TNF-α gene polymorphisms and juvenile idiopathic arthritis: Influence on disease outcome and therapeutic response.

OBJECTIVE: To investigate the genetic contribution of TNF-α gene polymorphisms on the disease course and therapeutic response in patients with juvenile idiopathic arthritis (JIA). METHODS: 74 Caucasian patients with JIA were recruited with a control group of 77 healthy children. DNA was extracted for analysis of TNF-α gene promoter polymorphisms at positions -163, -244, -238, -376, and -308. RESULTS: No SNPs at position -163 were observed, while we observed only SNPs at positions -244 and -376 in the controls. No differences were observed in the prevalence of SNPs at -238 and -308 between JIA and controls. In JIA patients no significant differences were observed between the -238 and -308 G/A genotypes and different disease phenotypes. We observed a significant lower disease activity expressed in the carriers of -308 GG genotype with respect to GA and AA genotypes after 6 (p = 0.008 and p = 0.013, respectively) and 12 months of disease (p = 0.02 and p = 0.08, respectively). Also the -238 GG genotypes showed a better disease course after 12 months of disease. Moreover, the -238/-308 GG genotypes presented the higher reduction of disease activity both after 6 (p < 0.01 vs GA and p < 0.01 vs AA) and 12 months from baseline (p < 0.01 vs GA and p < 0.01 vs AA). After 12 months of biologic therapy, a significant higher disease activity was observed in patients with genotype -308 AA respect to both GA (p = 0.012) and GG (p = 0.016). CONCLUSIONS: JIA patients carrying the TNF-α -308 GA/AA and -238 GA genotypes are associated with a worse prognosis and with a lower response to anti-TNF-α drugs.

Efficacy of an interleukin-1ß receptor antagonist (anakinra) in idiopathic recurrent pericarditis.

Pericarditis may recur in up to 30 % of adult patients, but recurrent pericarditis is a rare disease in childhood. The etiology of the initial attack and the causes of recurrences often remain unknown. Recurrent pericarditis is accompanied by a high morbidity rate and may represent a challenge to the clinician due to problems in management. Therapeutic strategies are not specific and include nonsteroidal antiinflammatory drugs, corticosteroids, immunosuppressive drugs, colchicine, and pericardiectomy. Controlled trials have demonstrated that colchicine can reduce the recurrent rate of pericarditis, whereas early corticosteroid therapy promotes recurrences. Anakinra, a recombinant human interleukin-1ß receptor antagonist, is a promising new biologic agent for the treatment of autoinflammatory diseases such as cryopyrinopathies, tumor necrosis factor receptor-associated periodic syndrome, and hyperimmunoglobulinemia D with periodic fever syndrome. This report describes an 11-year-old boy successfully treated with anakinra for a steroid-dependent recurrent pericarditis unresponsive to conventional treatment.

Autoinflammatory syndromes: diagnosis and management.

During the last decades the description of autoinflammatory syndromes induced great interest among the scientific community. Mainly rheumatologists, immunologists and pediatricians are involved in the discovery of etiopathogenesis of these syndromes and in the recognition of affected patients. In this paper we will discuss the most important clues of monogenic and non-genetic inflammatory syndromes to help pediatricians in the diagnosis and treatment of these diseases.

Gradenigo's syndrome with lateral venous sinus thrombosis: successful conservative treatment.

Gradenigo's syndrome (GS) is a rare disease characterised by the triad otitis media, pain in the region innervated by the first and the second division of trigeminal nerve and abducens nerve palsy. Septic sinus thrombosis is one of the most frequent and relevant complication of GS; it is often due to persistent damage and late diagnosis. Computed tomography (CT) scan and magnetic resonance imaging (MRI) allow the correct diagnosis in most cases. Surgical therapy may be necessary for a better and more rapid resolution of the disease. We report the case of a 4-year-old child that was admitted for facial nerve palsy and abducens nerve palsy subsequent to a 2-week persistent pain in the right ear. MRI showed infective acute process of the right mastoid and partial ipsilateral sinus thrombophlebitis. The child was treated with high-dose intravenous antibiotics and with oral anticoagulants. A complete resolution of symptoms and radiological alterations were observed within 7 weeks. In conclusion, lateral sinus thrombosis and Gradenigo's syndrome are rare but potential fatal complications of otitis media and mastoiditis. High-dose intravenous antibiotics and a low dose of anticoagulant can achieve a complete recovery without surgery.

Thyroid hormones in children with epilepsy during long-term administration of carbamazepine and valproate.

OBJECTIVE: This study evaluates the effects of long-term carbamazepine (CBZ) and valproate acid (VPA) therapy on thyroid function in epileptic children. DESIGN: A prospective study performed in 32 newly diagnosed pediatric patients, subdivided into two groups: 18 patients treated with CBZ and 14 patients treated with VPA. Thirty-two sex- and age- matched subjects served as controls. METHODS: Serum TSH, thyroxine (T(4)), triiodothyronine (T(3)), free thyroxine (fT(4)), free triiodothyronine (fT(3)), thyroid peroxidase antibodies (TPO-Ab), and thyroglobulin antibodies (TG-Ab) were evaluated at baseline and at the 3rd, 6th, and 12th month in all patients and in the control group. A TRH stimulation test was performed in all epileptic patients at baseline and at the 3rd, 6th, and 12th month evaluations while in controls only baseline assessment was carried out. RESULTS: At baseline evaluation, thyroid function was normal in all epileptic children. After 3 months, CBZ-treated patients showed serum T(4) and fT(4) levels significantly lower than baseline evaluation and control subjects. Serum T(4) and fT(4) concentrations were unaffected by VPA monotherapy. Serum T(3) and fT(3) were normal in both CBZ-treated and VPA-treated patients. TRH test was normal in all patients. At 6th and 12th month evaluations, the same alterations were present in CBZ-treated patients while thyroid function remained normal in VPA-treated patients. TRH test responses were normal in all epileptic patients. TPO-Ab and TG-Ab were always absent in all patients. CONCLUSIONS: Our data suggest that VPA monotherapy does not alter thyroid hormones. On the contrary, alterations of thyroid hormones occur in CBZ-treated children. However, the patients are euthyroid and thyroid hormone alterations are not associated with clinical or subclinical hypothyroidism.

Antiepileptic drugs and thyroid function.

Antiepileptic drugs (AED) are a heterogeneous group of compounds widely used in both adults and children. These drugs are related to various adverse effects involving several organs and endocrinological and metabolic functions. In particular, relevant effects on thyroid function have been described. Subclinical hypothyroidism and alterations in thyroid hormone serum levels are reported in the literature; phenytoin, valproate and carbamazepine, in particular, seem to be involved in these alterations. The aim of this review is to analyse critically the principal alterations in thyroid function caused by AED therapy.

Increased oxidative stress in epileptic children treated with valproic acid.

PURPOSE: To determine influence of Valproic Acid (VPA) treatment on oxidative status in non-obese and overweight epileptic children. METHODS: A prospective study was conducted at the Departments of Pediatrics, University of Chieti and Bologna. Thirty-one epileptic children were studied before and after 1 year of therapy with VPA. Also 31 sex-, age- and BMI-matched healthy controls were evaluated. Insulin and glucose serum levels and plasma Vitamin E, Lag phase and Malondialdehyde (MDA) levels were determined. RESULTS: Before the beginning of VPA therapy, insulin and glucose serum values and plasma Vitamin E, Lag phase and MDA levels were normal in all subjects. At the end of follow-up, 11 (35.5%) epileptic patients developed obesity. In obese VPA treated patients, we found lower serum levels of antioxidant (Vitamin E, p<0.001) and higher levels of oxidant markers (MDA, p<0.001; Lag phase, p<0.001) compared to VPA-treated non-obese patients and controls. CONCLUSION: After 1 year of VPA therapy oxidative stress occurs only in overweight children. This increase in the levels of oxidant markers, probably caused by obesity, might contribute to the development of endothelial dysfunction and atherosclerosis later in life.

Topiramate: its pharmacological properties and therapeutic efficacy in epilepsy.

Since 1990 eight new antiepileptic drugs (AEDs) have been developed. Among these new drugs, Topiramate (TPM) is one of the latest AEDs available for treating drug resistant partial epilepsy both in adults and in children. The mechanisms underlying TPM antiepileptic activity are still incompletely understood. However, TPM, a sulfamate-substituted derivative of the naturally occurring monosaccharide D-fructose, has a different structure from other known AEDs. The antiepileptic activity of TPM in animal models of partial and generalized tonic-clonic seizures has been shown to be more effective as compared to other AEDs. Proposed mechanisms of action include reduction of epileptiform discharges through a voltage-dependent block of Na(+) channels, enhancement of the activity of gamma-aminobutyrate at some subtypes of gamma-aminobutyrate receptors, and antagonism of non- N-methyl-D-aspartate (NMDA) glutamate receptors. The pharmacokinetic profile of TPM, which is characterized by its rapid and almost complete absorption after oral administration, linear pharmacokinetics, minimal protein binding and predominantly renal excretion, makes the drug a good option for the treatment. TPM was found to be effective and well tolerated in many studies conducted in adults and pediatric patients suffering from epilepsy. This review, summarising the main studies in this field, provides an overview of the current knowledge about the relevant pharmacological and clinical information on the efficacy and tolerability of TPM.