Precision medicine in child neurology

Uvod: Precizna medicina obuhvaća metode liječenja usmjerene prema potrebama individualnog bolesnika na osnovi genskih karakteristika, biomarkera, fenotipa ili psihosocijalnih karakteristika uz prilagođavanje medicinskih postupaka individualnim karakteristikama svakog bolesnika. Diskusija: Za uspješnost i učinkovitost precizne medicine postoji potreba za klasifikacijom bolesnika na osnovi podložnosti određenoj bolesti ili na osnovi odgovora na liječenje, čime se omogućava usmjeravanje preventivnih ili terapijskih intervencija za one koji će imati najveću korist. U neuropedijatriji precizna medicina zauzela je najčvršće mjesto u epilepsijama, a primjena se nalazi i u neuromišićnim i drugim bolestima. Sudjelujući u studijama i prikupljajući multidimenzionalne podatke o našim bolesnicima pomičemo granice precizne medicine kako bi sljedeće generacije ovaj novi koncept mogle još bolje definirati i upotrijebiti za veći broj bolesnika. Zaključak: Pred nama je još uvijek dug put do integracije precizne medicine u kliničku praksu. Visoka cijena liječenja, precizne informacije o riziku i koristi liječenja kao i konsenzus o standardizaciji evaluacije učinkovitosti pojedinog dijagnostičkog postupka ili metode liječenja još stoje kao neostvareni ciljevi precizne medicine prema kojima moramo težiti.Introduction: Precision medicine is defined as methods of treatment targeted towards needs of individual patient based on genetic characteristics, biomarkers, phenotype, or psychosocial characteristics with modifications of medical procedures to the individual needs of each patient. Discussion: To achieve success and efficacy of precision medicine there is a need for classifying patients based on their affinity to disease or based on their response to therapeutical interventions what enables focusing of preventive or therapeutical interventions to those who will benefit the most. In child neurology precision medicine is strongest in epilepsies, but the relevance is seen in neuromuscular and other diseases. By participating in clinical studies and collecting multidimensional dana on our patients we move the limits of precision medicine to allow future generation to define this concept even better and to use it for even more patients. Conclusion: We still have a long way to full integration of precision medicine to clinical practice. High cost of treatment, precise information on risks and benefits of treatment, as well as consensus on standardization of efficacy evaluation for particular diagnostic procedure or treatment method still stand as goals of precision medicine that we need to strive to

Napadaji posteriornog korteksa - izazovi u pedijatriji

Posterior cortex seizures have a complex semiologic presentation that is especially challenging in the pediatric population. Therefore, using clinical presentation in localizing ictal involvement is not sufficient in children, thus making this type of epilepsy quite under-recognized. As most of the ictal symptoms are subjective and could well be overshadowed by symptoms arising from adjacent cortices, primarily temporal and central ones, it is necessary not to overlook this large source of pharmacoresistant epilepsies. The parietal lobe as part of an extensive synaptic network is a great imitator, thus quite often producing inaccurate localization readings on scalp electroencephalography (EEG) due to very scattered interictal discharges and uninformative ictal recordings. Using direct cortical recordings in delineating the epileptogenic zone is helpful in some cases but even highly experienced epileptologists may erroneously interpret some features as arising from other localizations, especially the frontal lobe. Epilepsy surgery from the posterior quadrant is still quite rare and relatively unsuccessful, especially in non-lesional epilepsies due to elaborate mechanisms of connectivity, misleading semiology, and non-localizing EEG recordings, possibly due to insufficiency of parietal cortex synchronicity. Applying the aforementioned to the pediatric age makes it perhaps the most difficult challenge for a pediatric epileptologist.Napadaji posteriornog korteksa imaju složemu semiologiju koja je osobito izazovna u pedijatrijskoj populaciji. Upravo zato primjena kliničke prezentacije u lokalizaciji iktalnog ishodišta nije dovoljno u djece, čime je ova vrsta epilepsije slabo prepoznata. S obzirom na to da je većina iktalnih simptoma subjektivna i može biti skrivena simptomima susjednih korteksa, primarno temporalnim i centralnim, važno je ne preskočiti ovaj važan izvor farmakorezistentnih epilepsija. Uz semiologiju, parijetalni je režanj kao dio velike sinaptičke mreže veliki imitator i često stvara netočnu lokalizaciju na elektroencefalogramu (EEG) zbog velike distribucije interiktalnih izbijanja i neinformativnih iktalnih zapisa. Korištenje direktnih kortikalnih zapisa u definiciji epileptogene zone je korisno u nekim slučajevima, no čak i vrlo iskusni epileptolozi mogu pogrešno protumačiti neke značajke s ishodom iz drugih izvora, osobito frontalnog režnja. Operacije epilepsije posteriornog kvadranta su vrlo rijetke i prilično neuspješne, osobito u ne-lezionalnim epilepsijama zbog osebujnih mehanizama povezanosti, zavaravajuće semiologije i ne-lokalizirajućeg EEG zapisa moguće zbog nedovoljne sinkroniziranosti parijetalnog korteksa. Primjena navedenog na pedijatrijsku dob čini epilepsije ovog dijela korteksa možda najvećim izazovom za pedijatrijske epileptologe

Karakterističan fenotip u djevojčice s Rettovim sindromom i delecijom 25 bp zbog nove mutacije u 4. eksonu (.881_905del25, nm_004992.3) gena MECP2

Rett syndrome is a pervasive developmental disorder with a variable clinical presentation, which is caused by point mutations or large deletions/duplications in the X-linked methyl-CpG-binding protein 2 (MECP2) gene. The aim is to describe variation in the clinical course related to the mutation identifi ed in exon 4 of the MECP2 gene. Retrospective review of data, electroencephalography and treatment was done in a 19-year-old girl previously diagnosed with a MECP2 gene mutation. Born after an uneventful pregnancy, the female patient’s growth and psychomotor development were normal, except for delayed speech. At the age of 3 years, tonic-clonic seizures started and at the age of 3.5 years autistic behavior was observed, followed by rapid mental deterioration, loss of speech and motor skills, with periods of hyperventilation. At the age of 5 years, she showed occasionally „hand-washing“ movements. Extensive neuro-metabolic investigation was nondiagnostic. Genetic analysis revealed a novel 25 bp deletion mutation in exon 4 (c.881_905del25) of the MECP2 gene. Until now, multiple epileptic seizure types, refractory to all antiepileptic polytherapy and with normal video EEG background, have occurred daily. She is spastic and ataxic, but still able to walk slowly with a wide based gait. In this female patient, the onset of symptoms manifested much later than encountered in typical cases of Rett syndrome. Epilepsy with daily frequency is however drug resistant. Unexpectedly, she is still able to walk at the age of 19 years. A genotype-phenotype correlation is suspected.Rettov sindrom (RTT) pervazivni je razvojni poremećaj s različitim kliničkim slikama, a uzrokovan najčešće točkastim mutacijama ili delecijom/duplikacijom metil-CpG-vezanog proteina 2 (MECP2) na genu X. Cilj je opisati različitosti kliničkog tijeka bolesti koje su vezane za nađenu mutaciju na 4. eksonu gena MECP2. Retrospektivna analiza anamnestičkih podataka, electroencefalograma i liječenja kod 19-godišnje djevojke s nalazom mutacije na genu MECP2. Djevojčica je rođena nakon uredne trudnoće kao 4. dijete u obitelji, rast i psihomotorni razvoj su bili uredni, osim zaostatka u razvoju govora. Sa 3 godine započeli su toničko-klonički grčevi, a sa 3,5 godine uočava se autistično ponašanje, nakon čega je uslijedila mentalna deterioracija s prestankon govora, smetnjama motorike i povremenim kratkotrajnim javljanjima hiperventilacije. Sa 5 godina povremeno su se uočavali pokreti „pranja ruku“. Velikim opsegom neurometaboličkih pretraga nije se našao uzrok smetnjama. Genetičkom analizom nađena je delecija 25 bp kao jedna od novih mutacija u 4. eksonu (c.881_905del25) gena MECP2. Uslijedili su razni oblici epileptičkih napadaja koji su bili tvrdokorni na antiepileptičku terapiju, uz urednu osnovnu aktivnost na video-elektroencefalogramu. Djevojka ima povišen mišićni tonus, ataktičan hod i može samostalno hodati na širokoj osnovi. U ove djevojke simptomi su počeli kasnije nego u tipičnim slučajevima Rettovog sindroma. Epileptički napadaji su svakodnevni i tvrdokorni na terapiju, a 19-godišnja djevojka još hoda, a najvjerojatniji razlog je međusobna povezanost genotipa i fenotipa

Značenje kontinuiranog mjerenja arterijskog tlaka u djece i adolescenata

The objective of this study was to present our data on ambulatory blood pressure monitoring (ABPM) in children and adolescents referred to our Department because of casual BP elevation over the 95th percentile on at least 3 visits in primary care office. ABPM studies in 139 children, 94 boys and 45 girls, mean age 14.14 (range 4-19) years, were reviewed. A total of 107 (76.98%) children had hypertension according to the ABPM criteria. Primary hypertension (PH) was diagnosed in 89 (64.03%), secondary hypertension (SH) in 18 (12.95%) and white coat hypertension (WCH) in 32 (23.02%) children. In both PH and SH groups, hypertension was predominantly systolic (60.67% and 55.56%, respectively). There was no statistically significant difference in diurnal and nocturnal systolic and diastolic blood pressure (BP) loads between PH and SH groups. The non-dipping phenomenon was detected in 49.44%, 66.66% and 40.62% of children with PH, SH and WCH, respectively. The mean pulse pressure values were 60.41, 58.58 and 52.25 mm Hg in the PH, SH and WCH groups, respectively. A statistically significant difference was found in pulse pressure values between PH and WCH (df=55, t=6.15, p<0.01) groups and between SH and WCH groups (df=31, t=3.18, p=0.001). Target organ damage was diagnosed in 16 (17.98%) children with PH and in 5 (27.78%) children with SH. None of the children with WCH had target organ damage. ABPM is indispensable for establishing the diagnosis of hypertension in children. It is the only reliable method of WCH diagnosis.Cilj istraživanja bio je prikazati naše rezultate kontinuiranog mjerenja arterijskog tlaka (KMAT) u djece i adolescenata upućenih u našu Kliniku zbog povišenog krvnog tlaka (BP) iznad 95. percentile izmjerenog u ordinacijama liječnika primarne zdravstvene zaštite u 3 ili više navrata. Analizirali smo rezultate KMAT-a u 139 djece, 94 dječaka i 45 djevojčica. Srednja dob bila je 14,14 (4-19) godina. Prema nalazu KMAT-a 107 (76,98%) djece imalo je hipertenziju. Primarna hipertenzija (PH) utvrđena je u 89 (64,03%), sekundarna hipertenzija (SH) u 18 (12,95%) i hipertenzija bijele kute (WCH) u 32 (23,02%) djece. I u PH i u SH radilo se većinom o sistoličnoj hipertenziji (60,67% odnosno 55,56%). Nije bilo statistički značajne razlike u vrijednostima postotka povišenog krvnog tlaka iznad 95. centile (engl. BP load) između dnevnog i noćnog sistoličnog i dijastoličnog tlaka između PH i SH. Fenomen non-dipping utvrđen je u 49,44% djece s PH, 66,66% djece sa SH te 40,62% djece s WCH. Srednja vrijednost tlaka pulsa bila je 60,41 mm Hg u PH, 58,58 mm Hg u SH i 52,25 mm Hg u WCH. Statistički značajna razlika nađena je u tlaku pulsa između PH i WCH (df=55, t=6,15, p<0,01), te između SH i WCH (df=31, t=3,18, p=0,001). Oštećenje ciljnih organa ustanovljeno je kod 16 (17,98%) djece s PH i 5 (27,78%) djece sa SH. Oštećenje ciljnih organa nije ustanovljeno kod djece s WCH. KMAT je neophodan za dijagnosticiranje hipertenzije u djece i predstavlja jedinu pouzdanu metodu za dijagnosticiranje WCH

Suočavanje sa stresom u djece s epilepsijom - evaluacija kognitivno-bihevioralne intervencije

A pilot study was conducted to examine the efficiency and satisfaction of cognitive behavioral therapy (CBT) intervention in youth with epilepsy regarding coping strategies. The CBT intervention was based on the main principles and empirically supported cognitive-behavioral techniques. The intervention consists of epilepsy education, stress education, and coping skill strategies. Seventeen children and adolescents aged 9-17 diagnosed with epilepsy for at least one year, with at least average intelligence and no history of serious mental illness completed the CBT intervention during summer camp, providing data on the efficiency of and satisfaction with CBT intervention. Upon completion of the CBT intervention, study subjects achieved significantly higher scores on the following Scale of Coping with Stress subscales: Problem solving; Seeking for social support from friends; Seeking for social support from family; and Cognitive restructuring, for both measures of usage frequency and effectiveness of each subscale. The participants reported a high level of satisfaction with the CBT intervention. This study provided explanation of research limitations and recommendations for future clinical trials.U ovom istraživanju ispitivala se učinkovitost i zadovoljstvo kognitivno-bihevioralnom terapijom (KBT) za strategije suočavanja sa stresom kod djece i adolescenata s epilepsijom. Provedena intervencija KBT temelji se na osnovnim postulatima znanstveno utemeljene KBT. Intervencija se sastojala od edukativnih radionica o epilepsiji kao bolesti, stresu te o strategijama suočavanja sa stresom. Sveukupno 17 djece i adolescenata u dobi 9-17 godina, prosječnih kognitivnih sposobnosti, s dijagnosticiranom epilepsijom najmanje godinu dana te bez komorbiditeta psihičkih bolesti bilo je uključeno u intervenciju KBT tijekom ljetnog kampa. Nakon završetka intervencije KBT na Ljestvici suočavanja sa stresom za djecu i adolescente ispitanici su postigli značajno bolje rezultate na sljedećim podljestvicama: Rješavanje problema, Traženje socijalne podrške od prijatelja, Traženje socijalne podrške od obitelji te Kognitivno restrukturiranje, i to za obje mjere: frekvencija i učinkovitost svake spomenute podljestvice. Ispitanici su potvrdili visoko zadovoljstvo provedenom kognitivno-bihevioralnom intervencijom. Konačno, provedeno istraživanje definiralo je ograničenja u provedenom istraživanju te dalo smjernice i preporuke za slična buduća klinička ispitivanja