The value of additional electrodes when stereo-electroencephalography is inconclusive.

OBJECTIVE: Stereo-electroencephalography (SEEG) is the preferred method for intracranial localization of the seizure-onset zone (SOZ) in drug-resistant focal epilepsy. Occasionally SEEG evaluation fails to confirm the pre-implantation hypothesis. This leads to a decision tree regarding whether the addition of SEEG electrodes (two-step SEEG - 2sSEEG) or placement of subdural electrodes (SDEs) after SEEG (SEEG2SDE) would help. There is a dearth of literature encompassing this scenario, and here we aimed to characterize outcomes following unplanned two-step intracranial EEG (iEEG). METHODS: All 225 adult SEEG cases over 8 years at our institution were reviewed to extract patient data and outcomes following a two-step evaluation. Three raters independently quantified benefits of additional intracranial electrodes. The relationship between two-step iEEG benefit and clinical outcome was then analyzed. RESULTS: Fourteen patients underwent 2sSEEG and nine underwent SEEG2SDE. In the former cohort, the second SEEG procedure was performed for these reasons-precise localization of the SOZ (36%); defining margins of eloquent cortex (21%); and broadening coverage in the setting of non-localizable seizure onsets (43% of cases). Sixty-four percent of 2sSEEG cases were consistently deemed beneficial (Light's κ = 0.80). 2sSEEG performed for the first two indications was much more beneficial than when onsets were not localizable (100% vs 17%, p = .02). In the SEEG2SDE cohort, SDEs identified the SOZ and enabled delineation of margins relative to eloquent cortex in all cases. SIGNIFICANCE: The two-step iEEG is useful if the initial evaluation is broadly concordant with the original electroclinical hypothesis, where it can clarify onset zones or delineate safe surgical margins; however, it provides minimal benefit when the implantation hypothesis is erroneous, and we recommend that 2sSEEG not be generally utilized in such cases. SDE implantation after SEEG minimizes the need for SDEs and is helpful in delineating surgical boundaries relative to ictal-onset zones and eloquent cortex.

Kindling in humans: Does secondary epileptogenesis occur?

The relevance of secondary epileptogenesis for human epilepsy remains a controversial subject decades after it was first described in animal models. Whether or not a previously normal brain region can become independently epileptogenic through a kindling-like process has not, and cannot, be definitely proven in humans. Rather than reliance on direct experimental evidence, attempts to answering this question must depend on observational data. In this review, observations based largely upon contemporary surgical series will advance the case for secondary epileptogenesis in humans. As will be argued, hypothalamic hamartoma-related epilepsy provides the strongest case for this process; all the stages of secondary epileptogenesis can be observed. Hippocampal sclerosis (HS) is another pathology where the question of secondary epileptogenesis frequently arises, and observations from bitemporal and dual pathology series are explored. The verdict here is far more difficult to reach, in large part because of the scarcity of longitudinal cohorts; moreover, recent experimental data have challenged the claim that HS is acquired consequent to recurrent seizures. Synaptic plasticity more than seizure-induced neuronal injury is the likely mechanism of secondary epileptogenesis. Postoperative running-down phenomenon provides the best evidence that a kindling-like process occurs in some patients, evidenced by its reversal. Finally, a network perspective of secondary epileptogenesis is considered, as well as the possible role for subcortical surgical interventions.

Can the Oral Bioavailability of the Discontinued Prostate Cancer Drug Galeterone Be Improved by Processing Method? KinetiSol® Outperforms Spray Drying in a Head-to-head Comparison.

Galeterone, a novel prostate cancer candidate treatment, was discontinued after a Phase III clinical trial due to lack of efficacy. Galeterone is weakly basic and exhibits low solubility in biorelevant media (i.e., ~ 2 µg/mL in fasted simulated intestinal fluid). It was formulated as a 50-50 (w/w) galeterone-hypromellose acetate succinate spray-dried dispersion to increase its bioavailability. Despite this increase, the bioavailability of this formulation may have been insufficient and contributed to its clinical failure. We hypothesized that reformulating galeterone as an amorphous solid dispersion by KinetiSol® compounding could increase its bioavailability. In this study, we examined the effects of composition and manufacturing technology (Kinetisol and spray drying) on the performance of galeterone amorphous solid dispersions. KinetiSol compounding was utilized to create galeterone amorphous solid dispersions containing the complexing agent hydroxypropyl-ß-cyclodextrin or hypromellose acetate succinate with lower drug loads that both achieved a ~ 6 × increase in dissolution performance versus the 50-50 spray-dried dispersion. When compared to a spray-dried dispersion with an equivalent drug load, the KinetiSol amorphous solid dispersions formulations exhibited ~ 2 × exposure in an in vivo rat study. Acid-base surface energy analysis showed that the equivalent composition of the KinetiSol amorphous solid dispersion formulation better protected the weakly basic galeterone from premature dissolution in acidic media and thereby reduced precipitation, inhibited recrystallization, and extended the extent of supersaturation during transit into neutral intestinal media.

Pre-Processing a Polymer Blend into a Polymer Alloy by KinetiSol Enables Increased Ivacaftor Amorphous Solid Dispersion Drug Loading and Dissolution.

This study compares the effects of pre-processing multiple polymers together to form a single-phase polymer alloy prior to amorphous solid dispersion formulation. KinetiSol compounding was used to pre-process a 1:1 (w/w) ratio of hypromellose acetate succinate and povidone to form a single-phase polymer alloy with unique properties. Ivacaftor amorphous solid dispersions comprising either a polymer, an unprocessed polymer blend, or the polymer alloy were processed by KinetiSol and examined for amorphicity, dissolution performance, physical stability, and molecular interactions. A polymer alloy ivacaftor solid dispersion with a drug loading of 50% w/w was feasible versus 40% for the other compositions. Dissolution in fasted simulated intestinal fluid revealed that the 40% ivacaftor polymer alloy solid dispersion reached a concentration of 595 µg/mL after 6 h, 33% greater than the equivalent polymer blend dispersion. Fourier transform infrared spectroscopy and solid-state nuclear magnetic resonance revealed changes in the ability of the povidone contained in the polymer alloy to hydrogen bond with the ivacaftor phenolic moiety, explaining the differences in the dissolution performance. This work demonstrates that the creation of polymer alloys from polymer blends is a promising technique that provides the ability to tailor properties of a polymer alloy to maximize the drug loading, dissolution performance, and stability of an ASD.

Safety and efficacy of bihemispheric sampling via transmidline stereoelectroencephalography.

OBJECTIVE: Stereoelectroencephalography (SEEG) is designed to target distributed cortical networks responsible for electroclinical seizure syndrome and to enable localization of the site of seizure onset in patients with intractable epilepsy. When the preimplantation hypothesis invokes the bilateral mesial frontal lobes, sampling of several deep-seated cortical sites in both hemispheres is required. In this study, the authors have demonstrated the feasibility of sampling bihemispheric areas with intentional implantation of an SEEG electrode crossing the midline (SECM) for sampling the cortex on both sides of the interhemispheric fissure. METHODS: An analysis of 231 consecutive SEEG procedures over 8 years was used to identify instances of bihemispheric sampling by using the transmidline SEEG technique. RESULTS: The authors identified 53 SEEG cases, with a total of 126 electrodes that crossed the interhemispheric fissure; all were in the frontal lobes. Eighty-three electrodes targeted the cingulate gyrus (18 rostral, 43 anterior, and 22 middle), 31 targeted the posterior orbitofrontal region, 8 sampled the medial prefrontal cortex, and 4 targeted nodular heterotopia around the frontal horns. The ictal onset zone was localized to the frontal lobe in 16 cases. SECM isolated interictal and ictal activity in the contralateral hemisphere in 6 cases and independent bihemispheric seizure activity in 2 cases. No hemorrhagic or infectious complications were noted in any of these cases. CONCLUSIONS: Based on this extensive experience of bihemispheric sampling, the authors concluded that this technique is safe and effective. In this series, SECM showed contralateral interictal and/or ictal epileptiform activity in 8 (15%) cases, and 9 (16%) cases (with unilateral implantation) had sufficient data to discard contralateral involvement, contributing to support of the epileptogenic network. SECM may reduce the number of electrodes used to sample bilateral mesial frontal or orbitofrontal cortices, and such an approach may lower the risk of hemorrhage and costs.

Increasing Drug Loading of Weakly Acidic Telmisartan in Amorphous Solid Dispersions through pH Modification during Hot-Melt Extrusion.

Oral drug therapy requiring large quantities of active pharmaceutical ingredients (APIs) can cause a substantial pill burden, which can increase nonadherence and worsen healthcare outcomes. Maximizing the drug loading of APIs in oral dosage forms is essential to reduce pill burden. This can be challenging for poorly water-soluble APIs without compromising performance. We show a promising strategy for maximizing the drug loading of pH-dependent APIs in amorphous solid dispersions (ASDs) produced by hot-melt extrusion (HME) without compromising their dissolution performance. We examine potential increases in the drug loading (w/w) of telmisartan in ASDs by incorporating bases to modify pH during HME. Telmisartan is a weakly acidic, poorly water-soluble API with pH-dependent solubility. It is practically insoluble at physiological pH, but its solubility increases exponentially at pH values above 10. Telmisartan was extruded with the polymer Soluplus and various bases. With no base, the maximum drug loading achieved by extrusion was only 5% before crystalline telmisartan was detected. Including a strong, water-soluble base (NaOH or KOH) increased the maximum amorphous drug loading to 50%. These results indicate that telmisartan has pH-dependent solubility in a molten polymer, similar to that in an aqueous solution. We also examine the stability of Soluplus when extruded with a strong base, using solid-state nuclear magnetic resonance (ssNMR) to determine that NaOH (but not KOH) causes degradation by hydrolysis. Supersaturation was maintained for at least 20 h during dissolution testing of a 50% telmisartan ASD in biorelevant media.

Specific mechanical energy - An essential parameter in the processing of amorphous solid dispersions.

Specific mechanical energy (SME) is a frequently overlooked but essential parameter of hot-melt extrusion (HME). It can determine whether an amorphous solid dispersion (ASD) can be successfully processed. A minimum combination of thermal input and SME is required to convert a crystalline active pharmaceutical product (API) into its amorphous form. A maximum combination is allowed before it or the carrier polymer chemically degrades. This has important implications on design space. SME input during HME provides information on the totality of the effect of various independent processing parameters such as screw speed, feed rate, and complex viscosity. If only these independent processing parameters are considered separately instead of SME, then important information would be lost regarding the interaction of these parameters and their ability to affect ASD formulation. A complete understanding of the HME process requires an analysis of SME. This paper provides a review of SME use in the pharmaceutical processing of ASDs, the importance of SME in terms of a variety of formulation qualities, and novel future uses of SME. Theoretical background is discussed, along with the relative importance of thermal and mechanical input on various nonsolvent ASD processing methods.

Ternary Amorphous Solid Dispersions Containing a High-Viscosity Polymer and Mesoporous Silica Enhance Dissolution Performance†.

The aim of this study was to evaluate the benefits of a ternary amorphous solid dispersion (ASD) that was designed as an immediate-release tablet with a high drug load (e.g., 40% w/w) to produce heightened maintenance of drug supersaturation during dissolution testing, which will be henceforth referred to as the "maintenance ability". Ternary ASD granules were produced by hot melt extrusion (HME) and were comprised of itraconazole (ITZ) 50%, hypromellose (HPMC) 20%, and mesoporous silica (XDP) 30%, where amorphous ITZ incorporated into HPMC was efficiently absorbed in XDP pores. The ternary ASD granules containing a high-viscosity HPMC (AF4M) produced a significantly heightened maintenance ability of drug supersaturation in neutral pH dissolution media in which crystalline ITZ solubility is below 1 µg/mL. The final tablet formulation contained 80% w/w of the ASD granules (40% w/w ITZ), had an acceptable size, and exhibited both sufficient tablet hardness and disintegration. The dissolution behavior of the ternary ASD tablet exhibited a supersaturation maintenance ability similar to that of the ASD granules. Under neutral conditions, the ternary ASD tablet showed immediate and higher ITZ release compared with the binary ASD tablets, and this phenomenon could be explained by the difference in ITZ/AF4M particle size in the tablet. In high-resolution scanning electron microscopy (SEM), it was observed that ITZ and AF4M in the ternary formulation could easily form nano-sized particles (<1 µm) during the absorption process into/onto XDP pores prepared by HME, which contributed to the immediate ITZ release from the ternary ASD tablet under neutral pH conditions. Therefore, the ternary ASD containing high-viscosity HPMC and mesoporous silica prepared by HME made it possible to design a high ASD content, small-size tablet with an ideal dissolution profile in biorelevant media, and we expect that this technology can be applied for continuous HME ASD manufacturing.

Analysis of Morbidity and Outcomes Associated With Use of Subdural Grids vs Stereoelectroencephalography in Patients With Intractable Epilepsy.

Importance: A major change has occurred in the evaluation of epilepsy with the availability of robotic stereoelectroencephalography (SEEG) for seizure localization. However, the comparative morbidity and outcomes of this minimally invasive procedure relative to traditional subdural electrode (SDE) implantation are unknown. Objective: To perform a comparative analysis of the relative efficacy, procedural morbidity, and epilepsy outcomes consequent to SEEG and SDE in similar patient populations and performed by a single surgeon at 1 center. Design, Setting and Participants: Overall, 239 patients with medically intractable epilepsy underwent 260 consecutive intracranial electroencephalographic procedures to localize their epilepsy. Procedures were performed from November 1, 2004, through June 30, 2017, and data were analyzed in June 2017 and August 2018. Interventions: Implantation of SDE using standard techniques vs SEEG using a stereotactic robot, followed by resection or laser ablation of the seizure focus. Main Outcomes and Measures: Length of surgical procedure, surgical complications, opiate use, and seizure outcomes using the Engel Epilepsy Surgery Outcome Scale. Results: Of the 260 cases included in the study (54.6% female; mean [SD] age at evaluation, 30.3 [13.1] years), the SEEG (n = 121) and SDE (n = 139) groups were similar in age (mean [SD], 30.1 [12.2] vs 30.6 [13.8] years), sex (47.1% vs 43.9% male), numbers of failed anticonvulsants (mean [SD], 5.7 [2.5] vs 5.6 [2.5]), and duration of epilepsy (mean [SD], 16.4 [12.0] vs17.2 [12.1] years). A much greater proportion of SDE vs SEEG cases were lesional (99 [71.2%] vs 53 [43.8%]; P < .001). Seven symptomatic hemorrhagic sequelae (1 with permanent neurological deficit) and 3 infections occurred in the SDE cohort with no clinically relevant complications in the SEEG cohort, a marked difference in complication rates (P = .003). A greater proportion of SDE cases resulted in resection or ablation compared with SEEG cases (127 [91.4%] vs 90 [74.4%]; P < .001). Favorable epilepsy outcomes (Engel class I [free of disabling seizures] or II [rare disabling seizures]) were observed in 57 of 75 SEEG cases (76.0%) and 59 of 108 SDE cases (54.6%; P = .003) amongst patients undergoing resection or ablation, at 1 year. An analysis of only nonlesional cases revealed good outcomes in 27 of 39 cases (69.2%) vs 9 of 26 cases (34.6%) at 12 months in SEEG and SDE cohorts, respectively (P = .006). When considering all patients undergoing evaluation, not just those undergoing definitive procedures, favorable outcomes (Engel class I or II) for SEEG compared with SDE were similar (57 of 121 [47.1%] vs 59 of 139 [42.4%] at 1 year; P = .45). Conclusions and Relevance: This direct comparison of large matched cohorts undergoing SEEG and SDE implantation reveals distinctly better procedural morbidity favoring SEEG. These modalities intrinsically evaluate somewhat different populations, with SEEG being more versatile and applicable to a range of scenarios, including nonlesional and bilateral cases, than SDE. The significantly favorable adverse effect profile of SEEG should factor into decision making when patients with pharmacoresistant epilepsy are considered for intracranial evaluations.

Development and Phantom Validation of a 3-D-Ultrasound-Guided System for Targeting MRI-Visible Lesions During Transrectal Prostate Biopsy.

OBJECTIVE: Three- and four-dimensional transrectal ultrasound transducers are now available from most major ultrasound equipment manufacturers, but currently are incorporated into only one commercial prostate biopsy guidance system. Such transducers offer the benefits of rapid volumetric imaging, but can cause substantial measurement distortion in electromagnetic tracking sensors, which are commonly used to enable 3-D navigation. In this paper, we describe the design, development, and validation of a 3-D-ultrasound-guided transrectal prostate biopsy system that employs high-accuracy optical tracking to localize the ultrasound probe and prostate targets in 3-D physical space. METHODS: The accuracy of the system was validated by evaluating the targeted needle placement error after inserting a biopsy needle to sample planned targets in a phantom using standard 2-D ultrasound guidance versus real-time 3-D guidance provided by the new system. RESULTS: The overall mean needle-segment-to-target distance error was 3.6 ± 4.0 mm and mean needle-to-target distance was 3.2 ± 2.4 mm. CONCLUSION: A significant increase in needle placement accuracy was observed when using the 3-D guidance system compared with visual targeting of invisible (virtual) lesions using a standard B-mode ultrasound-guided biopsy technique.

Intracranial evaluation and laser ablation for epilepsy with periventricular nodular heterotopia.

Surgical treatment of focal epilepsy in the presence of periventricular nodular heterotopia (PVNH) poses a challenge, as the relative roles of the nodular tissue and the overlying cortex in the generation of seizures can be complex and variable. Here, we review the literature on chronic invasive EEG recordings in humans with this substrate and present two illustrative cases from our practice. We found that while inter-ictal spiking from nodules is common, clinical seizures rarely arise solely from nodular tissue. More typically, ictal onset is simultaneous with overlying neocortex or mesial temporal structures. Surgical outcome is more favorable in cases with unilateral (as opposed to bilateral) PVNH, and when a substantial or complete ablation of PVNH is performed. In rare cases, nodular ablation alone may be sufficient, as may be completed by MRI-guided laser interstitial thermal therapy. The mechanism(s) by which PNVH interacts with overlying cortex are not fully understood, but we suggest that PVNH either orchestrates or amplifies local network epileptogenicity. At present, invasive recordings with penetrating depth electrodes are required prior to surgical therapy, as illustrated in our cases.

Highly Epileptiform Bursts Are Associated With Seizure Recurrence.

PURPOSE: Pharmacologic sedation is often used to induce burst suppression in cases of refractory status epilepticus, but there is little evidence to guide the weaning of sedation. Similarly, the morphologic feature of bursts is of unknown clinical relevance. Recently, the standardized American Clinical Neurophysiology Society terminology of critical care EEG introduced the term highly epileptiform bursts (HEBs). Knowing the association of HEBs with seizure may direct the therapy for refractory status epilepticus. METHODS: Consecutive adult patients classified as having burst suppression were identified in our EEG database. Those of an anoxic etiology were excluded. Available EEG records were reviewed, both visually and quantitatively, for the presence of burst suppression. Using the American Clinical Neurophysiology Society terminology, burst suppression was dichotomized into HEBs or nonepileptiform bursts. Periods of transition out of burst suppression were identified, and whether burst suppression was followed by seizure or a continuous slow EEG within 24 hours was determined. RESULTS: Twenty-four patients were identified with a burst suppression pattern followed by either seizure or a continuous slow EEG within 24 hours, with some patients having multiple (maximal 5) transitions out of burst suppression, for a total of 33 examples of burst suppression. HEBs were associated with subsequent seizure (P = 0.0001), independent of medication exposure. CONCLUSIONS: Whether or not HEBs are indeed predictive of recurrent seizure or may be used to direct the therapy for status epilepticus, specifically the weaning of anesthetic medications, requires further prospective study in a larger cohort of patients.

Interictal Infraslow Activity in Stereoelectroencephalography: From Focus to Network.

PURPOSE: Infraslow activity (ISA) occurring during the interictal state in focal epilepsy is largely unstudied. In this exploratory analysis, the authors aimed to characterize features of interictal ISA in a cohort of patients studied by stereoelectroencephography. METHODS: The interictal stereoelectroencephography records for 15 consecutive adult patients were retrospectively analyzed, after application of both conventional (1.6-70 Hz) and infraslow (0.01-0.1 Hz) bandpass filters. Visual analysis was complemented by time-frequency analysis to quantify the change in ISA power over hours. Linear correlation coefficient (R) calculations were used to map interictal connectivity in the infraslow band. RESULTS: Interictal ISA background fluctuations were present throughout the interictal state in all patients, manifesting as recurrent and stereotyped oscillations. These oscillations had an apparent modulatory effect on conventional-band activities and spikes ("spike-crested oscillations"). In the infraslow band, the correlations between electrode contacts were shown to have a stable structure over time. CONCLUSIONS: Infraslow activity exists as a fundamental component of wideband cortical dynamics in focal epilepsy, with features suggestive of scale-free (1/f) dynamics: evidence of phase-amplitude coupling and functional connectivity in the infraslow band. Rather than viewed as a focal paroxysmal activity, interictal ISA may be better understood as a network process, although this requires further study.

Auditory aura in frontal opercular epilepsy: sounds from afar.

Auditory auras are typically considered to localize to the temporal neocortex. Herein, we present two cases of frontal operculum/perisylvian epilepsy with auditory auras. Following a non-invasive evaluation, including ictal SPECT and magnetoencephalography, implicating the frontal operculum, these cases were evaluated with invasive monitoring, using stereoelectroencephalography and subdural (plus depth) electrodes, respectively. Spontaneous and electrically-induced seizures showed an ictal onset involving the frontal operculum in both cases. A typical auditory aura was triggered by stimulation of the frontal operculum in one. Resection of the frontal operculum and subjacent insula rendered one case seizure- (and aura-) free. From a hodological (network) perspective, we discuss these findings with consideration of the perisylvian and insular network(s) interconnecting the frontal and temporal lobes, and revisit the non-invasive data, specifically that of ictal SPECT.

A novel pathway for regulation of glucose-dependent insulinotropic polypeptide (GIP) receptor expression in beta cells.

Glucose-dependent insulinotropic polypeptide (GIP) is secreted postprandially and acts in concert with glucose to stimulate insulin secretion from the pancreas. Here, we describe a novel pathway for the regulation of GIP receptor (GIPR) expression within clonal beta-cell lines, pancreatic islets, and in vivo. High (25 mM) glucose was able to significantly reduce GIPR mRNA levels in INS(832/13) cells after only 6 h. In contrast, palmitic acid (2 mM) and WY 14643 (100 microM) stimulated approximate doublings of GIPR expression in INS(832/13) cells under low (5.5 mM), but not high (25 mM), glucose conditions, suggesting that fat can regulate GIPR expression via PPARalpha in a glucose-dependent manner. Both MK-886, an antagonist of PPARalpha, and a dominant negative form of PPARalpha transfected into INS(832/13) cells caused a significant reduction in GIPR expression in low, but not high, glucose conditions. Finally, in hyperglycemic clamped rats, there was a 70% reduction in GIPR expression in the islets and a 71% reduction in GIP-stimulated insulin secretion from the perfused pancreas. Thus, evidence is presented that the GIPR is controlled at normoglycemia by the fatty acid load on the islet; however, when exposed to hyperglycemic conditions, the GIPR is down-regulated, which may contribute to the decreased responsiveness to GIP that is observed in type 2 diabetes.