Andres M. Kanner

Bio: Andres M. Kanner is an academic researcher from University of Miami. The author has contributed to research in topics: Epilepsy & Mood disorders. The author has an hindex of 68, co-authored 276 publications receiving 18437 citations. Previous affiliations of Andres M. Kanner include Rush University & Comprehensive Epilepsy Center.

Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy

Abstract: Summary Purpose: We report a multicenter, double-blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization-related epilepsy Methods: Participants were adults with medically refractory partial seizures, including secondarily generalized seizures Half received stimulation and half no stimulation during a 3-month blinded phase; then all received unblinded stimulation Results: One hundred ten participants were randomized Baseline monthly median seizure frequency was 195 In the last month of the blinded phase the stimulated group had a 29% greater reduction in seizures compared with the control group, as estimated by a generalized estimating equations (GEE) model (p = 0002) Unadjusted median declines at the end of the blinded phase were 145% in the control group and 404% in the stimulated group Complex partial and “most severe” seizures were significantly reduced by stimulation By 2 years, there was a 56% median percent reduction in seizure frequency; 54% of patients had a seizure reduction of at least 50%, and 14 patients were seizure-free for at least 6 months Five deaths occurred and none were from implantation or stimulation No participant had symptomatic hemorrhage or brain infection Two participants had acute, transient stimulation-associated seizures Cognition and mood showed no group differences, but participants in the stimulated group were more likely to report depression or memory problems as adverse events Discussion: Bilateral stimulation of the anterior nuclei of the thalamus reduces seizures Benefit persisted for 2 years of study Complication rates were modest Deep brain stimulation of the anterior thalamus is useful for some people with medically refractory partial and secondarily generalized seizures

De novo mutations in epileptic encephalopathies

Abstract: Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders.

Cognitive Function at 3 Years of Age after Fetal Exposure to Antiepileptic Drugs

Abstract: BACKGROUND Fetal exposure of animals to antiepileptic drugs at doses lower than those required to produce congenital malformations can produce cognitive and behavioral abnormalities, but cognitive effects of fetal exposure of humans to antiepileptic drugs are uncertain. METHODS Between 1999 and 2004, we enrolled pregnant women with epilepsy who were taking a single antiepileptic agent (carbamazepine, lamotrigine, phenytoin, or valproate) in a prospective, observational, multicenter study in the United States and the United Kingdom. The primary analysis is a comparison of neurodevelopmental outcomes at the age of 6 years after exposure to different antiepileptic drugs in utero. This report focuses on a planned interim analysis of cognitive outcomes in 309 children at 3 years of age. RESULTS At 3 years of age, children who had been exposed to valproate in utero had significantly lower IQ scores than those who had been exposed to other antiepileptic drugs. After adjustment for maternal IQ, maternal age, antiepileptic-drug dose, gestational age at birth, and maternal preconception use of folate, the mean IQ was 101 for children exposed to lamotrigine, 99 for those exposed to phenytoin, 98 for those exposed to carbamazepine, and 92 for those exposed to valproate. On average, children exposed to valproate had an IQ score 9 points lower than the score of those exposed to lamotrigine (95% confidence interval [CI], 3.1 to 14.6; P=0.009), 7 points lower than the score of those exposed to phenytoin (95% CI, 0.2 to 14.0; P=0.04), and 6 points lower than the score of those exposed to carbamazepine (95% CI, 0.6 to 12.0; P=0.04). The association between valproate use and IQ was dose dependent. Children's IQs were significantly related to maternal IQs among children exposed to carbamazepine, lamotrigine, or phenytoin but not among those exposed to valproate. CONCLUSIONS In utero exposure to valproate, as compared with other commonly used antiepileptic drugs, is associated with an increased risk of impaired cognitive function at 3 years of age. This finding supports a recommendation that valproate not be used as a first-choice drug in women of childbearing potential.

Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

Abstract: Objective: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide—reviewed in the order in which these agents received approval by the US Food and Drug Administration) in the treatment of children and adults with newly diagnosed partial and generalized epilepsies. Methods: A 23-member committee, including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy, evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until September 2002, with selected manual searches up until 2003. Results: There is evidence either from comparative or dose-controlled trials that gabapentin, lamotrigine, topiramate, and oxcarbazepine have efficacy as monotherapy in newly diagnosed adolescents and adults with either partial or mixed seizure disorders. There is also evidence that lamotrigine is effective for newly diagnosed absence seizures in children. Evidence for effectiveness of the new AEDs in newly diagnosed patients with other generalized epilepsy syndromes is lacking. Conclusions: The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with newly diagnosed epilepsy and identify those seizure types and syndromes where more evidence is necessary.

The molecular neurobiology of depression

Abstract: Unravelling the pathophysiology of depression is a unique challenge. Not only are depressive syndromes heterogeneous and their aetiologies diverse, but symptoms such as guilt and suicidality are impossible to reproduce in animal models. Nevertheless, other symptoms have been accurately modelled, and these, together with clinical data, are providing insight into the neurobiology of depression. Recent studies combining behavioural, molecular and electrophysiological techniques reveal that certain aspects of depression result from maladaptive stress-induced neuroplastic changes in specific neural circuits. They also show that understanding the mechanisms of resilience to stress offers a crucial new dimension for the development of fundamentally novel antidepressant treatments.

Model of autism: increased ratio of excitation/inhibition in key neural systems

Abstract: Autism is a severe neurobehavioral syndrome, arising largely as an inherited disorder, which can arise from several diseases. Despite recent advances in identifying some genes that can cause autism, its underlying neurological mechanisms are uncertain. Autism is best conceptualized by considering the neural systems that may be defective in autistic individuals. Recent advances in understanding neural systems that process sensory information, various types of memories and social and emotional behaviors are reviewed and compared with known abnormalities in autism. Then, specific genetic abnormalities that are linked with autism are examined. Synthesis of this information leads to a model that postulates that some forms of autism are caused by an increased ratio of excitation/inhibition in sensory, mnemonic, social and emotional systems. The model further postulates that the increased ratio of excitation/inhibition can be caused by combinatorial effects of genetic and environmental variables that impinge upon a given neural system. Furthermore, the model suggests potential therapeutic interventions.