Michael Duchowny

Practice Parameter: Medical Treatment of Infantile Spasms Report of the American Academy of Neurology and the Child Neurology Society

Objective: To determine the current best practice for treatment of infantile spasms in children. Methods: Database searches of MEDLINE from 1966 and EMBASE from 1980 and searches of reference lists of retrieved articles were performed. Inclusion criteria were the documented presence of infantile spasms and hypsarrhythmia. Outcome measures included complete cessation of spasms, resolution of hypsarrhythmia, relapse rate, developmental outcome, and presence or absence of epilepsy or an epileptiform EEG. One hundred fifty-nine articles were selected for detailed review. Recommendations were based on a four-tiered classification scheme. Results: Adrenocorticotropic hormone (ACTH) is probably effective for the short-term treatment of infantile spasms, but there is insufficient evidence to recommend the optimum dosage and duration of treatment. There is insufficient evidence to determine whether oral corticosteroids are effective. Vigabatrin is possibly effective for the short-term treatment of infantile spasm and is possibly also effective for children with tuberous sclerosis. Concerns about retinal toxicity suggest that serial ophthalmologic screening is required in patients on vigabatrin; however, the data are insufficient to make recommendations regarding the frequency or type of screening. There is insufficient evidence to recommend any other treatment of infantile spasms. There is insufficient evidence to conclude that successful treatment of infantile spasms improves the long-term prognosis. Conclusions: ACTH is probably an effective agent in the short-term treatment of infantile spasms. Vigabatrin is possibly effective.

LAMOTRIGINE-ASSOCIATED RASH: RISK/BENEFIT CONSIDERATIONS IN ADULTS AND CHILDREN

Summary: Purpose: Lamotrigine (LTG) is an antiepileptic drug (AED) recently released in several countries. It is effective for a variety of seizure types in adults and children both as an add‐on agent and in monotherapy, and is generally well tolerated. This report reviews the apparent risk factors for rash associated with LTG to determine whether and how the risk of serious rash can be minimized in practice.

Long-term treatment with responsive brain stimulation in adults with refractory partial seizures.

Objective: The long-term efficacy and safety of responsive direct neurostimulation was assessed in adults with medically refractory partial onset seizures. Methods: All participants were treated with a cranially implanted responsive neurostimulator that delivers stimulation to 1 or 2 seizure foci via chronically implanted electrodes when specific electrocorticographic patterns are detected (RNS System). Participants had completed a 2-year primarily open-label safety study (n = 65) or a 2-year randomized blinded controlled safety and efficacy study (n = 191); 230 participants transitioned into an ongoing 7-year study to assess safety and efficacy. Results: The average participant was 34 (±11.4) years old with epilepsy for 19.6 (±11.4) years. The median preimplant frequency of disabling partial or generalized tonic-clonic seizures was 10.2 seizures a month. The median percent seizure reduction in the randomized blinded controlled trial was 44% at 1 year and 53% at 2 years (p < 0.0001, generalized estimating equation) and ranged from 48% to 66% over postimplant years 3 through 6 in the long-term study. Improvements in quality of life were maintained (p < 0.05). The most common serious device-related adverse events over the mean 5.4 years of follow-up were implant site infection (9.0%) involving soft tissue and neurostimulator explantation (4.7%). Conclusions: The RNS System is the first direct brain responsive neurostimulator. Acute and sustained efficacy and safety were demonstrated in adults with medically refractory partial onset seizures arising from 1 or 2 foci over a mean follow-up of 5.4 years. This experience supports the RNS System as a treatment option for refractory partial seizures. Classification of evidence: This study provides Class IV evidence that for adults with medically refractory partial onset seizures, responsive direct cortical stimulation reduces seizures and improves quality of life over a mean follow-up of 5.4 years.

A placebo-controlled trial of lamotrigine add-on therapy for partial seizures in children

Objective: To compare the safety and efficacy of add-on lamotrigine and placebo in the treatment of children and adolescents with partial seizures. Background: Add-on and monotherapy lamotrigine is safe and effective in adults with partial seizures, and reports of preliminary uncontrolled trials suggest similar benefits in children. Methods: We studied 201 children with diagnoses of partial seizures of any subtype currently receiving stable conventional regimens of antiepileptic therapy at 40 study sites in the United States and France. After a baseline observation period (to confirm that more than four seizures occurred in each of two consecutive 4-week periods), patients were randomized to add-on lamotrigine or placebo therapy. A 6-week dose-escalation period was followed by a 12-week maintenance period. Results: Compared with placebo, lamotrigine significantly reduced the frequency of all partial seizures and the frequency of secondarily generalized partial seizures in these treatment-resistant patients. The most commonly reported adverse events in the lamotrigine-treated patients were vomiting, somnolence, and infection; the frequency of these and other adverse events was similar to that in the placebo-treated group, with the exception of ataxia, dizziness, tremor, and nausea, which were more frequent in the lamotrigine-treated group. The frequency of withdrawals for adverse events was similar between groups. Two patients were hospitalized for skin rash, which resolved after discontinuation of lamotrigine therapy. Conclusions: Lamotrigine was effective for the adjunctive treatment of partial seizures in children and demonstrated an acceptable safety profile.

Surgery for Epilepsy Due to Cortical Malformations: Ten‐year Follow‐up

Summary:u2002 Children with malformations of cortical development represent a significant proportion of pediatric epilepsy surgery candidates. From a cohort of 40 children operated on between 1980 and 1992 with malformation of cortical development, 38 were alive and had data 10 years after surgery. Age at surgery ranged from 6 months to 18 years (mean, 9.6 years). Thirty‐six had partial seizures, and two had infantile spasms; 20 were nonlesional. Pathologic diagnoses were cortical dysplasia (n = 31) and developmental tumor (n = 7). At 10‐year follow‐up, 15 (40%) were seizure free, 10 (26%) had >90% seizure reduction, and 13 (34%) were improved or unchanged. Children seizure free at two‐year follow‐up were likely to remain seizure free. Ten‐year seizure freedom was 72% in children with developmental tumors and 32% in the cortical dysplasia group. Complete resection was statistically significant for favorable outcome, and no patient with an incomplete resection was seizure free.

Diagnostic methods and treatment options for focal cortical dysplasia.

Our inability to adequately treat many patients with refractory epilepsy caused by focal cortical dysplasia (FCD), surgical inaccessibility and failures are significant clinical drawbacks. The targeting of physiologic features of epileptogenesis in FCD and colocalizing functionality has enhanced completeness of surgical resection, the main determinant of outcome. Electroencephalography (EEG)–functional magnetic resonance imaging (fMRI) and magnetoencephalography are helpful in guiding electrode implantation and surgical treatment, and high‐frequency oscillations help defining the extent of the epileptogenic dysplasia. Ultra high‐field MRI has a role in understanding the laminar organization of the cortex, and fluorodeoxyglucose–positron emission tomography (FDG‐PET) is highly sensitive for detecting FCD in MRI‐negative cases. Multimodal imaging is clinically valuable, either by improving the rate of postoperative seizure freedom or by reducing postoperative deficits. However, there is no level 1 evidence that it improves outcomes. Proof for a specific effect of antiepileptic drugs (AEDs) in FCD is lacking. Pathogenic mutations recently described in mammalian target of rapamycin (mTOR) genes in FCD have yielded important insights into novel treatment options with mTOR inhibitors, which might represent an example of personalized treatment of epilepsy based on the known mechanisms of disease. The ketogenic diet (KD) has been demonstrated to be particularly effective in children with epilepsy caused by structural abnormalities, especially FCD. It attenuates epigenetic chromatin modifications, a master regulator for gene expression and functional adaptation of the cell, thereby modifying disease progression. This could imply lasting benefit of dietary manipulation. Neurostimulation techniques have produced variable clinical outcomes in FCD. In widespread dysplasias, vagus nerve stimulation (VNS) has achieved responder rates >50%; however, the efficacy of noninvasive cranial nerve stimulation modalities such as transcutaneous VNS (tVNS) and noninvasive (nVNS) requires further study. Although review of current strategies underscores the serious shortcomings of treatment‐resistant cases, initial evidence from novel approaches suggests that future success is possible.

MR-guided laser interstitial thermal therapy for pediatric drug-resistant lesional epilepsy

To report the feasibility, safety, and clinical outcomes of an exploratory study of MR‐guided Laser Interstitial Thermal Therapy (MRgLITT) as a minimally invasive surgical procedure for the ablation of epileptogenic foci in children with drug‐resistant, lesional epilepsy.

Seizures after convulsive therapy: A retrospective case survey

We reviewed all documented cases of spontaneous seizures that followed convulsive therapy. Nineteen studies provided information in 81 cases. The average annual incidence of spontaneous seizures was 114 per 100,000,5 times more frequent than an age-adjusted nonpsychiatric cohort. Host susceptibility rather than treatment-features influenced seizure development. A longer latency to first seizure was associated with greater likelihood of seizure recurrence, a relationship also observed in posttraumatic epilepsy.

Aberrant neural circuits in malformations of cortical development and focal epilepsy

Article abstract Malformations of cortical development (MCD) account for a high proportion of medically resistant partial seizures in children and figure prominently in pediatric surgical series. In contrast to the results of epilepsy surgery for postnatally acquired lesions, seizure freedom in patients with MCD is less certain owing to difficulties in defining the epileptic zone, and fully excising the epileptogenic cortex. The authors present evidence that, compared with postnatally acquired lesions such as those due to tumors or trauma, focal epileptogenesis associated with MCD is best conceptualized as a disorder of widespread and patchy disturbance of cortical networks. This developmental perspective implies that the epileptogenic region in MCD is rarely discrete even in patients with focal anatomic lesions, and may include remote cortical or subcortical areas. Preoperative investigative protocols based on this model have improved surgical results, but outcome remains far from optimal and further progress in understanding the complex developmentally based features of MCD is required.

Visual evoked responses in childhood cortical blindness after head trauma and meningitis. A longitudinal study of six cases.

Six children with cortical blindness following head trauma or meningitis had visual evoked response studies initially performed shortly after the onset of blindness. On long-term follow-up examination, three had evidence of visual deficit and five exhibited varying degrees of psychomotor retardation. Initial and follow-up visual evoked responses were analyzed and correlated with changes in visual and clinical status. The analyses suggest that change in short latency visual evoked response components correlates with visual ability whereas change in longer latency visual evoked response components correlates with level of psychomotor function.