Effects of long-term antiepileptic polytherapy on bone biochemical markers in ambulatory children and adolescents and possible benefits of vitamin D supplementation: a prospective interventional study.

PURPOSE: Our aim was to investigate any adverse effects of long-term polytherapy (VPA and add-on-therapy) on bone biochemical markers in ambulatory children and adolescents with epilepsy and the possible benefits of vitamin D supplementation on the same markers. METHODS: In this prospective interventional study, the levels of 25(OH)D and the bone turnover markers of CrossLaps (CTX), total alkaline phosphatase (tALP), osteoprotegerin (OPG), and the receptor activator for nuclear factor kB (RANK) ligand (sRANKL) were determined in forty-two ambulatory children with epilepsy on polytherapy (valproic acid + one or more other from levetiracetam, topiramate, lamotrigine, or rufinamide). The same markers were assessed after a year's supplementation of vitamin D (400 IU/d) and were compared with those of clinically healthy controls. The respective mean (±SD) ages were 11.9 ±â€¯4.6 and 11.4 ±â€¯4.4 yrs. RESULTS: The basal mean 25(OH)D levels in the patients did not differ from controls (23.9 ±â€¯11.5 vs 27.4 ±â€¯13.3 ng/ml), but increased significantly after the vitamin D intake (31.1 ±â€¯13.3 ng/ml, p < 0.01). In parallel, basal serum CTX levels were found to be significantly lower in the patients than controls (0.89 ±â€¯0.63 vs 1.22 ±â€¯0.58 ng/ml, p < 0.02), but not tALP. Osteoprotegerin was higher in the patients (5.7 ±â€¯7.7 pmol/L vs 2.6 ±â€¯1.0 pmol/L, p < 0.03), while sRANKL did not differ. After vitamin D, the CTX levels increased to comparable levels in controls (0.99 ±â€¯0.57 ng/ml), and those of OPG decreased to levels that did not differ from controls (4.9 ±â€¯5.1 pmol/L). The ratio of OPG/sRANKL was higher in patients than controls before treatment (0.030 ±â€¯0.045 vs 0.009 ±â€¯0.005, p < 0.03), but decreased (0.026 ±â€¯0.038) to comparable values in controls later. CONCLUSIONS: These findings imply a lower bone turnover in the young patients on long-term polytherapy (VPA and add-on-therapy), but after one year's vitamin D intake, bone biochemical markers improved.

Evaluation of Genotypes and Epidemiology of Spinal Muscular Atrophy in Greece: A Nationwide Study Spanning 24 Years.

BACKGROUND: Promising genetic treatments targeting the molecular defect of severe early-onset genetic conditions are expected to dramatically improve patients' quality of life and disease epidemiology. Spinal Muscular Atrophy (SMA), is one of these conditions and approved therapeutic approaches have recently become available to patients. OBJECTIVE: Analysis of genetic and clinical data from SMA patients referred to the single public-sector provider of genetic services for the disease throughout Greece followed by a retrospective assessment in the context of epidemiology and genotype-phenotype associations. METHODS: Molecular genetic analysis and retrospective evaluation of findings for 361 patients tested positive for SMA- and 862 apparently healthy subjects from the general population. Spearman rank test and generalized linear models were applied to evaluate secondary modifying factors with respect to their impact on clinical severity and age of onset. RESULTS: Causative variations- including 5 novel variants- were detected indicating a minimal incidence of about 1/12,000, and a prevalence of at least 1.5/100,000. For prognosis a minimal model pertaining disease onset before 18 months was proposed to include copy numbers of NAIP (OR = 9.9;95% CI, 4.7 to 21) and SMN2 (OR = 6.2;95% CI, 2.5-15.2) genes as well as gender (OR = 2.2;95% CI, 1.04 to 4.6). CONCLUSIONS: This long-term survey shares valuable information on the current status and practices for SMA diagnosis on a population basis and provides an important reference point for the future assessment of strategic advances towards disease prevention and health care planning.

Vitamin D supplementation and bone markers in ambulatory children on long-term valproic acid therapy. A prospective interventional study.

PURPOSE: Our aim was to investigate any adverse effects of long-term valproic acid (VPA) therapy on bone biochemical markers in ambulatory children and adolescents with epilepsy, and the possible benefits of vitamin D supplementation on the same markers. METHODS: In this single center, the prospective interventional study levels of 25-hydroxyvitamin D (25OHD) and the bone turnover indices of Crosslaps (CTX), total alkaline phosphatase (tALP), osteoprotegerin (OPG), and the receptor activator for nuclear factor kB (RANK) ligand (sRANKL) were assessed before and after one year of vitamin D intake (400 IU/d) and were compared with those of clinically healthy controls. Fifty-four ambulatory children with mean (±standard deviation [SD]) age 9.0 ±â€¯4.5 yrs on VPA (200-1200 mg/d) long-term monotherapy (mean: 3.2 ±â€¯2.6 yrs) were studied, before and after a year's vitamin D intake (400 IU/d). RESULTS: Nearly half of the cases were vitamin D insufficient/deficient with mean levels 23.1 ±â€¯12.8 vs 31.8 ±â€¯16.2 ng/mL of controls (p = 0.004) and after the year of vitamin D intake increased to 43.2 ±â€¯21.7 ng/mL (p < 0.0001). In parallel, serum CTX and tALP had a decreasing trend approaching control levels but OPG and sRANKL did not change and were not different from controls. However, after vitamin D intake, a positive correlation was seen between 25OHD and OPG but not before. CONCLUSIONS: The findings imply a higher bone turnover in the young patients on long-term VPA therapy that decreased after vitamin D intake.

UGT1A6- and UGT2B7-related valproic acid pharmacogenomics according to age groups and total drug concentration levels.

AIM: The role of UGT1A6 and UGT2B7 polymorphisms and the impact of total drug plasma concentration in valproic acid (VPA) pharmacogenomics. PATIENTS & METHODS: A total of 134 Greek patients were recruited (76 adults). Patients were genotyped for UGT1A6 19T>G, 541A>G and 552A>C and UGT2B7 802T>C polymorphisms. Patients' demographic and clinical data were registered. Natural logarithm of concentration-to-dose ratio (CDR) was also calculated as the final outcome. RESULTS: No significant genotype-related differences in VPA metabolism were noted among various subgroups. An increased lnCDR ratio was noted in children patients compared with adults suggesting increased metabolic capability in younger ages. CONCLUSION: UGT1A6 and UGT2B7 genotypes were not related to significant changes in VPA metabolism, even after controlling for total drug concentration levels. Younger ages were associated with increased VPA clearance rate.

Diffusion tensor imaging in children with tuberous sclerosis complex: tract-based spatial statistics assessment of brain microstructural changes.

BACKGROUND: There is evidence of microstructural changes in normal-appearing white matter of patients with tuberous sclerosis complex. OBJECTIVE: To evaluate major white matter tracts in children with tuberous sclerosis complex using tract-based spatial statistics diffusion tensor imaging (DTI) analysis. MATERIALS AND METHODS: Eight children (mean age ± standard deviation: 8.5 ± 5.5 years) with an established diagnosis of tuberous sclerosis complex and 8 age-matched controls were studied. The imaging protocol consisted of T1-weighted high-resolution 3-D spoiled gradient-echo sequence and a spin-echo, echo-planar diffusion-weighted sequence. Differences in the diffusion indices were evaluated using tract-based spatial statistics. RESULTS: Tract-based spatial statistics showed increased axial diffusivity in the children with tuberous sclerosis complex in the superior and anterior corona radiata, the superior longitudinal fascicle, the inferior fronto-occipital fascicle, the uncinate fascicle and the anterior thalamic radiation. No significant differences were observed in fractional anisotropy, mean diffusivity and radial diffusivity between patients and control subjects. No difference was found in the diffusion indices between the baseline and follow-up examination in the patient group. CONCLUSION: Patients with tuberous sclerosis complex have increased axial diffusivity in major white matter tracts, probably related to reduced axonal integrity.

Comparative study of the health-related quality of life of children with epilepsy and their parents.

PURPOSE: We aimed to evaluate the health-related quality of life (HRQoL) of schoolchildren with epilepsy and its determinants and the HRQoL of their parents in comparison with those of healthy children and their parents. MATERIALS AND METHODS: The study sample comprised 100 children with epilepsy (58 males), 8-16 years of age, diagnosed at least 6 months earlier. The children with epilepsy were divided into two subgroups: A, with well controlled idiopathic epilepsy, and B, with drug-resistant or symptomatic epilepsy and with concomitant neurodevelopmental problems. A control group consisted of 100 healthy age- and gender-matched children. One parent in each family completed two questionnaires standardized for use in Greece: KIDSCREEN-27 (version for parents) to assess the HRQoL of the children and SF-12 to assess the parental HRQoL. For each of the five dimensions of KIDSCREEN-27 and for the physical and mental component scales of the SF-12 tool, the standardized mean difference (SMD) was used for comparison between the various groups and subgroups. Linear regression analysis was used to explore the effect of specific illness-related factors on the five dimensions of KIDSCREEN-27 in the children with epilepsy. RESULTS: The parent-reported scores on KIDSCREEN-27 of the children with epilepsy were worse overall than those of healthy children, but the difference reached statistical significance only for the dimensions of "physical well-being" (p = 0.001) and "school environment" (p < 0.001). The differences were greater in adolescents (age group: 13.5-16years). The worst scores were recorded in subgroup B, the children with severe epilepsy, in the dimensions "physical well-being" (p < 0.001), "school environment" (p < 0.0001), and "peers and social support" (p = 0.044). The factors found to have a significant effect on all dimensions were mental retardation, physical disability, abnormal brain imaging findings, learning problems, and, to a lesser degree, administration of a large number of antiepileptic drugs and prolonged treatment. The parents of children with resistant epilepsy and accompanying neurodevelopmental problems scored significantly worse on the SF-12 mental health scale than those of healthy children (p < 0.001). CONCLUSIONS: Epilepsy, particularly severe epilepsy with concomitant neurodevelopmental problems, adversely affects the HRQoL of both schoolchildren and their parents.

A rare case report of simultaneous presentation of myopathy, Addison's disease, primary hypoparathyroidism, and Fanconi syndrome in a child diagnosed with Kearns-Sayre syndrome.

UNLABELLED: Kearns-Sayre syndrome (KSS) is a rare mitochondrial DNA deletion syndrome defined as the presence of ophthalmoplegia, pigmentary retinopathy, onset less than age 20 years, and one of the following: cardiac conduction defects, cerebellar syndrome, or cerebrospinal fluid protein above 100 mg/dl. KSS may affect many organ systems causing endocrinopathies, encephalomyopathy, sensorineural hearing loss, and renal tubulopathy. Clinical presentation at diagnosis is quite heterogeneous and, usually, few organs are affected with progression to generalized disease early in adulthood. We present the case of a boy with KSS presenting at the age of 5 years with myopathy, Addison's disease, primary hypoparathyroidism, and Fanconi syndrome. The proper replacement treatment along with the administration of mitochondrial metabolism-improving agents had a brief ameliorating effect, but gradual severe multisystemic deterioration was inevitable over the next 5 years. CONCLUSION: This report highlights the fact that in case of simultaneous presentation of polyendocrinopathies and renal disease early in childhood, KSS should be considered.

Caroli's disease: Description of a case with a benign clinical course.

Caroli's disease is a rare congenital disorder characterized by cystic dilatation of the large in-trahepatic bile ducts. The most frequent complications due to biliary stasis are cholelithiasis, cholangitis and sepsis as well as an increased risk of cholangiocarcinoma. Patients may have a history of intermittent abdominal pain, pruritus and/or symptoms of cholangitis. It is rarely diagnosed in childhood. A 12-year-old boy with isolated Caroli's disease is described. This child presented at the age of 2 years, with 4 episodes of recurrent bacterial infections. Interestingly he remained asymptomatic for over 10 years, between the second and third episode. During the 4th episode, when he presented with fever and slight abdominal pain, the diagnosis was made on the basis of radiological findings: U/S, CT, MRI and especially with MRCP, in relation with a more typical picture, resembling cholangitis. Since then he has been followed-up systematically for ten years and remains in good clinical condition without further relapses and with unchanged radiological findings. This atypically benign course of Caroli's disease, with intermittent asymptomatic periods, without any treatment, is very rare.

Idiopathic intracranial hypertension and facial palsy: case report and review of the literature.

We present the case of an 11-year-old obese girl who presented with idiopathic intracranial hypertension affecting first the lateral abducens nerve. She received acetazolamide, but 5 days later she developed lateral, peripheral facial palsy. Imaging evaluation was normal, which primarily excluded cerebral venous thrombosis and sustained the initial diagnosis. Despite some complicating factors (obesity, elevated intracranial pressure), prednisolone was administered for a short-term period to counteract the facial palsy. Ophthalmological residuals resolved within almost 1.5 months, while facial palsy receded after 4 months. Peripheral facial palsy is an extremely rare, but not unknown condition in idiopathic intracranial hypertension. As a symptom, it should be investigated thoroughly, primarily to exclude cerebral venous sinus thrombosis, before it can be attributed to idiopathic intracranial hypertension. As far as treatment is concerned, corticosteroids can be added to the initial treatment with acetazolamide, without worsening already elevated intracranial hypertension or ophthalmologic findings.

A prospective multicenter study of childhood encephalitis in Greece.

Encephalitis is associated with significant childhood morbidity and mortality worldwide, however not much is known about the contemporary epidemiology and outcome. In this prospective multicenter pediatric encephalitis study conducted in Greece for 3 years, 42 cases were diagnosed and the presumptively or definitely causative pathogen was identified in 24 (57.1%). Leading pathogens included herpes viruses (10 patients), enteroviruses (6), and Streptococcus pneumoniae (2). No fatalities were observed; however, deficits remained in 5 of 42 (11.9%) children.

Blue rubber bleb nevus syndrome with simultaneous neurological and skeletal involvement.

Blue rubber bleb nevus syndrome (BRBNS) is a rare disorder characterized by venous malformations usually affecting the skin and the gastrointestinal tract. These skin haemangiomas are present at birth and deteriorate as the body grows, causing primarily cosmetic problems. The haemangiomas of the gastrointestinal tract may appear later in life and may bleed, causing chronic anaemia, or may present with severe complications such as rupture, intestinal torsion, and intussusception. Other organs may also be involved. This article describes a 13-year-old boy with multiple haemangiomas of the skin, the mucous membranes, and the gastrointestinal tract, which caused anaemia and ileoileic intussusception. In this patient, the nervous system was significantly affected with a haemangioma of the left occipital lobe, with complications of stroke. He also had multiple paravertebral heamangiomas, which caused pressure signs and symptoms. This boy suffered from complex partial and generalized seizures and cerebral palsy. Multiple skeletal anomalies were also present from birth. In the relevant literature, this is the first case of BRBNS with simultaneous neurological and skeletal involvement. Such cases should be recognized early, as they can lead to serious multiple health problems and handicaps.