Faculty Bibliography

We report 2 pediatric patients who presented initially with seizures followed by subacute language regression characterized by a verbal auditory agnosia. These previously normal children had no evidence of expressive aphasia during their symptomatic periods. Further, in both cases, auditory agnosia was associated with sleep-activated electroencephalographic (EEG) epileptiform activity, consistent with Landau-Kleffner syndrome. However, both cases are unique since the episodic auditory agnosia and sleep-activated EEG epileptiform activity rapidly responded to combination therapy with pulse benzodiazepine and corticosteroids. Further, in each case, recurrences were characterized by similar symptoms, EEG findings, and beneficial responses to the pulse benzodiazepine and corticosteroid therapy. These observations suggest that pulse combination high-dose corticosteroid and benzodiazepine therapy may be especially effective in Landau-Kleffner syndrome.

OBJECTIVE: Describe the characteristics of persons with epilepsy (PWEs) and caregivers that have or have not heard of sudden unexpected death in epilepsy (SUDEP) prior to completing a survey through the Internet or in the clinical setting. METHODS: An online survey for adult PWEs and caregivers was solicited by e-mail and newsletter to Epilepsy Therapy Project members. A similar survey was implemented in a clinic setting of a community hospital. The survey asked about seizure characteristics, epilepsy management, fear of death, and familiarity with the term SUDEP. Respondents that never heard of SUDEP read a definition and responded to questions about their initial reactions. RESULTS: Surveys from 1,392 PWEs and 611 caregivers recruited through an epilepsy Website and a clinic demonstrated that Internet respondents were much more likely to have heard about SUDEP than the clinic population (71.1% vs. 38.8%; p < 0.001), and caregivers of PWEs were more likely to have heard about SUDEP than PWEs (76.2% vs. 65.2%; p < 0.001). Prior awareness was related to an increased level of education, more severe and longer duration of epilepsy, and having an epileptologist as the primary care provider. Although most PWEs and caregivers reported feelings of fear, anxiety, and sadness after first hearing of SUDEP, they wanted to discuss it with their doctor. Persons with epilepsy, and especially their caregivers, often worry that the PWEs may die of epilepsy or seizures. This worry escalated with knowledge of SUDEP and increased epilepsy severity. Approximately half of PWEs and caregivers believed that knowledge about SUDEP would influence their epilepsy management. SIGNIFICANCE: Our results may help epilepsy care providers determine when to facilitate a discussion about epilepsy-related mortality and SUDEP among patients and caregivers, and to educate those at high risk about the importance of seizure control as well as reduce fears about death in patients with well-controlled and nonconvulsive epilepsies.

Septal nuclei, located in basal forebrain, are strongly connected with hippocampi and important in learning and memory, but have received limited research attention in human MRI studies. While probabilistic maps for estimating septal volume on MRI are now available, they have not been independently validated against manual tracing of MRI, typically considered the gold standard for delineating brain structures. We developed a protocol for manual tracing of the human septal region on MRI based on examination of neuroanatomical specimens. We applied this tracing protocol to T1 MRI scans (n=86) from subjects with temporal epilepsy and healthy controls to measure septal volume. To assess the inter-rater reliability of the protocol, a second tracer used the same protocol on 20 scans that were randomly selected from the 72 healthy controls. In addition to measuring septal volume, maximum septal thickness between the ventricles was measured and recorded. The same scans (n=86) were also analysed using septal probabilistic maps and Dartel toolbox in SPM. Results show that our manual tracing algorithm is reliable, and that septal volume measurements obtained via manual and automated methods correlate significantly with each other (p<.001). Both manual and automated methods detected significantly enlarged septal nuclei in patients with temporal lobe epilepsy in accord with a proposed compensatory neuroplastic process related to the strong connections between septal nuclei and hippocampi. Septal thickness, which was simple to measure with excellent inter-rater reliability, correlated well with both manual and automated septal volume, suggesting it could serve as an easy-to-measure surrogate for septal volume in future studies. Our results call attention to the important though understudied human septal region, confirm its enlargement in temporal lobe epilepsy, and provide a reliable new manual delineation protocol that will facilitate continued study of this critical region.

OBJECTIVE: Patients with tuberous sclerosis complex (TSC) commonly present with significant neurologic deficits, including seizures, autism, and intellectual disability. Previous evidence suggests that the TSC2 mutation genotype may be associated with a more severe disease phenotype. This study evaluates the association of the TSC1 and TSC2 genotype with patient and disease characteristics in a retrospective review of a large TSC Natural History Database consisting of 919 patients with TSC. METHODS: Univariate logistic regression was conducted to evaluate the association of the TSC1 and TSC2 gene mutations with patient and disease characteristics. RESULTS: As compared to patients with the TSC1 mutation, patients with the TSC2 mutation were younger (p = 0.02), more likely to have partial epilepsy (odds ratio (OR) 1.74, p = 0.0015), complex partial seizures (OR 2.03, p = 0.02), infantile spasms (IS) (OR 1.67, p = 0.01), subependymal giant-cell astrocytomas (SEGAs) (OR 1.64, p = 0.01), and intellectual disability (OR 2.90, p = 0.0002). SIGNIFICANCE: The clinical presentation of TSC is highly variable and not well understood. Our findings confirm and supplement existing literature that TSC2 mutation is likely to be associated with a more severe, earlier presenting TSC phenotype, including infantile spasms. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

OBJECTIVES: Patients with tuberous sclerosis complex (TSC) frequently have autism spectrum disorders and neuropsychiatric disorders. Subependymal giant cell astrocytomas (SEGAs) have been reported to occur in 5-20% of patients with TSC; however, the relationship between SEGAs and neuropsychiatric disorders in TSC remains unknown. We utilized a large multicenter database to study associations between SEGAs and neuropsychiatric disorders in patients with TSC. METHODS: Associations between the presence of SEGAs and neuropsychiatric disorders were examined in a retrospective review of 916 patients enrolled in the TSC Natural History Database Project (Tuberous Sclerosis Alliance). RESULTS: Among the 916 TSC patients, 226 had SEGAs (25%) and 155 had autism spectrum disorder (ASD) (17%). Compared to patients without SEGAs, patients with SEGAs were 1.83 (95% confidence interval [CI] 1.26-2.66) times more likely to have ASD. No significant relationship was found between SEGAs and intellectual disability, attention-deficit/hyperactive disorder, or major depressive disorder. SIGNIFICANCE: The clinical presentation of TSC is highly variable and not well understood. These data show that SEGAs are associated with ASD in patients with TSC, suggesting that the pathologic changes leading to SEGA formation may also predispose patients to ASD. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

To present a summary of current scientific evidence about the cannabinoid, cannabidiol (CBD) with regard to its relevance to epilepsy and other selected neuropsychiatric disorders. We summarize the presentations from a conference in which invited participants reviewed relevant aspects of the physiology, mechanisms of action, pharmacology, and data from studies with animal models and human subjects. Cannabis has been used to treat disease since ancient times. Delta9 -Tetrahydrocannabinol (Delta9 -THC) is the major psychoactive ingredient and CBD is the major nonpsychoactive ingredient in cannabis. Cannabis and Delta9 -THC are anticonvulsant in most animal models but can be proconvulsant in some healthy animals. The psychotropic effects of Delta9 -THC limit tolerability. CBD is anticonvulsant in many acute animal models, but there are limited data in chronic models. The antiepileptic mechanisms of CBD are not known, but may include effects on the equilibrative nucleoside transporter; the orphan G-protein-coupled receptor GPR55; the transient receptor potential of vanilloid type-1 channel; the 5-HT1a receptor; and the alpha3 and alpha1 glycine receptors. CBD has neuroprotective and antiinflammatory effects, and it appears to be well tolerated in humans, but small and methodologically limited studies of CBD in human epilepsy have been inconclusive. More recent anecdotal reports of high-ratio CBD:Delta9 -THC medical marijuana have claimed efficacy, but studies were not controlled. CBD bears investigation in epilepsy and other neuropsychiatric disorders, including anxiety, schizophrenia, addiction, and neonatal hypoxic-ischemic encephalopathy. However, we lack data from well-powered double-blind randomized, controlled studies on the efficacy of pure CBD for any disorder. Initial dose-tolerability and double-blind randomized, controlled studies focusing on target intractable epilepsy populations such as patients with Dravet and Lennox-Gastaut syndromes are being planned. Trials in other treatment-resistant epilepsies may also be warranted. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.