Seizures in some 30% to 40% of patients with epilepsy fail to respond to antiepileptic drugs or other treatments. While much has been made of the risks of new drug therapies, not enough attention has been given to the risks of uncontrolled and progressive epilepsy. This critical review summarizes known risks associated with refractory epilepsy, provides practical clinical recommendations, and indicates areas for future research. Eight international epilepsy experts from Europe, the United States, and South America met on May 4, 2013, to present, review, and discuss relevant concepts, data, and literature on the consequences of refractory epilepsy. While patients with refractory epilepsy represent the minority of the population with epilepsy, they require the overwhelming majority of time, effort, and focus from treating physicians. They also represent the greatest economic and psychosocial burdens. Diagnostic procedures and medical/surgical treatments are not without risks. Overlooked, however, is that these risks are usually smaller than the risks of long-term, uncontrolled seizures. Refractory epilepsy may be progressive, carrying risks of structural damage to the brain and nervous system, comorbidities (osteoporosis, fractures), and increased mortality (from suicide, accidents, sudden unexpected death in epilepsy, pneumonia, vascular disease), as well as psychological (depression, anxiety), educational, social (stigma, driving), and vocational consequences. Adding to this burden is neuropsychiatric impairment caused by underlying epileptogenic processes ("essential comorbidities"), which appears to be independent of the effects of ongoing seizures themselves. Tolerating persistent seizures or chronic medicinal adverse effects has risks and consequences that often outweigh risks of seemingly "more aggressive" treatments. Future research should focus not only on controlling seizures but also on preventing these consequences.

SUMMARYPurpose: To determine the frequency and determinants of subnormal global cognitive function in a representative, community-based sample of children prospectively identified at the time of initial diagnosis of epilepsy. Methods: In children enrolled with newly diagnosed epilepsy and followed a median of 10.5 years, level of cognitive function (within normal, borderline, mild, moderate to severe mental retardation (MR), neurologically devastated, and impaired but not further classified (NFC)) was determined based upon neurologists' and school records, repeated parental interviews, and, in over half the participants, standardized neuropsychological testing. For multivariable analyses, subnormal cognitive function was designated as consistent with a full scale IQ < 80. Results: Global cognitive function was considered within normal, N = 451 (73.6%), borderline, N = 31 (5.1%), mild MR, N = 21 (3.4%), more severe MR, N = 45 (7.3%), devastated, N = 29 (4.7%), and impaired-NFC, N = 36 (5.9%). Age at onset <5 years, symptomatic etiology, epileptic encephalopathy, remission status and current AED treatment were each strongly associated with level of cognitive function (all p-values <0.0001). In a multivariable logistic regression model, all variables except remission status independently contributed to subnormal global cognitive function. Discussion: Evidence of subnormal global cognitive function is apparent in approximately one of four children with epilepsy. Young age at onset, symptomatic cause, epileptic encephalopathy, and continued treatment, despite their strong intercorrelations, are independently associated with this outcome. KEY WORDS: Cognition, Neuropsychology, Children, Epilepsy.Epilepsy is associated with significant cognitive comorbidity (Lhatoo & Sander, 2001) although the frequency of such comorbidity in people with epilepsy in the general population is often hard to determine. This association between epilepsy and cognitive comorbidity is due to a number of factors including the underlying causes of and risk factors for epilepsy which themselves may be associated (Hack et al., 1996;Pinto-Martin et al., 1999;Wood et al., 2000). The association between mental retardation (MR) and epilepsy has been well described in the literature (Curatolo et al., 1995;Eriksson et al., 1998). The effects of chronic seizures on brain development, structure and function (Holmes, 2001;Fuerst et al., 2003;Hermann et al., 2006); the medication used to treat seizures (Meador, 1994(Meador, , 2006; and possibly an independent effect of the physiological disturbances that predispose the brain to seizures in the first place (Berg et al., 2005) may all contribute to cognitive morbidity in people with epilepsy. Many of these factors are strongly intercorrelated. The overall burden of cognitive co-morbidity in people with epilepsy and the independent contribution of 608 609 Cognitive Function in Epilepsy each of these factors to abnormal cognitive function have not, to our knowledge, been clearly delineated.In the context of l...

Hippocampal atrophy and a history of absence of generalized tonic clonic seizures were the sole predictors of 2-year remission, and only for medial temporal resections.

An individual patient's risk for postoperative verbal memory decline following dominant or nondominant ATL can be predicted using clinical data routinely available preoperatively (side of surgery, qualitative MRI, baseline memory testing, IAP performance). This information may be useful for preoperative patient counseling.

Removal of the anterior temporal lobe (ATL) is an effective surgical treatment for intractable temporal lobe epilepsy but carries a risk of language and verbal memory deficits. Preoperative localization of functional zones in the ATL might help reduce these risks, yet fMRI protocols in current widespread use produce very little activation in this region. Based on recent evidence suggesting a role for the ATL in semantic integration, we designed an fMRI protocol comparing comprehension of brief narratives (Story task) with a semantically shallow control task involving Corresponding Author: Jeffrey R. Binder, MD, MEB Room 4550, 8701 Watertown Plank Road, Milwaukee, WI 53226 USA, Phone: 1-414-456-4662, Fax: 1-414-456-6562, jbinder@mcw.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroimage. Author manuscript; available in PMC 2012 January 15. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript serial arithmetic (Math task). The Story > Math contrast elicited strong activation throughout the ATL, lateral temporal lobe, and medial temporal lobe bilaterally in an initial cohort of 18 healthy participants. The task protocol was then implemented at 6 other imaging centers using identical methods. Data from a second cohort of participants scanned at these centers closely replicated the results from the initial cohort. The Story-Math protocol provides a reliable method for activation of surgical regions of interest in the ATL. The bilateral activation supports previous claims that conceptual processing involves both temporal lobes. Used in combination with language lateralization measures, reliable ATL activation maps may be useful for predicting cognitive outcome in ATL surgery, though the validity of this approach needs to be established in a prospective surgical series.