Aim. To assess the efficacy and tolerability of perampanel as an additional therapy in epilepsy patients treated in St. Luke Association of medical institutions (including Svt. Luka’s Institute of Child Neurology and Epilepsy / Svt. Luka’s Institute of Pediatric and Adult Neurology and Epilepsy) with a focus on the order of perampanel administration (in groups of early and late additional therapy with perampanel).

Materials and methods. This study included 270 patients aged 4 to 43 years (125 males and 145 females; 255 children and adolescents aged 4–18 years; 15 adult patients; mean age at the time of perampanel therapy initiation was 11.8 years) who received perampanel and for whom we managed to collect clinical data for at least 6 months.

The study sample included 114 patients with structural and presumably structural focal epilepsy, 120 patients with genetic and presumably genetic epilepsy (including Dravet and Angelman syndromes, Lafora disease, mutations in genes PCDH19, PHACTR1, CDKL5, ARX, PING, SCN2A, KIAA2022, chromosomal microdeletions, etc.), and 36 patients with focal epilepsy of unknown etiology. In all patients, perampanel was used as an additional antiepileptic drug (AED), primarily in combination with valproate. The next most common AEDs were carbamazepine, oxcarbazepine, vigabatrin, ethosuximide (mainly in combination with valproate), levetiracetam, and topiramate; other AEDs were used significantly less often. Drug titration was performed in accordance with recommendations (dosage increase by 2 mg each 1–2 weeks) up to the therapeutic dose of 4–12 mg / day taken before sleep. The majority of patients received perampanel at a dose of 6 mg.

Total duration of perampanel therapy varied between 4 and 11 months. Patients were divided into three groups: patients in group 1 received perampanel as a second drug in additional therapy (n = 21); patients in group 2 received perampanel as a third drug in additional therapy (n = 54); patients in group 3 received perampanel as at least forth drug in additional therapy (n = 195). Groups 1 and 2 were considered as groups of early additional perampanel therapy, whereas group 3 was considered as a group of late additional perampanel therapy.

To evaluate perampanel efficacy, we measured proportions of responders (who demonstrated at least 50 % reduction seizure frequency compared to baseline, including patients in remission) and patients who achieved remission (no seizures over the last 6 months). Patients with a less than 50 % reduction in seizure frequency were considered as those with no significant effect. Patients who had no therapeutic effect or had aggravation (more frequent or severe seizures) in response to perampanel initiation or change of other AED to perampanel were considered as those with no effect or aggravation. We also assessed 6-month and 12-month retention rates. The main tolerability criteria were the number of side effects and proportion of patients who discontinued perampanel due to pronounced side effects.

Results. The overall proportion of responders was 76 % (206 out of 270); 21.4 % of patients achieved remission (58 out of 270). No significant effect was observed in 19.6 % of patients (53 out of 270), while 4 % of patients (11 out of 270) had no effect or even aggravation. In group 1 (early therapy with perampanel as a second additional drug; n = 21), 8 out of 21 patients (38 %) achieved an at least 6-month remission; the proportion of responders reached 95.2 % (20 out of 21), while 1 patient had no significant effect. In group 2 (early therapy with perampanel as a third additional drug; n = 54), there were 83 % of responders (45 out of 54) and 25.9 % patients with remission (14 out of 54); 16.7 % of patients demonstrated no significant effect (9 out of 54); none of the patients had aggravation. Cumulative analysis of the data in groups 1 and 2 (early additional therapy with perampanel; n = 75) showed that the proportion of responders reached 86.7 % (65 out of 75), while the proportion of patients with remission was 29.3 % (22 out of 75). Ten out of 75 patients from groups 1 and 2 (13.3 %) had no significant effect; none of the patients had aggravation. In group 3 (late additional therapy with perampanel; n = 195), the proportion of responders and patients with remission was 72.3 % (141 out of 195) and 18.4 % (36 out of 195), respectively. Forty-three patients in group 3 (22 %) demonstrated no significant effect; 11 patients had no effect or aggravation (5.6 %).

Thus, we observed significant differences in treatment efficacy between the groups of early and late additional perampanel therapy: 29.3 % vs 18.4 % of patients with remission and 86.7 % vs 72.3 % of responders in early and late therapy groups, respectively.

Although perampanel was initiated late in the majority of patients (as forth or subsequent AED used) due to the existing recommendations and, therefore, groups of early and late additional therapy differed significantly in the number of patients, our findings predict a significant increase in perampanel efficacy if it is initiated as an early additional therapy.

Of note, despite the fact that the majority of patients started to receive perampanel late, the overall perampanel efficacy was relatively high as demonstrated by 76 % of responders and 21.4 % of patients with remission.

Perampanel was characterized by good tolerability, which did not differ between the groups. A total of 129 out of 270 patients (47.8 %) reported side effects, most of them were mild or moderate. Importantly, 80 cases of side effects were considered desirable, including improved sleep (sedative effect of perampanel in combination with taking the drug before bedtime) and decreased muscle tone (45 % of parents of children with cerebral palsy reported decreased spastic hypertension in their children). The most common side effects included drowsiness, lethargy, decreased muscle tone, dizziness, and decreased appetite. We observed no cases of pronounced cognitive impairments related to perampanel. Behavioral side effects, such as aggression, excitability, and behavioral disorders, were registered in 22 patients (8.14 %) and were considered the most problematic. In 7 patients, these side effects were mitigated by perampanel dose reduction. Perampanel was discontinued in 15 patients (5.5 %) due to behavioral side effects, including 2 patients (0.7 %) who developed psychosis and one patient (0.37 %) with panic attacks and episodes of derealization.

The 6-month and 12-month perampanel retention rates were 85.2 % (230 out of 270) and 75.9 % (205 out of 270), respectively.

Conclusion. Perampanel is highly effective in patients with genetic and structural focal epilepsy, regardless of their age. Perampanel is characterized by a convenient mode of administration (once a day, before bedtime) simple slow titration mode, and is well tolerated during long-term therapy. Our results suggest that perampanel is significantly more effective if initiated early (as early additional therapy) at an earlier disease stage before the development of pharmacoresistance. We observed significant differences in perampanel efficacy between the groups of early and late therapy. We found that perampanel was highly effective in patients with some forms of genetic epilepsy.

Perampanel should be used not only in patients with drug-resistant epilepsy, but also as an additional drug in comprehensive therapy, which will lead to an improved treatment efficacy and better tolerability.

Balo's concentric sclerosis, a rare demyelinating disease of the central nervous system with the formation of concentric areas of demyelination in the white matter of the brain, was previously classified as an atypical form of multiple sclerosis with a fulminant course and a poor prognosis. However, recent clinical observations have cast doubt on this statement. To date, it has been established that the outcomes of the disease can vary from complete recovery to significant disability or death. The classification of Balo's concentric sclerosis as a distinct disease or form of multiple sclerosis remains a matter of debate. The article describes a clinical case of a 29-year-old female patient with Balo's concentric sclerosis. A description of nosological data, diagnostic criteria, and approaches to therapy is provided.

The author presents a literature review on the safety and efficacy of antisense oligonucleotides in the treatment of Duchenne muscular dystrophy using the exon skipping method using Viltepso® (viltolarsen), the only drug of this class registered in Russia, as an example. The analysis of international publications on clinical trials showed a high level of efficacy and safety of Viltepso®. This article, among other things, describes a 4-year clinical trial of viltolarsen. To date, this is the longest clinical trial of drugs of this group for the treatment of Duchenne muscular dystrophy. At the same time, it should not be forgotten that any pathogenetic therapy for Duchenne muscular dystrophy does not cure, but only slows down the progression of the disease, transferring it to a clinical form similar to Becker muscular dystrophy, provided that therapy is started early. In this regard, none of the currently available pathogenetic therapy can be considered as a monotherapy for the disease. Pathogenetic therapy will be most effective and will bring the desired results only with timely initiation of treatment and in combination with glucocorticosteroid therapy, symptomatic therapy and medical rehabilitation.

Angiocentric glioma is an extremely rare low-grade neuroepithelial tumor introduced into the World Health Organization classification of tumors of the central nervous system in 2007. Microscopically, it is a cluster of monomorphic bipolar cells with a predominant diffuse growth pattern and focal perivascular aggregation of tumor cells around blood vessels, which forms a specific angiocentric pattern. Despite the fact that a little more than 100 cases of detection of angiocentric glioma have been described in the literature, a number of clinical, pathomorphological and radiological criteria specific for this tumor have been identified that are characteristic long-term epilepsy associated tumors. The article presents the experience of complex, interdisciplinary diagnosis of angiocentric glioma in a child with focal structural epilepsy and a review of the literature. It should be noted that this is the first case of describing pathomorphologically confirmed angiocentric glioma on the territory of the Russian Federation.

Rehabilitation of children with spastic cerebral palsy (CP) is highly relevant considering the impaired movement, support and posture in these patients with spasticity of various muscles. Spasticity in CP patients may lead to severe secondary bone changes, such as hip dislocation, severe foot deformities (equinovarus or planovalgus), scoliosis, severe multiple contractures of the upper limb joints. Despite being a good agent to relieve spasticity, botulinum toxin is not able to completely address the problems associated with deformities and movement disorders due to muscle rigidity and changes in muscle structure.

Reducing muscle rigidity using Longidase® (hyaluronidase azoximer) is an important stage of rehabilitation of CP children. Longidase® has a prolonged enzymatic activity and contributes to a pronounced antioxidant and anti-inflammatory effect. Longidase® also has antifibrotic properties since it mitigates inflammation and regulates the production of inflammatory mediators. Longidase® is capable of depolymerizing connective tissue matrix in fibrous granulomatous formations. Moreover, it suppresses the negative feedback reaction aimed at the production of connective tissue components, which is very important in case of muscle spasticity in both children and adult patients. Longidase® reduces tissue edema, thereby increasing the range of motion in joints, reducing contractures, and preventing their formation. The development of step-by-step rehabilitation, which includes botulinum toxin therapy at the first stage and Longidase® injections into spastic muscles at the second stage, will increase muscle elasticity and range of motion and facilitate orthosis in childhood, thus postponing surgery.

We report a case of CP in a 7-year-old girl who was treated in Saint Petersburg State Pediatric Medical University. The patient had regular courses of botulinum toxin A therapy to reduce muscle spasticity and prevent persistent contractures. In addition to that, the patient received a course of ultrasound-guided Longidase® injections into spastic lower limb muscles a week following botulinum toxin therapy. Muscle echogenicity was assessed using ultrasound examination. Spasticity in the upper and lower extremities was detected in more than one joint. Patient’s score on the Modified Ashworth Scale was 3 for the lower limb. Longidase® injections significantly increased the range of motion in the ankle joint and ensured smooth sliding of muscle groups during physical exercises. Longidase® therapy was considered because of the need for surgery, while parents wanted to try alternative treatment strategies to postpone surgery.

Thus, botulinum toxin therapy followed by intramuscular Longidase® injections reduced rigidity of spastic muscles and increased the amplitude of passive and active movements in the ankle joint, as demonstrated by goniometry and ultrasound, as well as changes in the perimysium and endomysium.

A brief literature review of the rare genetic Smith–Magenis syndrome, which is manifested by mental retardation, dyssomnia, and specific behavioral disorders, is presented. Epilepsy occurs in approximately 50 % of patients. A description of long-term follow-up of a patient with this syndrome and epilepsy in the form of development and epileptic encephalopathy with spike-wave activation in sleep is given. Epilepsy onset was at the age of 5 years with focal, bilateral tonic-clonic seizures and status epilepticus. On the electroencephalogram of nocturnal sleep, spike-wave activity was detected in the centrotemporal regions on both hemispheres, with an index of up to 100 %. The patient was able to choose antiepileptic therapy, a long-term remission was achieved, the seizures were stopped.

The main forms of orphan Wilson–Konovalov disease – cerebral, abdominal and mixed forms, with copper accumulation in the central nervous system, patients debut spastic and dystonic attacks. The authors demonstrate the clinical example of the efficiency and safety of botulinum toxin type A for the relief of spastic and dystonic attacks and pain syndrome in a 12-year-old child with severe multiple contractures of the upper and lower limbs with a resistant Wilson–Konovalov disease’s form. A 12-year-old patient (male) with primary diagnosed resistant form of Wilson–Konovalov disease with deformities of pyramidal-extropyramidal type was diagnosed with contractures of the tongue, deviation of the mandible; contractures of the right shoulder joint, flexor contracture of the right elbow joint, flexion-ulnar contracture of the right wrist joint, flexion contracture of the fingers and severe extensor contracture of the left elbow joint, extensor-ulnar contracture of the left wrist joint, equinovarus contracture of the ankle joints. The patient received two-stage botulinum therapy according to the spasticity and dystonia protocol. Carrying out the first stage of botulinum therapy according to the spasticity protocol gave positive dynamics. Less frequency of the dystonic attacks, the relief of pain syndrome. The extensor contracture was preserved, and a second stage of botulinum therapy was performed to preserve the joint for the soft tissue surgery. Botulinum neuroprotein therapy is fundamental in the treatment of resistant forms of Wilson–Konovalov disease in order to relief dystonic attacks, spasticity and pain syndrome, that can keep joints healthy.