Epilepsy in children with periventricular leukomalacia

Objective

We aimed to analyze the development of epilepsy in a patient group with periventricular leukomalacia followed at a tertiary pediatric neurology center.

Patients and methods

The study included 108 children aged between 2 and 8 years with radiologically proven periventricular leukomalacia who had been regularly observed at the Istanbul University, Istanbul Faculty of Medicine, Department of Pediatrics, Pediatric Neurology outpatient clinic between January 2006 and December 2011.

Results

Neonatal seizures were reported in 22 patients (20.3%), 14 of whom developed epilepsy. A significant correlation was found between neonatal seizures and prematurity and newborn asphyxia (p = 0.013 and p = 0.010, respectively). Epilepsy developed in 35 patients (32.4%), history of neonatal seizures and more severe loss of white matter, periventricular hyperintensity and corpus callosum involvement were found to be correlated with epilepsy (p = 0.001, p = 0.004, p = 0.016, and p = 0.004, respectively). The most common seizure pattern observed was generalized tonic clonic seizures (n = 13) and complex partial seizures (n = 11). Those with focal EEG findings had a significantly better neurodevelopmental and cognitive level than those with multifocal/generalized EEG findings (p = 0.024). Seizures continued with varying frequency in 14 epileptic patients (40%) despite antiepileptic treatment.

Conclusion

Almost a third of patients with periventricular leukomalacia develop epilepsy that can be intractable in substantial part. Neonatal seizures and severe MRI findings are important clues that can indicate the development of epilepsy in these patients.     

Is late adolescence a real risk factor for an adverse outcome of pregnancy?

Objective: To compare the obstetrical and neonatal outcomes of late adolescent (LA) and adult pregnancies.

Methods: Between January 2012 and December 2012, a total of 313 late adolescent pregnant aged between 16 and 19 years and 418 adult pregnant women aged between 20 and 35 years having given birth in our maternity service were enrolled into this case–control study. The demographic and clinical data were reviewed from hospital database and patients’ medical records.

Results: The incidence of preterm birth (PB) in the LA group was significantly higher than in the adult group (p?=?0.001), while the incidence of gestational diabetes mellitus was significantly lower (p?=?0.001). The mean birth weight and the rate of delivered macrosomic fetuses in the study group were lower than in the control group (p?=?0.03). The LA group had significantly higher rate of vaginal delivery when compared to the adult group (p?=?0.001). Both the rate of pregnancy induced hypertensive disorders and postpartum hemorrhage were not statistically different between the two groups (p?=?0.31; p?=?0.38, respectively). The LA group had lower rate of stillbirth when compared to the adult group; however, the difference was statistically insignificant (0.3% versus 1.2%) (p?=?0.24).

Conclusions: The LA pregnancy should be closely followed up during their antenatal care period due to the significantly higher rate of PB.     

Peripheral neuropathy in patients with diabetes mellitus presenting as Bell's palsy

The aim of this study is to evaluate the peripheral nerves in diabetes mellitus with or without peripheral facial paralysis (PFP). A total of 49 diabetic patients with PFP within the last year (23 females, mean age 60.3 +/- 9.3), and 83 diabetic patients without PFP (41 females, mean age 59.5 +/- 9.9) were enrolled. The neurological examination, eye-blinking response, needle EMG and electrophysiological parameters of peripheral nerves were evaluated. The neuropathic pain, other positive and negative sensory symptoms were statistically more frequent in controls than the PFP group, while no difference was noted in total neuropathy score. Sural sensorial nerve action potential amplitudes were same in both groups, but median nerve amplitudes were significantly lower in the PFP group. It is suggested that PFP is not a part of multifocal neuropathy in diabetes mellitus. However, at least some parts of the nerve conduction studies were involved, focal neuropathies were more frequent while sensory neuropathies with small nerve fiber involvement were less frequent in diabetes patients with PFP.     

The endogenous cannabinoid anandamide inhibits cromakalim-activated K+ currents in follicle-enclosed Xenopus oocytes

The effect of the endogenous cannabinoid anandamide on K(+) currents activated by the ATP-sensitive potassium (K(ATP)) channel opener cromakalim was investigated in follicle-enclosed Xenopus oocytes using the two-electrode voltage-clamp technique. Anandamide (1-90 microM) reversibly inhibited cromakalim-induced K(+) currents, with an IC(50) value of 8.1 +/- 2 microM. Inhibition was noncompetitive and independent of membrane potential. Coapplication of anandamide with the cannabinoid type 1 (CB(1)) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR 141716A) (1 microM), the CB(2) receptor antagonist N-[(1S)endo-1,3,3-trimethyl bicyclo heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528) (1 microM), or pertussis toxin (5 microg/ml) did not alter the inhibitory effect of anandamide, suggesting that known cannabinoid receptors are not involved in anandamide inhibition of K(+) currents. Similarly, neither the amidohydrolase inhibitor phenylmethylsulfonyl fluoride (0.2 mM) nor the cyclooxygenase inhibitor indomethacin (5 microM) affected anandamide inhibition of K(+) currents, suggesting that the effects of anandamide are not mediated by its metabolic products. In radioligand binding studies, anandamide inhibited the specific binding of the K(ATP) ligand [(3)H]glibenclamide in the oocyte microsomal fractions, with an IC(50) value of 6.3 +/- 0.4 microM. Gonadotropin-induced oocyte maturation and the cromakalim-acceleration of progesterone-induced oocyte maturation were significantly inhibited in the presence of 10 microM anandamide. Collectively, these results indicate that cromakalim-activated K(+) currents in follicular cells of Xenopus oocytes are modulated by anandamide via a cannabinoid receptor-independent mechanism and that the inhibition of these channels by anandamide alters the responsiveness of oocytes to gonadotropin and progesterone.     

Trunk muscle strength in relation to balance and functional disability in unihemispheric stroke patients

OBJECTIVE: To evaluate trunk muscle strength in unihemispheric stroke patients and to assess how it relates to body balance and functional disability in this patient group. DESIGN: This prospective case-comparison study investigated isometric and isokinetic reciprocal trunk flexion and extension strength at angular velocities in 38 unihemispheric stroke patients and 40 healthy volunteers. The Berg balance scale was used to assess balance and stability, and the FIM instrument was used to evaluate functional disability in the patient group. Patients were evaluated as soon as they were able to stand long enough for testing. RESULTS: Peak torque values for trunk flexion and extension were lower in the stroke patients than in the controls. The differences were significant for trunk flexion and for trunk extension. In both groups, peak torque values for trunk flexors were greater than peak torque values for trunk extensors. There was a significant positive correlation between trunk muscle strength and Berg balance scale score at discharge. Trunk muscle strength was not correlated with FIM total score or FIM motor score, but the locomotion-transfers FIM subscore at discharge was positively correlated with trunk muscle torque values, except for isometric extension. CONCLUSION: The findings indicate trunk flexion and extension muscle weakness in unihemispheric stroke patients, which can interfere with balance, stability, and functional disability.     

The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion-mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase

Primary drug resistance is a major problem in multiple myeloma, an incurable disease of the bone marrow. Cell adhesion-mediated drug resistance (CAM-DR) causes strong primary resistance. By coculturing multiple myeloma cells with bone marrow stromal cells (BMSCs), we observed a CAM-DR of about 50% to melphalan, treosulfan, doxorubicin, dexamethasone, and bortezomib, which was not reversed by secreted soluble factors. Targeting the adhesion molecules lymphocyte function-associated antigen 1 (LFA-1) and very late antigen 4 (VLA-4) by monoclonal antibodies or by the LFA-1 inhibitor LFA703 reduced CAM-DR significantly. Only statins such as simvastatin and lovastatin, however, were able to completely restore chemosensitivity. All these effects were not mediated by deadhesion or reduced secretion of interleukin 6. Targeting geranylgeranyl transferase (GGTase) and Rho kinase by specific inhibitors (GGTI-298 and Y-27632), but not inhibition of farnesyl transferase (FTase) by FTI-277, showed similar reduction of CAM-DR. Addition of geranylgeranyl pyrophosphate (GG-PP), but not of farnesyl pyrophosphate (F-PP), was able to inhibit simvastatin-induced CAM-DR reversal. Our data suggest that the 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA)/GG-PP/Rho/Rho-kinase pathway mediates CAM-DR and that targeting this pathway may improve the efficacy of antimyeloma therapies by reduction of CAM-DR.     

Myeloma in patients younger than age 50 years presents with more favorable features and shows better survival: an analysis of 10 549 patients from the International Myeloma Working Group

We analyzed the presenting features and survival in 1689 patients with multiple myeloma aged younger than 50 years compared with 8860 patients 50 years of age and older. Of the total 10 549 patients, 7765 received conventional therapy and 2784 received high-dose therapy. Young patients were more frequently male, had more favorable features such as low International Staging System (ISS) and Durie-Salmon stage as well as less frequently adverse prognostic factors including high C-reactive protein (CRP), low hemoglobin, increased serum creatinine, and poor performance status. Survival was significantly longer in young patients (median, 5.2 years vs 3.7 years; P < .001) both after conventional (median, 4.5 years vs 3.3 years; P < .001) or high-dose therapy (median, 7.5 years vs 5.7 years; P = .04). The 10-year survival rate was 19% after conventional therapy and 43% after high-dose therapy in young patients, and 8% and 29%, respectively, in older patients. Multivariate analysis revealed age as an independent risk factor during conventional therapy, but not after autologous transplantation. A total of 5 of the 10 independent risk factors identified for conventional therapy were also relevant for autologous transplantation. After adjusting for normal mortality, lower ISS stage and other favorable prognostic features seem to account for the significantly longer survival of young patients with multiple myeloma with age remaining a risk factor during conventional therapy.     

European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma

Multiple myeloma management has undergone profound changes in the past thanks to advances in our understanding of the disease biology and improvements in treatment and supportive care approaches. This article presents recommendations of the European Myeloma Network for newly diagnosed patients based on the GRADE system for level of evidence. All patients with symptomatic disease should undergo risk stratification to classify patients for International Staging System stage (level of evidence: 1A) and for cytogenetically defined high- versus standard-risk groups (2B). Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit patients remains the standard of care (1A). Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone (1A), or with cyclophosphamide and dexamethasone (2B). Currently, allogeneic stem cell transplantation may be considered for young patients with high-risk disease and preferably in the context of a clinical trial (2B). Thalidomide (1B) or lenalidomide (1A) maintenance increases progression-free survival and possibly overall survival (2B). Bortezomib-based regimens are a valuable consolidation option, especially for patients who failed excellent response after autologous stem cell transplantation (2A). Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients (1A). Melphalan-prednisone-lenalidomide with lenalidomide maintenance increases progression-free survival, but overall survival data are needed. New data from the phase III study (MM-020/IFM 07-01) of lenalidomide-low-dose dexamethasone reached its primary end point of a statistically significant improvement in progression-free survival as compared to melphalan-prednisone-thalidomide and provides further evidence for the efficacy of lenalidomide-low-dose dexamethasone in transplant-ineligible patients (2B).     

The long-term results of childhood acute lymphoblastic leukemia at two centers from Turkey: 15 years of experience with the ALL-BFM 95 protocol

Dramatic progress in the treatment of childhood acute lymphoblastic leukemia (ALL) has been achieved during the last two decades in Western countries, where the 5-year event-free survival (EFS) rate has risen from 30 to 85 %. However, similarly high cure rates have not always been achieved in all centers in developing countries due to limited sources. We evaluated the treatment results of the ALL-Berlin–Frankfurt–Münster (BFM) 95 protocol as used between 1995 and 2009 in the pediatric hematology departments of two university hospitals. A retrospective analysis of 343 children newly diagnosed with ALL (M/F 200/143, median age 6.8 years) was performed. The overall survival (OS) and EFS according to age, initial leukocyte count, immunophenotype, chemotherapy responses (on days 8, 15, and 33), and risk groups were analyzed by Kaplan–Meier survival analysis. Median follow-up time was 6.4 years. Complete remission was achieved in 97 % of children. Five-year EFS and OS were found to be 78.4 and 79.9 %, respectively. Children younger than 6 years old had significantly better EFS and OS (83.7 and 85.2 %) than children aged ≥6 years (71.4 and 72.8 %). Adolescents achieved 63 % EFS and 65 % OS. Patients who had initial leukocyte counts of <20?×?10⁹/L had better EFS and OS (82.2 and 84.6 %) than children with higher initial leukocyte counts (72.6 and 72.6 %). EFS for B-cell precursor and T-cell ALL was 81.5 and 66.7 %, respectively. Children with a good response to prednisolone on day 8 (87 %) achieved significantly better EFS and OS (81.2 and 81.9 % vs. 55.3 and 60.5 %). Children whose bone marrow on day 15 was in complete remission had higher EFS and OS (83.7 and 86.6.1 % vs. 56.4 and 61.5 %). Children in the standard-risk and medium-risk groups obtained statistically significantly higher EFS (95.5 and 82.7 %) and OS (97.7 and 82.3 %) compared to the high-risk group (EFS 56.3 %, OS 63.4 %). The relapse rate was 14.8 %. The median relapse time from diagnosis was 23.2 months. Death occurred in 69 of 343 patients (20.1 %). The major causes of death were infection and relapse. None of the patients died of drug-related toxicity. The ALL-BFM 95 protocol was applied successfully in these two centers. In developing countries in which minimal residual disease cannot be monitored, this protocol can still be used with high survival rates.