COX-1 and COX-2 polymorphisms in susceptibility to cerebral palsy in very preterm infants.

Cerebral palsy (CP) is a nonprogressive motor disorder caused by white matter damage in the developing brain. Recent epidemiological and clinical data suggest intrauterine infection/inflammation as the most common cause of preterm delivery and neonatal complications, including CP. Cyclooxygenases are key enzymes in the conversion of arachidonic acid to prostaglandins. The COX family consists of two isoforms, COX-1 and COX-2. In the brain, COX-2 is constitutively expressed at high levels on pyramidal neurons, while COX-1 is predominantly expressed by microglia and can be upregulated in pathological conditions, such as infection, ischemia and traumatic brain injury. Single nucleotide polymorphisms in the COX-1 and COX-2 gene could have profound effects on COX-1 and COX-2 expression and, directly or indirectly, influence the pathogenesis, development and severity of CP. In this study we investigated the association between single nucleotide polymorphisms of the COX-1 and COX-2 gene and susceptibility to cerebral palsy in very preterm infants. The results of our study showed the association between COX-1 high expression genotype (-842 AA) and COX-1 high expression allele -842A and risk of CP in infants with cystic periventricular leucomalacia (cPVL). Our results support an important role of COX-1 enzyme on microglial activation during neuroinflammation resulting in huge neuroinflammatory response and the proinflammatory mediator overproduction, with the serious white matter damage and CP development as a consequence.

The association between proinflammatory cytokine polymorphisms and cerebral palsy in very preterm infants.

Cerebral palsy (CP) is a nonprogressive motor disorder caused by white matter damage in the developing brain and is often accompanied with cognitive and sensory disabilities. The risk of CP is higher among infants born preterm than in more mature infants. Intrauterine infection/inflammation, activation of the cytokine network and elevated levels of proinflammatory cytokines in neonatal blood or in amniotic fluid to which the preterm infant is exposed, has been identified as the most common cause of preterm delivery, periventricular leukomalacia (PVL) and CP. The aim of our study was to evaluate the possible association of four TNFα promoter single nucleotide polymorphisms (SNPs) (-1031 T/C, -857 C/T, -308 G/A and -238 G/A), two IL1ß SNPs (-511 C/T and +3954 C/T) and one IL6 (-174 C/G) polymorphism with susceptibility to CP in very preterm infants. Statistically significant association between TNFα -1031 T/C high expression genotypes (TC and CC) (OR, 2.339; p=0.016) as well as between TNFα -1031 C high expression allele (OR, 2.065; p=0.013) and risk of CP was observed. In addition, statistically significant association was found between TNFα TC, CC, GG, GG -1031/-857/-308/-238 genotypes combination (OR, 3.286; p=0.034) and risk of CP. Statistically significant association between IL1ß TT, CC -511/+3954 genotypes combination and risk of CP (OR, 4.000; p=0.027) was also found. In CP patients with cystic PVL (cPVL) statistically significant association was found between TNFα -1031 T/C high expression genotypes (TC and CC) (OR, 2.361; p=0.038), IL1ß -511 C/T high expression genotype TT (OR, 3.215; p=0.030) as well as IL1ß -511 T high expression allele (OR, 1.956; p=0.019) and risk of CP. Statistically significant association was also found in patients with cPVL between TNFα TC, CC, GG, GG -1031/-857/-308/-238 genotypes combination (OR, 4.107; p=0.024), as well as IL1ß TT, CC -511/+3954 genotypes combination (OR, 7.333; p=0.005) and risk of CP. Our results suggest the role of TNFα and IL1ß polymorphisms which have previously been associated with higher circulating levels of these cytokines in genetic susceptibility to white matter damage and consequently CP in very preterm infants.

[Electroencephalography in status epilepticus in sleep (ESES) in various clinical pictures]. / Elektroencefalografski epilepticni status tijekom spavanja u razlicitim klinickim slikama.

Electroencephalographic epileptic status during sleep (ESES--according to Electrical Status Epilepticus in Sleep) is characterized with paroxysmal attacks of 1.5-3.5 (even to 5) Hz/s spikes and waves during NREM. A case is presented of a 7-year-old boy who had normal development until 3 years of age when epileptic attacks started. First to appear were left-sided, hemifacial twitches with orofacio-lingual deficits. Despite treatment with various types and combinations of antiepileptic medications, the attacks persisted and became more frequent. About a year after the onset of the disease, the spectrum of epileptic attacks had expanded (left-sided tonic-clonic, atonic-astatic, myoclonic, atypical absences, and then drop attacks and negative myoclonic seizures became dominant). The boy appeared mentally retarded. During the course of the disease, the diagnoses varied: hemifacial twitches, partial epilepsy, left-sided partial epilepsy, atypical benign epilepsy, Landau-Kleffner syndrome, myoclonic-astatic epilepsy. A year and a half after the onset of the disease EEG (polysomnographic whole-night recording) revealed electrical status epilepticus in sleep (ESES) with spike-wave index > 85%. It appeared that this was continuous spike and wave during slow wave sleep syndrome (CSWS) with characteristic attacks, bifrontal atrophies on brain CT and right frontotemporal EEG focus. Treatment with valproate and ethosuximide combined with vigabatrin and clonazepam seemed to be effective. In the last 20 months ESES is rare and transitory, mental and neuropsychological functions have improved, but he still has several hemifacial twitches daily. The two brain MRI scans were normal. Differential diagnosis can be atypical benign epilepsy (suspected familial diagnosis). Family history of atopy, 'persistent' colds and obstructive bronchitis in the boy and treatment with antiepileptic medications (especially carbamazepine, phenobarbital and phenytoin) could have been provoking or modulating factors of the epileptic disease. So far we have not identified an epileptic syndrome because it seems that multiple clinical pictures overlap. ESES could be diagnosed using polysomnographic whole-night recording with calculated spike-wave index. Follow-up of the spike-wave index could be useful in differentiation, but not in precise diagnosis of epileptic syndrome. Clinical course could be modulated by different factors. Continuous following over a long period could be helpful in the classification of epilepsy.