Pradeep N. Modur

Ictal high‐frequency oscillations in neocortical epilepsy: implications for seizure localization and surgical resection

Purpose:  To investigate the characteristics of intracranial ictal high‐frequency oscillations (HFOs).

Seizure localization using broadband EEG: Comparison of conventional frequency activity, high-frequency oscillations, and infraslow activity

Summary: In neocortical epilepsy, we showed that the seizure onset defined by ictal high-frequency oscillations (HFO: ≥70 Hz) with subsequent evolution into slower frequency activity (i.e., HFOs+) was smaller in spatial distribution than that defined by conventional frequency activity (1–70 Hz), and that resection of HFO+ areas resulted in favorable seizure outcome. This study further investigates ictal broadband EEG in the same cohort of patients by examining the infraslow activity, including ictal baseline (“direct current”) shifts (IBS) and peri-ictal infraslow activity (0.02 to 0.2 Hz). The seizure onset zone had been defined and resected based on HFO+ by a prospectively defined protocol. We reviewed 11 representative seizures from 6 patients by visual and spectral analyses using appropriate filters and timescales. The HFO seizure onset, in the high gamma or ripple frequency, preceded or followed the IBS closely (<300 ms). The IBS were negative or positive, ∼1 mV in amplitude and 2 to 3 seconds long. Although the HFO+ were always ipsilateral to the surgical hemisphere, the IBS could be ipsilateral or contralateral. Compared with conventional frequency activity, the HFO+ and IBS were significantly smaller in spatial distribution and likely to be concordant. The peri-ictal infraslow activity consisted of distinct periodic or rhythmic (0.12 to 0.16 Hz) patterns, poorly concordant with IBS or HFO+. Although not statistically significant, better seizure outcome tended to correlate with smaller seizure onset zones and more complete resection of the HFO+ and IBS contacts. We conclude that IBS, like HFO+, define a smaller seizure onset zone and probably a more accurate epileptogenic zone in neocortical epilepsy.

Effectiveness of multimodality treatment for autoimmune limbic epilepsy.

We evaluated the outcome of multimodality treatment in autoimmune limbic epilepsy in 3 consecutive patients (2 male and 1 female; age 33-55 years) presenting with a combination of focal non-convulsive status epilepticus, memory impairment, and psychosis. MRI showed right or bitemporal T2 or FLAIR hyperintensity. Video-EEG showed seizures of right temporo-occipital or bitemporal independent onset. Extensive workup failed to reveal infectious aetiology or an underlying tumour. However, the autoantibody panel was positive for one or more of these antibodies: anti-VGKC, anti-GABAB, anti-VGCC (P/Q, N types), and anti-GAD65. All patients received: (1) conventional antiepileptic drugs including levetiracetam, lacosamide, phenobarbital, lamotrigine, and valproate; (2) immunomodulatory therapy including methylprednisolone, plasmapheresis, and intravenous immunoglobulin; and (3) rituximab. After a 4-6-week in-hospital course, the seizures resolved in all patients but 2 had persistent memory impairment. None had treatment-related complications. At the time of last follow-up, 2-3 months later, 2 patients remained seizure-free while 2 had residual memory impairment. Our findings suggest that multimodality treatment with a combination of conventional AEDs, immunomodulatory therapy, and rituximab is effective and safe in autoimmune limbic epilepsy.

Predictors of Postoperative Seizure Recurrence: A Longitudinal Study of Temporal and Extratemporal Resections

Objective. We investigated the longitudinal outcome of resective epilepsy surgery to identify the predictors of seizure recurrence. Materials and Methods. We retrospectively analyzed patients who underwent resections for intractable epilepsy over a period of 7 years. Multiple variables were investigated as potential predictors of seizure recurrence. The time to first postoperative seizure was evaluated using survival analysis and univariate analysis at annual intervals. Results. Among 70 patients, 54 (77%) had temporal and 16 (23%) had extratemporal resections. At last follow-up (mean 48 months; range 24–87 months), the outcome was Engel class I in 84% (n = 59) of patients. Seizure recurrence followed two patterns: recurrence was “early” (within 2 years) in 82% of patients, of whom 83% continued to have seizures despite optimum medical therapy; recurrence was “late” (after 2 years) in 18%, of whom 25% continued to have seizures subsequently. Among the variables of interest, only resection site and ictal EEG remained as independent predictors of seizure recurrence over the long term (p < 0.05). Extratemporal resection and discordance between ictal EEG and resection area were associated with 4.2-fold and 5.6-fold higher risk of seizure recurrence, respectively. Conclusions. Extratemporal epilepsy and uncertainty in ictal EEG localization are independent predictors of unfavorable outcome. Seizure recurrence within two years of surgery indicates poor long-term outcome.

High frequency oscillations and infraslow activity in epilepsy

In pre-surgical evaluation of epilepsy, there has been an increased interest in the study of electroencephalogram (EEG) activity outside the 1-70 Hz band of conventional frequency activity (CFA). Research over the last couple of decades has shown that EEG activity in the 70-600 Hz range, termed high frequency oscillations (HFOs), can be recorded intracranially from all brain regions both interictally and at seizure onset. In patients with epilepsy, HFOs are now considered as pathologic regardless of their frequency band although it may be difficult to distinguish them from the physiologic HFOs, which occur in a similar frequency range. Interictal HFOs are likely to be confined mostly to the seizure onset zone, thus providing a new measure for localizing it. More importantly, several studies have linked HFOs to underlying epileptogenicity, suggesting that HFOs can serve as potential biomarkers for the illness. Along with HFOs, analysis of ictal baseline shifts (IBS; or direct current shifts) and infraslow activity (ISA) (ISA: <0.1 Hz) has also attracted attention. Studies have shown that: IBSs can be recorded using the routine AC amplifiers with long time constants; IBSs occur at the time of conventional EEG onset, but in a restricted spatial distribution compared with conventional frequencies; and inclusion of IBS contacts in the resection can be associated with favorable seizure outcome. Only a handful of studies have evaluated all the EEG frequencies together in the same patient group. The latter studies suggest that the seizure onset is best localized by the ictal HFOs, the IBSs tend to provide a broader localization and the conventional frequencies could be non-localizing. However, small number of patients included in these studies precludes definitive conclusions regarding post-operative seizure outcome based on selective or combined resection of HFO, IBS and CFA contacts. Large, preferably prospective, studies are needed to further evaluate the implications of different EEG frequencies in epilepsy.

Sequential intrarectal diazepam and intravenous levetiracetam in treating acute repetitive and prolonged seizures

In this retrospective study of institutionalized patients with mental retardation, we present the efficacy and safety of sequential treatment with intrarectal diazepam (IRD) gel (Diastat) and intravenous levetiracetam (IVL) in comparison with either treatment alone for acute repetitive or prolonged seizures (ARPS). We defined ARPS as ≥3 seizures of any type within 1 h or a single seizure of any type lasting ≥3 min. Eighty‐eight ARPS episodes were treated in 25 patients (14 female, age 21–72 years), with mainly symptomatic generalized epilepsy. There were no adverse events directly attributable to the administration of IRD or IVL. Seizure recurrence within 4 h of treatment, the primary outcome measure, was significantly lower after combined sequential IRD + IVL treatment (3 of 36) compared to IRD alone (6 of 24, p = 0.048) or IVL alone (10 of 28, p = 0.039). There was no statistically significant difference between the individual IRD and IVL treatments (p = 0.604). The estimated odds ratio (OR) indicated that the risk of seizure recurrence was higher after IRD or IVL monotherapy compared to combined IRD + IVL treatment. Subsequent emergency room (ER) transfers following seizure recurrence were least likely after IVL treatment (10%) compared to combined IRD + IVL (67%) or IRD (83%) treatment. These findings suggest that although IRD or IVL monotherapy is efficacious, the combination is superior in controlling ARPS in this special group of institutionalized patients. In addition, we speculate that a more reliable onset of action after IVL treatment results in rapid seizure control and fewer ER transfers, despite seizure recurrence.

Interictal high-frequency oscillations (HFOs) as predictors of high frequency and conventional seizure onset zones

We investigated the relationship between the interictal high-frequency oscillations (HFOs) and the seizure onset zones (SOZs) defined by the ictal HFOs or conventional frequency activity (CFA), and evaluated the usefulness of the interictal HFOs as spatial markers of the SOZs. We analysed seizures showing discrete HFOs at onset on intracranial EEGs acquired at ≥1000-Hz sampling rate in a training cohort of 10 patients with temporal and extratemporal epilepsy. We classified each ictal channel as: HFO+ (HFOs at onset with subsequent evolution), HFO- (HFOs at onset without evolution), CFA (1.6-70-Hz activity at onset with evolution), or non-ictal. We defined the SOZs as: hSOZ (HFO+ channels only), hfo+&-SOZ (HFO+ and HFO- channels), and cSOZ (CFA channels). Using automated methods, we detected the interictal HFOs and extracted five features: density, connectivity, peak frequency, log power, and amplitude. We created logistic regression models using these features, and tested their performance in a separate replication cohort of three patients. The models containing the five interictal HFO features reliably differentiated the channels located inside the SOZ from those outside in the training cohort (p<0.001), reaching the highest accuracy for the classification of hSOZ. Log power and connectivity had the highest odds ratios, both being higher for the channels inside the SOZ compared with those outside the SOZ. In the replication cohort of novel patients, the same models differentiated the HFO+ from HFO- channels, and predicted the extents of the hSOZ and hfo+&-SOZ (F1 measure >0.5) but not the cSOZ. Our study shows that the interictal HFOs are useful in defining the spatial extent of the SOZ, and predicting whether or not a given channel in a novel patient would be involved in the seizure. The findings support the existence of an abnormal network of tightly-linked ictal and interictal HFOs in patients with intractable epilepsy.

Temporal lobe volume predicts Wada memory test performance in patients with mesial temporal sclerosis

The Wada test is widely used in the presurgical evaluation of potential temporal lobectomy patients to predict postoperative memory function. Expected asymmetry (EA), defined as Wada memory lateralized to the nonsurgical hemisphere, or a higher score after injection of the surgical hemisphere would be considered favorable in terms of postoperative memory outcome. However, in some cases, nonlateralized memory (NM) results, with no appreciable asymmetry, may occur because of impaired scores after both injections, often leading to denial of surgery. The reason for such nonlateralized Wada memory in patients with intractable temporal lobe epilepsy (TLE) remains unclear. Given that quantitative morphometric magnetic resonance imaging studies in TLE patients have shown bilateral regional atrophy in temporal and extratemporal structures, we hypothesized that the volume loss in contralateral temporal structures could contribute to nonlateralized Wada memory performance. To investigate this, we examined the relationship between the volume changes of temporal structures and Wada memory scores in patients with intractable TLE with mesial temporal sclerosis (MTS) using an age- and gender-matched control group. Memory was considered nonlateralized if the absolute difference in the total correct recall scores between ipsilateral and contralateral injections was <11%. Among 21 patients, Wada memory was lateralized in 15 and nonlateralized in 6 patients, with all the nonlateralized scores being observed in left TLE. The recall scores after ipsilateral injection were significantly lower in patients with an NM profile than an EA profile (23 ± 14% vs. 59 ± 18% correct recall, p ≤ 0.001). However, the recall scores after contralateral injection were low but similar between the two groups (25 ± 17% vs. 25 ± 15% correct recall, p=0.97). Compared to controls, all the patients showed greater volume loss in the temporal regions. However, patients with a NM profile showed significantly more volume loss than those with a lateralized memory profile in both contralateral and ipsilateral temporal regions (p<0.05). Left hemispheric Wada memory performance correlated positively with the size of the left mesial and neocortical temporal structures (r=0.49-0.63, p=0.005-0.04). Our study suggests that volume loss in the nonsurgical temporal structures is associated with nonlateralized Wada memory results in patients with intractable TLE.

Teaching NeuroImages: Partial Brown-Séquard syndrome A rare presentation of CMV myelitis

A 53-year-old man with AIDS presented with left leg weakness and right leg numbness. Examination was significant for left lower extremity weakness in a pyramidal pattern (4/5), left knee and ankle hyperreflexia, left Babinski sign, and decreased pain and temperature sensation over right lower extremity extending up the right torso up to T5 dermatome. Vibration and proprioception were normal. Thoracic spine MRI showed hyperintensity in the left hemicord (figure, A and B). CSF analysis showed mild protein elevation with lymphocytic pleocytosis, and positive cytomegalovirus (CMV) PCR, consistent with CMV myelitis. Treatment with gancylcovir1 and foscarnet2 resulted in gradual improvement in the patients symptoms and examination.