RU2153891C2 - Method of treating epilepsy in children - Google Patents

Abstract

FIELD: neurology. SUBSTANCE: circulating blood in amount of 8% is sampled from child. After centrifugation, 100 mg/l adenosine triphosphate and 5-10 mg Relanium are added to cellular suspension and resulting mixture is incubated for 20 min at 37 C, after which it is intravenously injected into patient in dropwise mode. Such procedure is performed 3 times at 2-day intervals. EFFECT: enhanced treatment efficiency and reduced toxic effect of Relanium. 2 tbl, 2 ex

Description

 The proposed method relates to medicine, namely to surgery and treatment of patients with epilepsy in children.

 Epilepsy is a chronic disease of the brain of various etiologies, which is characterized by repeated epipressures resulting from neural discharges, and is accompanied by a variety of clinical and paraclinical symptoms.

 In children, epileptic phenomena are much more common than in adults, which makes up 5 to 7% of children.

 This is due to the anatomical and physiological characteristics of the child’s brain, due to the incompleteness of myelination processes, increased permeability of cerebral vessels, greater hydrophilicity, lability and generalization of excitation, instability of metabolic processes.

 The absence of a tendency to a decrease in the incidence of epilepsy in children, which is the leading one in the structure of pediatric neurological pathology, the progressive course of the disease, leading to personality changes and possible degradation, and often to disability, necessitates the discovery of new methods for a more effective pathogenetic treatment of this disease.

 A known method for the surgical treatment of epilepsy is stereotactic surgery [Karlov V.A. "Therapy of nervous diseases", M. 1996, pp. 492-493], used in the failure of conservative therapy.

 It was not widely used in children due to incomplete formation of the brain, its small size and a significant number of complications. A fundamentally new method of treating epilepsy by surgical implantation of a software neurostimulator on the neck in the neurovascular bundle is also not used in children.

 There is a method of drug treatment of epilepsy, which consists in continuous, long-term (sometimes throughout the patient’s life) administration of anticonvulsants [see V.A. Karlov, "Therapy of nervous diseases", pp. 437, 485-486, M., 1996].

 The duration of anticonvulsant intake is due to the impossibility of completely suppressing the epileptic focus, but only by a decrease in its activity. In addition, it is possible to develop addiction to these drugs with the development of relapses, which necessitates an increase in the dose. Also, these drugs have a number of side effects: nephro- and hepatotoxicity, changes in the blood picture, allergic reactions, visual disturbances, dyspeptic manifestations, central nervous activity disorders (see A.M. Wayne, "Anticonvulsants in psychiatric and neurological practice," p. 54 S-P 1994. see NEWS OF FORMATION AND MEDICINE N4 (147) 1994 Volume 28 p. 73-74.

 A known method of drug treatment is the parenteral use of relanium, which meets two basic principles of the treatment of epilepsy: suppression of the epileptic focus and blocking the activity of the reticular formation. Relanium stimulates specific benzodiazepine receptors located on the cell membrane of neurons in the limbic structures of the brain, hypothalamus, and thalamic nuclei. This leads to sensitization of GABA receptors in relation to this universal inhibitory mediator of the central nervous system. The increased action of GABA on its neurons also causes a decrease in the central nervous system excitability, the threshold of convulsive reactions and the flow of nerve impulses.

 After intravenous administration after 15 min, a therapeutic concentration of the drug with an adequate clinical effect is achieved [see V.A. Karlov, "Therapy of nervous diseases", p. 494, M., 1996].

 However, its use is limited to the treatment of an epileptic seizure, since prolonged use causes a rapid development of addiction and a large number of side effects.

 The closest method is the method of extracorporeal treatment of adult patients. In 1/3 of patients with uncurable epilepsy, a significant effect is achieved by the use of drug treatment enhanced by hemosorption or plasmapheresis [Karlov V.A. "Therapy of nervous diseases." M. 1996, p. 490]. However, the use of hemosorption in children is inhibited by the massive damage to the shaped elements and the difficulty of venous access. And the use of plasmapheresis in children is limited only by the discrete method and therefore less effective than the use of volume plasmapheresis in adults, requires the use of donor plasma or albumin, which increases the risk of blood transfusion complications.

 The objective of the invention is to increase the effectiveness of the treatment of epilepsy in children, taking into account the incomplete development of the nervous system in a child and the impossibility of using surgical and volumetric extracorporeal hemocorrection methods used in adult patients.

This goal is achieved by the fact that relanium at a dose of 5-10 mg (1-2 ml) is administered intravenously in an autologous cell mass after incubation at 37 ^o C in the presence of ATP. The whole cell mass obtained as a result of plasmapheresis from 8% of the circulating blood volume (BCC) of the patient is used, after adding to which ATP in a dose of 1-2 ml (100 mg / ml), depending on the age of the child, macrophage-phagocytic system is activated and capture Relanium cells. This allows you to reduce the toxic effect of Relanium on organs and systems and isolate it from the deactivating effect of the enzyme systems of the body.

The essence of the method is as follows:
1. A child receives 100-200 ml of blood (up to 8% of the volume of circulating blood) with the addition of heparin at a dose of 100 units / kg of body weight.

 2. Centrifugation at 2000 rpm for 15 min followed by plasma removal (centrifugal plasmapheresis).

 3. The introduction into the cell mass of ATP at a dose of 100 μg / ml (1-2 ml) and relanium at a dose of 5-10 mg (single dose).

4. Incubation of the mixture at a temperature of 37 ^o C for 20 minutes with constant shaking of the bottle.

 5. The return of the incubated mixture into the bloodstream of the patient by intravenous drip.

 The course of treatment is usually 3 sessions. The interval between the procedures is two days.

To justify these modes, the following provisions are given:
1. The volume of 8% of the BCC does not cause the patient rheological and hemodynamic disorders, significant changes in biochemical parameters and systemic hemodynamics.

 2. ATP at a dose of 100 μg / ml, added to the cell mass, as shown by us, activates the phagocytic activity of leukocytes, increasing, on average, the number of phagocytic leukocytes by half.

 3. Relanium containing leukocytes, whose chemotaxis is activated by ATP, migrate from the bloodstream to the site of inflammation, thereby carrying out targeted transport of the drug and maintaining therapeutic concentrations in the site of inflammation with a significant reduction in the daily and course dose.

 4. Fractional plasmapheresis helps to improve tissue respiration and increase cellular metabolism, which leads to the restoration of neuron function with the participation of Relanium.

 5. The interval between the procedures was chosen empirically, based on the fact that, based on our experience, the clinical effect of introducing relanium by this method lasts about 48 hours.

The positive effect of the proposed method:
1. Significant suppression of the focus of epileptic activity, and in some cases its complete disappearance according to electroencephalography (EEG).

 2. A significant decrease (two or more times), and in some cases, the abolition of the maintenance daily dose of anticonvulsants.

 3. Reducing the frequency and severity of side effects of drug therapy.

 4. The absence of repeated hospitalizations in the hospital during the year.

 5. Improving the mental status and intellectual development of the child with stabilization in the emotional sphere.

 Checking the claimed technical solution for compliance with its criterion of "significant differences" showed that neither the scientific nor the patent literature revealed a combination of features specified in the claims.

 The proposed technical solution, in our opinion, meets the criterion of "novelty," since in the literature available to us we have not seen reports of using relanium and ATP for incubation in the total cellular mass of blood with subsequent reinfusion in patients with epilepsy.

Example 1. M. Olga for 12 years was admitted with complaints:
1. for frequent, short-term attacks of loss of consciousness, up to 50-60 times a day, accompanied by a torso forward with simultaneous squinting or institution of the eyeballs upwards, attacks last for several seconds. 2. headaches in the frontotemporal region. 3. for increased fatigue, fatigue.

 Anamnesis of Zab: I’ve been sick since December 1990, when attacks for the first time occurred in the form of fading, the head threw back a little, looking up, the attacks lasted 10-15 seconds. For the first time, a neuropathologist visited 91 g in February, was diagnosed with epilepsy, 1/2 t (50 mg) of phenobarbital was prescribed • 3 r / d, was taken for 4 weeks, after which there were seizures: a sharp turn of the body, the girl could go into back side. After a month, tazepam was prescribed at 5 mg • 2 times a day for 3 weeks. In March 1991, she was examined in the city of Kemerovo, 300 mg • 2 times a day, Depokine was prescribed, and 0.1 • 2 times a day gluferal. From June 7 to June 23, she was treated in Prokopyevsk, the neurosurgeon received 20 mg of prednisone per day, chimes, methindole, finlepsin 0.2 • 2 times a day, depakine. Discharged with a sharp deterioration (seizures up to 70 times a day), computed tomography of the brain was done - without pathology. From September 23 to October 22, 91 was treated in a hospital. Suksilep received 1 cap • 2 rvd, tazepam 1/2 • 2 rvd seizures were supervised for 3 days, then reappeared, tremor of the eyelids appeared, in July 92 g received cerebrolysin 10 injections, seizures again, diphenin was added - 2 • 3 rvd, finlepsin 1 t • 3 rvd, in April 93 pitnedan 1 • 2 rvd was appointed. In May, 94 g was an attack of loss of consciousness with convulsions. In July 94, she was again examined by a neurologist in the city of Novokuznetsk, 1 t • 3 rvd was prescribed antilepsin, then 1 t • 3 rvd was administered phenobarbital, and from June 20, 94, the girl received 2 t • 3 rvd finlepsin, antilepsin and phenobarbital .

 Attacks do not stop, the girl learns at home, is inhibited during the day, her memory is reduced, her psyche has changed.

 Neurological status upon admission: rounded head, glottis D> S, pupils equal, pupil reaction to light equal, slight exophthalmos from 2 sides, squint inconsistent from 2 sides, converging more to the left, smoothness of n / g folds to the right, slight the deviation of the tongue to the right, the muscle tone in the arms and legs is evenly reduced, the reflexes are high, rougher in the legs, there are no pathological stop signs. In the Romberg position it is stable, it performs coordinating tests, the test for adiadokhokinesis on the left is a slight miss. Suffers, fine motor skills in the left hand, no meningeal signs, no dysfunction of the pelvic organs.

 The department was examined: a blood immunogram of 1gA-1.83, 1gM-1.12, 1gG-14.09, a phagocytic score of 0.34, HCT test-0.05, CEC - 0.012, and complementary serum activity-52. Blood on RW-neg. Total blood test: lake 4.8, erythrocytes 4.06, hemoglobin - 12.3 g / l, hematocrit-36.7%, ESR-2 mm / h, segm-31%, s / I-1%, lymph -55%, monots-10%, zosin-2%, basoph-1%. Blood sugar 5.0 mmol / L. Biochemical blood tests Na-147, K-4.0, CL-115, TCa-2.55, magnesium-1.32 (mmol / L). Urinalysis: lake-2, nit nit, reaction-5, yellow. epiphany spect-1.0 vp / sp, lake 1-2 in p / sp ECG-sinus rhythm 70 per min, moderate changes in the myocardium of the exchange character. Vascular ultrasonography of blood vessels g / m - High linear blood flow velocity in the carotid arteries, no significant hemodynamic obstacles to blood flow. Asymmetry of speed indicators in intracranial branches of the carotid arteries (D <S). Angioeptic manifestations? The fundus of the optic nerve discs is pale pink, the borders are clear, the vessels are not changed, the macula is without features. EEG - Secondary generalized epiactivity with manifestations of epileptogenesis in the right nape. Cerebral manifestations are organic. FKG-funkts. systole. noise. ECHO KG-sizes and contractility of the heart chambers are normal, valves are structurally and functionally unchanged. EEG from 06.24.96 compared with EEG from 06/07/96 - dynamics pos.

 Treatment: during the 1st week, anticonvulsant therapy was changed: the girl was transferred to filepsin (0.4 per day) and apilepsin (1350 mg per day) - the number of seizures decreased to 40-45 per day. Since the 2nd week, the girl had 3 PCM sessions with Relanium (2.0 each) - treatment was carried out every other day. The day after 1 session, the girl notes an improvement in well-being (headaches less frequently during the day, became more active), the number of attacks sharply decreased to 8-10. Over the next 4-5 days, the number of seizures decreased to 2-3 per day, a dose reduction of anticonvulsants began. Discharged on day 17 at a maintenance dose: finlepsin 0.2 per day, apilepsin 1050 mg per day in 3 divided doses. There are no bouts at discharge. Headaches disappeared, drowsiness, lethargy was not noted. On the EEG, there is a positive dynamics (cerebral manifestations, compensated by neurodynamics). The epileptic focus remains, but there is no generalization of epi-activity. After 1.5 months. - There were no attacks, headaches do not bother. ON EEG - without negative dynamics.

 Example 2. T. Sergey, 14 years old, was in DO1 GNKTS OZSH with DS: Epilepsy like Jackson.

 The boy entered with complaints of bouts of muscle cramps in his left arm, leg and left side of his face, without turning off consciousness. During the last year, when tonic convulsions in the arm first appeared, after 4 months simultaneously in the arm and leg, the boy did not tell anyone, the attack lasted for several seconds, 1-2 times a month. In the last 2 weeks, seizures became more frequent up to 5-6 times a day and convulsions spread to the left half of the face. Directed to hospitalization.

 In the Nst-head of the usual form, the palpebral fissure is D = S. Horizontal nystagmus with extreme leads of the eyeballs, no strabismus. The tongue is straight, the smoothness of the nasolabial folds on the left. Swallowing, smell, touch are not broken. The muscle tone in the arms and legs is not changed, the reflexes are animated with some hypereflexion on the left. Abdominal living equal. There are no meningeal signs. Sensitivity saved. There is no dysfunction of the pelvic organs.

 Examination: General analysis of blood, urine - without features. Computed tomography of the brain without pathology. Ultrasound dopplerography of cerebral vessels - high peripheral resistance in the arteries. Changes in the supra-lateral arteries as a type of difficulty in cerebral perfusion. Probably an increase in intracranial pressure. ECG sinus rhythm 86 / min vertical position of the electrical axis, syndrome of early repolarization of the ventricles (as a normal option). FCG-free pathology. Ultrasound of the thyroid gland without pathology. ENT without pathology. Craniogram-free pathology. X-ray of the cervical spine and the first cervical vertebra through the mouth-straightening of lordosis. EEG-general cerebral manifestations are organic, the focus of epileptogenesis in the right temple, without secondary stem generalization. Dentist examined. Optometrist-Hypertensive Antipathy 1 tbsp. ECHO-Encephalography - without pathology. EEG - compared with the EEG from 5.04, there is a positive trend. Mild cerebral changes persist, no epileptic manifestations in the right temple. Orthopedist without pathology.

 Treatment: anticonvulsants are prescribed: suxilep 2 capsules (0.5 in the morning and 1 capsule (0.25 - lunch, 2 capsules (0.5-evening, luminal 0.1 - 2 r, then 3 sessions of incubation of the cell mass ATP + relanium 2 ml. At the beginning of treatment, the boy had 3 seizures before the first session, the seizures stopped, the second session was well tolerated, but a short seizure was observed the next day. After 3 seizures, the seizures disappeared. It is recorded with improvement without seizures. Positive dynamics are observed on the EEG with the disappearance of the epileptic focus. upon discharge: luminal 0.1-at night, suxilep 1 capsule (0.25 x 3 times a day). Repeated EEG after 1 month - mild cerebral manifestations, no epileptic activity. After 6 months - anticonvulsants are canceled. During the year no attacks.

 So, as a result, in our Center for a year of extracorporeal administration of Relanium by incubation in the cell mass in the presence of ATP in children with epilepsy, we managed to achieve good results. Convulsive seizures with the disappearance of epileptic foci on the electroencephalogram were stopped in half of the children, all supported the dose of anticonvulsants reduced by two or more times, and in some of them the drug therapy was completely canceled. We consider this method the most effective of all existing methods of treating epilepsy in children.

Claims (1)

A method for the treatment of epilepsy in children, consisting in drug treatment and plasmapheresis, characterized in that after centrifugation of the blood collected from the child’s blood, ATP at a dose of 100 mg / ml and Relanium 5-10 mg are introduced into the resulting cell mass, the mixture is incubated at 37 ^o C for 20 minutes and then administered intravenously to the patient, while the course of treatment is 3 sessions with an interval of 2 days between them.

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