David T. Hsieh

Neurologic manifestations of Angelman syndrome.

Angelman syndrome is a neurogenetic disorder characterized by the loss or reduction of the ubiquitin-protein ligase E3A enzyme. Angelman syndrome results from a deletion or mutation of the maternally inherited 15q11.2-13.1 region, paternal uniparental disomy of chromosome 15, or an imprinting error. Epilepsy is common and may present with multiple seizure types, including nonconvulsive status epilepticus. Seizures are often intractable and typically require broad-spectrum antiepileptic medications. Dietary therapy has also proved successful in Angelman syndrome. Electroencephalographic patterns include notched δ and rhythmic θ activity and epileptiform discharges. Sleep disorders are also common, often characterized by abnormal sleep-wake cycles. Movement disorders are nearly universal in Angelman syndrome, most frequently presenting with ataxia and tremor. Neurocognitive impairment is always present to varying degrees, and expressive speech is typically severely affected. Individuals with Angelman syndrome often manifest psychiatric comorbidities including hyperactivity, anxiety, and challenging behaviors such as aggression and self-injury. We focus on a comprehensive whole-child approach to the diagnosis and long-term clinical care of individuals with Angelman syndrome.

Efficacy and safety of rufinamide in pediatric epilepsy

Rufinamide is a novel anticonvulsant medication approved by the US Food and Drug Administration (FDA) in 2008 for the treatment of seizures associated with Lennox–Gastaut syndrome in patients 4 years of age and older, based upon clinical trials demonstrating clinical efficacy and tolerability. Rufinamide is especially effective for tonic–atonic seizures in Lennox–Gastaut syndrome, but is subsequently proving to be safe and effective in clinical practice for a broad patient population with refractory epilepsy. Although further research and clinical experience is needed, rufinamide holds the promise to positively impact the care of children with epilepsy. In this review, we review the use of rufinamide in pediatric epilepsy, with a focus on efficacy and safety.

Epileptic spasms in tuberous sclerosis complex

PURPOSE To characterize epileptic spasms (ES) occurring after the age of two years in patients with tuberous sclerosis complex (TSC), particularly treatment response to vigabatrin (VGB), which is extremely effective for infantile spasms (IS) in TSC. METHODS The authors retrospectively reviewed 19 patients with TSC and ES. Medical records were assessed for clinical and treatment data, neurocognitive, EEG, MRI data, and genetic analyses. RESULTS Of 391 patients with TSC, 19 (4.8%) had ES. Of those with detailed clinical data, six had infantile spasms that persisted after 2 years old, six recurred after an initial remission of infantile spasms (range 2-24 years old), and four occurred de novo over the age of two (range 2-20 years old). All concurrently had other seizure types. One had hypsarrhythmia on EEG. All had brain MRI stigmata typical of TSC. Thirteen had a mutation in TSC2, and one in TSC1. Six patients became spasm-free with medication treatment, including four with VGB, one with VGB in combination with the low glycemic index dietary treatment, and one with felbamate. Five became spasm-free after epilepsy surgery. VGB was not effective for seven patients. The majority continued to have refractory epilepsy. CONCLUSIONS ES are not uncommon in patients with TSC, especially those with TSC2 mutations. ES in TSC occur in the setting of other seizure types and refractory epilepsy. Hypsarrhythmia is rare. VGB can be effective, but the success of VGB for ES in TSC is not equivalent to that of IS in TSC.

Vigabatrin-related magnetic resonance imaging abnormalities in an infant with tuberous sclerosis complex and infantile spasms.

A newborn with hypopigmented skin macules, cardiac rhabdomyomas, and cerebral magnetic resonance imaging (MRI) demonstrating cortical tubers and subependymal nodules (Figure, A) was diagnosed with tuberous sclerosis complex (TSC). Clusters of flexor spasms began at 3 months of age, infantile spasms was diagnosed. Treatment was commenced with vigabatrin, an irreversible inhibitor of g-aminobutyric acid transaminase, and the spasms ceased within 1 week. Routine follow-up MRI demonstrated the interval development of asymptomatic abnormalities, including restricted diffusion in the bilateral brainstem, basal ganglia, and thalami (Figure, B). After 1 year of successful treatment, the vigabatrin was discontinued and follow-up MRI demonstrated full resolution of these abnormalities (Figure, C). TSC is a genetic disorder characterized by hamartomatous lesions inmultiple organ systems. Infantile spasmsare common in TSC, occurring in one-third of patients. Vigabatrin is considered first-line therapy for infantile spasms in patients with TSC due to its remarkable effectiveness (>95%). These striking drug-relatedMRI abnormalities due to vigabatrin therapyoccur primarily in infancy, are dose dependent, and are apparently asymptomatic and fully reversible. The pathophysiology is

Tuberous sclerosis complex Five new things

Purpose of review Tuberous sclerosis complex (TSC) is a variably expressed neurocutaneous genetic disorder characterized by hamartomatous growths in multiple organ systems. Neurologic involvement often confers the most severe symptoms, and can include epilepsy, increased intracranial pressure from hydrocephalus, intellectual deficits, and autism. The purpose of this review is to provide a neurologically focused update in the diagnosis and treatment of these complications in patients with TSC. Recent findings We highlight 5 new areas of understanding in TSC: the neurobiology of TSC and its translation into clinical practice, vigabatrin in the treatment of infantile spasms, the role of tubers and epilepsy surgery, the treatment of subependymal giant cell astrocytomas, and TSC-related neuropsychiatric disorders. Summary These recent advances in diagnosis and treatment give our patients with TSC and their families hope for the future for improved care and possible preventive cures, to the end goal of improving quality of life.

Journal Club: Randomized phase III study 306 Adjunctive perampanel for refractory partial-onset seizures

A working understanding of antiepileptic drug development, critical appraisal of drug trial design, and interpretation of study results are fundamental for the neurologist and epileptologist, to incorporate newer anticonvulsant medications into clinical practice. In this Journal Club, we evaluate a phase III study by Krauss et al.1 that demonstrates efficacy and safety of adjunctive perampanel for refractory partial-onset seizures.