Caregiver's perception of epilepsy treatment, quality of life and comorbidities in an international cohort of CDKL5 patients.

OBJECTIVE: CDKL5 is a genetic condition associated with drug-resistant epilepsy and intellectual disability. There is limited information on its natural history. We investigated the natural history, complications, and the effectiveness of current treatment strategies. METHODS: This study was conducted in conjunction with the CDKL5-UK Charity, with patients recruited from the USA and Europe. Online questionnaires were completed by parents/carers and included information relating to demographics, growth, development, epilepsy, comorbid conditions, and efficacy and side effects of antiepileptic treatments. RESULTS: Thirty-nine of the 44 patients were female. Median age was five years (range five months to 31 years), and all had a history of epilepsy. All patients had developmental delay, with 4/21 able to run and 4/22 able to climb. Gastrointestinal problems were reported in 31/43. Cardiac arrhythmia was seen in 11/29. Over one-quarter of the patients had tried ten or more antiepileptic medications. Vigabatrin was reportedly the most effective AED (antiepileptic drug) in 12/23; clobazam (most effective in 6/14); sodium valproate (most effective in 5/27), and levetiracetam (most effective in 3/27). VNS (Vagal Nerve Stimulator) was reported to be effective in 9/12. One year after VNS insertion, 9/12 reported improved (QoL), and there were improvements in mood, school achievement and concentration in (9/11). The ketogenic diet was considered effective and to have improved QoL in (12/23). CONCLUSION: Vigabatrin appears to be more effective than other AEDs. VNS and ketogenic diet are also relatively effective. Gastrointestinal and cardiovascular system complications are common. The results may help to guide management of epilepsy in CDKL5. It highlights a possible link between CDKL5 and potentially treatable life-threatening complications such as cardiac arrhythmia. More research in this area may help us develop a more systematic approach to treating these patients. HIPPOKRATIA 2017, 21(3): 130-135.

Mortality from childhood stroke in England and Wales, 1921-2000.

OBJECTIVE: Stroke is an important but under-recognised cause of childhood mortality. The authors aimed to describe the trends in mortality from childhood stroke in England and Wales between 1921 and 2000. DESIGN: The study searched the Office for National Statistics mortality database for the years 1921-2000 using appropriate, previously validated International Classification of Diseases codes. Mortality rates were analysed by period of death, gender, age at death, birth cohort and stroke subtype. RESULTS: 6029 deaths from childhood stroke were found between 1921 and 2000. Analysis by period of death demonstrated an initial decline in mortality followed by a steep rise in the 1940s. Subsequently, rates declined from the late 1960s onwards. At all time points males had a higher mortality rate than females. Infants had a relatively high mortality rate (24.5 per million person years) but rates fell steeply in early childhood (2.5 per million person years at age 5-9 years) before rising again in late adolescence (7.5 per million person years at age 15-19 years). An increased rate was found for males at all ages (RR = 1.24, p<0.0001) but was greatest in infancy (RR = 1.45, p<0.0001). Haemorrhagic stroke accounted for 71% of stroke deaths. Birth cohort analysis showed a trend of declining mortality with each successive generation since the 1950s. CONCLUSIONS: This study describes characteristics and temporal changes in childhood stroke mortality in the 20(th) century. In particular, the higher mortality rates in males and infants, the importance of deaths from haemorrhagic stroke and the finding of a decline in birth cohort mortality since the 1950s provide aetiological insights.

Cerebral venous sinus thrombosis: a case series including thrombolysis.

BACKGROUND: Cerebral venous sinus thrombosis (CVST) in children is associated with a high incidence of serious morbidity and mortality. The presenting features are variable. It can be diagnostically challenging and the optimal treatment is uncertain. AIM: To describe the features of a series of children with CVST treated in a single paediatric neurology centre and to discuss the role of local thrombolysis. METHODS: Electronic databases were searched using diagnostic labels and International Classification of Diseases (ICD) codes to identify children aged 1 month to under 17 years with CVST. Their records were reviewed. RESULTS: 21 children were identified over a period of 8.25 years with a median age of 7.1 years. The presenting symptoms included headache (15 children), vomiting (14 children) and visual disturbance (eight children). Signs found included papilloedema (16 children), fever (six children) and sixth nerve palsy (six children). The most common underlying condition was middle ear infection (13 children). All cases received unfractionated heparin and four severe cases received local pharmacological thrombolysis. 48% of cases had an adverse outcome (death, chronic intracranial hypertension, residual hemiparesis or sixth nerve palsy). DISCUSSION: CVST has non-specific presenting features and a high risk of significant morbidity. CVST is typically found in association with a predisposing condition. Although heparin is the mainstay of treatment, thrombolysis may reverse deterioration as seen in three cases in this series. However, there is insufficient evidence to recommend the routine use of thrombolysis at present.

Preparation and in vitro evaluation of ethyl cellulose microspheres containing stavudine by the double emulsion method.

The aim of this study was to formulate and evaluate microspheres of stavudine by water-in-oil-in-oil (w/o/o) double emulsion solvent diffusion method using ethyl cellulose and ethyl cellulose in combination with polyvinyl pyrrolidone. A mixed solvent system consisting of acetonitrile and dichloromethane in an 1: 1 ratio and light liquid paraffin was chosen as primary and secondary oil phase, respectively. Span 80 was used as surfactant for stabilizing the secondary oil phase. The influence of formulation factors like stirring speed, surfactant concentration on particle size and polymer:drug ratio and combination of polymers on drug release characteristics of the microspheres was investigated. The prepared microspheres characterized by micrometric properties, drug loading, Fourier transform infrared spectroscopy, X-ray powder difractometry and scanning electron microscopy. The prepared microspheres were white, free flowing and spherical in shape, stable in nature, with 41-65% of drug entrapment efficiency. The best-fit release kinetics was achieved with Higuchi plot followed by first order and zero order. The release of stavudine was influenced by the drug to polymer ratio, particle size and polymer combination.

The effects of aminophylline and pentoxifylline on multiple organ damage after Escherichia coli sepsis.

We studied the effects of the methylxanthines, aminophylline (AMPH) and pentoxifylline (PTXF), on multiple organ damage following Escherichia coli sepsis in guinea pigs. To assess multiple organ damage, 125I-labeled albumin accumulation was measured in bronchoalveolar lavage (BAL) fluid, lung, kidneys, liver, heart, adrenal glands, and spleen and expressed as a ratio of BAL fluid or tissue to 125I-labeled albumin plasma (albumin index: Al). Wet-to-dry lung weight (W/D) ratios were also measured. The methylxanthines were administered by a bolus injection followed by a continuous infusion. The seven experimental groups included: saline-control, AMPH-control, PTXF-control, E. coli septic-control, E. coli septic-AMPH high dose, E coli septic-AMPH low dose, and E. coli septic-PTXF. The AI of the BAL fluid and all examined organs significantly increased in the septic-control group compared to those in the saline-, AMPH-, and PTXF-control groups, In all septic-methylxanthine groups, the AI of the BAL fluid and all organs, except for the spleen, were significantly lower than those of the septic-control group. Compared to the saline-, AMPH-, and PTXF-control groups, the septic-control group revealed a significant increase in lung W/D ratios, whereas the septic-AMPH high and low dose groups and the septic-PTXF group did not. Of importance, the septic-PTXF group did not cause a significant decrease in mean arterial pressure (MAP) as compared to the control groups, whereas the septic-AMPH groups did cause a significant decrease in MAP compared to the septic-control group. Therefore, the data from this experiment demonstrate that both AMPH and PTXF attenuate the multiple organ albumin leak seen in septic guinea pigs. However, PTXF exerted this protective effect with no discernible effect on the MAP whereas the MAP of AMPH-treated guinea pigs was significantly decreased.

Multiple organ damage caused by tumor necrosis factor and prevented by prior neutrophil depletion.

The effect of TNF on nonpulmonary multiple organ damage (MOD) was studied. Since polymorphonuclear leukocytes (PMN) are thought to play an important role in septic or TNF-induced MOD, we investigated both neutrophil sufficient (PMN+) and neutropenic (PMN-) guinea pigs. Sepsis was induced by Escherichia coli administration (2 x 10(9)/kg) or recombinant human TNF (1.4 x 10(6) U/kg) was infused into PMN+ and PMN- guinea pigs. During necropsy, the PMN+/TNF and PMN+/E coli animals exhibited marked damage in the adrenal glands, kidneys and liver as evidenced by hemorrhage, congestion, and PMN sequestration on histopathologic examination. There was also increased tissue albumin accumulation in the adrenal glands, kidneys, spleen, heart, and liver as demonstrated by 125I-labeled albumin determinations. In contrast, the PMN-/TNF group did not reveal histopathologic damage in any organ system and there was no abnormal organ accumulation of 125I-albumin. However, in PMN-/E coli animals, marked histopathologic damage in the adrenal glands and liver was evident. Furthermore, there were marked accumulations of 125I-albumin in the adrenals, heart, kidneys, liver, and spleen. Moreover, the PMN-/E coli guinea pigs had a much greater accumulation (p less than 0.01) of 125I-albumin in the kidneys than any other group including the PMN+/E coli group. Thus, nonpulmonary MOD in guinea pigs is caused by TNF administration and can be prevented by PMN depletion. However, while E coli administration also caused marked nonpulmonary MOD in neutrophil sufficient guinea pigs, equivalent or greater damage was produced in neutropenic animals. This suggests that while TNF-induced MOD may be primarily mediated by PMN, E coli-induced MOD seems to be mediated by more than PMN.