Small 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. PubMed 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. We 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. The 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.
To determine the diagnostic accuracy and prognostic value of 18FDG-PET in a recent series of patients operated for intractable partial epilepsy associated with histologically proven Taylor-type focal cortical dysplasia (TTFCD) and negative MRI.
Methods:
Of 23 consecutive patients (12 male, 7–38 years old) with negative 1.5-Tesla MRI, 10 exhibited subtle nonspecific abnormalities (e.g., unusual sulcus depth or gyral pattern) and the 13 others had strictly normal MRI. FDG-PET was analyzed both visually after coregistration on MRI and using SPM5 software. Metabolic data were compared with the epileptogenic zone (EZ) determined by stereo-EEG (SEEG) and surgical outcome.
Results:
Visual PET analysis disclosed a focal or regional hypometabolism in 18 cases (78%) corresponding to a single gyrus (n = 9) or a larger cortical region (n = 9). PET/MRI coregistration detected a partially hypometabolic gyrus in 4 additional cases. SPM5 PET analysis (n = 18) was concordant with visual analysis in 13 cases. Location of PET abnormalities was extratemporal in all cases, involving eloquent cortex in 15 (65%). Correlations between SEEG, PET/MRI, and histologic findings (n = 20) demonstrated that single hypometabolic gyri (n = 11) corresponded to EZ and TTFCD, which was localized at the bottom of the sulcus. Larger hypometabolic areas (n = 9) also included the EZ and the dysplastic cortex but were more extensive. Following limited cortical resection (mean follow-up 4 years), seizure freedom without permanent motor deficit was obtained in 20/23 patients (87%).
Conclusions:
18FDG-PET coregistered with MRI is highly sensitive to detect TTFCD and greatly improves diagnosis and surgical prognosis of patients with negative MRI.
Summary: Purpose: To study separately the functional value of each cerebral hemisphere in hemimegalencephaly (HME). HME is a unique model of unilateral hemispheric lesion, but one suspects that the non‐HME hemisphere also could be functionally impaired because the postsurgery outcome is less favorable than expected. Methods: We performed simultaneous prolonged EEG and 133‐xenon SPECT (single‐photon emission computed tomography); we measured the absolute values of cerebral blood flow (CBF) in both hemispheres and compared them with the normal values previously acquired. Thirteen patients (aged 5–38 months) underwent 31 examinations, 20 before surgery (hemispherotomy) and 11 after. Results: In the HME hemisphere, we confirmed the presurgical mixture of increased and decreased CBF due to intermittent ictal discharges. After surgery, CBF was decreased in most cases. In the non‐HME hemisphere, presurgery CBF was abnormal in 60% of the patients, increased and related mostly to diffuse interictal spikes on the same side, whereas normal CBF cases had focal spikes. After surgery, CBF was normal in 82% of cases, corresponding to an EEG without diffuse spikes. In the six patients longitudinally studied, CBF dramatically decreased after surgery in the HME hemisphere, whereas in the non‐HME hemisphere, CBF was mostly normal very early (three fourths before 2 months), increased as soon as 3 months, and normalized only after hemispherotomy, the more rapidly the child was operated on, the earlier it was. Conclusions: This study shows that the function of the nonmalformed hemisphere is impaired as soon as the first months of the course of HME but can be restored after surgery. Our data support the recommendations to operate on the children as early as possible.
Presurgical language mapping in dominant hemisphere epilepsy to evaluate the risk of postoperative deficit is particularly difficult in children. Extraoperative invasive cortical stimulation can show some areas critical to language, but not all of them, due to scarce sampling, poor cooperation, cortical immaturity, or network reorganization, whereas functional magnetic resonance imaging (fMRI) displays entire networks involved in, but not necessarily critical to, language. In a homogeneous series of children with epilepsy, we compared the contributions of language fMRI and depth electrode stimulations to optimize language mapping.Eight children (7.5-15.5 years) with left frontal or temporal epilepsy underwent language fMRI and language stimulation with depth electrodes as part of their comprehensive presurgical workup. fMRI data collected during sentence generation were analyzed using statistical parametric mapping (SPM2) (false discovery rate [FDR] p < 0.05). Bipolar stimulations were performed during language production tasks. By coregistering fMRI and postimplantation computed tomography (CT) images, we were able to directly compare the cortical areas identified by both investigations.fMRI during sentence generation robustly showed activation in the whole perisylvian regions with little reorganization (left hemisphere dominant in 7). Of the 184 electrode contacts tested for language, only 8 were positive (language disruption) in three of the seven patients with periictal language impairment and left language dominance. All of the positive contacts colocalized with an fMRI activated cluster, that is, fMRI did not miss any region critical to language (sensitivity = 100%). However, 54 of the 176 negative contacts were within activated clusters (low specificity).In children with epilepsy, the sensitivity of fMRI during sentence generation allows for the detection of all critical regions displayed by cortical stimulation within the large perisylvian language network, but with a low specificity. It is, therefore, useful to optimize the placement of intracranial electrodes when language mapping is necessary. Systematic planning of the electrode placement according to language fMRI maps should increase the yield of extraoperative cortical stimulation, which appears rather low in children when compared to adults.
Summary: Purpose: Stiripentol (STP) is currently an efficient drug for add‐on therapy in infantile epilepsies because it improves the efficacy of antiepileptic drugs (AEDs) through its potent inhibition of liver cytochromes P450. In addition, STP directly reduces seizures in several animal models of epilepsy, suggesting that it might also have anticonvulsive effects of its own. However, its underlying mechanisms of action are unknown. Methods: We examined the interactions of STP with γ‐aminobutyric acid (GABA) transmission by using patch‐clamp methods in CA3 pyramidal neurons in the neonatal rat. Results: STP markedly increased miniature inhibitory postsynaptic current (mIPSC) decay‐time constant in a concentration‐dependent manner. The prolongation of mIPSC duration does not result from an interaction with GABA transporters because it persisted in the presence of GAT‐1 inhibitors (SKF‐89976A and NO‐711). An interaction with benzodiazepine or neurosteroid binding sites also was excluded because STP‐mediated increase of decay time was still observed when these sites were initially saturated (by clobazam, zolpidem, or pregnanolone) or blocked (by flumazenil or dehydroepiandrosterone sulfate), respectively. In contrast, saturating barbiturate sites with pentobarbital clearly occluded this effect of STP, suggesting that STP and barbiturates interact at the same locus. This was directly confirmed by using outside‐out patches, because STP increased the duration and not the frequency of opening of GABA A channels. Conclusions: At clinically relevant concentrations, STP enhances central GABA transmission through a barbiturate‐like effect, suggesting that STP should possess an antiepileptic effect by itself.
