Anna Rosati

Familial perisylvian polymicrogyria: a new familial syndrome of cortical maldevelopment

Two familial X‐linked dominant syndromes of cortical maldevelopment have recently been described: double cortex/lissencephaly syndrome and bilateral periventricular nodular heterotopia. We report on 12 kindreds with familial perisylvian polymicrogyria (FPP) presenting at 10 centers, examine the clinical presentation in these familial cases, and propose a possible mode of inheritance. The clinical and radiological pattern was variable among the 42 patients, with clinical differences among the families and even within members of the same family. Pseudobulbar signs, cognitive deficits, epilepsy, and perisylvian abnormalities on imaging studies were not found in all patients. When present, they displayed a spectrum of severity. The only clear correlation in this study was between bilateral imaging findings and abnormal tongue movements and/or pronounced dysarthria. Most of the families provided evidence suggestive of, or compatible with, X‐linked transmission. On the other hand, the pedigrees of 2 families ruled out X‐linked inheritance. The most likely mode of inheritance for these 2 families was autosomal dominant with decreased penetrance; however, autosomal recessive inheritance with pseudodominance could not be ruled out in 1 family. We conclude that FPP appears to be genetically heterogeneous. However, most of the families probably represent a third previously undescribed X‐linked syndrome of cortical maldevelopment. Ann Neurol 2000;48:39–48

Experimental designs for small randomised clinical trials: An algorithm for choice

BackgroundSmall clinical trials are necessary when there are difficulties in recruiting enough patients for conventional frequentist statistical analyses to provide an appropriate answer. These trials are often necessary for the study of rare diseases as well as specific study populations e.g. children. It has been estimated that there are between 6,000 and 8,000 rare diseases that cover a broad range of diseases and patients. In the European Union these diseases affect up to 30 million people, with about 50% of those affected being children. Therapies for treating these rare diseases need their efficacy and safety evaluated but due to the small number of potential trial participants, a standard randomised controlled trial is often not feasible. There are a number of alternative trial designs to the usual parallel group design, each of which offers specific advantages, but they also have specific limitations. Thus the choice of the most appropriate design is not simple.MethodsPubMed was searched to identify publications about the characteristics of different trial designs that can be used in randomised, comparative small clinical trials. In addition, the contents tables from 11 journals were hand-searched. An algorithm was developed using decision nodes based on the characteristics of the identified trial designs.ResultsWe identified 75 publications that reported the characteristics of 12 randomised, comparative trial designs that can be used in for the evaluation of therapies in orphan diseases. The main characteristics and the advantages and limitations of these designs were summarised and used to develop an algorithm that may be used to help select an appropriate design for a given clinical situation. We used examples from publications of given disease-treatment-outcome situations, in which the investigators had used a particular trial design, to illustrate the use of the algorithm for the identification of possible alternative designs.ConclusionsThe algorithm that we propose could be a useful tool for the choice of an appropriate trial design in the development of orphan drugs for a given disease-treatment-outcome situation.

Efficacy and safety of ketamine in refractory status epilepticus in children

Objective: To evaluate the efficacy and safety of ketamine (KE) in the management of refractory convulsive status epilepticus (RSE) in children. Methods: In November 2009, we started using KE for treating all children consecutively referred for RSE. Clinical and treatment data were analyzed. Results: Between November 2009 and June 2011, 9 children with RSE received IV KE. In 8 patients, SE had persisted for more than 24 hours (super-refractory RSE), with a median of 6 days (mean 8.5 ± 7.5; range 2–26 days). Prior to KE administration, conventional anesthetics were used, including midazolam, thiopental, and propofol in 9, 5, and 4 patients each. Median dose of KE in continuous IV infusion was 40 gamma(μg)/kg/min (mean 36.5 ± 18.6 gamma[μg]/kg/min; range 10–60 gamma[μg]/kg/min). Midazolam was administered add-on to prevent emergence reactions. The use of KE was associated with resolution of RSE in 6 children. None of the patients experienced serious adverse events. Among the 3 individuals who did not respond to KE, 2 were cured by surgical removal of epileptogenic focal cortical dysplasia. Conclusion: In this small, open-label, unblinded series with no concurrent control group, KE appears effective and safe in treating RSE in children. Larger, randomized studies are needed to confirm data emerging from this preliminary observation. Classification of evidence: This study provides Class IV evidence that IV KE can be effective in treating children with RSE (no statistical analysis was done).

AUTONOMIC AND HORMONAL ICTAL CHANGES IN GELASTIC SEIZURES FROM HYPOTHALAMIC HAMARTOMAS

OBJECTIVES We describe two patients with hypothalamic hamartoma and gelastic seizures. METHODS We performed ictal neurophysiological studies with polygraphic recordings of autonomic parameters and hormonal ictal plasma concentration measurements. RESULTS Ictal recordings showed a stereotyped modification of autonomic parameters: increase in blood pressure and heart rate, peripheral vasoconstriction and modification of respiratory activity. At seizure onset, the norepinephrine plasma level was high and epinephrine unchanged, whereas prolactin and adrenocorticotropic hormone were increased in both cases. Growth hormone and cortisol plasma concentrations in each patient showed a different response to seizures. CONCLUSIONS These data provide evidence that gelastic seizures are accompanied by an abrupt sympathetic system activation, probably due to the direct paroxysmal activation of limbic and paralimbic structures or other autonomic centres of the hypothalamus and medulla.

Epileptic drop attacks in partial epilepsy: clinical features, evolution, and prognosis

OBJECTIVES Sudden falls have been described in patients with partial epilepsy. However, no study has detailed the clinical, EEG, and evolutive features of partial epilepsies with drop attacks. METHODS In a consecutive series of 222 patients with partial epilepsy admitted for uncontrolled seizures over a 10 year period, 31 patients presented with epileptic drop attacks during evolution of their illness. Twenty two patients had frontal, five temporal, and four multifocal or undefinable lobe epilepsy; 74% of the cases showed an EEG pattern of secondary bilateral synchrony during evolution. A statistical comparison of some clinical and EEG features between the patients with epileptic drop attacks and patients with partial epilepsy without drop attacks (control group of 191 patients) was carried out. RESULTS Seventy four per cent of patients had a poor prognosis and 45% were mentally retarded; 52% of patients with epileptic drop attacks continued to have epileptic falls associated with partial seizures and mental deterioration at the end of the follow up. These characteristics of patients with epileptic drop attacks were significantly different from the control group. CONCLUSION Almost all literature reports concur that the physiopathogenetic substrate of epileptic drop attacks is a mechanism of secondary bilateral synchrony. A localised epileptic focus may lead to a process of secondary epileptogenesis involving the whole brain, causing a progressive cerebral disturbance with worsening of the epileptic seizures and higher cerebral functions.

Safety and Tolerability of Antiepileptic Drug Treatment in Children with Epilepsy

The aim of treating epilepsy is to control or at least decrease seizures without producing unacceptable adverse effects that impair quality of life. Antiepileptic drugs (AEDs) have been considered amongst the drugs most frequently associated with fatal suspected adverse drug reactions. Physicians must therefore be as familiar with safety and tolerability data of AEDs as they are with the expected therapeutic effects.AEDs may cause dose-related adverse effects (i.e. drowsiness, fatigue, dizziness, blurry vision and incoordination) that, in most cases, may be obviated by lowering the dosage, reducing the number of drugs or switching to a better tolerated AED. AEDs also have the potential of precipitating idiosyncratic adverse effects (i.e. serious cutaneous, haematological and hepatic events), which are more common in children and usually require withdrawal of the AED. Although occurrence of idiosyncratic adverse effects can only rarely be predicted or prevented, there are known risk factors that can help in identifying patients at high risk. Occurrence of an idiosyncratic event in a close relative, a concomitant autoimmune disease, co-treatment with specific drugs, history of a previous allergic drug reaction, starting treatment with high doses and rapid titration have all been associated with a higher risk of idiosyncratic adverse effects.New AEDs have been developed in the last two decades with the aim of improving the benefit-risk balance of AED therapy. Available evidence suggests that the newer AEDs are no more effective but may be somewhat better tolerated than older molecules.We performed a literature review with the aim of evaluating safety and tolerability of second- and third-generation AEDs in children. A PubMed search was conducted with the purpose of identifying English-language studies published between 1 January 1989 and 1 January 2011 that reported any adverse event having occurred in children with epilepsy in whom second- and third-generation AEDs were administered.

The medical and surgical treatment of tumoral seizures: current and future perspectives.

Epilepsy surgery represents the main treatment option for epileptogenic brain tumors. Scalp video–electroencephalography (EEG) and magnetic resonance imaging (MRI) may suffice for defining lesional area and seizure‐onset zone in discrete, surgically resectable lesions. The choice of timing for surgery requires a multidisciplinary evaluation, especially in children, when a “wait and see” approach is chosen. Discordant electroclinical and neuroimaging data and an ill‐defined epileptogenic lesion require invasive investigations. A multimodal integrated approach may maximize the extent of resection while preserving cerebral function in the eloquent cortex. Radical removal of the tumor is the most important predictor of seizure freedom. Additional predictors include histopathology, age at surgery, duration of epilepsy, and seizure type. Patients with brain tumors are highly vulnerable in relation to the frequent drug‐resistance of seizures, the potential interactions between antiepileptic drugs (AEDs) and chemotherapeutic agents (CMTs), and the risk of AED‐related cognitive adverse events (24% higher than in the rest of the epilepsy population), in addition to brain damage resulting from tumor itself, surgery, and radiotherapy. No robust, randomized, controlled evidence supports the choice of AEDs for the treatment of seizures in patients with brain tumors. Newer AEDs have limited or no enzyme‐inducing profile, prevalent renal excretion, lower plasma protein binding and, consequently, fewer interactions with CMTs. Enzyme‐inducing AEDs can lower serum levels of concomitantly administered CMTs. Class I evidence suggests that in patients with brain tumors who do not have a history of seizures, prophylactic use of AEDs is neutral or ineffective.

Adjunctive zonisamide therapy in the long‐term treatment of children with partial epilepsy: Results of an open‐label extension study of a phase III, randomized, double‐blind, placebo‐controlled trial

To investigate the safety/tolerability and efficacy of long‐term adjunctive zonisamide and its impact on growth and development in children (6–18 years) with partial epilepsy.

Effectiveness and tolerability of perampanel in children and adolescents with refractory epilepsies—An Italian observational multicenter study

PURPOSE To evaluate the efficacy and tolerability of Perampanel (PER) in children and adolescents with refractory epilepsies in daily clinical practice conditions. PATIENTS AND METHODS This Italian multicenter retrospective observational study was performed in 16 paediatric epilepsy centres. Inclusion criteria were: (i) ≤18 years of age, (ii) history of refractory epilepsy, (iii) a follow-up ≥5 months of PER add-on therapy. Exclusion criteria were: (i) a diagnosis of primary idiopathic generalized epilepsy, (ii) variation of concomitant AEDs during the previous 4 weeks. Response was defined as a ≥50% reduction in monthly seizure frequency compared with the baseline. RESULTS 62 patients suffering from various refractory epilepsies were included in this study: 53% were males, the mean age was 14.2 years (range 6-18 years), 8 patients aged <12 years. Mean age at epilepsy onset was 3.4 years and the mean duration of epilepsy was 10.8 years (range 1-16), which ranged from 2 seizures per-month up to several seizures per-day (mean number=96.5). Symptomatic focal epilepsy was reported in 62.9% of cases. Mean number of AEDs used in the past was 7.1; mean number of concomitant AEDs was 2.48, with carbamazepine used in 43.5% of patients. Mean PER daily dose was 7.1mg (2-12mg). After an average of 6.6 months of follow-up (5-13 months), the retention rate was 77.4% (48/62). The response rate was 50%; 16% of patients achieved ≥75% seizure frequency reduction and 5% became completely seizure free. Seizure aggravation was observed in 9.7% of patients. Adverse events were reported in 19 patients (30.6%) and led to PER discontinuation in 4 patients (6.5%). The most common adverse events were behaviour disturbance (irritability and aggressiveness), dizziness, sedation and fatigue. CONCLUSION PER was found to be a safe and effective treatment when used as adjunctive therapy in paediatric patients with uncontrolled epilepsy.

Therapeutic drug monitoring of carbamazepine and its metabolite in children from dried blood spots using liquid chromatography and tandem mass spectrometry.

Carbamazepine (CBZ) is a first-line drug for the treatment of different forms of epilepsy and the first choice drug for trigeminal neuralgia. CBZ is metabolized in the liver by oxidation into carbamazepine-10,11-epoxide (CBZE), its major metabolite which is equipotent and known to contribute to the pharmacological activity of CBZ. The aim of the present study was to develop and validate a reliable, selective and sensitive liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of CBZ and its active metabolite in dried blood spots (DBS). The extraction process was carried out from DBS using methanol-water-formic acid (80:20:0.1, v/v/v). Chromatographic elution was achieved by using a linear gradient with a mobile phase consisting of acetonitrile-water-0.1% formic acid at a flow rate of 0.50mL/min. The method was linear over the range 1-40mg/L and 0.25-20mg/L for CBZ and CBZE, respectively. The limit of quantification was 0.75mg/L and 0.25mg/L for CBZ and CBZE. Intra-day and inter-day assay precisions were found to be lower than 5.13%, 6.46% and 11.76%, 4.72% with mean percentage accuracies of 102.1%, 97.5% and 99.2%, 97.8% for CBZ and CBZE. We successfully applied the method for determining DBS finger-prick samples in paediatric patients and confirmed the results with concentrations measured in matched plasma samples. This novel approach allows quantification of CBZ and its metabolite from only one 3.2mm DBS disc by LC-MS/MS thus combining advantages of DBS technique and LC-MS/MS in clinical practice.