Current dipole orientation and distribution of epileptiform activity correlates with cortical thinning in left mesiotemporal epilepsy.

To evaluate cortical architecture in mesial temporal lobe epilepsy (MTLE) with respect to electrophysiology, we analyze both magnetic resonance imaging (MRI) and magnetoencephalography (MEG) in 19 patients with left MTLE. We divide the patients into two groups: 9 patients (Group A) have vertically oriented antero-medial equivalent current dipoles (ECDs). 10 patients (Group B) have ECDs that are diversely oriented and widely distributed. Group analysis of MRI data shows widespread cortical thinning in Group B compared with Group A, in the left hemisphere involving the cingulate, supramarginal, occipitotemporal and parahippocampal gyri, precuneus and parietal lobule, and in the right hemisphere involving the fronto-medial, -central and -basal gyri and the precuneus. These results suggest that regardless of the presence of hippocampal sclerosis, in a subgroup of patients with MTLE a large cortical network is affected. This finding may, in part, explain the unfavorable outcome in some MTLE patients after epilepsy surgery.

Fast human brain magnetic resonance responses associated with epileptiform spikes.

Neuronal currents produce local electromagnetic fields that can potentially modulate the phase of the magnetic resonance signal and thus provide a contrast mechanism tightly linked to neuronal activity. Previous work has demonstrated the feasibility of direct MRI of neuronal activity in phantoms and cell culture, but in vivo efforts have yielded inconclusive, conflicting results. The likelihood of detecting and validating such signals can be increased with (i) fast gradient-echo echo-planar imaging, with acquisition rates sufficient to resolve neuronal activity, (ii) subjects with epilepsy, who frequently experience stereotypical electromagnetic discharges between seizures, expressed as brief, localized, high-amplitude spikes (interictal discharges), and (iii) concurrent electroencephalography. This work demonstrates that both MR magnitude and phase show large-amplitude changes concurrent with electroencephalography spikes. We found a temporal derivative relationship between MR phase and scalp electroencephalography, suggesting that the MR phase changes may be tightly linked to local cerebral activity. We refer to this manner of MR acquisition, designed explicitly to track the electroencephalography, as encephalographic MRI (eMRI). Potential extension of this technique into a general purpose functional neuroimaging tool requires further study of the MR signal changes accompanying lower amplitude neuronal activity than those discussed here.

A prospective study of smoking, caffeine, and alcohol as risk factors for seizures or epilepsy in young adult women: data from the Nurses' Health Study II.

PURPOSE: Seizures and epilepsy are associated with significant disability and substantial treatment costs, yet little is known about primary prevention. We prospectively examined the association of cigarette smoking, caffeine use, and alcohol intake with risk of seizure or epilepsy among women, aged 25-42 years, in the Nurses' Health Study II. METHODS: Participants provided dietary and cigarette smoking information on multiple questionnaires beginning in 1989. Among 116,363 women at-risk for incident seizure or epilepsy, we confirmed 95 cases of seizure and 151 cases of epilepsy occurring from 1989-2005 using information from a detailed supplementary questionnaire and medical records. Multivariable-adjusted relative risks (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression. RESULTS: Compared with never smoking, current cigarette smoking was associated with an increased risk of seizure (RR 2.60, 95% CI 1.53-4.42), after adjustment for stroke and other potential confounding factors. Past smoking was not associated with risk of seizure, but was associated with modestly increased risk of epilepsy (RR 1.46, 95% CI 1.01-2.12). Long-term caffeine and moderate alcohol intake were not associated with seizure or epilepsy. DISCUSSION: Cigarette smoking may be associated with increased risk of seizure. More prospective studies are needed to investigate potential factors to ultimately prevent the development of seizures or epilepsy.

A comparison of anastrozole and testosterone versus placebo and testosterone for treatment of sexual dysfunction in men with epilepsy and hypogonadism.

Hyposexuality is commonly associated with low bioavailable testosterone (BAT) and relative estradiol elevation in men with epilepsy. This prospective, randomized, double-blind trial compared the effects of depotestosterone+the aromatase inhibitor anastrozole (T-A) versus depotestosterone+placebo (T-P) on sexual function, hormone levels, mood, and seizure frequency in men with epilepsy. Forty men with focal epilepsy, hyposexuality, and hypogonadism were randomized 1:1 to two groups (T-A or T-P) for a 3-month treatment trial of depotestosterone+either anastrozole or matching placebo. Outcomes included both efficacy and safety measures. Normalization of sexual function (S-score) occurred with greater frequency in the T-A (72.2%) than in the T-P (47.4%) group, but the difference was not statistically significant. T-A resulted in significantly lower estradiol levels and S-scores correlated inversely with estradiol levels at baseline and during treatment. Beck Depression Inventory II (BDI-II) scores improved significantly in both groups and changes in S-score correlated inversely with changes in BDI-II score. Changes in seizure frequency correlated with changes in BDI-II score. Seizure frequency decreased with both treatments and showed significant correlations with estradiol levels. Triglyceride levels increased with T-P and decreased with T-A. The difference in triglyceride changes between the two treatments was significant and correlated with changes in estradiol levels. Significant correlations between estradiol levels and S-scores, as well as seizure outcomes and triglyceride levels, suggest further study regarding a potential role for anastrozole in the treatment of men with epilepsy who have hyposexuality and hypogonadism.

Perinatal use of anticonvulsants: differences in attitudes and recommendations among neurologists and psychiatrists.

We surveyed opinions and recommendations about perinatal anticonvulsant (AC) treatment among 166 neurologists (n = 88) and psychiatrists (n = 78) practicing in Massachusetts. They were similar in the recommendation of routinely informing patients of potential teratogenic risks of ACs and avoiding valproate during pregnancy. Neurologists were more likely to encourage pregnancy and nursing during AC-use than psychiatrists, and psychiatrist were more cautious regarding perinatal safety, citing potential neurobehavioral risks and complications of breastfeeding. These observations indicate substantial differences in opinions between psychiatrists and neurologists regarding AC use during pregnancy.

Auditory auras in patients with postencephalitic epilepsy: case series.

Many previously healthy patients who present with new seizures or status epilepticus appear to have encephalitis for which no specific pathogen is identified. A significant portion of these patients develop epilepsy. We describe five patients with adult-onset, medically intractable, postencephalitic epilepsy characterized by auditory auras ranging from unformed buzzing to structured language. Auras of any type were common among patients with postencephalitic epilepsy in our referral database: 62% experienced at least one type of aura. The proportion of postencephalitic patients with auditory auras (38%), which may reflect lateral temporal cortical pathology, was higher than that of other adult epilepsy populations. Although no pathogen was identified in four of the five cases, we suggest that the pathophysiology of viral encephalitides may share common targets in the temporal lobes, especially the superior temporal gyrus and surrounding areas, which may account for possibly increased occurrence of auditory auras in this population.

Is there a circadian variation of epileptiform abnormalities in idiopathic generalized epilepsy?

Epileptiform abnormalities often occur at specific times of day or night, possibly attributable to state of consciousness (sleep vs. wake) and/or influences from the endogenous circadian pacemaker. In this pilot study we tested for the existence of circadian variation of interictal epileptiform discharges (IEDs), independent of changes in state, environment, or behavior. Five patients with generalized epilepsy underwent a protocol whereby their sleep/wake schedule was evenly distributed across the circadian cycle while undergoing full-montage electroencephalography and hourly plasma melatonin measurements. Light was <8 lux to prevent circadian entrainment. All patients completed the protocol, testifying to its feasibility. All patients had normal circadian rhythmicity of plasma melatonin relative to their habitual sleep times. In the three patients with sufficient IEDs to assess variability, most IEDs occurred during non-rapid eye movement (NREM) sleep (ratio NREM:wake=14:1, P<0.001). In both patients who had NREM at all circadian phases, there was apparent circadian variation in IEDs but with different phases relative to peak melatonin.

Comparison of outcomes of video/EEG monitoring between patients with epileptic seizures and those with psychogenic nonepileptic seizures.

We followed 103 patients for 6-16 months after discharge from elective long-term video/EEG monitoring to compare clinical outcomes and quality of life between patients diagnosed with epileptic (ES) and those diagnosed with psychogenic nonepileptic (PNES) seizures. Outcome measures determined at telephone or mail follow-up included seizure frequency, antiepileptic drug use, and self-reported quality of life using the Quality of Life in Epilepsy inventory. Of the 62 responders, 41 were diagnosed with ES and 11 with PNES, using strictly applied criteria. Those with ES reported significant improvement in Seizure Worry (P=0.003), Medication Side Effects (P<0.001), and Social Function (P<0.001). In addition, both groups showed a decrease in seizure frequency. Furthermore, both groups showed a significant decrease in antiepileptic drug use at follow-up, with a greater, and sustained, decrease for the PNES group. Approximately half the patients in each group reported an improvement in overall condition.

Antiepileptic drug use in women of childbearing age.

Research on antiepileptic drug (AED) teratogenesis has demonstrated an increased risk for valproate. The impact of these findings on current AED prescribing patterns for women of childbearing age with epilepsy is uncertain. The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study is an ongoing prospective multicenter observational investigation that enrolled pregnant women with epilepsy on the most common AED monotherapies from October 1999 to February 2004 (carbamazepine, lamotrigine, valproate, and phenytoin). A 2007 survey of AED use in women of childbearing age at eight NEAD centers found a total of 932 women of childbearing age with epilepsy (6% taking no AED, 53% monotherapy, 41% polytherapy). The most common monotherapies were lamotrigine or levetiracetam. Since 2004, prescriptions of carbamazepine, phenytoin, and valproate have decreased, whereas those for levetiracetam have increased. Except for the top two AED monotherapies, there were marked differences in other monotherapies and in polytherapies between U.S. and UK centers. Future investigations are needed to examine reasons for drug choice.

Frequency and patterns of MRI abnormalities due to status epilepticus.

BACKGROUND: MRI changes due to status epilepticus (SE) often suggest a combination of cytotoxic and vasogenic edema, but it is unclear why only certain patients have MRI changes. OBJECTIVES: To determine the frequency of MRI changes due to SE and the associated patient characteristics. METHODS: We reviewed records for demographics, medical history, and MRI changes attributable to seizures of all patients admitted to Brigham and Women's Hospital or Massachusetts General Hospital for SE from 1/1999 to 7/2003 and who had MRI during admission. RESULTS: Ten (11.6%) of the eighty-six patients identified had MRI abnormalities likely due to seizures. Four, two with pre-existing epilepsy and two with extratemporal structural lesions, had focally increased signal on T2 and diffusion-weighted imaging (DWI) in the hippocampus ipsilateral to the seizure focus. One, with elevated levels of clozapine, had increased signal on T2 weighted images and variably restricted diffusion in the splenium. Five had gyral distribution of restricted diffusion and increased signal on T2 weighted images; they had complex medical comorbidities and possible hypoperfusion or hypoxia associated with SE. CONCLUSIONS: Among patients with SE who had MRI changes, those with previous epilepsy or extratemporal structural lesions showed increased diffusion in the hippocampus and may have selective hippocampal vulnerability to seizure-induced hyperexcitability. Patients with hyperintense signal in the cortical gray matter had episodes of possible hypoperfusion or hypoxia.

Valproate teratogenicity and epilepsy syndrome.

Maternal valproate (VPA) use is associated with a significant risk for congenital malformations in the exposed fetus. Since VPA is commonly used in epilepsy syndromes with a presumed genetic cause (idiopathic epilepsies), it is possible that maternal genetic background contributes to this outcome. We reviewed responses to telephone questionnaires and medical records, when available, of enrollees in the North American Antiepileptic Drug Pregnancy Registry, classifying reason for treatment as idiopathic generalized epilepsy (IGE), partial epilepsy (PE), nonclassifiable epilepsy (NCE), or not epilepsy (NE). Of 284 VPA-exposed pregnancies, 30 (11.0%) were associated with malformations: IGE = 15/126 (12%), PE = 4/28 (14%), NCE = 9/105 (9%), NE = 2/25 (8%) (p > 0.7 for all comparisons). There was a trend toward increased malformation risk with higher VPA doses (p = 0.07). VPA, and not the underlying genetic syndrome, seems to be associated with the elevated risk for malformations in the drug-exposed fetus.

Status Epilepticus Severity Score (STESS): a tool to orient early treatment strategy.

BACKGROUND: Status epilepticus (SE) treatment ranges from small benzodiazepine doses to coma induction. For some SE subgroups, it is unclear how the risk of an aggressive therapeutic approach balances with outcome improvement. We recently developed a prognostic score (Status Epilepticus Severity Score, STESS), relying on four outcome predictors (age, history of seizures, seizure type and extent of consciousness impairment), determined before treatment institution. Our aim was to assess whether the score might have a role in the treatment strategy choice. METHODS: This cohort study involved adult patients in three centers. For each patient, the STESS was calculated before primary outcome assessment: survival vs. death at discharge. Its ability to predict survival was estimated through the negative predictive value for mortality (NPV). Stratified odds ratios (OR) for mortality were calculated considering coma induction as exposure; strata were defined by the STESS level. RESULTS: In the observed 154 patients, the STESS had an excellent negative predictive value (0.97). A favorable STESS was highly related to survival (P < 0.001), and to return to baseline clinical condition in survivors (P < 0.001). The combined Mantel-Haenszel OR for mortality in patients stratified after coma induction and their STESS was 1.5 (95 % CI: 0.59-3.83). CONCLUSION: The STESS reliably identifies SE patients who will survive. Early aggressive treatment could not be routinely warranted in patients with a favorable STESS, who will almost certainly survive their SE episode. A randomized trial using this score would be needed to confirm this hypothesis.

Complex inheritance and parent-of-origin effect in juvenile myoclonic epilepsy.

BACKGROUND: Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epilepsy (IGE) with complex inheritance. Previous studies have suggested maternal inheritance and female excess in IGEs but have not been specific for JME. We investigated evidence for maternal inheritance, female excess and patterns of familial seizure risk in a well-characterized sample of JME families. METHODS: We ascertained 89 families through a JME proband and 50 families through a non-JME IGE proband. JME families were divided into those with and without evidence of linkage to the EJM1 susceptibility locus on chromosome 6. We analyzed transmission in 43 multigenerational families, calculated the adjusted sex ratio for JME, and looked for evidence of seizure specific risk in 806 family members. RESULTS: We found evidence for preferential maternal transmission in both EJM1-linked and unlinked families (2.7:1), evidence even more marked when potential selection factors were excluded. The adjusted female: male risk ratio was very high in JME (RR=12.5; 95% CI: 1.9-83.7). Absence seizures in JME probands increased the overall risk of seizures in first degree relatives (15.8% vs. 7.0%, P=0.011), as well as first-degree relatives' specific risk of absence seizures (6% vs. 1.6%, P=0.01), but not myoclonic seizures. CONCLUSIONS: We have confirmed the finding of maternal inheritance in JME, which is not restricted to JME families linked to the EJM1 locus. The striking female excess in JME may relate to anatomical and/or endocrine sexual dimorphism in the brain. Evidence for independent inheritance of absence and myoclonic seizures in JME families reinforces a model in which combinations of loci confer susceptibility to the component seizure types of IGE.

Postictal psychosis: presymptomatic risk factors and the need for further investigation of genetics and pharmacotherapy.

BACKGROUND: Postictal psychosis (PIP), an episode of psychosis occurring after a cluster of seizures, is common and may be associated with profound morbidity, including chronic psychosis. Symptoms are often pleomorphic, involving a range of psychotic symptoms, including hallucinations and disorders of thought. PIP is treatable and may be averted if presymptomatic risk factors are considered in susceptible patients and treatment is initiated. CASE PRESENTATION: In this report, we present an illustrative case of PIP. The patient, Mr. R, presented to our emergency room with delusions and disordered thought process following a cluster of seizures. He recovered after admission, sedation and treatment with antipsychotic medication. DISCUSSION: A list of presymptomatic risk factors is established based on review of current literature. Identification of such risk factors may potentially help with prophylactic treatment; however, little empirical research exists in this area and treatment guidelines are thus far largely based on expert opinion. Further, while the neurobiology of schizophrenia is advancing at a rapid pace, largely due to advances in genetics, the pathophysiology of PIP remains largely unknown. Considering the progress in schizophrenia research in the context of the clinical features of PIP and existing studies, potential neurobiological mechanisms for PIP are herein proposed, and further genetic analyses, which may help identify those susceptible, are warranted. CONCLUSION: While PIP is an important problem that may present first to general hospital psychiatrists, as in the case presented, this topic is under-represented in the medical psychiatry literature. As discussed in this article, further research is needed to develop presymptomatic screens and treatment pathways to help prevent morbidity.

Refractory status epilepticus: effect of treatment aggressiveness on prognosis.

BACKGROUND: Administration of antiepileptic drugs for coma induction in refractory status epilepticus (RSE) has not been widely studied. Moreover, the effect on outcome of electroencephalographic (EEG) burst suppression remains unclear. OBJECTIVE: To investigate whether various coma-inducing options are associated with different prognoses after RSE. DESIGN: Retrospectively assessed case series. SETTING: Two tertiary referral hospitals in Boston, Mass. PATIENTS: Among 127 consecutive episodes (107 patients) of status epilepticus, we identified episodes that were refractory to first-line and second-line antiepileptic drugs, needing induced coma with barbiturates, propofol, or midazolam for clinical management. MAIN OUTCOME MEASURES: Short-term mortality and prevalence of return to functional baseline after the acute episode of status epilepticus were analyzed in relation to demographic and clinical variables and to treatment option (antiepileptic agents and EEG burst suppression). RESULTS: Forty-nine episodes of RSE (47 patients) were found, occurring more frequently in incident than in recurrent episodes of status epilepticus (P = .06). Mortality was 23% for patients with RSE and 8% for those without RSE (P = .05). Return to baseline occurred more often in the non-RSE group (P = .04). In 20 (61%) of 33 monitored episodes, EEG burst suppression was achieved. Demographic data, clinical variables, and outcome did not differ significantly with the various coma-inducing agents or between episodes with and without EEG burst suppression. CONCLUSIONS: Refractory status epilepticus is more prevalent in incident than in recurrent status epilepticus and is associated with higher mortality; clinical status is less likely to return to baseline than with non-RSE. Outcome was independent of the specific coma-inducing agents used and the extent of EEG burst suppression, suggesting that the underlying cause represents its main determinant.

Recurrent nightmares and disorders of arousal in temporal lobe epilepsy.

Sleep is known to be severely altered in temporal lobe epilepsy (TLE). Furthermore, sleep deprivation is one of the key factors contributing to cognitive deficits and drug resistance in TLE. In the past, "non-ictal" parasomnias, as well as parasomnia-like nocturnal episodes ultimately diagnosed as seizures, have been documented in epileptic patients. However, recurrence of possibly "ictal" parasomnias in TLE has not been adequately appreciated. Through questionnaires and diaries distributed to TLE patients and their families in a tertiary center for epilepsy, 20 out of 168 patients seen in the last 2 years have been identified as, probands and extensively recorded during sleep. Patients presented with confusional arousals were 16, 14 with nightmares, and 2 with sleep walking episodes. Episodes (25) corresponding to clinical or subclinical seizures have been video-polygraphically recorded in 10/20 patients. Therapy optimization, pharmacological or surgical, resolved the episodes in 17/20 patients. A better seizure control with improved quality of life can be achieved by increasing and extending the practice of nocturnal recording in TLE patients.

Clinical use of anticonvulsants: a neurologist's perspective.

Seizures may have an acute, reversible cause; antiepileptic drugs (AEDs) are not needed for every patient who presents with a seizure. The neurologist's decision concerning whether to initiate drug therapy depends on verifying that one or more seizures has occurred, on determining the likelihood of recurrence, and on balancing the risks of future seizures against the risks of treatment. Choice of AED is guided by classification of the seizure type and epilepsy syndrome, and by assessment of the likelihood of successful use based on patient characteristics such as age, childbearing potential, and comorbidities, balanced against drug characteristics such as pharmacokinetic profile and common side effects. Dose adjustment depends on communication between the physician and patient regarding seizure control and adverse drug effects. Patients who do not respond adequately to the first two or three appropriate AEDs should be referred for a comprehensive evaluation to verify the diagnosis and determine suitability for alternative treatments such as epilepsy surgery.

Epilepsy in patients with brain tumors and other cancers.

Epilepsy is common among patients with supratentorial, especially slow-growing tumors. Several newer antiepileptic drugs have fewer side effects and drug interactions than do older drugs. Seizure control, however, may require complete lesion resection, with or without removal of an additional "epileptogenic zone." Among patients with systemic cancer, parenchymal or leptomeningeal metastases can cause epilepsy, and potentially reversible medical and neurologic perturbations can lead to acute symptomatic seizures.

Intraoperative magnetic resonance for the surgical treatment of lesions producing seizures.

Seizures are a major presenting feature of several non-neoplastic cerebral lesions. We reviewed the experience at the Brigham and Women's Hospital, Boston, on the surgical management of benign intracerebral lesions presenting with seizures with intraoperative magnetic resonance imaging (iMRI) guidance. Our aim was to demonstrate that this is an effective and efficient treatment for these lesions. The histories of thirteen patients who presented with seizures secondary to benign intraaxial lesions treated by craniotomy and resection within the iMRI unit at our institution were reviewed. The surgical results, histology and clinical outcomes were reviewed. The mean follow-up was 22.1 months (range 2-48). In all cases, lesions were accurately located with iMRI. After initial macroscopic resection, 5 cases were found to have residual lesion. All had complete radiological resection at the end of the procedure. At follow-up, five patients had no seizures, 5 had rare seizures and the remaining 3 had worthwhile improvement in seizure frequency. Intraoperative MRI is a safe and effective adjunct for the surgical treatment of benign intracerebral lesions presenting with seizures. It provides effective and efficient intraoperative guidance for planning and approach to the lesion and the assurance that the lesion is totally removed. Surgical resection with iMRI may, therefore, provide a useful approach to these lesions.