Longitudinal Studies and Eye-Movement-Based Treatments of Infantile Nystagmus Syndrome: Estimated and Measured Therapeutic Improvements in Three Complex Cases.

INTRODUCTION AND PURPOSE: To demonstrate the utility of using eye-movement data to reveal the diagnostic characteristics of infantile nystagmus syndrome (INS), determine treatment, and both estimate and document therapeutic improvements in three patients with well-developed foveation periods, fairly broad, lateral gaze "nulls," head turns, strabismus, and complex, multiplanar nystagmus. PATIENTS AND METHODS: Infrared reflection, magnetic search coil, and high-speed digital video systems were used to record the eye movements of INS patients, pre- and post-Kestenbaum null-point correction surgery (horizontal or vertical). Data were analyzed and estimations made, using the eXpanded Nystagmus Acuity Function (NAFX) that is part of the OMtools toolbox for MATLAB. RESULTS: In all three subjects (S1-S3), both peak NAFX and longest foveation domain (LFD) improved from their pre-Kestenbaum values. S1: 0.700-0.745 (6.4%) and 25-34° (36%), respectively. S2: 0.445-0.633 (42.4%) and >40° to >50° (10%), respectively. S3: 0.250-0.300 (20%) and 13° to ≫18° (see text), respectively. CONCLUSIONS: S1: Even at the high ends of the pre-therapy NAFX and LFD spectra, INS foveation (and therefore, visual-function) improvements may be adequate to justify nystagmus surgery and provide clinical improvements beneficial to the patient. S2: INS foveation improvements in the vertical plane are equal to those originally estimated using the horizontal data in prior patients. S3: Two apparent NAFX peaks can be converted into a very broad peak by surgery based on the preferred lower peak.

Subcortical SISCOM hyperperfusion: Should we pay more attention to it?

PURPOSE: Demonstrating cerebral blood flow changes during seizures, ictal-interictal single photon emission computed tomography (SPECT) with co-registration to MRI (SISCOM) reflects brain activation and its pathways of spread. To investigate subcortical ictal hyperperfusion patterns during focal seizures, we retrospectively reviewed SISCOM analysis of patients who became seizure-free after cortical resection. Our aim was to evaluate the relationship between epileptogenic zones and subcortical hyperperfusion. METHOD: 67 patients were identified as having SISCOM evaluation and having remained seizure-free for at least one year after surgical resection. SISCOM analysis was blindly reviewed for localization of basal ganglia (BG), thalamic (TN) and cerebellar (CH) hyperperfusion based on three different thresholds. Subcortical activation and epilepsy characteristics were then compared between patients. For a given region of interest and threshold, the sensitivity, specificity and positive and negative predictive value for correct lateralization of the epilepsy side was calculated. RESULTS: Depending on the threshold used, BG hyperperfusion was found in 37.3-73.9% of patients, TN hyperperfusion in 31.3-68.1% and CH hyperperfusion in 13.5-29%. For a threshold of 1.5, the best predictive positive value for correct lateralization of the epilepsy side was obtained with BG/CH coactivation (89%). For a threshold of 2.0 and 2.5, it was obtained with BG/TN coactivation (88%) and BG activation (82%), respectively. CONCLUSION: Subcortical SISCOM hyperperfusion could offer additional clues in terms of lateralization.

Juvenile Myoclonic Epilepsy Shows Potential Structural White Matter Abnormalities: A TBSS Study.

Background: Several studies on patients with juvenile myoclonic epilepsy (JME) showed widespread white matter (WM) abnormalities in the brain. The aim of this study was to investigate potential structural abnormalities in JME patients (1) compared to healthy controls, (2) among JME subgroups with or without photoparoxysmal responses (PPR), and (3) in correlation with clinical variables. Methods: A selection of 31 patients with JME (12 PPR positive) and 27 age and gender matched healthy controls (HC) were studied at a tertiary epilepsy center. Fractional anisotropy (FA) was calculated and intergroup differences analyzed using Tract Based Spatial Statistics (TBSS). Results: Compared to HC the JME group showed reduced FA widespread and bilateral in the longitudinal fasciculus, inferior fronto-occipital fasciculus, corticospinal tract, anterior and posterior thalamic radiation, corona radiata, corpus callosum, cingulate gyrus and external capsule (p < 0.01). Subgroup analysis revealed no significant differences of WM alterations between PPR positive and negative patients and with clinical and epilepsy-related factors. Conclusions: Widespread microstructural abnormalities among patients with JME have been identified.Prior findings of frontal and thalamofrontal microstructural abnormalities have been confirmed. Additionally, microstructural abnormalities were found in widespread extra-frontal regions that may help to validate pathophysiological concepts of JME.

Prevalence and outcome of late-onset seizures due to autoimmune etiology: A prospective observational population-based cohort study.

OBJECTIVE: The increasing incidence of new-onset seizures with age is well known. Often, the etiology cannot be clarified. In the present study, patients with unprovoked late-onset seizures and without known neoplasm, who might have had paraneoplastic encephalitis, were investigated for a potentially underlying autoimmunity. METHODS: Sixty-six consecutive patients (36 women; aged ≥55 years) after having at least one seizure or seizures for ≤6 months were prospectively identified over a period of 4.75 years. All patients were tested for serum and cerebrospinal fluid (CSF) antibodies (Abs) to both neural cell-surface and intracellular antigens. Forty-five (68%) underwent brain magnetic resonance imaging (MRI). Follow-up in Ab-positive cases was ≥6 months. RESULTS: Two patients had high titers of anti-CASPR2 (contactin-associated protein-like 2) Abs in serum and CSF and fulfilled the diagnostic criteria of definite limbic encephalitis. Another two patients had bilateral encephalitic temporal MRI abnormalities. They also satisfied the criteria of definite limbic encephalitis, even though they had no Abs in serum or CSF. All four were in the age range of 55-70 years. They received immunotherapy and/or antiepileptic drug treatment and became seizure-free. SIGNIFICANCE: Our findings suggest that autoimmunity should be considered an important etiology in patients with late-onset seizures. Testing for neural antibodies and brain MRI may be worthwhile in this patient group.

Connectivity in ictal single photon emission computed tomography perfusion: a cortico-cortical evoked potential study.

Subtraction ictal and interictal single photon emission computed tomography can demonstrate complex ictal perfusion patterns. Regions with ictal hyperperfusion are suggested to reflect seizure onset and propagation pathways. The significance of ictal hypoperfusion is not well understood. The aim of this study was to verify whether ictal perfusion changes, both hyper- and hypoperfusion, correspond to electrically connected brain networks. A total of 36 subtraction ictal and interictal perfusion studies were analysed in 31 consecutive medically refractory focal epilepsy patients, evaluated by stereo-electroencephalography that demonstrated a single focal onset. Cortico-cortical evoked potential studies were performed after repetitive electrical stimulation of the ictal onset zone. Evoked responses at electrode contacts outside the stimulation site were used as a measure of connectivity. The evoked responses at these electrodes were compared to ictal perfusion values noted at these locations. In 67% of studies, evoked responses were significantly larger in hyperperfused compared to baseline-perfused areas. The majority of hyperperfused contacts also had significantly increased evoked responses relative to pre-stimulus electroencephalogram. In contrast, baseline-perfused and hypoperfused contacts mainly demonstrated non-significant evoked responses. Finally, positive significant correlations (P < 0.05) were found between perfusion scores and evoked responses in 61% of studies. When the stimulated ictal onset area was hyperperfused, 82% of studies demonstrated positive significant correlations. Following stimulation of hyperperfused areas outside seizure onset, positive significant correlations between perfusion changes and evoked responses could be seen, suggesting bidirectional connectivity. We conclude that strong connectivity was demonstrated between the ictal onset zone and hyperperfused regions, while connectivity was weaker in the direction of baseline-perfused or hypoperfused areas. In trying to understand a patient's epilepsy, one should consider the contribution of all hyperperfused regions, as these are likely not random, but represent an electrically connected epileptic network.

MEG May Reveal Hidden Population of Spikes in Epilepsy With Porencephalic Cyst/Encephalomalacia.

Porencephalic cyst/encephalomalacia is often associated with intractable epilepsy. A limited number of studies reported magnetoencephalography's (MEG's) potential to help construct treatment strategy for epilepsies associated with porencephalic cyst/encephalomalacia. The authors present here simultaneous electroencephalography (EEG) and MEG findings in three adult patients with pediatric-onset epilepsy due to porencephalic cyst/encephalomalacia. There were two types of spikes: one type was detected by MEG only (EEG-/MEG+), and the other detected by both EEG and MEG (EEG+/MEG+). Both types were seen in all three cases. The EEG-/MEG+ spikes all formed tight clusters; in contrast, the majority of EEG+/MEG+ spikes formed loose clusters. These data suggest that MEG may be helpful to better identify spike populations in epilepsy patients with porencephalic cyst/encephalomalacia. If hidden spike populations were to be found by MEG, this information would affect the interpretation of patient's pathophysiology and planning of intracranial electrode placement.

Predictive value of EFHC1 variants for the long-term seizure outcome in juvenile myoclonic epilepsy.

OBJECTIVE: This study aimed to determine the contribution of EFHC1 variants to the phenotypic variability of juvenile myoclonic epilepsy (JME) and to evaluate their diagnostic value regarding previously identified clinical long-term seizure outcome predictors in a consecutive cohort of patients with JME. METHODS: Thirty-eight probands and three family members affected with JME were studied at a tertiary epilepsy center with a review of their medical records and a subsequent face-to-face interview. All coding EFHC1 exons and adjacent exon/intron boundaries were directly sequenced. RESULTS: The previously reported EFHC1 mutation F229L was found in two cases who presented with early generalized tonic-clonic seizure (GTCS) onset and appeared to be associated with milder subtypes of JME. Variant R294H was identified in two further probands who had a subtype of JME developing from childhood absence epilepsy. However, segregation of the phenotype with this variant could not be confirmed in one family. CONCLUSIONS: Our findings corroborate the heterogeneity of JME as an electroclinical epilepsy syndrome and provide evidence that genetic factors may influence and help predict the long-term seizure outcome in patients with JME.

Fusion maldevelopment (latent/manifest latent) nystagmus syndrome: effects of four-muscle tenotomy and reattachment.

PURPOSE: To examine the waveform and clinical effects of the four-muscle tenotomy and reattachment procedure in fusion maldevelopment nystagmus syndrome (FMNS) and to compare them to those documented in infantile nystagmus syndrome (INS) and acquired nystagmus. METHODS: Both infrared reflection and high-speed digital video systems were used to record the eye movements in a patient with FMNS (before and after tenotomy and reattachment). Data were analyzed using the eXpanded Nystagmus Acuity Function (NAFX) that is part of the OMtools software. Model simulations and predictions were performed using the authors' behavioral ocular motor system model in MATLAB Simulink (The MathWorks, Inc., Natick, MA). RESULTS: The model predicted, and the patient's data confirmed, that the tenotomy and reattachment procedure produces improvements in FMN waveforms across a broader field of gaze and decreases the Alexander's law variation. The patient's tenotomy and reattachment plots of NAFX after surgery versus gaze angle were higher and had lower slope than before surgery. Clinically, despite moderate improvements in both peak measured acuity and stereoacuity, dramatic improvements in the patient's abilities and lifestyle resulted. CONCLUSIONS: The four-muscle tenotomy and reattachment nystagmus surgery produced beneficial therapeutic effects on FMN waveforms that are similar to those demonstrated in INS and acquired nystagmus. These results support the authors' prior recommendation that tenotomy and reattachment nystagmus should be added to required strabismus procedures in patients who also have FMNS (ie, perform tenotomy and reattachment on all unoperated muscles in the plane of the nystagmus). Furthermore, when strabismus surgery is not required, four-muscle tenotomy and reattachment may be used to improve FMN waveforms and visual function.

Linking MRI postprocessing with magnetic source imaging in MRI-negative epilepsy.

OBJECTIVE: MRI-negative (MRI-) pharmacoresistant focal epilepsy (PFE) patients are most challenging for epilepsy surgical management. This study utilizes a voxel-based MRI postprocessing technique, implemented using a morphometric analysis program (MAP), aiming to facilitate detection of subtle focal cortical dysplasia (FCD) in MRI- patients. Furthermore, the study examines the concordance between MAP-identified regions and localization from magnetic source imaging (MSI). METHODS: Included in this retrospective study were 25 MRI- surgical patients. MAP was performed on T1-weighted MRI, with comparison to a normal database. The pertinence of MAP+ areas was confirmed by MSI, surgical outcome and pathology. Analyses of MAP and MSI were performed blindly from patients' clinical information and independently from each other. RESULTS: The detection rate of subtle changes by MAP was 48% (12/25). Once MAP+ areas were resected, patients were more likely to be seizure-free (p=0.02). There were no false positives in the 25 age-matched normal controls. Seven patients had a concordant MSI correlate. Patients in whom a concordant area was identified by both MAP and MSI had a significantly higher chance of achieving a seizure-free outcome following complete resection of this area (p=0.008). In the 9 resected MAP+ areas, pathology revealed FCD type IA in 7 and type IIB in 2. INTERPRETATION: MAP shows promise in identifying subtle FCD abnormalities and increasing the diagnostic yield of conventional MRI visual analysis in presurgical evaluation of PFE. Concordant MRI postprocessing and MSI analyses may lead to the noninvasive identification of a structurally and electrically abnormal subtle lesion that can be surgically targeted.

Cephalic aura after frontal lobe resection.

A cephalic aura is a common sensory aura typically seen in frontal lobe epilepsy. The generation mechanism of cephalic aura is not fully understood. It is hypothesized that to generate a cephalic aura extensive cortical areas need to be excited. We report a patient who started to have cephalic aura after right frontal lobe resection. Magnetoencephalography (MEG) showed interictal spike and ictal change during cephalic aura, both of which were distributed in the right frontal region, and the latter involved much more widespread areas than the former on MEG sensors. The peculiar seizure onset pattern may indicate that surgical modification of the epileptic network was related to the appearance of cephalic aura. We hypothesize that generation of cephalic aura may be associated with more extensive cortical involvement of epileptic activity than that of interictal activity, in at least a subset of cases.

Clinical predictors of the long-term social outcome and quality of life in juvenile myoclonic epilepsy: 20-65 years of follow-up.

OBJECTIVE: The long-term social outcome in patients with juvenile myoclonic epilepsy (JME) is still controversial. The aim of this study was both to investigate the long-term social outcome in relation to clinical variables and to identify epilepsy-related factors that affect the quality of life (QoL) in JME patients with a follow-up of at least 20 years. METHODS: A retrospective selection of 33 of 90 patients (21 female) from a tertiary epilepsy center diagnosed with JME and followed for ≥20 years (mean 37.8 years) was studied. All patients were evaluated with a thorough review of their medical records, and a subsequent face-to-face or telephone interview. QOLIE-31-P questionnaire (QoL In Epilepsy) and Beck Depression Inventory-II were used to assess the QoL and the presence and severity of depressive symptoms, respectively. RESULTS: Of 33 patients, 18 (54.5%) became seizure-free; in 4 of the patients (22.2%), antiepileptic drug (AED) treatment was discontinued. Early and long-term seizure freedom improves both social adjustment (p = 0.02) and occupational integration (p = 0.02) and associates with a better QoL (odds ratio [OR] 2.25). A high seizure burden highly affects both aspects of personal life-family and work; notably the occurrence of frequent and/or late onset generalized tonic-clonic seizures increases the risk of concomitant diseases (p = 0.05) and lifelong AED treatment (p = 0.03), decreases the patient's employability (p = 0.02), increases the rate of employment disability pension (p = 0.05), and considerably increases public/social spending. Seizure freedom significantly increases the QoL (p = 0.001), whereas more severe courses of epilepsy (OR 3.2), AED side effects (p = 0.04), depression (p = 0.02), and sleep disturbances (OR 2.7) considerably decrease the patient's QoL. SIGNIFICANCE: Although patients with JME are a heterogeneous group, several predictors for the long-term social, family, educational, and occupational outcome have been identified in our study and should be considered in the effort to both improve the patient's QoL as well as preserve economic resources.

Magnetoencephalography correlate of EEG POSTS (positive occipital sharp transients of sleep).

PURPOSE: In contrast to EEG, which has guidelines for interpretation and a plethora of textbooks, the full range of activity seen in magnetoencephalography (MEG) has not been fleshed out. Currently, magnetoencephalographers apply criteria for EEG waveforms to MEG signals based on an assumption that MEG activity should have morphology that is similar to EEG. The purpose of this article was to show the characteristic MEG profile of positive occipital sharp transients of sleep. METHODS: Simultaneous MEG-EEG recordings of two cases are shown. RESULTS: In both the cases, the morphologic features of positive occipital sharp transients of sleep in MEG vary and sometimes mimic epileptic spikes. CONCLUSION: This report raises a caution that a normal variant may have an even more epileptic appearance on MEG than on EEG. Using the simultaneously recorded EEG to avoid misinterpretation of spikey-looking positive occipital sharp transients of sleep in MEG is a natural and prudent practice.

Sensitivity of scalp 10-20 EEG and magnetoencephalography.

Although previous studies have investigated the sensitivity of electroencephalography (EEG) and magnetoencephalography (MEG) to detect spikes by comparing simultaneous recordings, there are no published reports that focus on the relationship between spike dipole orientation or sensitivity of scalp EEG/MEG and the "gold standard" of intracranial recording (stereotactic EEG). We evaluated two patients with focal epilepsy; one with lateral temporal focus and the other with insular focus. Two MEG recordings were performed for both patients, each recorded simultaneously with initially scalp EEG, based on international 10-20 electrode placement with additional electrodes for anterior temporal regions, and subsequently stereotactic EEG. Localisation of MEG spike dipoles from both studies was concordant and all MEG spikes were detected by stereotactic EEG. For the patient with lateral temporal epilepsy, spike sensitivity of MEG and scalp EEG (relative to stereotactic EEG) was 55 and 0%, respectively. Of note, in this case, MEG spike dipoles were oriented tangentially to scalp surface in a tight cluster; the angle of the spike dipole to the vertical line was 3.6 degrees. For the patient with insular epilepsy, spike sensitivity of MEG and scalp EEG (relative to stereotactic EEG) was 83 and 44%, respectively; the angle of the spike dipole to the vertical line was 45.3 degrees. For the patient with lateral temporal epilepsy, tangential spikes from the lateral temporal cortex were difficult to detect based on scalp 10-20 EEG and for the patient with insular epilepsy, it was possible to evaluate operculum insular sources using MEG. We believe that these findings may be important for the interpretation of clinical EEG and MEG.

Magnetoencephalography reveals a unique neurophysiological profile of focal-onset epileptic spasms.

Epilepsy is defined as a disorder of the brain characterized by an enduring predisposition to experience epileptic seizures and the neurobiological, cognitive, psychological, and social difficulties relating to the condition. An epileptic spasm (ES) is a type of seizure characterized by clusters of short contractions involving axial muscles and proximal segments. However, the precise mechanism of ESs remains unknown. Despite the potential of magnetoencephalography (MEG) as a tool for investigating the neurophysiological mechanism of ESs, it has been difficult to use this methodology due to magnetic artifacts attributable to patient movement. We report on an 8-year-old girl suffering from intractable epileptic spasms from the age of 7 months. She was diagnosed with possible Aicardi syndrome [corrected] (AGS), characterized by the triad of callosal agenesis, infantile spasms, and chorioretinal lacunae. She is now intellectually delayed and suffers from intractable ES. We used both MEG and electroencephalography to investigate her epilepsy. The recording captured two series of spasm clusters. Spikes were clearly identified with MEG in about four-fifths of all spasms but were identified poorly or not at all in the remainder. MEG findings support previous studies that used intracranial electrodes to analyze patients with ESs and that showed variability in ES-associated spikes in terms of manner of cortical involvement and magnitude. Given the limitations of intracranial electrodes, such as sampling restrictions and invasiveness, MEG may be a helpful tool for non-invasively investigating the unique pathophysiological profile of focal-onset ESs.

Utility of temporally-extended signal space separation algorithm for magnetic noise from vagal nerve stimulators.

OBJECTIVE: To evaluate the utility of a temporally-extended signal space separation algorithm (tSSS) for patients with vagal nerve stimulator (VNS). METHODS: We evaluated median nerve somatosensory evoked responses (SER) of magnetoencephalography (MEG) in 27 VNS patients (48 sides) with/without tSSS processing. We classified SER dipoles as 'acceptable' if: (A) the location of the dipole was in the expected location in the central sulcus, and (B) the goodness of fit value (GOF) was greater than 80%. We evaluated (1) the number of sides which produced acceptable dipoles in each dataset (i.e. with/without tSSS processing), and in cases where the both data produced reliable dipoles, (2) compared their GOFs and the 95% confidence volumes (CV) (mm(3)). Statistical differences in the GOF and CV between with/without tSSS conditions were determined by paired t test. RESULTS: Only 11 (23%) responses had reliable dipoles without tSSS processing, while all 48 (100%) had acceptable dipoles under tSSS processing. Additionally, the latter group had significantly higher GOF (increased by 7% on average) and lower CV (mean decrease of 200 mm(3)) than the former (p<0.01). CONCLUSIONS: Processing with tSSS quantitatively improves dipole fitting of known sources in VNS patients. SIGNIFICANCE: This algorithm permits satisfactory MEG testing in the relatively commonly encountered epilepsy patient with VNS.

Use of simultaneous depth and MEG recording may provide complementary information regarding the epileptogenic region.

Simultaneous SEEG-MEG recording has the potential to define the epileptic spike source accurately. We present a case of a 55-year-old female with intractable left temporal lobe epilepsy in whom we evaluated the relationship between the amplitude recorded from SEEG electrodes, inserted in the lateral temporal region, and their distance from the MEG-modelled spike. We found a quadratic fall-off relationship between the amplitude and distance. This result supports the concept that the MEG dipoles reflect the "centre" of spike locations and may provide comprehensive information for SEEG which records spike activities directly but is inherently limited in spatial sampling.

Magnetoencephalography in fronto-parietal opercular epilepsy.

OBJECTIVE: To clarify the clinical and neurophysiological profiles of fronto-parietal opercular epilepsy in which epileptic spikes are detected with magnetoencephalography (MEG) but not with scalp electroencephalography (EEG). METHODS: Four patients presented with epileptic spikes localized to the fronto-parietal opercular cortex, which were only appreciated following MEG recordings. RESULTS: In all cases, seizure semiology suggested early activation of the operculum and lower peri-rolandic cortex consistent with the somatotopic organization of this region, i.e. tingling sensation involving the throat and hemi-face or contralateral upper limb, and spasms of the neck and throat. MEG spikes were localized in the fronto-parietal operculum. Three of the four patients underwent invasive electrocorticography and/or stereo-EEG recordings, and spikes were confirmed to arise from the estimated area of MEG dipole localization. Two patients remained seizure-free for over 1 year after resection of the epileptogenic region; the other patient declined resective surgery due to proximity to the language cortex. CONCLUSION: This study demonstrates the usefulness of MEG in localizing spikes arising from within the fronto-parietal opercular regions, and implies that MEG may provide localizing information in patients with symptoms suggestive of opercular epilepsy, even if scalp EEG recordings fail to disclose any epileptogenic activities.

Clinical evidence for the utility of movement compensation algorithm in magnetoencephalography: successful localization during focal seizure.

A movement compensation (MC) algorithm may help to evaluate seizure focus in magnetoencephalography despite patient movement. We report a boy whose ictal MEG focus was localized to the same sublobar region before and after head turning when MC was applied, but which was erroneously localized to a different area without MC. This study provides the first clinical evidence for utility of MC in magnetoencephalography for localizing focal seizures.

Imag(in)ing seizure propagation: MEG-guided interpretation of epileptic activity from a deep source.

Identification and accurate localization of seizure foci is vital in patients with medically-intractable focal epilepsy, who may be candidates for potentially curative resective epilepsy surgery. We present a patient with difficult-to-control seizures associated with an occult focal cortical dysplasia residing within the deeper left parietal operculum and underlying posterior insula, which was not detected by conventional MRI analysis. Propagated activities from this deeper generator produced misleading EEG patterns both on surface and subdural electrode recordings suggesting initial activation of the perirolandic and mesial frontal regions. However, careful spatio-temporal analysis of stereotyped interictal activities recorded during MEG, using sequential dipole modeling, revealed a consistent pattern of epileptic propagation originating from the deeper source and propagating within few milliseconds to the dorsal convexity. In this instance, careful dissection of noninvasive investigations (interictal MEG along with ictal SPECT findings) allowed clinicians to dismiss the inaccurate and misleading findings of the traditional "gold-standard" intracranial EEG. In fact, this multimodal noninvasive approach uncovered a subtle dysplastic lesion, resection of which rendered the patient seizure-free. This case highlights the potential benefits of dynamic analysis of interictal MEG in the appropriate clinical context. Pathways of interictal spike propagation may help elucidate essential neural networks underlying focal epilepsy.