Role of observational studies in supporting extrapolation of efficacy data from adults to children with epilepsy - A systematic review of the literature using lacosamide as an example.

Extrapolation of efficacy data from adults to children is accepted for focal epilepsy - the antiepileptic drug, lacosamide, has been approved for the treatment of children ≥4 years of age on this basis. Since many small-scale, open-label studies are reported in the literature before approval, a systematic review was conducted to ascertain whether results of these could be used to support extrapolation in epilepsy in the future. In the absence of randomised trials, a second analysis was conducted for reports on lacosamide use in adults with generalized epilepsies. Twenty-seven articles were included in the paediatric qualitative synthesis, and 14 in the adult. Paediatric studies were analysed separately based on seizure type: focal, generalised and mixed. In focal epilepsy, safety and seizure-related findings mirrored those observed in the adult Phase II/III trials, supporting the feasibility of data extrapolation. Few studies reported outcomes in children with epilepsies associated with generalised seizures, and those that included children with different seizure types, mostly did not provide results separately. Lacosamide treatment appeared beneficial for children and adults experiencing tonic-clonic and myoclonic seizures. Reports of seizure aggravation were inconsistent and, in many cases, could not be clearly attributed to lacosamide. Given the absence of sufficient data, evidence for the feasibility of extrapolation was not as clear-cut as it was in focal epilepsy. These results highlight the complexities of conducting trials in the generalised epilepsy setting, and the importance of studies in the real-life setting and of analysing efficacy data per generalized seizure type and syndrome.

Cortical Activation Through Passive-Motion Functional MRI.

BACKGROUND AND PURPOSE: Functional brain mapping is an important technique for neurosurgical planning, particularly for patients with tumors or epilepsy; however, mapping has traditionally involved invasive techniques. Existing noninvasive techniques require patient compliance and may not be suitable for young children. We performed a retrospective review of our experience with passive-motion functional MR imaging in anesthetized patients to determine the diagnostic yield of this technique. MATERIALS AND METHODS: A retrospective review of patients undergoing passive-motion fMRI under general anesthesia at a single institution over a 2.5-year period was performed. Clinical records were evaluated to determine the indication for fMRI, the ability to detect cortical activation, and, if present, the location of cortical activation. RESULTS: We identified 62 studies in 56 patients in this time period. The most common indication for fMRI was epilepsy/seizures. Passive-motion fMRI identified upper-extremity cortical activation in 105 of 119 (88%) limbs evaluated, of which 90 (86%) activations were in an orthotopic location. Lower-extremity cortical activation was identified in 86 of 118 (73%) limbs evaluated, of which 73 (85%) activations were in an orthotopic location. CONCLUSIONS: Passive-motion fMRI was successful in identifying cortical activation in most of the patients. This tool can be implemented easily and can aid in surgical planning for children with tumors or candidates for epilepsy surgery, particularly those who may be too young to comply with existing noninvasive functional measures.

Rapid infusion with valproate sodium is well tolerated in patients with epilepsy.

Many IV antiepileptic drugs administered in emergency situations to patients with prolonged seizures have serious adverse effects. For this reason, the authors conducted a multicenter, open-label, prospective, dose-escalation study of IV valproate sodium administered to patients with epilepsy at rates of infusion of up to 6 mg/kg/minute and doses of up to 30 mg/kg. Valproate sodium had no clinically significant negative effects on blood pressure and pulse rate and caused only mild-to-moderate, reversible adverse events.

Does magnetoencephalography add to scalp video-EEG as a diagnostic tool in epilepsy surgery?

OBJECTIVE: The authors evaluated the sensitivity and selectivity of interictal magnetoencephalography (MEG) versus prolonged ictal and interictal scalp video-electroencephalography (V-EEG) in order to identify patient groups that would benefit from preoperative MEG testing. METHODS: The authors evaluated 113 consecutive patients with medically refractory epilepsy who underwent surgery. The epileptogenic region predicted by interictal and ictal V-EEG and MEG was defined in relation to the resected area as perfectly overlapping with the resected area, partially overlapping, or nonoverlapping. RESULTS: The sensitivity of a 30-minute interictal MEG study for detecting clinically significant epileptiform activity was 79.2%. Using MEG, we were able to localize the resected region in a greater proportion of patients (72.3%) than with noninvasive V-EEG (40%). MEG contributed to the localization of the resected region in 58.8% of the patients with a nonlocalizing V-EEG study and 72.8% of the patients for whom V-EEG only partially identified the resected zone. Overall, MEG and V-EEG results were equivalent in 32.3% of the cases, and additional localization information was obtained using MEG in 40% of the patients. CONCLUSION: MEG is most useful for presurgical planning in patients who have either partially or nonlocalizing V-EEG results.

Periventricular heterotopia associated with chromosome 5p anomalies.

Periventricular heterotopia (PH) is characterized by neuronal nodules along the lateral ventricles. Whereas mutations in X-linked FLNA cause such cortical malformations, the authors report two cases of PH localizing to chromosome 5p. Both subjects have complex partial seizures. MRI demonstrated bilateral nodular PH, with subcortical heterotopia or focal gliosis. FISH identified a duplication of 5p15.1 [46,XX,dup(5)(p15.1p15.1)] and a trisomy of 5p15.33 [46,XY,der(14)t(5;14)(p15.33;p11.2) mat]. These findings suggest a new PH locus along the telomeric end of chromosome 5p.

[Insights into brain function though magnetic source imaging: A review of research and clinical applications]. / Aproximación a la función cerebral a través de la imagen de fuente magnética: aplicaciones clínicas y experimentales.

INTRODUCTION AND DEVELOPMENT: The paper presents a brief outline of the rationale behind the use of non invasive functional imaging and of the features that any imaging technique should display in order to make a substantial contribution to the search of the brain mechanisms responsible for cognitive functions. One such technique, magnetic source imaging (MSI), that meets these specifications, is described in more detail. Advantages of MSI include the capacity to provide direct measures of regional neurophysiological activity, a millisecond range temporal resolution, and the capacity to provide images of brain activity on an individual basis. We then describe applications of MSI to the study of brain mechanisms involved in various language functions such as oral comprehension and reading. Among these applications, the accuracy of MSI protocols in determining hemispheric dominance for language functions and in identifying the precise location and extent language specific cortex (Wernicke s area) has been verified through comparison with standard invasive techniques (Wada procedure and electrocortical stimulation mapping) in over 60 consecutive cases. In another series of studies we combined data from MSI and direct cortical stimulation to determine the role of temporoparietal areas in phonological analysis of spoken language and in phonological decoding of print. Finally, we have used MSI to gain unique insights into the brain mechanisms that support reading in developmental reading disability. CONCLUSION: Results from over 21 children diagnosed with this disorder suggest that impaired reading is associated with aberrant functional connections between temporal and temporoparietal areas of the left hemisphere that are normally engaged in reading.

Clinical experience with topiramate dosing and serum levels in children 12 years or under with epilepsy.

Only a limited topiramate dosing range (5-9 mg/kg/day) is approved by the U.S. Food and Drug Administration (FDA). We reviewed our topiramate dosing (mg/kg/d) and corresponding serum levels (microg/mL) (n = 77) in 41 children who were treated to clinical response or tolerability. The patients were divided into older (6-12 years [n = 21]) and younger (< or = 5 years [n = 20]) groups. Topiramate was given as monotherapy (n = 9), with an enzyme-inducing antiepileptic drug (n = 16) (phebarbital, phenytoin, or carbamazepine), or as polytherapy (n =17) (another antiepileptic drug). In the older children, there was a good dosage to serum level correspondence. However, younger children on topiramate monotherapy or cotherapy with an enzyme-inducing antiepileptic drug had relatively lower serum levels, but the serum level was increased if they were on polytherapy without an enzyme-inducing drug. This study supports a wider dosing range (7-22 mg/kg/day) of topiramate and dosage escalation beyond the approved range. Serum levels are useful in guiding topiramate dosing, especially in young children.

Vagus nerve stimulation therapy in pediatric patients with refractory epilepsy: retrospective study.

This six-center, retrospective study evaluated the effectiveness, tolerability, and safety of vagus nerve stimulation in children. Data were available for 125 patients at baseline, 95 patients at 3 months, 56 patients at 6 months, and 12 patients at 12 months. The typical patient, aged 12 years, had onset of seizures at age 2 years and had tried nine anticonvulsants before implantation. Collected data included preimplant history, seizures, implant, device settings, quality of life, and adverse events. Average seizure reduction was 36.1% at 3 months and 44.7% at 6 months. Common adverse events included voice alteration and coughing during stimulation. Rare adverse events, unique to this age group, included increased drooling and increased hyperactivity. Quality of life improved in alertness, verbal communication, school performance, clustering of seizures, and postictal periods. We concluded that vagus nerve stimulation is an effective treatment for medically refractory epilepsy in children.

Mapping of expressive language cortex using magnetic source imaging.

The accurate localization of primary language cortex is one of the goals in the evaluation of brain surgery candidates. In this paper we describe the localization of expressive language cortex using magnetic source imaging (MSI) in a patient with refractory epilepsy caused by a tumor affecting the left inferior frontal gyrus. The magnetoencephalographic recordings during an expressive language task were co-registered with a magnetic resonance imaging (MRI) scan obtained after subdural grid placement and provided a cluster of sources of brain activation in the vicinity of the lesion. This map of expressive language provided by MSI was verified with electrocortical stimulation before the operation. No speech problems were reported in our patient after the resection of the lesion, suggesting that MSI is an accurate non-invasive method for the pre-surgical mapping of expressive language in cases where there is clear functional risk during tumor resection.

Vagus nerve stimulation in children with refractory seizures associated with Lennox-Gastaut syndrome.

PURPOSE: Vagus nerve stimulation (VNS) is approved for use for refractory partial seizures. Nevertheless, information regarding VNS therapy for special populations, including Lennox-Gastaut syndrome (LGS) is limited. We discuss the effectiveness, tolerability, and safety of VNS therapy in patients with LGS. METHODS: A six-center, retrospective study evaluated the effectiveness of VNS therapy in patients with LGS at 3 and 6 months and compared preimplant and postimplant seizure frequency. Adverse effects and quality of life (QOL) were included as secondary measures. RESULTS: Fifty patients, median age 13 years, with medically refractory epilepsy, were implanted. Median age at onset of seizures was 1.4 years, and a median of nine anticonvulsants (AEDs) had been tried before implantation. Data-collection forms were designed for retrospectively gathering data on each patient's preimplant history, seizures, implants, device settings, QOL, and adverse events. Median reductions in total seizures were 42% at 1 month, 58.2% at 3 months, and 57.9% at 6 months. The most common adverse events reported were voice alteration and coughing during stimulation. Other uncommon adverse events included increased drooling and behavioral changes. Investigators noted that QOL had improved for some patients in the study. CONCLUSIONS: VNS is an effective treatment for medically refractory epilepsy in LGS. This treatment is well tolerated, safe, and may improve QOL.

Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females.

Periventricular heterotopia (PH) is a human neuronal migration disorder in which many neurons destined for the cerebral cortex fail to migrate. Previous analysis showed heterozygous mutations in the X-linked gene filamin 1 (FLN1), but examined only the first six (of 48) coding exons of the gene and hence did not assess the incidence and functional consequences of FLN1 mutations. Here we perform single-strand conformation polymorphism (SSCP) analysis of FLN1 throughout its entire coding region in six PH pedigrees, 31 sporadic female PH patients and 24 sporadic male PH patients. We detected FLN1 mutations by SSCP in 83% of PH pedigrees and 19% of sporadic females with PH. Moreover, no PH females (0/7 tested) with atypical radiographic features showed FLN1 mutations, suggesting that other genes may cause atypical PH. Surprisingly, 2/24 males analyzed with PH (9%) also carried FLN1 mutations. Whereas FLN1 mutations in PH pedigrees caused severe predicted loss of FLN1 protein function, both male FLN1 mutations were consistent with partial loss of function of the protein. Moreover, sporadic female FLN1 mutations associated with PH appear to cause either severe or partial loss of function. Neither male could be shown to be mosaic for the FLN1 mutation in peripheral blood lymphocytes, suggesting that some neurons in the intact cortex of PH males may be mutant for FLN1 but migrate adequately. These results demonstrate the sensitivity and specificity of DNA testing for FLN1 mutations and have important functional implications for models of FLN1 protein function in neuronal migration.

Idiopathic cardiac asystole presenting as an intractable adult onset partial seizure disorder.

Asystole can occur during partial seizures. Conversely, asystole may produce clinical features associated semiologically with partial or secondarily generalized tonic--clonic seizures. Management is so profoundly different that accurate diagnosis is critical. We performed simultaneous scalp video electroencephalographic (EEG) and electrocardiographic (ECG) recordings in three patients who presented with an intractable seizure disorder. Habitual events were captured and reviewed. These revealed similar clinical features and temporal association with the ECG and EEG findings. Idiopathic asystole was detected as the cause in all three. All underwent emergency cardiac pacemaker implantation with resultant cessation of their paroxysmal episodes. If this diagnostic study had been delayed or not performed, all of our patients could have presented as sudden unexpected death in epilepsy (SUDEP). Early video-EEG and ECG monitoring is essential in adults with intractable seizure disorders.

Vagus nerve stimulation and the ketogenic diet.

Antiepileptic drugs are the primary form of treatment for patients with epilepsy. In the United States, hundreds of thousands of people do not achieve seizure control, or have significant side effects, or both. Only a minority of patients with intractable epilepsy are candidates for traditional epilepsy surgery. Vagus nerve stimulation is now the second most common treatment for epilepsy in the United States. Additionally, the ketogenic diet has established itself as a valid treatment. This article discusses the history, mechanism of action, patient selection, efficacy, initiation, complications, and advantages of vagus nerve stimulation and the ketogenic diet.

Brain plasticity for sensory and linguistic functions: a functional imaging study using magnetoencephalography with children and young adults.

In this report, the newest of the functional imaging methods, magnetoencephalography, is described, and its use in addressing the issue of brain reorganization for basic sensory and linguistic functions is documented in a series of 10 children and young adults. These patients presented with a wide variety of conditions, ranging from tumors and focal epilepsy to reading disability. In all cases, clear evidence of reorganization of the brain mechanisms of either somatosensory or linguistic functions or both was obtained, demonstrating the utility of magnetoencephalography in studying, completely noninvasively, the issue of plasticity in the developing brain.

Language dominance in children as determined by magnetic source imaging and the intracarotid amobarbital procedure: a comparison.

This study evaluated the validity of data derived from magnetic source imaging regarding hemispheric dominance for language in children and adolescents with intractable seizure disorder by comparison with results of the intracarotid amobarbital procedure. Functional imaging of the receptive language cortex using a whole-head neuromagnetometer was performed in 19 consecutive epilepsy patients, ages 8 to 18 years, who also underwent the intracarotid amobarbital procedure. During magnetic source imaging recordings, patients engaged in a continuous recognition memory task for words in visual and auditory modalities. This task has previously been shown to be valid for the purpose of lateralization and localization of language cortex in adult epilepsy patients who undergo the intracarotid amobarbital procedure and intraoperative language mapping allowing confirmation of magnetic source imaging findings. Results indicated that language laterality indices formed for the intracarotid amobarbital procedure and magnetic source imaging procedures were highly correlated (R = .87). In addition, clinical judgments regarding cerebral dominance for language made by independent raters using the two methods were in excellent agreement. We conclude that magnetic source imaging is a promising method for determination of cerebral dominance for language in children and adults.

Left vagal nerve stimulation in six patients with hypothalamic hamartomas.

Six patients with medically refractory epilepsy secondary to hypothalamic hamartomas were treated with intermittent stimulation of the left vagal nerve. Three of the patients had remarkable improvements in seizure control. Four of these six patients had severe autistic behaviors. Striking improvements in these behaviors were observed in all four during treatment with intermittent stimulation. This finding suggests that vagal nerve stimulation can control seizures and autistic behaviors in patients with hypothalamic hamartomas.

Prospective long-term study of vagus nerve stimulation for the treatment of refractory seizures.

PURPOSE: To determine the long-term efficacy of vagus nerve stimulation (VNS) for refractory seizures. VNS is a new treatment for refractory epilepsy. Two short-term double-blind trials have demonstrated its safety and efficacy, and one long-term study in 114 patients has demonstrated a cumulative improvement in efficacy at 1 year. We report the largest prospective long-term study of VNS to date. METHODS: Patients with six or more complex partial or generalized tonic-clonic seizures enrolled in the pivotal EO5 study were prospectively evaluated for 12 months. The primary outcome variable was the percentage reduction in total seizure frequency at 3 and 12 months after completion of the acute EO5 trial, compared with the preimplantation baseline. Subjects originally randomized to low stimulation (active-control group) were crossed over to therapeutic stimulation settings for the first time. Subjects initially randomized to high settings were maintained on high settings throughout the 12-month study. RESULTS: The median reduction at 12 months after completion of the initial double-blind study was 45%. At 12 months, 35% of 195 subjects had a >50% reduction in seizures, and 20% of 195 had a >75% reduction in seizures. CONCLUSIONS: The efficacy of VNS improves during 12 months, and many subjects sustain >75% reductions in seizures.