[Influence of the Poly(ADP-Ribose) Polymerase 1 Level on the Status of Base Excision Repair in Human Cells].

Base excision repair (BER) is aimed at repair of damaged bases, which are the largest group of DNA lesions. The main steps of BER are recognition and removal of the aberrant base, cutting of the DNA sugar-phosphate backbone, gap processing (including dNMP insertion), and DNA ligation. The precise function of BER depends on the regulation of each step by regulatory/accessory proteins, the most important of which is poly(ADP-ribose) (PAR) polymerase 1 (PARP1). PARP1 plays an important role in DNA repair, maintenance of genome integrity, and regulation of mRNA stability and decay. PARP1 can therefore affect BER both at the level of BER proteins and at the level of their mRNAs. There is no systematic data on how the PARP1 content affects the activities of key BER proteins and the levels of their mRNAs in human cells. Whole-cell extracts and RNA preparations obtained from the parental HEK293T cell line and its derivative HEK293T/P1-KD cell line with reduced PARP1 expression (shPARP1-expressing cells, a PARP1 knockdown) were used to assess the levels of mRNAs coding for BER proteins: PARP1, PARP2, uracil DNA glycosylase (UNG2), AP endonuclease 1 (APE1), DNA polymerase ß (POLß), DNA ligase III (LIG3), and XRCC1. Catalytic activities of the enzymes were evaluated in parallel. No significant effect of the PARP1 content was observed for the mRNA levels of UNG2, APE1, POLß, LIG3, and XRCC1. The amount of the PARP2 mRNA proved to be reduced two times in HEK293T/P1-KD cells. Activities of these enzymes in whole-cell extracts did not differ significantly between HEK293T and HEK293T/P1-KD cells. No significant change was observed in the efficiencies of the reactions catalyzed by UNG2, APE1, POLß, and LIG3 in conditions of PAR synthesis. A DNA PARylation pattern did not dramatically change in a HEK293T/P1-KD cell extract with a reduced PARP1 content as compared with an extract of the parental HEK293T cell line.

[Efficacy and tolerability of perampanel as adjunctive treatment of focal and generalized tonic-clonic epileptic seizures in children over 4 years of age]. / Effektivnost' i perenosimost' perampanela kak dopolnitel'nogo preparata v lechenii fokal'nykh i generalizovannykh toniko-klonicheskikh epilepticheskikh pristupov u detei v vozraste ot 4 do 12 let.

The article is a short review of an observational study that proves the good efficacy and tolerability of perampanel suspension in the adjunctive treatment of epilepsy in children over 4 years of age. The study demonstrated a high level of 50% responders: 47% with focal seizures, 65% with transition of focal seizures to bilateral tonic-clonic seizures, 65% with primary generalized tonic-clonic seizures. Cessation of seizures was achieved in 12%, 19% and 55% of patients, respectively. The most common side-effects were fatigue (26%), nasopharyngitis (19%), lightheadedness, irritability, fever (13% each), and vomiting (11%). There were no significant clinical negative changes in cognitive functions according to the assessment on the Aldenkamp-Baker scale, both on the total score and subscales. Also, there were no significant changes in laboratory data, vital functions and ECG parameters.

The contribution of PARP1, PARP2 and poly(ADP-ribosyl)ation to base excision repair in the nucleosomal context.

The regulation of repair processes including base excision repair (BER) in the presence of DNA damage is implemented by a cellular signal: poly(ADP-ribosyl)ation (PARylation), which is catalysed by PARP1 and PARP2. Despite ample studies, it is far from clear how BER is regulated by PARPs and how the roles are distributed between the PARPs. Here, we investigated the effects of PARP1, PARP2 and PARylation on activities of the main BER enzymes (APE1, DNA polymerase ß [Polß] and DNA ligase IIIα [LigIIIα]) in combination with BER scaffold protein XRCC1 in the nucleosomal context. We constructed nucleosome core particles with midward- or outward-oriented damage. It was concluded that in most cases, the presence of PARP1 leads to the suppression of the activities of APE1, Polß and to a lesser extent LigIIIα. PARylation by PARP1 attenuated this effect to various degrees depending on the enzyme. PARP2 had an influence predominantly on the last stage of BER: DNA sealing. Nonetheless, PARylation by PARP2 led to Polß inhibition and to significant stimulation of LigIIIα activities in a NAD+-dependent manner. On the basis of the obtained and literature data, we suggest a hypothetical model of the contribution of PARP1 and PARP2 to BER.

[ECONOMIC BURDEN AND CURRENT STATUS OF THE DRUG SUPPLY MANAGEMENT FOR IMMUNE INFLAMMATORY DISEASES (BY EXAMPLE OF ULCERATIVE COLITIS AND CROHN'S DISEASE)].

AIM: to estimate the quality and availability of medical care for patients with ulcerative colitis (UC) and Crohn's disease (CD), to assess the impact of the economic burden of these diseases on the healthcare budget of Russia and to systematize the main problems in the organization of medical care and drug supply for patients with inflammatory bowel diseases (IBD). Regional IBD databases (2016-2018), official statistical databases, costs of treatment and results of expert interviews with specialists in IBD were used in the study. The analyzed databases showed 104,668 patients with UC in Russia in 2018 (prevalence rate 71 per 100,000 people) and 66,647 patients with CD (prevalence rate of 45 per 100,000 people). The economic burden including agents for biologic therapy (ABT) for the UC was 39.54 billion rubles a year (495 rubles per capita), and CD - 32.98 billion rubles a year (378 rubles per capita). It requires an additional 9.87 billion rubles annually for UC and 9.20 billion rubles annually for CD patients to provide the complete supply with ABT. The annual burden of IBD is 72.52 billion rubles, which is comparable to the costs of other socially significant diseases, including malignant tumors. It shows the high social and economic value of IBD for the country. The main problems of medical care and drug supply for IBD patients are the mismatch of official statistical data and real IBD prevalence in Russia due to absence of comprehensive register and the insufficient supply with ABT due to limited funding. A federal center for IBD should be founded for better quality of registration, for the precise monitoring and for the active management of personal drug supply.

[The problem of comorbidity of epilepsy and psychogenic paroxysms]. / Problema komorbidnosti epilepsii i psikhogennykh paroksizmov.

A review of publications over the last two decades is presented. Psychogenic paroxysms develop in approximately 12% of patients with epilepsy. The analysis of social and demographic data, history details, semiological features and results of electrophysiological and neuroimaging studies does not unequivocally support the comorbidity of epilepsy and psychogenic paroxysms. The pathogenetic mechanisms of the development of comorbidity are various and depend on the presence of pharmacoresistance, psychological traumas in the past, intellectual disability etc. Video-EEG-monitoring is the gold standard in the diagnosis of comorbidity of epilepsy and psychogenic paroxysms. Treatment of such cases includes anticonvulsants and cognitive-behavioral therapy.

Impact of PARP1, PARP2 & PARP3 on the Base Excision Repair of Nucleosomal DNA.

DNA is constantly attacked by different damaging agents; therefore, it requires frequent repair. On the one hand, the base excision repair (BER) system is responsible for the repair of the most frequent DNA lesions. On the other hand, the formation of poly(ADP-ribose) is one of the main DNA damage response reactions that is catalysed by members of the PARP family. PARP1, which belongs to the PARP family and performs approximately 90% of PAR synthesis in cells, could be considered a main regulator of the BER process. Most of the experimental data concerning BER investigation have been obtained using naked DNA. However, in the context of the eukaryotic cell, DNA is compacted in the nucleus, and the lowest compaction level is represented by the nucleosome. Thus, the organization of DNA into the nucleosome impacts the DNA-protein interactions that are involved in BER processes. Poly(ADP-ribosyl)ation (PARylation) is thought to regulate the initiation of the BER process at the chromatin level. In this review, we focus on the mechanisms involved in BER in the nucleosomal context and the potential effect of PARylation, which is catalysed by DNA-dependent PARP1, PARP2 and PARP3 proteins, on this process.

Important problems in the diagnosis and treatment of primary sclerosing cholangitis (based on the Russian consensus on diagnosis and treatment autoimmune hepatitis. Moscow, 2018).

The article is published based on the results of the Russian Consensus on the diagnosis and treatment of primary sclerosing cholangitis (PSC), discussed at the 44th annual Scientific Session of the CNIIG "Personalized Medicine in the Era of Standards" (March 1, 2018). The aim of the review is to highlight the current issues of classification of diagnosis and treatment of patients with PSC, which causes the greatest interest of specialists. The urgency of the problem is determined by the multivariate nature of the clinical manifestations, by often asymptomatic flow, severe prognosis, complexity of diagnosis and insufficient study of PSC, the natural course of which in some cases can be considered as a function with many variables in terms of the nature and speed of progression with numerous possible clinical outcomes. In addition to progression to portal hypertension, cirrhosis and its complications, PSC can be accompanied by clinical manifestations of obstructive jaundice, bacterial cholangitis, cholangiocarcinoma and colorectal cancer. Magnetic resonance cholangiography is the main method of radial diagnostics of PSC, which allows to obtain an image of bile ducts in an un-invasive way. The use of liver biopsy is best justified when there is a suspicion of small-diameter PSC, autoimmune cross-syndrome PSC-AIG, IgG4-sclerosing cholangitis. Currently, a drug registered to treat primary sclerosing cholangitis which can significantly change the course and prognosis of the disease does not exist. There is no unified view on the effectiveness and usefulness of ursodeoxycholic acid and its dosage in PSC. Early diagnosis and determination of the phenotype of PSC is of clinical importance. It allows to determine the tactics of treatment, detection and prevention of complications.

Thioflexithrix psekupsensis gen. nov., sp. nov., a filamentous gliding sulfur bacterium from the family Beggiatoaceae.

A sulfur-oxidizing, filamentous, gliding micro-organism, strain D3T, was isolated from a sulfidic spring in Goryachy Klyuch, Krasnodar, Russia. The cell walls were Gram-negative. The new isolate was a microaerophilic facultative anaerobe and an obligate chemolithoautotroph. The pH range for growth was pH 6.8-7.6, with an optimum at pH 7.2. The temperature range for growth was 10-46 °C, with an optimum at 32 °C. The G+C content of DNA was 42.1 mol%. Phylogenetic analysis of the 16S rRNA gene showed that strain D3T belongs to the family Beggiatoaceae, order Thiotrichales and was distantly related to the genera of the family Beggiatoaceae(86-88 % sequence similarity). The major respiratory quinone was ubiquinone-6. Major fatty acids were C18:1 ω7 (37.6 %), C16 : 0 (34.7 %) and C16: 1 ω7 (27.7 %). On the basis of its physiological properties and the results of phylogenetic analysis, strain D3T is considered to represent a novel species of a new genus, for which the name Thioflexithrix psekupsensis gen. nov., sp. nov. is proposed. The type strain is D3T (=KCTC 62399=UNIQEM U981).

[Difficulties in the diagnosis, prognosis and treatment of genetic epileptic encephalopathies: the view of a neurologist]. / Trudnosti v diagnostike, prognoze i lechenii geneticheskikh épilepticheskikh éntsefalopatii: vzgliad nevrologa.

Genetic epileptic encephalopathies are a rather wide spectrum of childhood epilepsies with onset of epilepsy in the first 1.5-2 years of life, regression or delayed psychomotor and speech development and 'massive' epileptiform activity on electroencephalogram (EEG). The review discusses the difficulties of choosing the optimal method of genetic examination, problems with the interpretation of the results obtained, the formulation of the diagnosis, the determination of the prognosis of the course and targeted therapy. It is emphasized that the interpretation of the identified genetic variants is not an easy task, requiring close interaction between specialists in molecular genetics, bioinformatics, neurology and clinical genetics. The possibilities of targeted treatment of genetic epileptic encephalopathies are still limited, but knowledge of the genetic cause of epilepsy allows making a more informed choice of the treatment.

[Why the diagnosis of Lennox-Gastaut syndrome is a rare one?] / Pochemu tak redko stavitsia diagnoz sindroma Lennoksa-Gasto?

The review addresses the problem of the diagnosis of Lennox-Gastaut syndrome, a severe epileptic encephalopathy. Despite the presence of a vivid clinical and encephalographic picture, classical Lennox-Gastaut syndrome, which meets all of its diagnostic criteria, is quite rare. Many authors believe that the diagnosis of the syndrome is possible if the patient has tonic seizures and typical ictal and interictal patterns on the electroencephalogram (EEG). The diagnosis of the syndrome is considered probable if there are typical EEG patterns of wakefulness and sleep, but no tonic seizures are recorded. Diagnosis of the syndrome is complicated by its polyetiology (clinical and EEG manifestations can vary significantly), the evolution of seizure types and EEG characteristics as the patient matures, the presence of other epileptic syndromes similar to Lennox-Gastaut syndrome.

A New DNA Break Repair Pathway Involving PARP3 and Base Excision Repair Proteins.

Poly(ADP-ribosyl)ation, which is catalyzed by PARP family proteins, is one of the main reactions in the cell response to genomic DNA damage. Massive impact of DNA-damaging agents (such as oxidative stress and ionizing radiation) causes numerous breaks in DNA. In this case, the development of a fast cell response, which allows the genomic DNA integrity to be retained, may be more important than the repair by more accurate but long-term restoration of the DNA structure. This is the first study to show the possibility of eliminating DNA breaks through their PARP3-dependent mono(ADP-ribosyl)ation followed by ligation and repair of the formed ribo-AP sites by the base excision repair (BER) enzyme complex. Taken together, the results of the studies on ADP-ribosylation of DNA and the data obtained in this study suggest that PARP3 may be a component of the DNA break repair system involving the BER enzyme complex.

[Epilepsy and autism spectrum disorders in children]. / Épilepsiia i rasstroistva autisticheskogo spektra u detei.

The problem of epilepsy comorbidity with autism spectrum disorders in children is discussed. The incidence data of autism spectrum disorders in epilepsy, epileptiform discharges on the EEG in autism spectrum disorders and epilepsy in autism spectrum disorders are reviewed. The following types of epilepsy and autism co-occurrence are discussed: both conditions are independent, have different causes and may co-occur by chance; epilepsy and autism are associated, both being independent consequences of the same genetic disorder or early cerebral damage; autism is caused by the epileptic process which interferes with the function of specific brain networks involved in the development of communication and social behavior; autism is a result of the withdrawal reaction in the epileptic child. The known genetic causes of epilepsy and autism spectrum disorders comorbidity are provided. The practical issues are discussed, in particular the rational indication of antiepileptic drugs to the children suffering autism spectrum disorders.

Circular RNA: New Regulatory Molecules.

Circular RNA are a family of covalently closed circular RNA molecules, formed from pre-mRNA of coding genes by means of splicing (canonical and alternative noncanonical splicing). Maturation of circular RNA is regulated by cis- and trans-elements. Complete list of biological functions of these RNA is not yet compiled; however, their capacity to interact with specific microRNA and play a role of a depot attracts the greatest interest. This property makes circular RNA active regulatory transcription factors. Circular RNA have many advantages over their linear analogs: synthesis of these molecules is conservative, they are universal, characterized by clearly determined specificity, and are resistant to exonucleases. In addition, the level of their expression is often higher than that of their linear forms. It should be noted that expression of circular RNA is tissue-specific. Moreover, some correlations between changes in the repertoire and intensity of expression of circular RNA and the development of some pathologies have been detected. Circular RNA have certain advantages and can serve as new biomarkers for the diagnosis, prognosis, and evaluation of response to therapy.

Effect of everolimus on skin lesions in patients treated for subependymal giant cell astrocytoma and renal angiomyolipoma: final 4-year results from the randomized EXIST-1 and EXIST-2 studies.

BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder associated with tumour growth in various organs, including the brain, kidneys, heart and skin. Cutaneous lesions are prevalent manifestations of TSC, occurring in up to 90% of patients. Oral mammalian target of rapamycin inhibitors, such as everolimus, is believed to be effective for treatment of TSC-associated lesions because they act on the underlying disease pathophysiology. OBJECTIVE: We evaluated the long-term effect of oral everolimus on TSC-associated skin lesions as a secondary objective in the phase III studies EXIST-1 (NCT00789828) and EXIST-2 (NCT00790400) after approximately 4 years of treatment. MATERIALS AND METHODS: Everolimus was dosed 4.5 mg/m2 /day (titrated to trough 5-15 ng/mL) in patients with TSC-associated subependymal giant cell astrocytoma in EXIST-1, and 10 mg/day initially in adult patients with TSC- or sporadic lymphangioleiomyomatosis-associated renal angiomyolipoma in EXIST-2. Following positive results from the core phase, remaining patients were offered open-label everolimus in an extension. Skin lesion response rate was the proportion of patients achieving complete or partial clinical response. RESULTS: A total of 105 patients in EXIST-1 and 107 in EXIST-2 received everolimus and had ≥1 skin lesion at baseline. Skin lesion response rate (95% confidence interval) was 58.1% (48.1-67.7%) in EXIST-1 and 68.2% (58.5-76.9%) in EXIST-2; most were partial responses. At week 192 (EXIST-1: n = 55; EXIST-2: n = 56), 69% and 66% had a response. Most common drug-related adverse event was stomatitis (41-45%). CONCLUSION: Oral everolimus improved TSC-related skin lesions, with responses sustained over 4 years of treatment in EXIST-1 and EXIST-2.

Dna is a New Target of Parp3.

Most members of the poly(ADP-ribose)polymerase family, PARP family, have a catalytic activity that involves the transfer of ADP-ribose from a beta-NAD+-molecule to protein acceptors. It was recently discovered by Talhaoui et al. that DNA-dependent PARP1 and PARP2 can also modify DNA. Here, we demonstrate that DNA-dependent PARP3 can modify DNA and form a specific primed structure for further use by the repair proteins. We demonstrated that gapped DNA that was ADP-ribosylated by PARP3 could be ligated to double-stranded DNA by DNA ligases. Moreover, this ADP-ribosylated DNA could serve as a primed DNA substrate for PAR chain elongation by the purified proteins PARP1 and PARP2 as well as by cell-free extracts. We suggest that this ADP-ribose modification can be involved in cellular pathways that are important for cell survival in the process of double-strand break formation.

[Vaccination, febrile seizures and epilepsy]. / Vaktsinatsiia u detei, febril'nye sudorogi i épilepsiia.

This literature review addresses the risk of vaccination complications including neurological ones. Some vaccines associated with vaccine-induced febrile seizures (FS), e.g. vaccines against pertussis, diphtheria and tetanus, can provoke FS but they are not their cause. Therefore, delaying a vaccination to an older age does not reduce the risk of FS. The author also considers international and Russian recommendations on vaccination in children with epilepsy, West syndrome and Drave's syndrome.

Russian consensus on exo- and endocrine pancreatic insufficiency after surgical treatment.

The Russian consensus on exo- and endocrine pancreatic insufficiency after surgical treatment was prepared on the initiative of the Russian "Pancreatic Club" on the Delphi method. His goal was to clarify and consolidate the opinions of specialists on the most relevant issues of diagnosis and treatment of exo- and endocrine insufficiency after surgical interventions on the pancreas. An interdisciplinary approach is provided by the participation of leading gastroenterologists and surgeons.

[The Russian consensus on the diagnosis and treatment of chronic pancreatitis: Enzyme replacement therapy]. / Rossiiskii konsensus po diagnostike i lecheniiu khronicheskogo pankreatita: zamestitel'naia fermentnaia terapiia.

Pancreatology Club Professional Medical Community, 1A.S. Loginov Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow; 2A.I. Evdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia, Moscow; 3Kazan State Medical University, Ministry of Health of Russia, Kazan; 4Kazan (Volga) Federal University, Kazan; 5Far Eastern State Medical University, Ministry of Health of Russia, Khabarovsk; 6Morozov City Children's Clinical Hospital, Moscow Healthcare Department, Moscow; 7I.I. Mechnikov North-Western State Medical University, Ministry of Health of Russia, Saint Petersburg; 8Siberian State Medical University, Ministry of Health of Russia, Tomsk; 9M.F. Vladimirsky Moscow Regional Research Clinical Institute, Moscow; 10Maimonides State Classical Academy, Moscow; 11V.I. Razumovsky State Medical University, Ministry of Health of Russia, Saratov; 12I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow; 13S.M. Kirov Military Medical Academy, Ministry of Defense of Russia, Saint Petersburg; 14Surgut State Medical University, Ministry of Health of Russia, Surgut; 15City Clinical Hospital Five, Moscow Healthcare Department, Moscow; 16Nizhny Novgorod Medical Academy, Ministry of Health of Russia, Nizhny Novgorod; 17Territorial Clinical Hospital Two, Ministry of Health of the Krasnodar Territory, Krasnodar; 18Saint Petersburg State Pediatric Medical University, Ministry of Health of Russia, Saint Petersburg; 19Rostov State Medical University, Ministry of Health of Russia, Rostov-on-Don; 20Omsk Medical University, Ministry of Health of Russia, Omsk; 21Russian Medical Academy of Postgraduate Education, Ministry of Health of Russia, Moscow; 22Novosibirsk State Medical University, Ministry of Health of Russia, Novosibirsk; 23Stavropol State Medical University, Ministry of Health of Russia, Stavropol; 24Kemerovo State Medical University, Ministry of Health of Russia, Kemerovo; 25N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia, Moscow; 26A.M. Nikiforov All-Russian Center of Emergency and Radiation Medicine, Russian Ministry for Civil Defense, Emergencies and Elimination of Consequences of Natural Disasters, Saint Petersburg; 27Research Institute for Medical Problems of the North, Siberian Branch, Russian Academy of Sciences, Krasnoyarsk; 28S.P. Botkin City Clinical Hospital, Moscow Healthcare Department, Moscow; 29Tver State Medical University, Ministry of Health of Russia, Tver The Russian consensus on the diagnosis and treatment of chronic pancreatitis has been prepared on the initiative of the Russian Pancreatology Club to clarify and consolidate the opinions of Russian specialists (gastroenterologists, surgeons, and pediatricians) on the most significant problems of diagnosis and treatment of chronic pancreatitis. This article continues a series of publications explaining the most significant interdisciplinary consensus statements and deals with enzyme replacement therapy.

[New classifications of epilepsies and seizure types created by the International League against Epilepsy (2017)]. / Novye mezhdunarodnye klassifikatsii épilepsii i épilepticheskikh pristupov Mezhdunarodnoi ligi po bor'be s épilepsiei (2017).

This review presents the recently published revised classifications of epilepsies and seizure types developed by the International League Against Epilepsy (ILAE). The Classification of Epilepsies includes several diagnostic levels (steps): 1) from seizure type to epilepsy type (generalized/focal/combined generalized and focal/unknown), 2) diagnosis of epilepsy syndrome 3) etiology (genetic/ structural/ infectious/ metabolic/ immune/unknown). A clinician can use any level of the classification. Operational classification of seizure types is replaced by the previous classification that was grounded on the anatomical basis. Seizures are classified by the onset (focal, generalized or unknown). All types of seizures can be motor or non-motor. Focal seizure may evolve to bilateral tonic-clonic (previously called secondary-generalized). Atonic, clonic, tonic, myoclonic seizures and epileptic spasms can be either of focal or generalized onset. Unclassified type of seizure was introduced. New types of seizures (absence with eyelid myoclonia, myoclonic absence, myoclonic atonic and clonic-tonic-clonic seizures) were added. New terminology, definitions and some concepts developed by ILAE are presented.

[The decreased level of plasma carnitine in patients with epilepsy]. / Snizhenie kontsentratsii karnitina u patsientov s épilepsiei.

Antiepileptic drugs (AEDs) have long been known to affect carnitine metabolism, dropping the plasma free carnitine. Valproate (VPA) was considered to be the strongest carnitine-reducing agent. VPA-induced hyperammonemic encephalopathy and hepatotoxicity are well known, and pre-existing carnitine deficiency can be a predisposing factor, especially in congenital metabolic disorders. Several studies have shown that carnitine supplementation in patients receiving VPA to result in subjective and objective improvements and to prevent VPA-induced hepatotoxicity and encephalopathy, in parallel with increases in carnitine serum concentrations. Level of free plasma carnitine <20 micromol/l (syn. carnitine deficiency) in patients with epilepsy (in 15-30% of cases) may occur not only with administration of VPA but with administration of other AEDs (phenobarbital, phenytoin, carbamazepine) and low nutritional intake of carnitine. Some findings indicate that the number of AEDs used is a risk factor for carnitine deficiency. It was established that body weight, height and multidrug therapy are significantly associated with low level of free plasma in epileptic patients. Carnitine deficiency can have severe consequences; but most epileptic patients suffering from it are asymptomatic. Although carnitine deficiency is not uncommon among patients receiving AEDs, it seems not necessary to routinely monitor carnitine levels in epileptic ambulatory patients, this is reasonable only in groups of risk. L-carnitine supplementation is clearly indicated in case of VPA-induced hepatotoxicity (i.v. administration) VPA overdose (i.v. administration), primary carnitine-transporter defect and is strongly recommended in specific secondary carnitine deficiency syndromes, symptomatic VPA-associated hyperammonemia, infants and young children receiving VPA, especially those younger than 2 years, patients with a complex neurologic disorder, who are receiving multiple AEDs, patients who have risk factors for hepatotoxicity and carnitine insufficiency. In the absence of double blind trials, clinical practice is based on empiric observation, clinical experience, and theory. Well-designed studies of specific and general uses of L-carnitine replacement therapy in patients with epilepsy are needed.