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High-frequency phase-locked oscillations have been hypothesized to facilitate integration (‘binding’) of information encoded across widespread cortical areas. Ripples (∼100ms long ∼90Hz oscillations) co-occur broadly in multiple states and locations, but have only been associated with memory replay. We tested whether cortico-cortical co-ripples subserve a general role in binding by recording intracranial EEG during reading. Co-rippling strongly increased to words versus consonant-strings in visual, wordform and semantic areas when letters are binding into words, and words to meaning. Similarly, co-ripples increased prior to correct responses between executive, response, wordform and semantic sites when word meanings are binding to instructions and response. These effects dissociated from non-oscillatory activation and memory reinstatement. Co-ripples were phase-locked at zero-lag, even at long distances, supporting a general role in cognitive binding.

Current treatments for autism spectrum disorders (ASD) are limited in efficacy and are often associated with substantial side effects. These medications typically ameliorate problem behaviors associated with ASD, but do not target core symptom domains. As a result, there is a significant amount of research underway for development of novel experimental therapeutics. Endocannabinoids are arachidonic acid-derived lipid neuromodulators, which, in combination with their receptors and associated metabolic enzymes, constitute the endocannabinoid (EC) system. Cannabinoid signaling may be involved in the social impairment and repetitive behaviors observed in those with ASD. In this review, we discuss a possible role of the EC system in excitatory-inhibitory (E-I) imbalance and immune dysregulation in ASD. Novel treatments for the core symptom domains of ASD are needed and phytocannabinoids could be useful experimental therapeutics for core symptoms and associated domains.

Intellectual disability (ID) affects about 3% of the population and has a male gender bias. Of at least 700 genes currently linked to ID, more than 100 have been identified on the X chromosome, including KIAA2022. KIAA2022 is located on Xq13.3 and is expressed in the developing brain. The protein product of KIAA2022, X‐linked Intellectual Disability Protein Related to Neurite Extension (XPN), is developmentally regulated and is involved in neuronal migration and cell adhesion. The clinical manifestations of loss‐of‐function KIAA2022 mutations have been described previously in 15 males, born from unaffected carrier mothers, but few females. Using whole‐exome sequencing, we identified a cohort of five unrelated female patients with de novo probably gene damaging variants in KIAA2022 and core phenotypic features of ID, developmental delay, epilepsy refractory to treatment, and impaired language, of similar severity as reported for male counterparts. This study supports KIAA2022 as a novel cause of X‐linked dominant ID, and broadens the phenotype for KIAA2022 mutations.

The widespread use of video-electroencephalogram monitoring has dramatically increased our recognition of the high prevalence and diversity of nonepileptic seizures. Nonepileptic seizures stand squarely in the interface between psychiatry and neurology, an area that has been both claimed and denied by both sides. Collaborative exploration of this border zone has provided new insights into a disorder that may be as ancient as epilepsy.

Epilepsy surgery is assuming greater importance in treating patients with partial epilepsy whose seizures are uncontrolled with antiepileptic drugs. Many good candidates for surgical treatment are not presented with the option of surgery. The evaluation for epilepsy surgery is extensive and includes several stages of noninvasive and invasive testing. As more sophisticated noninvasive tests develop, fewer patients require invasive monitoring studies such as depth or subdural electrodes. The principal forms of surgical treatment include focal resection, corpus callosotomy, and hemispherectomy. Temporal lobectomy remains the most common and effective form of epilepsy surgery. Frontiers of epilepsy surgery include resective surgery for intractable infantile spasms and multiple subpial transections for patients whose seizure foci are in sensory, motor, or languages cortex. Additional studies are needed to define the safety and efficacy of these new procedures.

We studied the clinical features of 85 cases of phenytoin toxicity in 76 patients treated at a general hospital. Serum levels of phenytoin on admission ranged from 30.3 to 95.0 micrograms/mL (median, 46.5). Iatrogenic causes of intoxication were common and included increased daily dosage and intravenous loading in the emergency room for single seizures in patients with subtherapeutic serum phenytoin levels. The most frequent neurologic findings were nystagmus (95%), ataxia (88%), lethargy (22%), and seizures (19%). Outcome was usually good, but three patients had serious complications.

Several studies suggest hemispheric lateralization of autonomic cardiovascular control. There is controversy regarding which hemisphere dominates sympathetic or parasympathetic activity. Hemispheric influences on baroreflex sensitivity (BRS) have not yet been evaluated. To determine hemispheric autonomic control in epilepsy patients, we assessed cardiovascular and baroreflex modulation before and during hemispheric inactivation. For 15 patients with drug-refractory epilepsy, we analyzed autonomic heart rate (HR) and blood pressure (BP) modulation and BRS before and during left and right intracarotid amobarbital procedure (IAP). After Blackman-Tukey spectral analysis, we calculated the low-frequency (LF: 0.04-0.15 Hz) and high-frequency (HF: 0.15-0.5 Hz) power of HR and BP as well as BRS as the LF transfer function gain between BP and HR. Right hemispheric inactivation induced a significant decrease of BP and an increase of HF power of HR and BP (p0.05). Left inactivation increased HR, BP, and LF power of both signals and decreased BRS by nearly 30% (p0.05). The results confirm previous IAP studies showing sympathetic lateralization in the right hemisphere and, moreover, demonstrate parasympathetic predominance and up-regulation of BRS in the left hemisphere. In epilepsy patients, unilateral electrical activity might derange autonomic balance between both hemispheres and contribute to cardiovascular dysregulation and sudden fatalities.

Knowledge about the comparative safety and efficacy of standard and new antiepileptic drugs (AEDs) is limited. Medications are selected on the basis of seizure type and epilepsy syndrome, adverse effect profiles, and cost. However, there are few data comparing the efficacy of the new AEDs for the treatment of recent-onset versus refractory partial seizures, simple versus complex partial seizures, frontal versus temporal lobe seizures, or other relevant clinical types. Few studies compare new AEDs. The next best approach has been the use of meta-analyses and compilation of data from clinical trials, which allow interstudy comparisons to define broad and rough comparative estimates. These analyses, however, do not define clear differences in the safety and efficacy of the new AEDs because of differences in study populations. The new AEDs have expanded our arsenal against seizures. As a group, they have favorable safety and efficacy profiles. The challenge is to define the differences in terms of clinical significance.

It is known that epilepsy patients diagnosed with neocortical temporal lobe epilepsy (NTLE), differ from those diagnosed with mesial temporal lobe epilepsy (MTLE), e.g., in hippocampal (HPC) pathology. In the present studies, we tested the hypothesis that NTLE and MTLE subtypes of human epilepsy might differ in regards to their HPC monoamine neurochemistry. Monoamine neurotransmitters were studied in separate signals and within s with semiderivative microvoltammetry, used in combination with stearate indicator, Ag-AgCl reference and stainless steel auxiliary microelectrodes. Anterior HPC specimens from the patients' epileptogenic zone, defined by electrocorticography, were resected neurosurgically from 13 consecutive patients with intractable temporal lobe epilepsy. Four patients were diagnosed with NTLE and nine with MTLE. The criteria for the diagnosis of NTLE versus MTLE was absence versus presence of HPC sclerosis, respectively, based on MRI examination of resected tissue. In addition, NTLE patients demonstrated seizure onset in anterolateral temporal neocortex on electroencephalography (EEG). HPC subparcellations studied were: (a) Granular Cells of the Dentate Gyrus (DG), (b) Polymorphic Layer of DG and (c) Pyramidal Layer: subfields, CA1 and CA2. Dopamine (DA), serotonin (5-HT), norepinephrine (NE) and ascorbic acid (AA) (co-factor in DA to NE synthesis), exhibited separate and characteristic half-wave potentials in millivolts. Each half-wave potential, i.e., the potential at which maximum current was generated, was experimentally established in vitro. Concentrations of neurotransmitters found in HPC subparcellations were interpolated from calibration curves derived in vitro from electrochemical detection of monoamines and AA in saline phosphate buffer. Significant differences between subtypes in concentration of monoamines were analyzed by the Mann Whitney rank sum test and those differences in probability distribution of monoamines were analyzed by the Fisher Exact test; in each case, P0.01 was the criteria selected for determining statistical significance. DA concentrations were higher in NTLE compared with MTLE in each HPC subparcellation [P=0.037, 0.024 and 0.007, respectively (P0.01)] and DA occurred more frequently in NTLE in the Pyramidal Layer [P=0.077 (P0.01)]. AA was present in one NTLE patient. NE concentrations were higher in MTLE vs. NTLE in each subparcellation [P=0.012, 0.067 and 0.07, respectively (P0.01)] and NE occurred more frequently in MTLE in Granular Cells of DG and Pyramidal Layer [P=0.052 and 0.014, respectively (P0.01)]. In MTLE, NE concentrations in the CA1 subfield of the Pyramidal Layer were decreased vs. the CA2 subfield [P=0.063 (P0.01)]. Serotonin was found in every HPC subparcellation of each subtype but 5-HT concentrations were higher in NTLE vs. MTLE in the Granular Cells of DG and the Pyramidal Layer (CA1 subfield) [P=0.076 and 0.095, respectively (P0.01)]. Thus, this preliminary study showed that marked differences in HPC monoamine neurochemistry occurred in NTLE patients as compared with MTLE patients.

This study was designed to further define the electroencephalographic abnormalities seen in the Landau-Kleffner syndrome variants and the associated clinical features.Landau-Kleffner syndrome is rare, but its putative variants are more common.We report two patients with centro-temporal spikes, autistic epileptiform regression, and variably prominent oro-motor symptoms.The epileptic aphasia pattern found among patients with prominent Rolandic spikes may more frequently involve expressive language than is seen in the typical Landau-Kleffner syndrome, where verbal auditory agnosia is the rule.This clinical difference likely reflects the location of the epileptiform activity (centrotemporal as opposed to anterior or mid-temporal) on buccal-lingual function, vocalization, and language production.

Repetitive vagal nerve stimulation (VNS) is a new, FDA-approved treatment for medically refractory epilepsy. The device is implanted subcutaneously in the left chest and sends intermittent impulses to the left vagus nerve through communicating leads. Twelve patients have been implanted to date. The ages of the patients range from 8 to 36 years and the average followup at this point is five months. Five patients have achieved a greater than 50 percent reduction in seizure frequency with no serious adverse effects.

A 49-year-old man with right temporal lobe epilepsy developed the chronic delusion that his body emitted a foul odor (olfactory reference syndrome). Before the delusional symptoms, he had partial seizures with unpleasant olfactory hallucinations. Subsequently ictal olfactory symptoms abated but a disabling delusional syndrome developed. The only prior case of the olfactory reference syndrome in a patient with epilepsy had a right frontal lesion. The case further supports the association of right hemisphere lesions and delusional disorders.

The authors examined interhemispheric memory transfer in 32 patients with lateralized temporal lobe complex partial epilepsy (15 right onsets, 17 left onsets). Visually presented verbal, nonverbal, and two types of dually encodable stimuli were displayed during amobarbital anesthesia, and recognition memory was tested with verbal and nonverbal (pointing) response modalities. No relationship was found between the material specificity of stimuli and response modality. The only significant findings were for poorer recognition memory after injection of the hemisphere contralateral to the seizure focus. Visual information presented predominantly to one hemisphere during anesthesia is available to the other hemisphere for recognition memory on clearing.

The authors investigated cognition in juvenile myoclonic epilepsy (JME), focusing on frontal functions as suggested by maximal spatial distribution of epileptiform activity seen over frontocentral regions. Fifteen patients with JME (mean age, 34.3 years; mean estimated IQ 101) were administered a battery of tests sensitive to frontal dysfunction. The number of patients with impaired test performance and the frequency of impairment per test were calculated. Performance on selected tests was compared with that of 15 patients with temporal lobe epilepsy (TLE) who were matched for estimated IQ using paired t-tests. Although the performance of the group with JME was not uniform--some patients showed marked impairment whereas others showed little or no deficit--a high frequency of impairment was found on tests of concept formation-abstract reasoning and mental flexibility, cognitive speed, and planning and organization. Significant differences were found between the group with JME and the group with TLE on tests requiring mental flexibility and concept formation-abstract reasoning. In conjunction with studies demonstrating intractable seizures in approximately 20% of patients, the results from this study suggest that JME is not a uniformly benign condition. Frontal deficits may have maladaptive behavioral consequences suggestive of personality dysfunction, as described anecdotally by previous investigators.

Antidepressants or stimulants are commonly used to treat attention deficit disorder (ADD). We report the results of an open-label trial of the recently marketed antidepressant venlafaxine in 16 adult patients with ADD. Patients were treated with venlafaxine (25 to 225 mg/day) for 8 weeks. Four patients discontinued treatment within the first week because of sedation, agitation, or nausea. In the remaining 12 patients, venlafaxine treatment decreased ADD ratings by almost half.

Seizures are an important adverse effect of clozapine therapy; a cumulative 10% risk of tonic-clonic seizures is estimated after 3.8 years of treatment. Although the risk of seizures may be increased by rapid upward titration and higher doses, recent data do not clearly confirm the dose-dependent effect. The vast majority of clozapine-related seizures are tonic-clonic, although myoclonic seizures also occur. The role of the EEG in predicting the occurrence of clozapine-induced seizures remains uncertain. In patients with clozapine-related seizures, either reducing the dose or adding an antiepileptic medication usually allows continuation of therapy.

Conventional wisdom and prevailing medical practice strongly support the belief that medication should be avoided during pregnancy. For the nearly one million women of childbearing age with epilepsy in the United States this is often difficult, if not impossible, and for many of these women becoming pregnant raises many conflicting issues. Women with epilepsy may face a possible increase in the frequency and severity of seizures, and in generalized tonic-clonic seizures there is a small but increased risk of miscarriage.

Legal issues must be considered in caring for patients with epilepsy. Doctors caring for people with epilepsy may be legally involved in three primary ways: as the agent of social control, as patient advocate, and as the target of liability or malpractice suits. This article examines these factors and the implications for patients and their caregivers.

Several new compounds are undergoing extensive investigation in the United States and Europe. The available animal and human studies suggest that these new antiepileptic drugs are very promising. Some or all of them will be approved for clinical use during the next decade. New antiepileptic drugs offer new options in the treatment of epilepsy. Although there already has been considerable testing of these drugs, additional studies that incorporate traditional medical outcome measures and quality of life measures remain to be done to establish the ultimate role of the new antiepileptic drugs in the treatment hierarchy for epilepsy.

We report seven patients with crying during video-EEG-documented simple or complex partial seizures. During simple partial seizures, crying occurred with or without appropriate affect. Crying occurred postictally in two patients and was associated with persistent spiking in one of them. Six patients had ictal activity in the nondominant hemisphere, maximal in the anteromesial temporal region in five and in the mesial frontal region in another. These cases support theories proposing a lateralization of emotion, with right hemisphere dominance for negative affective states.

The review of previous research and the studies undertaken at our center suggest an important role for mapping of nonlinguistic cognitive functions with cortical stimulation. Such mapping is usually restricted to language functions, which is understandable given the importance of language to daily activities and the reports of postoperative declines in naming. However, memory functions are also critical to adaptive daily living, and these studies show that memory may be effectively addressed through mapping procedures. Both Ojemann's studies and those at our center suggest an important role for much of the temporal convexity in memory processing, and we believe that postoperative memory declines can be minimized with mapping of the temporal lobe prior to resection. Patients presenting with unique abilities that may be susceptible to postoperative declines can also be effectively mapped with stimulation studies tailored to their unique abilities. We encourage the expansion of mapping paradigms beyond just the language domain and believe that such studies will both improve the quality of our patients' functioning and further our knowledge of brain-behavior relationships.

In 5 cases suffering from intractable seizures and ictal onset in exquisite (primary somatosensory or language related) cortex, surgical therapy has been done consisting wholly or in part of multiple subpial transections. In two cases with involvement of the primary somatosensory cortex, good seizure control without detectable neurological deficit was achieved. In the other three cases with involvement of the language cortex, deficits were minimal and cleared with time. Patients became seizure-free.

The authors present the case of a 13-year-old girl with episodes characterized by either staring with preserved consciousness or fear in whom functional illness was suspected. Video-EEG telemetry revealed no changes during 30 of 32 attacks. Subdural electrode recordings revealed epileptiform discharges in 30 of 37 episodes. The discharge was always localized to the electrodes recording from the inferomedial temporal region, with electrodes over the lateral convexity of the same temporal lobe showing no background changes. Although the detailed pathophysiology of panic attacks remains to be clarified, the authors point out that their case and other epileptic case studies are consistent with the possibility that excessive neuronal activity in medial temporal lobe structures is a necessary element of the underlying mechanism.

Treatment for PNES must be individualized. A combination of approaches is probably the most beneficial for improvement. Treatment should not simply emphasize removing maladaptive PNES behaviour, but should also focus on learning new coping skills and removing secondary gains. If PNES persist, therapy should be re-evaluated.