstein, E.S. Bondarenko, L.I. Bykova

Perinatal encephalopathies (PNE) include cerebral damage occurring from 28 weeks gestation to 7 day of life when the fetus or neonate have uniform physiological reactions and increased vulnerability. This is especially true for the central nervous system. The perinatal period includes:

• antenatal period (28^th wk to delivery) which corresponds to late fetogenesis and when fetus is viable extra uterus whenever delivery occurs (premature, mature, postmature)
• intranatal period, i.e. the delivery itself
• early neonatal period (first week of life)

According to B.N. Klosovski (1949-1960) embryo and fetus undergo 3 stages of brain formation and development:

• liquor stage (2-3 month of pregnancy)
• liquor-blood stage (4-5 month)
• blood stage (starting since 6^th month)
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It is shown that saturation of brain with oxygen is growing along with increasing of the role of RBC and Hb. Since 6 month of pregnancy when blood supply to brain prevails the fetus easily becomes hypoxic. Intrauterine hypoxia can be subdivided into 4 types:

• hypoxic hypoxia which develops because of insufficient oxygen saturation (the most frequent cause is placental abnormality)
• hemic hypoxia develops due to low Hb in blood and as a consequence – low tissue oxygen
• circulatory hypoxia – due to slow circulation
• tissue hypoxia which develops because of enzyme insufficiency and pathology of oxygenation

Intrauterine hypoxia (IH) is a nonspecific symptom of any late toxemia of pregnancy. Chronicity and degree of IH is determined by severity of gestosis and extragenital diseases of mother. It is known that brain is very sensitive to the lack of oxygen. Antenatal hypoxia leads to retardation of growth of brain capillaries, increases their permeability and fragility. Cell membrane permeability also increases. Metabolic acidosis develops. The result is ischemia of the brain, intracellular acidosis and cell death. Neonatal asphyxia is lack of oxygen during labor, i.e. hypoxia plus hypercapnia. Primary asphyxia is encountered is 5% of cases. Hypoxia and asphyxia impair brain circulation. One of the causes of hypoxia or asphyxia is functional immaturity of respiratory center or fetal respiratory movements with amniotic fluid aspiration. Fetus and neonatal are relatively resistant to hypoxia because of anaerobic glucolysis. When pronounced lack of oxygen is present disadaptation develops; and impairment of metabolism and structural changes of the brain, especially of the brain cortex takes place.

In asphyxia the brain and other organs are overfilled by blood. According to Yakunin (1981), hypoxia, in contrast to intracranial delivery trauma, is characterized by temporal vein hemorrhage, subependimar and subarachnoidal hemorrhages. Microscopic picture reflects duration of ante- and intranatal hypoxia. For example, intranatal hypoxia for 15-20 min causes structural reversible changes characterized by perivascular and pericellular swelling and diapedic petechiae. Long standing hypoxia causes dystrophy of neurons, proliferation of glia, sclerosis, and cyst formation at the place of necrotic brain tissue. Destruction is noted in the cortex (especially in the upper low differentiated layers), optic thalamus and subcortical nuclei. Premature infants have diffuse dystrophic changes and proliferation of glia along with marked prematurity of cerebral structures: low differentiation of cortex layers and undeveloped sulci. Children who die at an older age with history of perinatal hypoxia (asphyxia) have “empty neuronal fields” in their brain or calcifications, porencephaly, and local gliosis. Experimental works by T.P Zhukova (1984) described morphology of brain after IH (primary influence of hypoxia causing pathology of general and brain circulation and their reparation. The final result is the progressive atrophic changes of the brain).

Clinical picture of hypoxic pahtology of CNS is divided into 3 periods: acute period (first month of life), rehabilitation period (1month-1 year of life, up to 2 years in premature children), and final period.

In the acute period patient's condition is further divided by severity: mild (transient pathology of blood and CSF circulation), moderate (swelling and hemorrhages), and severe (generalized brain swelling and hemorrhages (subarachnoid hemorrhages are the most prevalent). Apgar score is used to estimate the severity of impairment of brain circulation.

Five clinical syndromes are known to occur in the acute period: increased neuro-reflectory excitation, hypertension-hydrocephalic, inhibition syndrome, and comatose syndrome. Usually, a mixture of syndromes is observed. Acute period is characterized by predominance of generalized cerebral abnormalities without pronounced local symptoms. For mild form of pathology (Apgar 6-7), increased neuro-reflectory excitation is the most characteristic. This syndrome mainly manifests as an increased spontaneous motor activity, superficial sleep, prolonged period of awakeness, difficulty falling asleep, frequent, non motivated crying, brisk congenital reflexes, muscular dystony, brisk patellar reflexes, limb and jaw tremor. Our results show that increased neuro-reflectory excitation syndrome (especially in premature newborns) is a clinical manifestation of decreased seizure threshold in 94% of cases. EEG demonstrating paroxysmal changes proves this fact. Patients who have low threshold of seizures are at risk of developing seizures and should be followed closely. According to our data, seizures develop in 20% of patients from this group.

The above-mentioned signs can as well signify intracranial hypertension, which is often the most important patogenetical factor in developing increased neuro-reflectory excitation syndrome.

Moderate severity form (Apgar 4-6) is manifested by hypertension-hydrocephalic and inhibition syndromes.

Hypertension-hydrocephalic syndrome is characterized by increased head (or thorax) size by 1-2 cm compared to normal, open sagittal suture (more than 0.5 cm), increased large fontanel (more than 3x3 cm). The following is also characteristic: brachicephaly with prominent frontal tubercules, or dolichocephaly with prominent occiput, Grefe's sign, sunset sign, intermittent horizontal nystagmus, bilateral esotropia, muscular dystony (more in the distal parts of the limbs: "seal's paws" sign). The majority of children especially in the first days of their lives the above signs are associated with paroxysm of shuddering, spontaneous Moro's reflex, impaired sleep, paroxysmal Arlekin's sign, general and local cyanosis. Hypertension-hydrocephalic syndrome can be seen alone or in combination with inhibition syndrome, and comatose syndromes.

Inhibition syndrome is manifested by flabbiness, decreased spontaneous activity, and generalized muscle hypotonia, hyporeflexia, inhibited neonatal reflexes, decreased reflex sucking and swallowing. All symptoms last for 7-14 days. At the same time excitation or even brief seizures can occur. Local signs are observed: exo- or enophoria, nystagmus, asymmetry and relaxation of lower jaw, asymmetry of facial muscles, bulbar or pseudobulbar signs. This syndrome occurs within acute period and disappears after 1 month of life. If muscle hypotonia persists more than 10-12 days the physician should suspect other processes (especially congenital neuro-muscular diseases).

Inhibition or comatose syndromes usually accompany seizure syndrome in acute period. Seizure syndrome develops as a result of intracranial hemorrhages or metabolic processes (hypoglycemia, hypoMg-emia, etc). This syndrome is manifested in the first day of life by tonic-clonic or tonic seizures. Sometimes localized clonic seizures or hemiconvulsions are observed as well. Seizures in newborns last for a short time, start abruptly, reoccur chaotically (independent of sleep or awakeness, feeding pattern or other factors). Seizures can take form of low-amplitude tremor, short periods of apnea, tonic spasm of eyeballs (upper gaze paresis), simulation of sunset syndrome, nystagmus, automated chewing, paroxysmal feet clonuses, paroxysmal vasomotor reactions. Sometimes these seizures resemble spontaneous movements making the diagnosis difficult.

Comatose syndrome (Apgar 1-4). Clinically it presents with flabbiness, adynamy, muscle hypotony/atony, absence of congenital reflexes, narrow pupils, no or weak reaction to light, no reaction to pain, floating eye balls, horizontal or vertical nystagmus, inhibition of tendon reflexes, irregular breathing, frequent apnea, bradycardia, distant heart sounds. BP is low. Pulse is irregular. Seizures can recur with tonic predominance. Critical condition lasts for 10-15 days, suction and swallowing reflexes are absent. All this changes are consequences of brain swelling and hemorrhage that is why during first 10-12 days acute hydrocephalic develops: tense major fontanel, separation of skull sutures, protrusion of eye balls, fast growing head.

Rehabilitation period includes the following: increased neuro-reflectory excitation syndrome, hypertension-hydrocephalic, vegetation dysfunction syndrome, motor dysfunction syndrome, psychomotor development delay, and epileptic syndrome.

Increased neuro-reflectory excitation syndrome in the rehabilitation period can progress in 2 ways. If patient recovers symptoms of increased neuro-reflectory excitation decrease or disappear 4-6 month to 1 year or minimal brain dysfunction and asthenoneurotic syndrome develops after 1 year. Independent of age, especially if patient has repeated somatic diseases, epileptic syndrome can develop.

Hypertension-hydrocephalic syndrome has several variants of progression: a) Hypertension-hydrocephalic syndrome with favorable progression (disappearance of hypertension and delay of hydrocephalus); b) Unfavorable progression when hypertension-hydrocephalic syndrome is a part of organic cerebral defect. Echo-EG shows sustained progression of hypertension.

Hypertension-hydrocephalic syndrome can have the following ways of development:

1. Rapid disappearance of signs of intracranial hypertension, normalization of head growth with resulting minimal brain dysfunction; 2) Deterioration when hypertension-hydrocephalic syndrome is a part of organic (structural?) cerebral defect. Echo-CG shows a sustained progressing hypertension.

Hypertension-hydrocephalic syndrome can result in the following outcomes: 1) Rapid disappearance of signs of inctracranial hypertension leading to transformation into minimal (or, rarely, absent) brain dysfunction within 5-6 month of life; 2) Gradient disappearance of signs of inctracranial hypertension leading to transformation into compensated hydrocephalic syndrome by the end of first year of life; 3) progression of intracranial hypertension, separation of cranial sutures, and hydrocephalus. All the above symptoms are frequently accompanied by low seizures threshold.

Vegetovisceral dysfunction syndrome. Usually this syndrome develops at 1-1.5 month along with increased neuro-reflectory excitation and hypertension-hydrocephalic syndromes. Clinically it manifests as frequent spit-ups, persistent hypotrophy, irregular breathing and apnea, skin color changes, acrocyanosis, paroxysmal tachi- and bradypnoe, abnormalities of thermoregulation, gastro-intestinal dysfunction, temporal balding. Cerebral hypotrophy can be the most persistent sign.

Epileptic syndrome can develop at any age (as a sequence of postpartum seizures or after somatic infection). Newborns and infants with this syndrome have an “age face” i.e. paroxysm of seizures simulate movements that child already can perform.

In newborns (especially premature ones) and in infants seizure syndrome has many clinical forms: generalized seizure attacks (tonic-clonic, clonic, tonic), aborted, focal, vegetation, hemiconvulsions, and polymorphous, simple and complex absences. The most common are polymorphous seizures. According to our data premature children with perinatal CNS pathology propulsion and impulse paroxysms are not seen as a single form but rather observed as a part of polymorphous seizures. The most difficult to diagnose are abortive and nonseizure attacks.

Seizures simulate congenital motor reflexes: paroxysm of symmetrical tonic neck reflex with head bending and tonic contraction of arms and legs, asymmetrical tonic neck reflexes with head turning to the side and ipsilateral extension of arm and leg, first phase of Moro’s reflex with finger extension. Sometimes paroxysms of glance paresis with nystagmus and sunset symptom are seen. Attacks of redness or paleness with sweating or spit-ups are not infrequent. After 3-4 month of life when child is able to hold his head “nods” are seen, since 6-7 month “bends” can be detected. Characteristic features of seizures in premature children such as instability of clinical picture with polymorphous seizures predominance, abortive attacks, complex absences with simulation of congenital reflexes (first phase of Moro’s reflex, asymmetric clonic neck reflex) are all can be explained as a consequence of immaturity of brain structure. Increased frequency of attacks, increase of polymorphous symptoms, resistance to anti-seizure treatment should rise suspicion for forming organic pathology of CNS and indicates a poor prognosis.

Motor abnormality syndrome develops since first several weeks of life. It can manifest by muscle hypotonus or hypertonus. Muscular hypotonus causes decreased spontaneous motor activity, inhibited tendon reflexes and congenital reflexes. Motor abnormality syndrome with hypotonus can be seen alone or in combination with hypertonus-hypdocephalic syndrome, increased neuro-reflectory excitation syndrome with low seizure threshold. This syndrome has particularly unfavorable prognosis in combination with seizure syndrome.

Progression of muscle hypertonus in mature children, lateralization of symptoms should rise suspicion for possible development of cerebral palsy.

Psychomotor development delay syndrome becomes evident since 1-2 month by persistence of congenital reflexes. Symmetrical and asymmetrical tonic neck reflexes, early detection of reflex-canceling positions, delay in development of extension labyrinth chain reflexes is of diagnostic value. If psychological delay is more pronounced than the motor component one-month-old children have problems with eye fixation, which is easily fatigued. They do not react to mother’s voice, do not concentrate on sounds. When these children 2-3 month old they do not excite enough when in contact with someone, they cry expressionless, they do not vocalize, when they search for the source of sound they do not turn their heads, it is difficult to make them smile. Six month: decreased interest in toys and surroundings, not active when mother is present, vocalization is not active, delayed manipulation of objects, no active attention. If the developmental delay is темповая it begins to disappear if childcare is adequate. This group of children at the age of 4-5 month rapidly becomes more active, and their psychological development outpaces the motor one. They start to react emotionally to other people, become interested in toys.

Motor function starts to compensate after 6-7 month and is usually normal to 1-1.yaer. Long delay of psychological development signifies a poorer prognosis.

Diagnosis of hypoxic changes of the brain is based on the clinical picture and consideration of pregnancy and delivery course. It is important to analyze risk factors that can cause ante- and intranatal hypoxia: a) chronic diseases in mother (CVS, respiratory, liver, kidneys, diabetes, epilepsy, etc.) and occupational risks; b) complicated pregnancy (late toxemia, polyamnious, morphofunctional placental insufficiency, postterm, acute illnesses); c) pathological delivery (too long or too fast delivery, prolong (more than 6 hours) latent period, placenta previa, obstetric operations or assisted delivery). Clinical signs favoring the diagnosis of hypoxia are prenatal hypoxia and functional immaturity of adaptation mechanisms of fetus and newborn.

The diagnosis is made in the obstetrics clinic on the basis of classification of perinatal period and includes etiology (hypoxia, asphyxia), degree of severity (mild to severe) and neurological syndrome (or combination of syndromes).

There are 3 degrees of severity of impairment of cerebral circulation, which are identical to severity of acute period. Severity (as well as circulation impairment) is included in diagnosis only in the acute period, i.e. only during first month of life, later it is excluded from the diagnosis. After discharge for outpatient follow up or transfer to the hospital the diagnosis should include "enchephalopathy" with indication of etiology. "Perinatal enchephalopathy" is used only for newborns (it can be used for premature newborns up to 2 years of age). When the child is able to stand, as he develops psychologically, and his speech improves the diagnosis is substituted depending upon the outcomes.

Progression and prognosis. Progression of perinatal hypoxic encephalopathy depends upon the following: 1) degree and duration of antenatal hypoxia; 2) presence of intranatal asphyxia; 3) maturity of brain at the time of delivery; 4) general signs of prematurity in newborn and infant; 5) functional characteristics of homeostasis with immunologic "deficit" of the patient; 6) somatic problems during the first year of life. Combination of the above factors can cause different type of progression and different outcomes. The main factor is intrauterine chronic hypoxia, which can cause the developmental delay or pronounced damage to brain. Premature children delayed psychomotor development is often due to pathology of myelinization without marked damage of the brain tissue. These changes are called "темповая" delay and usually transient. On the other hand immune deficiency with repeated somatic illnesses; prolonged postnatal hypotrophy augments pathology of myelinization and can lead to development of pronounced cerebral pathology with clinical picture of cerebral palsy. Prognosis is determined by severity in the acute period and by combination of syndromes.

Perinatal syndromes are shown in the following Table:

Clinical classification of cerebral syndromes and outcomes in newborns

The diagnosis is confirmed by paraclinical methods. Fundoscopy shows changes. Mild: fundi are normal or more rarely – veins are overfilled. Moderate form: dilatation of veins, swelling, few hemorrhages. Severe form: pronounced swelling and dilatation of vessels, fuzzy disk borders, hemorrhages. Later these changes can progress to ocular atrophy.

CSF: changes are seen when intracranial hemorrhage is present. CFS contains fresh and alkalinized RBC. After 7-10 days of life CFS contains macrophages.

Beside CFS analysis and fundoscopy Echo-CG and skull transillumination are necessary. Both later methods can reveal important information. Echo-CG shows changes: from moderately increased echo-pulsations in mild pathology to ventricule dilatation and broadened M-echo in moderate to severe forms. Transillumination at early stages of hypertension-hydrocephalic syndrome shows diffuse broadening of the light spot to 4-6 cm. Enlightened areas are usually situated asymmetrically. Hypoxic changes are characterized by decreased enlightening at the place of preceding hemorrhage with later transformation into local diffuse enlightening.

For hospitalized patients EEG and reovasography (RVG) are indicated to confirm the diagnosis and select treatment.

EEG is done when patient is naturally or medically put into sleep. To determine the phase of sleep biological monitoring is used (electrooculography, electromyography, ECG, etc.). Evaluation is done during the slow phase of sleep.

In healthy mature and in relatively "healthy" premature children EEG shows alternating curve which later, by one month of age (up to 2 month in prematures) is replaced by delta and teta waves. During the second month of life so-called sleep spindles appear (periodic oscillations in the central areas of spindlesform shape, 12-16 Hz). By 5-6 month during sleep generalized rhythmical oscillations are seen, frequency=3-4 Hz. Frequency grows with age (falling asleep rhythm).

According to our data EEG in prematures with perinatal pathology of CNS shows mild, moderate or severe changes in 98%.

Mild changes in prematures: alternating type of the curve at 2 month in prematurity grade 3-4; absence of sleep spindles at 2 month in prematurity grade 1-2 and at 2-3 month in prematurity grade 3-4, insufficient expression of sleep spindles (short duration, irregularity) at 3 month in prematurity 1-2 and at 4 month in prematurity 3-4, exaltation of sleep spindles, increased polymorphism of EEG, bilateral, synchronous, paroxysmal slow waves.

Moderate changes: general low amplitude waves, alternating curve at 2 month in prematurity 1-2, and at 3 month in prematurity 3-4; absence of sleep spindles at 3 month in prematurity 1-2 and at 4 month at prematurity 3-4; sleep spindles in temporal areas at 4 month in prematurity 1-2 and at 5 month in prematurity 3-4; slowed sleep spindles (frequency less than 12 Hz); absence of organization of beta-rhythm (12-16 Hz) into spindles; absence of spindles in one hemisphere; bilateral specific paroxysmal (epileptic) activity; local asymmetry in the central and frontal areas; interhemisphere asymmetry (low amplitude of potentials, pathological synchronization of cortex rhythms, absence of sleep spindles, epileptic activity in a single focus); focal changes (focal decrease of cortex rhythms, focus of pathological slow wave activity, focus of epileptic activity); diffuse beta-rhythm in stages 3-4 of the slow sleep.

Severe changes: low amplitude curve (>50microV); pathological synchronization of cortex rhythms; absence of sleep spindles at 4 month for immaturity 1-2 and at 5 month in immaturity 3-4; polyfocal epileptic activity; absence of “falling asleep rhythm” at 6 month. Mild changes of EEG signify good prognosis, moderate and severe changes carry poor prognosis. Reliability of prognosis is increased with subsequent follow up EEG, with age, less degree of immaturity. With severe changes of EEG it is common to discover anatomic brain pathology in the first month of life.

EEG is very useful for diagnosis of seizure syndrome and screening for risk group for seizure syndrome. Paroxysmal changes of EEG can be a secondary sign of seizure syndrome and low seizure threshold. Repeated seizures cause an increase in paroxysmal activity.

In acute period REG shows labile tonus of vessels (from mild hypertonus to hypotonus), impaired venous flow, interhemishpere asymmetry.

Biochemical studies in acute period are used to access acidosis (can be from moderate mixed to severe metabolic). Plasma osmotic pressure is increased in severe condition. LDH level is high. LDH and other glycolytic enzymes are in correlation with clinical conditions both in acute and in rehabilitation period.

Outcomes. By one year age in the majority of mature children who developed speech and are able to walk it is possible to determine the outcome of perinatal encephalopathies. Complete recovery is seen in 10-15% of children. Anatomical changes of CNS are reliably diagnosed. The most difficult diagnostic problem are borderline diagnostic conditions (compensated hydrocephalic syndrome, febrile seizures, asthenoneurotic syndrome, minimal brain dysfunction).

Minimal brain dysfunction syndrome is one of the frequent outcomes of PNE. Minimal brain dysfunction is seen with mild pathology of CNS. Neurostatus: diffuse focal and local signs. The most typical is mild paresis of n.hypoglossus – mobility of the tongue is reduced (especially elevation and “making a tube”), moderate dysarthria is not uncommon. Phonation and speech breathing are impaired. Pyramidal insufficiency can be manifested by a variety of signs: hemisyndrome with muscular dystony, brisk tendon reflexes, Babinski persistent after 1 year, hyperkynetic movements (restlessness and hand tremor), mild instability walking. Poor fine movements are the most characteristic.

Psychological changes are absent but speech development delay is present: children can not make phrases until 2-3 yo, vocabulary is limited until 3-4 yo.

One of the most frequent manifestations of minimal dysfunction is motor disturbance. Concentration and fine movements and are poor, children are fuzzy and are constantly moving. Once in while children experience an outburst of anger while being in the state of “hurricane of movements”. In future these children sometimes demonstrate psychotic behavior with psychotic episodes. The above conditions should be differentiated from intellectual insufficiency of different origin. The discussed clinical picture can also be called “hypermotor child syndrome”, or “motor hyperreactivity syndrome”. These children are markedly infantile. Infantilism plus easy distraction and motor disturbance can create problems at school but symptoms usually lessen before the school age especially if appropriate treatment has been instituted. Studying can pose difficulties if speech delay, partial absence of memory and gnostic functions. These problems can be noted only at school at preschool year in the day care.

Patients of this type sometimes can not count and pronounce correctly (voiced versus voiceless consonants: б-п, д-т) and other dyslalias. On the other hand these children are not oligophrenic and with special preparation can study in a regular school.

Minimal dysfunction syndrome is usually a consequence of psychomotor development delay syndrome with some special aspects of motor and psychological changes that are manifested as a “minor neurological signs” (LT Jhurba, EM Mastukova, 1981): motor muscular dystonia, transient hyperkynesises and motor disturbance, delay of development of eye motor coordination and fine finger manipulations; delay of prespeech development and tongue manipulations; newborn reflexes persist, especially oral ones.

Active care during rehabilitation period is the most important for children with minimal brain dysfunction: exercise therapy, skill development with special attention to dystonia and motor asymmetry. Speech specialist care is necessary when children several month old, more than 6 month old and more than 1 year old. Speech specialist helps children to develop good breathing, suction, tongue position, boosts vocalization, during repeated consultations he establishes mental? orientation, playing skills, syllables and phrases.

Compensated hydrocephalic syndrome is characterized by big head at the time of suture closing with normal progression of the head size later (but the head size is increased, i.e. the process is completed already). Major fontanel is completely closed by 1.5 years. Psychomotor and speech development is normal. These patients do not active or prophylactic dehydration treatment. On the other hand when such patient have high fever they can have impairment of CFS circulation manifested by vomiting, headache, and meningeal signs. Also low seizure threshold is characteristic: patients develop seizures with any condition if fever is high (>39 C).

History of febrile seizures is indicative of low seizure threshold and there is a danger of recurrence. That is why such patients need a constant follow up for no less than 3 years, and prophylaxis is necessary when acute somatic illnesses develop, when vaccinations or operations are planned, and in acute period of skull trauma. If seizures recur antiseizure therapy is necessary along with EEG follow up.

In the majority of children (80-95%) febrile seizures have a good prognosis and never recur after 2.5-3 y.o. Pathogenesis includes low seizure threshold and metabolic abnormalities in acute period of illnesses in children with history of PNE.

Astheno-neurotic syndrome is a usual consequence of increased neuro-reflectory excitation and vegetative dysfunction syndromes. It is characterized by a constellation of somatoneurological abnormalities: diathesis *mild eczema or rash involving cheeks * (in 50-60% of children), repeated vomiting (worse with fever, forced feeding, and negative emotions), poor falling asleep pattern, long period of time before children fall asleep. During this period excitement, crying, and irritability are common. Sleep is superficial. Children sometimes start to have nightmares at the age of 1.5-2 y.o. Some children develop enuresis during day- and especially during night sleep. Other signs: increased sweating, acrocyanosis, cold extremities, and diffuse patchy red dermographism. Early development of vasovegetal dystonia (hypotensive type) is common as well as persistent low fever and fatigue during recovering after infectious diseases.

Treatment

Treatment is different for different periods. In the acute period after the initial intensive care pathogenetic therapy plus protective regime (maximal effort to avoid emotional and physical stresses) is used.

1. Metabolic correction and to decrease vessel wall permeability: vicasol (vit K)1% - 0.1 ml/kg; Na ascorbinate (vit C) 5% - 0.1 ml/kg IV or IM; ascorutin (vit C+ rutozid(?)) 0.001 bid; Ca gluconate 10% - 1.0-2.0 ml/kg IV).
2. Improvement of microcirculation, correction of hypotension and hypovolemia: concentrated plasma 5.0-10.0 ml/kg, albumin 10% - 5.0-10.0 ml/kg, reopolyglucin 7.0-10.0 ml/kg, hemodes 7.0-10.0 ml/kg (complex polyglucin solutions).
3. Dehydration: mannitol 20% - 5.0 ml/kg, lasix 1.0 mg/kg, Mg sulfate 25% - 0.2 ml/kg, hydrocortisone 3.0 – 10.0 mg/kg, prednisone 1.0-2.0 mg/kg.
4. Prophylaxis and treatment of seizure syndrome: phenobarbital 0.005 mg/kg, seduxen (diazepam) 1 mg/kg IM or IV, GOMK (gammaamino butirate *analogue of neurotransmitter) 50 mg/kg.
5. Improvement of tissue metabolism (with special attention to nervous tissue): vit. E 5% - 0.1 ml/day, ATP – 10.0 mg/kg, cocarboxylase (oxygenation enzyme) 8 mg/kg, glucose 10.0% - 7.0-10.0 mg/kg IV and PO, glutamic acid 1% - 5.0 tid PO.

In hospital and on out patient basis under pediatrician supervision the treatment should be started since 5-10 day of life on the basis of clinical picture:

1. Increased neuro-reflectory excitation syndrome especially with visceral dysfunctions (spit ups, anorexia, poor sleep) sedation is indicated: seduxen 0.001 g (1/5 of tabl.) bid, tazepam 0.001 g (1/10 of tabl.) bid, solution of sodium bromide 0.5% one teaspoon tid, mixture or solution of citrale (herbal med?) 2.0, MsSO4 3.0, glucose 10% - 200.0 – 1 teaspoon tid; since 2 month sedative herbal cocktail can be used 1 teaspoon bid-qid. All medications are used for 2-4 weeks.

Patients who are at risk for the seizure syndrome should receive prophylactic phenobarbital 0.001-0.002 g/kg bid-tid. Phenobarbital can cause rickets that is why vitamin D must be used (for prophylaxis or treatment).

2. Hypertension-hydrocephalic syndrome requires hydration therapy. Children 1 month old are treated with concentrated plasma 5-10 ml/kg (3-5 infusions), triampur and furosemid 0.002 g/kg qd in the morning plus panangin (drug holiday every forth day) for 1 month. Diacarb which is acidogenic and kaliiuric in acute period is indicated only in decompensated progressing hydrocephalus in large doses: 0.08 g (1/3 tab) – 0.12 g (1/2 tab) bid –tid. Since 2 month diacarb is used for active treatment sessions of hypertension-hydrocephalic syndrome 0.02 g/kg qd (drug holiday every forth day) for 2-3 weeks – 1-1.5 month with potassium supplementation.

Also glycerol can be useful: 1 teaspoon tid for 10-15 month. Potassium supplementations should be added to dehydration therapy: potassium acetat 5%, panangin, asparkam. Citrale demonstrates mild dehydrative effect (1 teaspoon tid for 1 month) and euphyllin (aminophylline) 0.003-0.005 u qd-bid for 1 month.

Since 6-10 day vit. B6 1% - 0.5 ml IM (or pyridoxine 0.01 g tid) and glutamic acid are indicated.

Children with early diathesis should receive pyridoxal phosphate 0.0025 h (1/4 tab) qd-bid for 1-2 month.

3. Motor dysfunction syndrome, especially if hypotrophy is present warrants the following: ATP 0.5 ml and cocarboxylase 25 U IM to improve metabolic processes in the brain and to boost respiratory center function. Later B6 1% - 0.54 ml, B1 6% - 0.2 ml, and glutamic acid should be added.

4. Delay of motor and psychomotor development syndrome: psychostimulants rehabilitation medications are indicated. The treatment usually starts with enchephabol (non-specific brain stimulant), which stimulates phospholipid metabolism: 20 drops of encephabol per kg/d in 2 doses for 1-2 month. Pyracetam (non-psecific brain stimulant), is also used 1 ml IM 15-20 injections or ? tabl (50 mg bid). Ireoidin (?) 0.005 bid.

To treat the present abnormalities the following should be added: trental ? tab qd, complamin (?) 1/6 tab bid since birth, euphyllin since birth and after 1 month 0.005 bid for 1 month.

At 2 month if delay of motor development is present it is more useful to start therapy with cerebrolysin(non-specific brain stimulant), vit B12, and dibasole (smooth musle relaxant). Doses should be individualized because the former two can precipitate seizures.

In children younger than 6 month cerebrolysin is prescribed in a following dose: 0.3 –0.5 ml IM #30. Vit B 12 dose is 50-100 mg #15-20 if no hypochomic anemia is present.

In psychomotor delay aminalon (analogue of GOMK), dose is 0.06 u (no more than ? tab). bid-tid #30-50. Seizures are contraindication for psychostimulators.

In psychomotor delay psychostimulators are used in combinations: a) vit. B12 + vit B6, b) enchephabol + vit B1 + vit B12, c) vit B 1+ vit B 6 + glutamic acid, d) nootropil (piracetam) 30-50 mg/kg in two divided doses. If delay is severe or above combinations are ineffective use the following: aminalon + B12; cerebrolysin B12, B6.

5. Seizure syndrome of the newborns requires active treatment. The basic medication is phenobarbital 0.001-0.002 g/kg bid-tid. If ineffective antiseizure mixture can be tried: phenobarbital, difenin 0.003-0.005, papaverin (smooth muscle relaxant) 0.0005-0.001, borax (?!) 0.3-0.5 g, Ca glucinate 0.05-0.1. The mixture is given bid or tid. In minor or brainstem seizures the mixture should be alternated with radedorm (nitrazepam) 0.0012 qd-bid. Trimetin (? not in the PDR) is not used in newborns. Dehydration therapy is required as well MgS04, diuretics. In no significant effect use convulex (valproic acid) or clonazepam. Prednisone can be also used (2 mg/kg). If metabolic abnormalities or Ca insufficiency is present phenobarbital is substituted for radedorm or clonazepam ? tab bid-tid.

Absorption therapy is indicated if history of intracerebral hemorrhage or inflammation is present. Aloe (herbal medication) and lidasa (lytic enzyme hialuronidase) are indicated. Aloe 0.3-0.5 ml IM is used #12-15. Aloe can be alternated with group B vitamins. Lidasa treatment begins with 2-3 injections 8-16 U SC, then 32 U SC daily or every other day. Contraindications: acute infections.

Massage and exercise therapy should be included in rehabilitation after acute period since 1-1.5 month old. Exercises improve neuro-muscular conduction and metabolism. Contraindications: frequent somatic diseases and frequent seizures.

Speech specialist consultations are indicated in rehabilitation period to stimulate psychic and prespeech development. All above measures should be individualized later depending of the outcome. Borderline conditions (minimal brain dysfunction, hypermotor child syndromes) are treated with sonapax (thiotidazine) + mild sedatives (meprobomat, trioxasine, tazepam).

Asthenoneurotic syndrome: tegretol, bellataminal, aevit (vit A+E) , Ca supplements.

Compensated hydrocephaly does not require treatment. If other acute disease develop diacarb (carbohydrase inhibitor) should be used.

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