JOURNAL CLUB: Longitudinal Qualitative Characterization of MRI Features After Laser Interstitial Thermal Therapy in Drug-Resistant Epilepsy.

OBJECTIVE: Laser interstitial thermal therapy (LITT), a method for ablating brain tissue under real-time MR thermometry, has been used more frequently in recent years to treat nonmalignant lesions. The purpose of this study is to longitudinally characterize MRI features after LITT in patients with drug-resistant epilepsy, primarily in the setting of mesial temporal sclerosis. MATERIALS AND METHODS: MR images from 23 consecutive patients who underwent LITT were retrospectively reviewed. All patients had images obtained immediately after the ablation. Multiple patients had follow-up imaging at various time points after treatment, from postoperative days 7 through 1539. A total of 54 MRI studies were reviewed. RESULTS: Immediately after LITT, MR images showed a ring-enhancing lesion at the ablation site with minimal surrounding edema. Seven images showed increased enhancement of the ipsilateral choroid plexus. Images in the subacute phase showed a mild increase in edema with similar enhancement. Images in the transitional phase showed a decrease in edema with variable enhancement. Images in the chronic phase showed minimal gliosis with or without cavity formation or cavity formation alone, with either decreased or no enhancement. CONCLUSION: This report describes the time course of the imaging findings after LITT for drug-resistant epilepsy. The typical stages include rim-enhancing lesion with minimal edema, followed by an increase in edema, to eventual gliosis and nonenhancing cavity formation. Radiologists need to be familiar with the postablation findings to minimize misdiagnosis and prevent unnecessary workup.

Seizure outcome after switching antiepileptic drugs: A matched, prospective study.

OBJECTIVE: Outcomes after changing antiepileptic drugs (AEDs) have largely been studied in single cohort series. We recently reported the first study to examine this question in a controlled manner. Here we expand on these results by using a matched, prospective methodology applied to both uncontrolled and well-controlled patients taking any AED. METHODS: We reviewed all outpatient notes over a 9-month period and identified patients with focal epilepsy who were on monotherapy. We classified those who switched AEDs as case patients, with those remaining on the same drug serving as controls. We matched cases with controls for seizure status (seizure-free in the preceding 6 months or not), current AED, and number of failed AEDs. We subsequently assessed outcome 6 months later. RESULTS: Seizure-free patients who switched drug (n = 12) had a 16.7% rate of seizure recurrence at 6 months, compared to 2.8% among controls remaining on the same drug (n = 36, p = 0.11). There was a 37% remission rate among uncontrolled patients who switched drug compared to 55.6% among controls (n = 27 per group, p = 0.18). Uncontrolled patients who had previously tried more than one AED were somewhat less likely to enter remission (p = 0.057). Neither AED mechanism of action nor change in dosage impacted outcome. SIGNIFICANCE: Herein we provide further estimation of the modest risk (~14%) associated with switching AEDs in patients in remission compared to being maintained on the same regimen. Uncontrolled patients were no more likely to enter remission after a drug switch than they were after remaining on the same drug, suggesting that spontaneous changes in disease state, and not drug response, underlie remission in this population.

Clinical features and postoperative seizure outcome in patients with drug-resistant gelastic seizures without hypothalamic hamartoma.

OBJECTIVES: The objective of this study was to describe the clinical characteristics and surgical outcome in patients with gelastic seizures without hypothalamic hamartoma. METHODS: We retrospectively reviewed all the video-EEG reports over a 5-year period (2007-2011) for the occurrence of the terms "laugh" or "giggle" in the text body. All the patients with at least one documented gelastic seizure at the epilepsy monitoring unit were studied. In patients who underwent epilepsy surgery, seizure outcomes were analyzed. RESULTS: Sixteen patients (10 females and 6 males) with a mean age of 46.3years were studied. Seven patients had invasive intracranial EEG recordings. Seizure onset zone was in a temporal lobe in four patients and the frontal lobe in one patient. Two patients did not have gelastic seizures during their intracranial EEG monitoring. Nine patients underwent resective epilepsy surgery for their seizures. Six patients (67%) were seizure-free after surgery. CONCLUSION: In adult patients, gelastic seizures can be seen in patients with focal epilepsy without hypothalamic hamartoma. Nonhypothalamic hamartoma gelastic seizures originating from the temporal lobe can be amenable to surgery.

Seizure recurrence and remission after switching antiepileptic drugs.

PURPOSE: Studies of seizure outcome in patients undergoing serial antiepileptic drug trials have all been uncontrolled, with no account made for the spontaneous changes in disease state that could confound the elucidation of drug effects. In addition, no study has ever looked at outcome following antiepileptic drug switch in seizure-free patients, despite the fact that this is done routinely in clinical practice. We aimed to address both of these issues using a matched case-cohort design. METHODS: We followed patients taking phenytoin or carbamazepine in monotherapy for focal epilepsy who were being crossed over to a newer agent as part of studies on the metabolic effects of anticonvulsant therapy. Many had been seizure-free but were being switched nonetheless due to side effects or concerns about long-term adverse consequences. Each patient was matched with two controls of the same seizure status who were taking anticonvulsant monotherapy and whose drug was not switched. Seizure freedom over the ensuing 6 months was the primary end point. KEY FINDINGS: There were 43 cases and 86 matched controls. Twenty-three patients (cases) had been seizure-free on their old drug; 5 (21.7%) had seizure recurrence after drug switch compared to 2 (4.3%) of 46 matched controls. Twenty patients (cases) were having seizures on their old drug; 6 (30%) entered remission after drug switch, compared to 8 of 40 matched controls (20%). The two groups differed at baseline in number of anticonvulsants previously failed, which was the most important factor for prognosis. After statistical adjustment to account for this, seizure-free patients had 6.53 times higher odds of seizure recurrence if switched to a new drug (95% confidence interval [CI] 1.02-61.19; p = 0.06). Non-seizure-free patients had 1.66 times higher odds of remission if they remained on the same drug compared to switching, although this was not significant (95% CI 0.36-8.42; p = 0.532). Neither dose changes, nor drug mechanism, nor duration of seizure freedom had any bearing upon the results. SIGNIFICANCE: Although the large majority of seizure-free patients remain so when switched to another agent, about one sixth have a recurrence attributable to the change. Conversely, our study design provides the first evidence to suggest that most improvements in drug-resistant patients are likely due to spontaneous remissions, not new drug introductions. These findings have conflicting implications for two competing models of comparative antiepileptic drug efficacy, which will require further study to elaborate.

B-vitamin deficiency in patients treated with antiepileptic drugs.

Enzyme-inducing antiepileptic drugs (AEDs) produce many alterations in metabolism, including vitamin levels. Whether they produce clinically relevant deficiency of B vitamins has rarely been assessed. We obtained B-vitamin levels in patients who were being converted from an inducing AED (phenytoin or carbamazepine) to a non-inducing AED (levetiracetam, lamotrigine, or topiramate), with measurements both before and ≥ 6 weeks after the switch. A group of normal subjects underwent the same studies. Neither folate nor B12 deficiency was seen in any patient. Vitamin B6 deficiency was found in 16/33 patients (48%) taking inducers, compared to 1/11 controls (9%; p=0.031). After switch to non-inducers, only 7 patients (21%) were B6 deficient (p=0.027). The incidence of deficiency was similar regardless of which inducing or non-inducing AED was being taken. Our findings demonstrate that treatment with inducing AEDs commonly causes pyridoxine deficiency, often severe. This could conceivably contribute to the polyneuropathy sometimes attributed to older AEDs, as well as other chronic heath difficulties.

Gray Matter Sampling Differences Between Subdural Electrodes and Stereoelectroencephalography Electrodes.

Objective: Stereoelectroencephalography (SEEG) has seen a recent increase in popularity in North America; however, concerns regarding the spatial sampling capabilities of SEEG remain. We aimed to quantify and compare the spatial sampling of subdural electrode (SDE) and SEEG implants. Methods: Patients with drug-resistant epilepsy who underwent invasive monitoring were included in this retrospective case-control study. Ten SEEG cases were compared with ten matched SDE cases based on clinical presentation and pre-implantation hypothesis. To quantify gray matter sampling, MR and CT images were coregistered and a 2.5mm radius sphere was superimposed over the center of each electrode contact. The estimated recording volume of gray matter was defined as the cortical voxels within these spherical models. Paired t-tests were performed to compare volumes and locations of SDE and SEEG recording. A Ripley's K-function analysis was performed to quantify differences in spatial distributions. Results: The average recording volume of gray matter by each individual contact was similar between the two modalities. SEEG implants sampled an average of 20% more total gray matter, consisted of an average of 17% more electrode contacts, and had 77% more of their contacts covering gray matter within sulci. Insular coverage was only achieved with SEEG. SEEG implants generally consist of discrete areas of dense local coverage scattered across the brain; while SDE implants cover relatively contiguous areas with lower density recording. Significance: Average recording volumes per electrode contact are similar for SEEG and SDE, but SEEG may allow for greater overall volumes of recording as more electrodes can be routinely implanted. The primary difference lies in the location and distribution of gray matter than can be sampled. The selection between SEEG and SDE implantation depends on sampling needs of the invasive implant.

Pregnancy outcomes of refractory epilepsy patients treated with Brain-responsive neurostimulation.

OBJECTIVE: To study the pregnancy outcomes, including obstetric complications and fetal outcomes, in pregnant women with epilepsy (WWE) treated with direct brain-responsive neurostimulation (RNS System). METHODS: Retrospective review of obstetric outcomes and fetal outcomes in WWE treated with the RNS System at nine comprehensive epilepsy centers in the United States from 2014-2020. In addition, changes in seizure frequency, anti-seizure medications, and RNS System setting adjustments during pregnancy were investigated. RESULTS: A total of 10 subjects and 14 pregnancies were identified. The mean age at conception was 30.6 ± 4.3 years old. The mean age at implantation was 29.8 ± 4.4 years old. The mean stimulation charge densities ranged from 1.0 to 3.0 µC/cm2 during pregnancy. Obstetric complications included recurrent miscarriage (1 patient), cesarean section (3 patients) due to preeclampsia, non-reassuring fetal heart rate tracing or prolonged labor, preterm birth (1 patient), and preeclampsia (1 patient). No still birth, gestational hypertension, gestational diabetes, eclampsia, or maternal mortality were observed. No RNS System-exposed pregnancies had major congenital malformations. One offspring had a minor congenital anomaly of cryptorchidism in a pregnancy complicated with risk factors of advanced maternal age and bicornuate uterus. SIGNIFICANCE: The present study is the first report of RNS System-exposed pregnancies in WWE to date. No major congenital malformations were identified. All of the obstetric complications were within the expected range of those in WWE based on previously published data. The sample size of our study is small, so accumulation of additional cases will further help depict the safety profile of treatment with the RNS System during pregnancy.

Effects of antiepileptic drugs on lipids, homocysteine, and C-reactive protein.

OBJECTIVE: The widely prescribed anticonvulsants phenytoin and carbamazepine are potent inducers of cytochrome P450 enzymes, which are involved in cholesterol synthesis. We sought to determine whether these drugs have an effect on cholesterol and other serological markers of vascular risk. METHODS: We recruited 34 epilepsy patients taking carbamazepine or phenytoin in monotherapy whose physicians had elected to change treatment to one of the noninducing anticonvulsants lamotrigine or levetiracetam. Fasting blood samples were obtained both before and 6 weeks after the switch to measure serum lipid fractions, lipoprotein(a), C-reactive protein, and homocysteine. A comparator group of 16 healthy subjects underwent the same serial studies. RESULTS: In the epilepsy patients, switch from either phenytoin or carbamazepine produced significant declines in total cholesterol (-24.8 mg/dl), atherogenic (non-high-density lipoprotein) cholesterol (-19.9 mg/dl), triglycerides (-47.1mg/dl) (all p < 0.0001), and C-reactive protein (-31.4%; p = 0.027). Patients who stopped taking carbamazepine also had a 31.2% decline in lipoprotein(a) level (p = 0.0004), whereas those taken off phenytoin had a decrease in homocysteine level (-1.7 micromol/L; p = 0.005). All of these changes were significant when compared with those seen in healthy subjects (p < 0.05). Results were similar whether patients were switched to lamotrigine or levetiracetam. INTERPRETATION: Switching epilepsy patients from the enzyme-inducers carbamazepine or phenytoin to the noninducing drugs levetiracetam or lamotrigine produces rapid and clinically significant amelioration in several serological markers of vascular risk. These findings suggest that phenytoin and carbamazepine may substantially increase the risk for cardiovascular and cerebrovascular disease.

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

OBJECTIVE: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years. METHODS: Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory. RESULTS: Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ2). CONCLUSIONS: Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low. CLINICALTRIALSGOV IDENTIFIER: NCT00572195. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.

Adult Focal Epilepsies.

PURPOSE OF REVIEW: Focal epilepsy is the most common type of epilepsy in adulthood. This article discusses the seizure symptomatology, EEG findings, and imaging findings of the various forms of focal epilepsy. The majority of the article focuses on temporal and frontal lobe epilepsy as these represent the majority of focal epilepsies. RECENT FINDINGS: While significant overlap exists in the clinical symptomatology of the focal epilepsies, detailed seizure descriptions can often provide useful clinical evidence to help establish an accurate diagnosis. EEG and MRI continue to serve as the main diagnostic tools for the diagnosis of focal epilepsy. SUMMARY: The various forms of focal epilepsy generate seizure presentations that are dependent on the anatomic structures that are involved in the seizure. By understanding the symptoms typically generated in each region of the brain, a better understanding of the possible seizure localizations can be made. Most forms of epilepsy have clear changes on EEG that permit accurate localization, but several pitfalls exist, which are discussed in this article. Imaging has revolutionized our ability to accurately identify lesions associated with epilepsy and increased our ability to localize seizures in the brain.

Spontaneous intracerebral hemorrhage: epidemiology, pathophysiology, and medical management.

This article introduces the basic epidemiology of intracerebral hemorrhage (ICH) and discusses the current available literature on the pathophysiology of primary ICH, hematoma enlargement, and cerebral edema. The article also includes a brief presentation of the basic steps regarding initial ICH management is presented as a framework for patient care.

Electroencephalography leads placed by nontechnologists using a template system produce signals equal in quality to technologist-applied, collodion disk leads.

The purpose of this study was to compare the quality of the electroencephalographic (EEG) data obtained with a BraiNet template in a practical use setting, to that obtained with standard 10/20 spaced, technologist-applied, collodion-based disk leads. Pairs of 8-hour blocks of EEG data were prospectively collected from 32 patients with a Glasgow coma score of ≤9 and clinical concern for underlying nonconvulsive status epilepticus over a 6-month period in the Neurocritical Care Unit at the Duke University Medical Center. The studies were initiated with the BraiNet template system applied by critical care nurse practitioners or physicians, followed by standard, collodion leads applied by registered technologists using the 10/20 system of placement. Impedances were measured at the beginning and end of each block recorded and variance in impedance, mean impedance, and the largest differences in impedances found within a given lead set were compared. Physicians experienced in reading EEG performed a masked review of the EEG segments obtained to assess the subjective quality of the recordings obtained with the templates. We found no clinically significant differences in the impedance measures. There was a 3-hour reduction in the time required to initiate EEG recording using the templates (P < 0.001). There was no difference in the overall subjective quality distributions for template-applied versus technologist-applied EEG leads. The templates were also found to be well accepted by the primary users in the intensive care unit. The findings suggest that the EEG data obtained with this approach are comparable with that obtained by registered technologist-applied leads and represents a possible solution to the growing clinical need for continuous EEG recording availability in the critical care setting.

Conversion from enzyme-inducing antiepileptic drugs to topiramate: effects on lipids and C-reactive protein.

PURPOSE: We previously demonstrated that converting patients from the enzyme-inducers phenytoin or carbamazepine to the non-inducers levetiracetam or lamotrigine reduces serum lipids and C-reactive protein (CRP). We sought to determine if the same changes would occur when patients were switched to topiramate, which has shown some evidence of enzyme induction at high doses. We also examined the effects of drug switch on low-density lipoprotein (LDL) particle concentration. METHODS: We converted 13 patients from phenytoin or carbamazepine monotherapy to topiramate monotherapy (most at doses of 100-150 mg/day). Fasting lipids, including LDL particle concentration, and CRP were obtained before and ≥6 weeks after the switch. A group of normal subjects had the same serial serologic measurements to serve as controls. RESULTS: Conversion from inducers to topiramate resulted in a -35 mg/dL decline in total cholesterol (p=0.033), with significant decreases in all cholesterol fractions, triglycerides, and LDL particle concentration (p≤0.03 for all), as well as a decrease of over 50% in serum CRP (p<0.001). Alterations in cholesterol fractions and CRP remained significant when compared to those seen in normal controls. CONCLUSIONS: Changes seen when inducer-treated patients are converted to TPM closely mimic those seen when inducer-treated patients are converted to lamotrigine or levetiracetam. These findings provide evidence that CYP450 induction elevates CRP and serum lipids, including LDL particles, and that these effects are reversible upon deinduction. Low-dose TPM appears not to induce the enzymes involved in cholesterol synthesis.

Frontal lobe seizures.

BACKGROUND AND OBJECTIVE: Frontal lobe epilepsy is the second most common localization-related or focal epilepsy. Frontal lobe seizures are challenging to diagnose as the clinical manifestations are diverse due to the complexity and variability of the patterns of epileptic discharges, and the scalp electroencephalograph (EEG) can often be normal or misleading. This review focuses on the clinical and EEG features of seizures arising from the frontal lobe. REVIEW SUMMARY: The clinical manifestations in patients with frontal lobe epilepsy are varied. Frontal lobe seizures can be divided into perirolandic, supplementary sensorimotor area, dorsolateral, orbitofrontal, anterior frontopolar, opercular, and cingulate types. Seizures originating from the perirolandic and supplementary sensorimotor areas are clinically distinct, characterized by motor activity or asymmetric tonic posturing with preserved awareness. Seizures arising from dorsolateral, orbitofrontal, frontopolar, and cingulate areas are not as well characterized and have more variable clinical manifestations. Scalp EEG recording is sometimes helpful in localization but is usually normal or misleading in frontal lobe epilepsy. The treatment is similar to other localization-related or focal epilepsies. Medications are the first line of therapy, and surgery is considered for patients who fail to respond to medications. The surgical outcome in frontal lobe resections is less favorable than in anterior temporal lobectomies due to the challenge in locating the epileptogenic zone and the presence of functional areas (eloquent cortex) that can limit the resection. CONCLUSIONS: Frontal lobe seizures are characterized by diverse behavioral manifestations. Only a few well-described frontal lobe syndromes exist. The variety of clinical manifestations reflects both the varying sites of seizure origin and propagation routes that seizures may take. Although this review provides a framework for the understanding of these seizures, one should remain cautious in diagnosing seizure localization based on clinical or EEG description. Only a few patients have well-described syndromes and can be diagnosed with confidence. For most patients, new diagnostic methods and genetic testing may help improve our ability to diagnose and treat the conditions discussed in this study.