Enhanced rates of detection and treatment of depression and anxiety disorders among adult patients with epilepsy using automated EMR-based screening.

OBJECTIVE: Depression and anxiety disorders are common among patients with epilepsy (PWE). These comorbidities have been shown to influence prognosis and may have a greater impact on quality of life than seizure control. Despite guideline recommendations and expert consensus to regularly screen for and treat both conditions, there is evidence that they are underdiagnosed and undertreated. Our goal was to test a novel screening method to determine if it would increase the rate of detecting and treating depression and anxiety disorders among PWE. METHOD: The Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) and the Brief Epilepsy Anxiety Survey Instrument (brEASI) were selected as validated screening instruments for depression and anxiety disorders, respectively. They were sent via an electronic medical record-linked patient portal to all patients of four epileptologists 48 h prior to their clinic appointment. We evaluated whether this increased the rate of detecting and treating depression and anxiety disorders relative to a historical control group. RESULTS: A total of 563 patients were included of whom 351 were sent the screening instruments. 62.7% of patients completed the screening instruments of whom 47.7% screened positive for either depression only (16.4%), anxiety disorders only (5.5%) or both (25.9%); a statistically significant increase relative to the control group. There was also a significantly increased proportion of patients for whom treatment was initiated for depression (p < 0.01), anxiety disorders (p < 0.01), or both (p < 0.01). CONCLUSIONS: We identified an easily applicable and efficient means of enhancing detection and treatment rates for depression and anxiety disorders among PWE in a busy clinic setting.

Video-EEG results and clinical characteristics in patients with psychogenic nonepileptic spells: The effect of a coexistent epilepsy.

RATIONALE: Epilepsy and psychogenic nonepileptic spells (PNES) can coexist, often posing diagnostic and therapeutic challenges. We sought to identify clinical and historical characteristics of two groups of patients, those with coexisting epilepsy and PNES and those with PNES alone, and determine the prevalence of coexisting epilepsy/PNES with strict diagnostic criteria in a large group of epilepsy monitoring unit (EMU) patients. METHODS: We reviewed the medical records of all consecutive patients admitted to the Vanderbilt University Medical Center Adult EMU between July 1, 2007 and June 30, 2012. We identified patients with recorded PNES and classified them as having coexisting epilepsy/PNES or PNES alone and then systematically compared the clinical characteristics of these two groups. RESULTS: A total of 1567 patient medical records were reviewed. The prevalence rate of coexisting epilepsy/PNES was 5.2% among all EMU admissions (12.3% of all patients with epilepsy and 14.8% of all patients with PNES). These rates were lower when patients with interictal epileptiform activity (IEA) alone and no recorded ictal discharges were not included in the group with epilepsy (2.6%, 6.2%, and 7.4%, respectively). The accuracy of pre-EMU clinical suspicion was significantly higher in the group with PNES-only. Patients with epilepsy/PNES were significantly more likely to require more than one EMU admission for definitive diagnosis. The first PNES event preceded an epileptic seizure (ES) in 94.4% of patients with epilepsy/PNES. The group with PNES-only had significantly higher suggestibility, and the group with epilepsy/PNES had a significantly higher presence of epilepsy risk factors. Abnormal neurological examination and abnormal brain MRI were also significantly more common in the group with epilepsy/PNES. CONCLUSIONS: Our study defined the prevalence of coexisting epilepsy/PNES in a large cohort with strict diagnostic criteria and outlined specific clinical and historical characteristics differentiating the two groups of patients with coexisting epilepsy/PNES and PNES-only. These findings should help guide clinicians to reach the correct diagnosis faster and provide appropriate treatment earlier.

Resting state functional connectivity of the hippocampus associated with neurocognitive function in left temporal lobe epilepsy.

The majority of patients with temporal lobe epilepsy (TLE) experience disturbances of episodic memory from structural damage or dysfunction of the hippocampus. The objective of this study was to use functional Magnetic Resonance Imaging (fMRI) to identify regions where resting state connectivity to the left hippocampus (LH) is correlated with neuropsychological measures of verbal memory retention in TLE patients. Eleven left TLE (LTLE) patients and 15 control subjects participated in resting state fMRI scans. All LTLE patients underwent neuropsychological testing. Resting state functional connectivity maps to the LH were calculated for each patient, and subsequently used in a multiple regression analysis with verbal memory retention scores as a covariate. The analysis identified brain regions whose connectivity to the LH was linearly related to memory retention scores across the group of patients. In LTLE patients, right sided (contralateral) clusters in the precuneus and inferior parietal lobule (IPL) exhibited increased connectivity to the LH with increased memory retention score; left sided (ipsilateral) regions in the precuneus and IPL showed increased connectivity to the LH with decreased retention score. Patients with high memory retention scores had greater connectivity between the LH-right parietal clusters than between the LH-left parietal clusters; in contrast, control subjects had significantly and consistently greater LH-left hemisphere than LH-right hemisphere connectivity. Our results suggest that increased connectivity in contralateral hippocampal functional pathways within the episodic verbal memory network represents a strengthening of alternative pathways in LTLE patients with strong verbal memory retention abilities.

Lateralization of temporal lobe epilepsy using resting functional magnetic resonance imaging connectivity of hippocampal networks.

PURPOSE: Early surgical intervention can be advantageous in the treatment of refractory temporal lobe epilepsy (TLE). The success of TLE surgery relies on accurate lateralization of the seizure onset. The purpose of this study was to determine whether resting functional MRI (fMRI) connectivity mapping of the hippocampus has the potential to complement conventional presurgical evaluations in distinguishing left from right TLE. In addition, we sought to determine whether this same network might separate patients with favorable from unfavorable postoperative outcomes. METHODS: Resting fMRI acquisitions were performed on 21 patients with TLE and 15 healthy controls. The patients included seven patients with left TLE and seven patients with right TLE with seizure-free postoperative outcome, and five patients with left TLE and two patients with right TLE with recurring seizures after surgery. Functional connectivity maps to each hippocampus were determined for each subject and were compared between the controls and the seizure-free patients with left TLE and with right TLE. The one network identified was then quantified in the patients with TLE and recurring seizures. KEY FINDINGS: The resting functional connectivity between the right hippocampus and the ventral lateral nucleus of the right thalamus was the most statistically significant network to distinguish between seizure-free patients with left TLE and with right TLE with high sensitivity and specificity. This connectivity was also significantly greater in the seizure-free patients with left TLE than the healthy controls. Finally, six of the seven patients in whom seizures recurred after surgery had connectivity values in this network unlike those who were seizure-free. SIGNIFICANCE: This study identified a region in the ventral lateral nucleus of the right thalamus whose connectivity to the hippocampi separates left from right TLE subjects. This suggests that the quantification of resting-state functional magnetic resonance imaging (MRI) connectivity across this network may be a potential indicator of lateralization of TLE that may be added to other presurgical MRI assessments. Further validation in a larger, independent cohort is required.

New observations in primary and secondary reading epilepsy: excellent response to levetiracetam and early spontaneous remission.

The response of reading epilepsy to new antiepileptic drugs is not known. Due to the rarity of this condition little is known about its natural history. We evaluated and treated three patients with primary and secondary reading epilepsy. Seizures in all patients were characterized by twitching of the jaw or lips with secondarily generalized tonic-clonic seizures if reading continued. One patient with primary reading epilepsy became seizure-free with divalproex monotherapy and another with levetiracetam monotherapy after failure of lamotrigine. One other patient with secondary reading epilepsy became seizure-free with levetiracetam add-on therapy. The divalproex-treated patient stopped therapy less than 3 years after seizure onset and remained seizure-free with 6 years of follow-up. We propose levetiracetam as a first-line treatment for primary and secondary reading epilepsy. Spontaneous medication-free remission of primary reading epilepsy may occur within 3 years of seizure onset, much earlier than previously reported.

Cross hippocampal influence in mesial temporal lobe epilepsy measured with high temporal resolution functional magnetic resonance imaging.

PURPOSE: Mesial temporal lobe epilepsy (mTLE) is a chronic disorder with spontaneous seizures recurring for years, or even decades. Many structural and functional changes have been detected in both the seizure focus and distal regions throughout the brain over this duration that may reflect the development of epileptogenic networks. Resting state functional magnetic resonance imaging (fMRI) connectivity mapping has the potential to elucidate and quantify these networks. The network between the left and right hippocampus may very likely be one of the most susceptible to changes due to long-term seizure propagation effects. Therefore, the objective of this study was to quantify cross hippocampal influence in mTLE using high temporal resolution fMRI, and to determine its relationship with disease duration. METHODS: fMRI images were acquired in the resting (interictal) state with 500 ms temporal resolution across the temporal lobes of 19 mTLE patients (13 left, 6 right). The left and right hippocampi were identified on each subject's images using both structurally defined and functionally defined boundaries. The cross hippocampal influence was quantified in two ways for each pair of regions: (1) the nondirectional hippocampal functional connectivity calculated as the Pearson's correlation between the average time series in the left and the right hippocampus regions, and (2) the Granger causality (GC) laterality measure, which implies directional influence by determining temporal precedence. Each of these measures was correlated with age, age of onset, and disease duration across subjects to investigate relationship to disease progression. KEY FINDINGS: The hippocampal connectivity was not significantly different between patients with left and right mTLE using either the structurally or the functionally defined regions. Across all patients, hippocampal connectivity was not correlated significantly with age of onset or duration of disease. However, as duration of disease increased after 10 years (nine patients), the hippocampal connectivity increased linearly. Using the functionally defined regions, the GC laterality was increased in the right mTLE over the left mTLE, indicating that the left hippocampus was influencing the right hippocampus more than the right influencing left. This was also positively correlated with age of onset. Furthermore, like hippocampal connectivity, the relationship between GC laterality and duration of disease changes after 10 years duration of disease. After this duration, the GC laterality was positive in the three of three patients with right mTLE (left influencing right), whereas the GC laterality was negative in five of six patients with left mTLE (right influencing left). SIGNIFICANCE: This study reveals a relationship between fMRI functional connectivity and causal influence of the left and right hippocampi and duration of disease in mTLE. During the interictal state, the interhemispheric hippocampal connectivity initially is disrupted and then linearly increases as the epilepsy progresses longer than 10 years. This increase in connectivity appears to be due to the hippocampus contralateral to the epileptogenic focus exerting more influence over the ipsilateral hippocampus. These findings may have implications in understanding the functional development of epileptic networks and possibly prediction of surgical outcome of mTLE.

Rhythmic delta activity represents a form of nonconvulsive status epilepticus in anti-NMDA receptor antibody encephalitis.

Anti-NMDA receptor antibody encephalitis is a limbic encephalitis with psychiatric manifestations, abnormal movements, coma, and seizures. The coma and abnormal movements are not typically attributed to seizure activity, and slow activity is the most common EEG finding. We report drug-resistant nonconvulsive status epilepticus as the basis for coma in a 19-year-old woman with anti-NMDA receptor antibodies and a mediastinal teratoma. The EEG showed generalized rhythmic delta activity, with evolution in morphology, frequency, and field typical of nonconvulsive status epilepticus. The status was refractory to antiepileptic drugs, repeated drug-induced coma, resection of the tumor, intravenous steroids, rituximab, and plasmapheresis. She awoke after the addition of felbamate, and the rhythmic delta activity ceased. The rhythmic delta activity described with coma in anti-NMDA receptor antibody encephalitis may represent a pattern of status epilepticus in some patients. Felbamate, which has NMDA receptor antagonist activity, should be studied as a therapeutic agent in this condition.

Focal seizure propagation illustrated by fMRI.

We report the pattern of seizure propagation as detected by functional MRI (fMRI) in a 24-year-old man with frequent recurrent electrographic seizures. The EEG seizure onset was left occipital with later spread to the left hemisphere and, to a lesser extent, the right hemisphere. The fMRI showed initial increase in blood oxygen level-dependent (BOLD) signal in the left occipital pole. The increased signal then propagated to the right occipital-posterotemporal region, and subsequently, the right and left mesial temporal regions. fMRI can be an effective tool to study seizure onset localization and seizure propagation in patients with frequent recurrent seizures.

Propofol withdrawal seizures: non-epileptic nature of seizures in a patient with recently controlled status epilepticus.

Seizures or seizure-like phenomena which are mostly convulsive have been observed during the induction, maintenance and withdrawal phases of propofol administration. The nature and mechanism of this phenomenon are not well understood and several case reports on these phenomena have presented only indirect evidence. We report on a patient who was administered propofol in order to control status epilepticus with success. However, every attempt at propofol withdrawal was followed by convulsive seizure-like activity. Continuous EEG monitoring showed muscle artefacts without any ictal discharges. Based on this finding, the propofol treatment was withdrawn and the seizure-like activity eventually attenuated and resolved. We propose that seizure-like phenomena associated with propofol withdrawal may not be ictal in nature and should not lead to unnecessary resumption of propofol infusion without documentation of an epileptic origin by EEG.

Avoiding anaesthetics after multiple failed drug-induced comas: an unorthodox approach to management of new-onset refractory status epilepticus (NORSE).

New-onset refractory status epilepticus (NORSE) is a rare, poorly understood and often catastrophic condition. There is little guidance available for management. Here, we describe the course of a 19-year-old man with NORSE who was treated successfully with a new approach. Our patient was initially treated with first-, second- and third-line agents including a total of seven failed drug-induced coma courses until the 30th day of hospitalization. When withdrawal of care was contemplated, management was then assumed by dedicated epileptologists and treatment course was changed. An unorthodox decision was made to avoid IV anaesthetics unless there were generalized bisynchronous tonic-clonic or generalized non-convulsive (electrographic) seizures. This approach allowed real-time assessment of treatment response to aggressive non-sedating AED therapy while the multifocal convulsive and non-convulsive seizures were ongoing. It also eliminated potentially fatal IV anaesthetic-induced complications and prevented anaesthetic withdrawal seizures. This was effective in achieving full recovery in our patient. The patient's awakening also changed the perspective of family members and care providers, avoiding premature withdrawal of care, which is often the cause of death in similar patients.

Lacosamide efficacy and tolerability in clinical practice - Post marketing analysis from a single dedicated epilepsy center.

OBJECTIVES: Post marketing analysis of anti-epileptic drug (AED) efficacy and tolerability is of great value to the clinician since it is more representative of clinical practice than clinical trial data. We analyzed our experience with lacosamide (LCM) in patients treated after marketing. PATIENTS AND METHODS: We identified all patients who were treated with LCM during the four year period after marketing, excluding patients who were in clinical trials. We recorded demographic data and analyzed efficacy and tolerability in patients who had at least one follow up visit or telephone call 3 months after the initiation of LCM. RESULTS: A total of 165 patients met our inclusion criteria. The mean age was 41 years. The majority of the cohort had focal epilepsy (146 patients) (88.4%). The mean duration of treatment was 31.2 months. Eighty one patients (49.1%) were continuing LCM at last follow up. Adverse effects (AEs) and discontinuation were significantly more common when LCM was added to one or more Na-channel blocking agents (NCB) (p = 0.0003 and 0.17). The 50% responder rate was 26% at 3 months and increased to 49% at 36 months. Patients were more likely to continue the drug and less likely to have AEs with slower titration over >4 weeks (p = 0.02 for each). Four or more previously failed AEDs predicted poorer response rate compared to three or less AEDs (p = 0.001). CONCLUSION: LCM use in clinical practice was associated with greater rate of seizure freedom than in clinical trials. Discontinuation and occurrence of AEs were significantly more likely with faster titration and adding LCM to NCB agents.

Functional networks in temporal-lobe epilepsy: a voxel-wise study of resting-state functional connectivity and gray-matter concentration.

Temporal-lobe epilepsy (TLE) involves seizures that typically originate in the hippocampus. There is evidence that seizures involve anatomically and functionally connected brain networks within and beyond the temporal lobe. Many studies have explored the effect of TLE on gray matter and resting-state functional connectivity in the brain. However, the relationship between structural and functional changes has not been fully explored. The goal of this study was to investigate the relationship between gray matter concentration (GMC) and functional connectivity in TLE at the voxel level. A voxel-wise linear regression analysis was performed between GMC maps and whole-brain resting-state functional connectivity maps to both the left thalamus (Lthal) and the left hippocampus (LH) in a group of 15 patients with left TLE. Twenty regions were found that exhibited GMC decreases linearly correlated with resting-state functional connectivity to either the LH or the Lthal in the patient group only. A subset of these regions had significantly reduced GMC, and one of these regions also had reduced functional connectivity to the LH in TLE compared to the controls. These results suggest a network of impairment in left TLE where more severe reductions in GMC accompany decreases (LH, Lthal, right midcingulate gyrus, left precuneus, and left postcentral gyrus) or increases (LH to right thalamus) in resting functional connectivity. However, direct relationships between these imaging parameters and disease characteristics in these regions have yet to be established.

Similar response to anti-epileptic medications among epileptic siblings.

BACKGROUND: When epilepsy does not respond to the initial anti-epileptic drug (AED) the subsequent search for an effective AED is predominantly a matter of trial and error, as only limited criteria exist for rational AED selection. Since epilepsy in siblings is likely to be relatively homogeneous, we hypothesized that an AED effective in one sibling would also be effective in the other. METHODS: We reviewed the antiepileptic medication response among nine sets of epileptic siblings (19 patients) in our practice. All but one patient were drug-resistant at one point during their treatment course. RESULTS: Eight sets of siblings (17 individuals) became seizure-free or almost seizure-free with treatment modification and using a medication proven effective for one sibling in the other siblings. The medication change that produced seizure freedom was lamotrigine monotherapy in two families, valproate monotherapy in one, lamotrigine adjunctive therapy in two, lamotrigine-levetiracetam combination in two, and lamotrigine-valproate combination in one family. In one remaining family with generalized epilepsy, one sibling was seizure-free on phenobarbital while the other had persistent seizures despite polytherapy. CONCLUSIONS: Our results indicated that siblings with epilepsy tend to respond to the same AED monotherapy or AED combination.

Levetiracetam Extended Release as Adjuvant Therapy for the Control of Partial-onset Seizures.

Extended release (XR) formulation of levetiracetam (LEV) is approved by the Food and Drug Administration as an add-on to other antiepileptic drugs (AEDs) for adults with partial onset seizures. This is based on class-I evidence demonstrating significant seizure reduction in once daily dosing. Keppra-XR is marketed with the brand name of Keppra XR since 2008 (UCB Pharma). Its original immediate release (IR) formulation has been in the market since 2000. LEV has a unique molecular structure which is chemically unrelated to existing AEDs. The precise mechanism of action is unknown. Animal studies showed binding to synaptic vesicle protein SV2A, thought to be involved in modulating synaptic neurotransmitter release. LEV-IR is proven effective as adjunctive therapy for partial-onset seizures, primary generalized tonic-clonic seizures and myoclonic seizures. It was shown to be equivalent to carbamazepine as first-line treatment for partial-onset seizures. The extended release formulation added advantages such as better tolerance and increased compliance.