Dileep Nair

Two‐year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: Final results of the RNS System Pivotal trial

To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci.

Chronic Enhancement of the Intrinsic Growth Capacity of Sensory Neurons Combined with the Degradation of Inhibitory Proteoglycans Allows Functional Regeneration of Sensory Axons through the Dorsal Root Entry Zone in the Mammalian Spinal Cord

Peripherally conditioned sensory neurons have an increased capacity to regenerate their central processes. However, even conditioned axons struggle in the presence of a hostile CNS environment. We hypothesized that combining an aggressive conditioning strategy with modification of inhibitory reactive astroglial-associated extracellular matrix could enhance regeneration. We screened potential treatments using a model of the dorsal root entry zone (DREZ). In this assay, a gradient of inhibitory chondroitin sulfate proteoglycans (CSPGs) stimulates formation of dystrophic end bulbs on adult sensory axons, which mimics regeneration failure in vivo. Combining inflammation-induced preconditioning of dorsal root ganglia in vivo before harvest, with chondroitinase ABC (ChABC) digestion of proteoglycans in vitro allows for significant regeneration across a once potently inhibitory substrate. We then assessed regeneration through the DREZ after root crush in adult rats receiving the combination treatment, ChABC, or zymosan pretreatment alone or no treatment. Regeneration was never observed in untreated animals, and only minimal regeneration occurred in the ChABC- and zymosan-alone groups. However, remarkable regeneration was observed in a majority of animals that received the combination treatment. Regenerated fibers established functional synapses, as demonstrated electrophysiologically by the presence of an H-reflex. Two different postlesion treatment paradigms in which the timing of both zymosan and ChABC administration were varied after injury were ineffective in promoting regeneration. Therefore, zymosan pretreatment, but not posttreatment, of the sensory ganglia, combined with ChABC modification of CSPGs, resulted in robust and functional regeneration of sensory axons through the DREZ after root injury.

Long-term treatment with responsive brain stimulation in adults with refractory partial seizures.

Objective: The long-term efficacy and safety of responsive direct neurostimulation was assessed in adults with medically refractory partial onset seizures. Methods: All participants were treated with a cranially implanted responsive neurostimulator that delivers stimulation to 1 or 2 seizure foci via chronically implanted electrodes when specific electrocorticographic patterns are detected (RNS System). Participants had completed a 2-year primarily open-label safety study (n = 65) or a 2-year randomized blinded controlled safety and efficacy study (n = 191); 230 participants transitioned into an ongoing 7-year study to assess safety and efficacy. Results: The average participant was 34 (±11.4) years old with epilepsy for 19.6 (±11.4) years. The median preimplant frequency of disabling partial or generalized tonic-clonic seizures was 10.2 seizures a month. The median percent seizure reduction in the randomized blinded controlled trial was 44% at 1 year and 53% at 2 years (p < 0.0001, generalized estimating equation) and ranged from 48% to 66% over postimplant years 3 through 6 in the long-term study. Improvements in quality of life were maintained (p < 0.05). The most common serious device-related adverse events over the mean 5.4 years of follow-up were implant site infection (9.0%) involving soft tissue and neurostimulator explantation (4.7%). Conclusions: The RNS System is the first direct brain responsive neurostimulator. Acute and sustained efficacy and safety were demonstrated in adults with medically refractory partial onset seizures arising from 1 or 2 foci over a mean follow-up of 5.4 years. This experience supports the RNS System as a treatment option for refractory partial seizures. Classification of evidence: This study provides Class IV evidence that for adults with medically refractory partial onset seizures, responsive direct cortical stimulation reduces seizures and improves quality of life over a mean follow-up of 5.4 years.

Predictors of outcome after temporal lobectomy for the treatment of intractable epilepsy

To assess short- and long-term seizure freedom, the authors reviewed 371 patients who underwent anterior temporal lobectomy to treat pharmacoresistant epilepsy. The mean follow-up duration was 5.5 years (range 1 to 14.1 years). Fifty-three percent of patients were seizure free at 10 years. The authors identified multiple predictors of recurrence. Results of EEG performed 6 months postoperatively correlated with occurrence and severity of seizure recurrence, in addition to breakthrough seizures with discontinuation of antiepileptic drugs.

Epileptogenicity of Focal Malformations Due to Abnormal Cortical Development: Direct Electrocorticographic–Histopathologic Correlations

Summary:  Purpose: Malformations due to abnormal cortical development (MCDs) are common pathologic substrates of medically intractable epilepsy. The in situ epileptogenicity of these lesions as well as its relation to histopathologic changes remains unknown. The purpose of this study was to correlate the cellular patterns of MCDs with the expression of focal cortical epileptogenicity as assessed by direct extraoperative electrocorticographic (ECoG) recordings by using subdural grids.

Focal Cortical Dysplasias in Eloquent Cortex: Functional Characteristics and Correlation with MRI and Histopathologic Changes

Summary:  Purpose: Focal cortical dysplasia (CD) is increasingly recognized as a common pathologic substrate of medically intractable epilepsy. As these lesions are often localized in the frontal lobe (therefore in potentially eloquent cortex), an understanding of the functional status of the involved region(s) and of its anatomic and pathologic correlates is of prime importance. The purpose of this study is to assess the function of focal CD in relation to magnetic resonance imaging (MRI) and histopathologic features.

Subdural electrode analysis in focal cortical dysplasia Predictors of surgical outcome

Objective: Patients undergoing epilepsy surgery for focal cortical dysplasia (FCD) guided by subdural EEG generally have a poor surgical outcome. Our objective was to identify predictors of postoperative seizure recurrence in this patient cohort. Methods: We retrospectively reviewed 48 consecutive surgeries guided by subdural electrode recordings between 1990 and 2004 in patients with a pathologic diagnosis of isolated FCD. Using survival analysis, we analyzed results of the noninvasive evaluation, MRI, subdural interictal and ictal EEG patterns, extent of resection, proximity to eloquent cortex, and postoperative EEG. Results: After a median follow-up of 2.7 years, 45% of patients were completely seizure-free. Most seizures recurred in the first 6 months or between years 2 and 3 after surgery. On univariate analysis, seizure recurrence was associated with bilateral EEG abnormalities, multiple semiologic seizure types, and incomplete resection of the ictal onset zone. The absence of an MRI lesion did not affect outcome, nor did proximity to eloquent cortex. Interictal paroxysmal fast and runs of repetitive spikes correlated with the ictal onset zone, whereas isolated spikes did not. The 6-month EEG predicted ultimate surgical failure in patients seizure-free at that stage. An ictal spread pattern from the edge of the subdural grids was an independent predictor of seizure recurrence on multivariate analysis. Conclusions: We have identified specific predictive factors that may guide the surgical evaluation of patients with focal cortical dysplasia and intractable epilepsy requiring subdural EEG monitoring. Successful surgical results can be obtained utilizing subdural EEG in carefully selected patients.

Long-term seizure outcome after resective surgery in patients evaluated with intracranial electrodes.

Purpose:  Despite advances in “noninvasive” localization techniques, many patients with medically intractable epilepsy require the placement of subdural (subdural grid electrode, SDE) and/or depth electrodes for the identification and definition of extent of the epileptic region. This study investigates the trends in longitudinal seizure outcome and its predictors in this group.

EEG and evoked potential recording from the subthalamic nucleus for deep brain stimulation of intractable epilepsy

OBJECTIVES The substantia nigra in the animal model has been implicated in the control of epilepsy. The substantia nigra pars reticulata (SNpr) receives afferents from the subthalamic nucleus (STN), which thus may have an effect on the control of epilepsy. There is evidence in the animal model of a direct connection from the cortex to the STN. High-frequency STN stimulation is being used in experimental trial for the management of intractable epilepsy. Our primary objective in this study was to determine if there was epileptiform activity recorded from the STN in association with scalp recorded epileptiform activity to support the presence of a pathway from the cortex to the STN in humans as described in animals that may be important for the management of epilepsy. This article describes the interictal and ictal electroencephalographic (EEG) findings as well as evoked potential recordings from the STN in these patients with intractable epilepsy. METHODS Four patients (3 males) ranging from 19 to 45 years with intractable focal epilepsy refractory to anti-epileptic drugs were studied. Two patients failed vagal nerve stimulation and one patient had previous epilepsy surgery. Depth electrodes were implanted stereotactically in the STN bilaterally. A comparative analysis of the interictal and ictal activities recorded from the scalp and STN electrodes was performed. Median nerve somatosensory evoked potentials (SEPs) and auditory evoked potentials (AEPs) were also recorded. RESULTS Interictal sharp waves recorded in the scalp EEG were always negative in polarity. These sharp waves were always associated with sharp waves recorded at the ipsilateral STN electrode contacts that were always positive in polarity. In addition repetitive spikes were recorded independently at the left or right STN electrode contacts, with no reflection at the scalp. These spikes were extremely stereotyped, of high amplitude and short duration, and were positive or negative in polarity. Focal scalp EEG seizures were also recorded at the ipsilateral STN electrodes. In 3 patients SEPs were recorded from the contralateral STN electrodes corresponding to the P14/N18 far-field complex. In two patients AEPs were recorded, and wave V (near-field) and wave VII (far-field) from the contralateral STN electrodes. CONCLUSIONS This study demonstrates that scalp recorded epileptiform activity is reflected at the ipsilateral STN either following or preceding the scalp sharp waves. The STN sharp waves are most probably an expression of the direct cortico-STN glutamatergic pathways that have been demonstrated previously in animals. This pathway in man may be important with regard to a possible mechanism for the treatment of epilepsy with STN stimulation.

Parieto-frontal network in humans studied by cortico-cortical evoked potential

Parieto‐frontal network is essential for sensorimotor integration in various complex behaviors, and its disruption is associated with pathophysiology of apraxia and visuo‐spatial disorders. Despite advances in knowledge regarding specialized cortical areas for various sensorimotor transformations, little is known about the underlying cortico‐cortical connectivity in humans. We investigated inter‐areal connections of the lateral parieto‐frontal network in vivo by means of cortico‐cortical evoked potentials (CCEPs). Six patients with epilepsy and one with brain tumor were studied. With the use of subdural electrodes implanted for presurgical evaluation, network configuration was investigated by tracking the connections from the parietal stimulus site to the frontal site where the maximum CCEP was recorded. It was characterized by (i) a near‐to‐near and distant‐to‐distant, mirror symmetric configuration across the central sulcus, (ii) preserved dorso‐ventral organization (the inferior parietal lobule to the ventral premotor area and the superior parietal lobule to the dorsal premotor area), and (iii) projections to more than one frontal cortical sites in 56% of explored connections. These findings were also confirmed by the standardized parieto‐frontal CCEP connectivity map constructed in reference to the Jülich cytoarchitectonic atlas in the MNI standard space. The present CCEP study provided an anatomical blueprint underlying the lateral parieto‐frontal network and demonstrated a connectivity pattern similar to non‐human primates in the newly developed inferior parietal lobule in humans. Hum Brain Mapp, 2012.