Withdrawal of antiepileptic drugs after stereotactic laser amygdalohippocampotomy for mesial temporal lobe epilepsy.

OBJECTIVE: This retrospective study investigated the success rate of withdrawal of antiepileptic drugs (AEDs) following stereotactic laser amygdalohippocampotomy (SLAH) for mesial temporal lobe epilepsy (MTLE), and identified predictors of seizure recurrence. MATERIALS AND METHODS: We retrospectively assessed 65 patients who underwent SLAH for MTLE (59 lesional). Patients' demographics, disease characteristics and post-surgical outcomes were evaluated for their potential to predict seizure recurrence associated with withdrawal of AEDs. RESULTS: The mean period of observation post SLAH was 51 months (range 12-96 months) and the mean period to initial reduction of AEDs was 21 months (range 12-60 months). Reduction of AEDs was attempted in 37 patients (57 %) who were seizure free post SLAH and it was successful in approximately 2/3 of them. From the remainder 1/3 who relapsed, nearly all regained seizure control after reinstitution of their AEDs. The likelihood of relapse after reduction of AEDs was predicted only by pre-operative seizure frequency. At the end of the observation period, approximately 14 % of all SLAH patients were seizure free without AEDs and approximately 54 % remained seizure free on AEDs. Compared with preoperative status, the number of AEDs were reduced in 37 % of patients, unchanged in 51 % of them and increased in 12 % of them. CONCLUSIONS: Successful SLAH for MTLE allows for reduction of AEDs in a significant portion of patients and complete withdrawal of AEDs in a subset of them. Patients with higher pre-operative seizure frequency exhibit a greater chance of relapse post reduction of AEDs.

MRI-guided stereotactic laser corpus callosotomy for epilepsy: distinct methods and outcomes.

OBJECTIVE: Several small series have described stereotactic MRI-guided laser interstitial thermal therapy for partial callosotomy of astatic and generalized tonic-clonic (GTC) seizures, especially in association with Lennox-Gastaut syndrome. Larger case series and comparison of distinct stereotactic methods for stereotactic laser corpus callosotomy (SLCC), however, are currently lacking. The objective of this study was to report seizure outcomes in a series of adult patients with epilepsy following anterior, posterior, and complete SLCC procedures and to compare the results achieved with a frameless stereotactic surgical robot versus direct MRI guidance frames. METHODS: The authors retrospectively reviewed sequential adult epilepsy surgery patients who underwent SLCC procedures at a single institution. They describe workflows, stereotactic errors, percentage disconnection, hospitalization durations, adverse events, and seizure outcomes after performing anterior, posterior, and complete SLCC procedures using a frameless stereotactic surgical robot versus direct MRI guidance platforms. RESULTS: Thirteen patients underwent 15 SLCC procedures. The median age at surgery was 29 years (range 20-49 years), the median duration of epilepsy was 21 years (range 9-48 years), and median postablation follow-up was 20 months (range 4-44 months). Ten patients underwent anterior SLCC with a median 73% (range 33%-80%) midsagittal length of callosum acutely ablated. Following anterior SLCC, 6 of 10 patients achieved meaningful (> 50%) reduction of target seizures. Four patients underwent posterior (completion) SLCC following prior anterior callosotomy, and 1 patient underwent complete SLCC as a single procedure; 3 of these 5 patients experienced meaningful reduction of target seizures. Overall, 8 of 10 patients in whom astatic seizures were targeted and treated by anterior and/or posterior SLCC experienced meaningful improvement. SLCC procedures with direct MRI guidance (n = 7) versus a frameless surgical robot (n = 8) yielded median radial accuracies of 1.1 mm (range 0.2-2.0 mm) versus 2.4 mm (range 0.6-6.1 mm; p = 0.0011). The most serious adverse event was a clinically significant intraparenchymal hemorrhage in a patient who underwent the robotic technique. CONCLUSIONS: This is the largest reported series of SLCC for epilepsy to date. SLCC provides seizure outcomes comparable to open surgery outcomes reported in the literature. Direct MRI guidance is more accurate, which has the potential to reduce the risks of SLCC. Methodological advancements and larger studies are needed.

Case Series: Unilateral Amygdala Ablation Ameliorates Post-Traumatic Stress Disorder Symptoms and Biomarkers.

BACKGROUND: Post-traumatic stress disorder is a severe psychobiological disorder associated with hyperactivity of the amygdala, particularly on the right side. Highly selective laser ablation of the amygdalohippocampal complex is an effective neurosurgical treatment for medically refractory medial temporal lobe epilepsy that minimizes neurocognitive deficits relative to traditional open surgery. OBJECTIVE: To examine the impact of amygdalohippocampotomy upon symptoms and biomarkers of post-traumatic stress disorder. METHODS: Two patients with well-documented chronic post-traumatic stress disorder who subsequently developed late-onset epilepsy underwent unilateral laser amygdalohippocampotomy. Prospective clinical and neuropsychological measurements were collected in patient 1. Additional prospective measurements of symptoms and biomarkers were collected pre- and post-surgery in patient 2. RESULTS: After laser ablation targeting the nondominant (right) amygdala, both patients experienced not only reduced seizures, but also profoundly abated post-traumatic stress symptoms. Prospective evaluation of biomarkers in patient 2 showed robust improvements in hyperarousal symptoms, fear potentiation of the startle reflex, brain functional magnetic resonance imaging responses to fear-inducing stimuli, and emotional declarative memory. CONCLUSION: These observations support the emerging hypothesis that the right amygdala particularly perpetuates the signs and symptoms of post-traumatic stress disorder and suggests that focal unilateral amydalohippocampotomy can provide therapeutic benefit.

Cingulum stimulation enhances positive affect and anxiolysis to facilitate awake craniotomy.

BACKGROUND: Awake neurosurgery requires patients to converse and respond to visual or verbal prompts to identify and protect brain tissue supporting essential functions such as language, primary sensory modalities, and motor function. These procedures can be poorly tolerated because of patient anxiety, yet acute anxiolytic medications typically cause sedation and impair cortical function. METHODS: In this study, direct electrical stimulation of the left dorsal anterior cingulum bundle was discovered to reliably evoke positive affect and anxiolysis without sedation in a patient with epilepsy undergoing research testing during standard inpatient intracranial electrode monitoring. These effects were quantified using subjective and objective behavioral measures, and stimulation was found to evoke robust changes in local and distant neural activity. RESULTS: The index patient ultimately required an awake craniotomy procedure to confirm safe resection margins in the treatment of her epilepsy. During the procedure, cingulum bundle stimulation enhanced positive affect and reduced the patient's anxiety to the point that intravenous anesthetic/anxiolytic medications were discontinued and cognitive testing was completed. Behavioral responses were subsequently replicated in 2 patients with anatomically similar electrode placements localized to an approximately 1-cm span along the anterior dorsal cingulum bundle above genu of the corpus callosum. CONCLUSIONS: The current study demonstrates a robust anxiolytic response to cingulum bundle stimulation in 3 patients with epilepsy. TRIAL REGISTRATION: The current study was not affiliated with any formal clinical trial. FUNDING: This project was supported by the American Foundation for Suicide Prevention and the NIH.

Stereotactic laser amygdalohippocampotomy for mesial temporal lobe epilepsy.

OBJECTIVE: To evaluate the outcomes 1 year and longer following stereotactic laser amygdalohippocampotomy for mesial temporal lobe epilepsy in a large series of patients treated over a 5-year period since introduction of this novel technique. METHODS: Surgical outcomes of a consecutive series of 58 patients with mesial temporal lobe epilepsy who underwent the surgery at our institution with at least 12 months of follow-up were retrospectively evaluated. A subgroup analysis was performed comparing patients with and without mesial temporal sclerosis. RESULTS: One year following stereotactic laser amygdalohippocampotomy, 53.4% (95% confidence interval [CI] = 40.8-65.7%) of all patients were free of disabling seizures (Engel I). Three of 9 patients became seizure-free following repeat ablation. Subgroup analysis showed that 60.5% (95% CI = 45.6-73.7%) of patients with mesial temporal sclerosis were free of disabling seizures as compared to 33.3% (95% CI = 15.0-58.5%) of patients without mesial temporal sclerosis. Quality of Life in Epilepsy-31 scores significantly improved at the group level, few procedure-related complications were observed, and verbal memory outcome was better than historical open resection data. INTERPRETATION: In an unselected consecutive series of patients, stereotactic laser amygdalohippocampotomy yielded seizure-free rates for patients with mesial temporal lobe epilepsy lower than, but comparable to, the outcomes typically associated with open temporal lobe surgery. Analogous to results from open surgery, patients without mesial temporal sclerosis fared less well. This novel procedure is an effective minimally invasive alternative to resective surgery. In the minority of patients not free of disabling seizures, laser ablation presents no barrier to additional open surgery. Ann Neurol 2018;83:575-587.

Direct electrical stimulation of the amygdala enhances declarative memory in humans.

Emotional events are often remembered better than neutral events, a benefit that many studies have hypothesized to depend on the amygdala's interactions with memory systems. These studies have indicated that the amygdala can modulate memory-consolidation processes in other brain regions such as the hippocampus and perirhinal cortex. Indeed, rodent studies have demonstrated that direct activation of the amygdala can enhance memory consolidation even during nonemotional events. However, the premise that the amygdala causally enhances declarative memory has not been directly tested in humans. Here we tested whether brief electrical stimulation to the amygdala could enhance declarative memory for specific images of neutral objects without eliciting a subjective emotional response. Fourteen epilepsy patients undergoing monitoring of seizures via intracranial depth electrodes viewed a series of neutral object images, half of which were immediately followed by brief, low-amplitude electrical stimulation to the amygdala. Amygdala stimulation elicited no subjective emotional response but led to reliably improved memory compared with control images when patients were given a recognition-memory test the next day. Neuronal oscillations in the amygdala, hippocampus, and perirhinal cortex during this next-day memory test indicated that a neural correlate of the memory enhancement was increased theta and gamma oscillatory interactions between these regions, consistent with the idea that the amygdala prioritizes consolidation by engaging other memory regions. These results show that the amygdala can initiate endogenous memory prioritization processes in the absence of emotional input, addressing a fundamental question and opening a path to future therapies.

The effect of seizure focus on regional language processing areas.

PURPOSE: To determine the effect of seizure focus location within the left hemisphere on the expression of regional language dominance. METHODS: In this cross-sectional study we investigated 90 patients (mean age 23.3 ± 12.9 years) with left hemisphere focal epilepsy (mean age onset 11.7 ± 8.3 years). Eighteen patients had a frontal lobe focus and 72 had a temporal lobe focus (43 mesial; 29 neocortical). Subjects performed an auditory word definition language paradigm using 3 Tesla blood oxygen level dependent (BOLD) EPI functional magnetic resonance imaging (fMRI). Data were analyzed in SPM2. Regional laterality indices (LIs) for inferior frontal gyrus (IFG), and Wernicke's area (WA), were calculated using a bootstrap method. Categorical language dominance and mean LI were analyzed. KEY FINDINGS: Mean WA LI was lower for subjects with a mesial temporal focus compared with a frontal focus (p = 0.04). There was a greater proportion of atypical language in WA for subjects with a mesial temporal focus compared with a frontal focus (χ(2) = 4.37, p = 0.04). WA LI did not differ for subjects with a neocortical focus compared with a mesial focus or a frontal focus. Mean IFG LI and proportion of atypical language in IFG were similar across seizure focus groups. Age and age of onset were not correlated with mean laterality in WA or IFG. Epilepsy duration tended to be negatively correlated with WA LI (r = -0.18, p = 0.10), but not IFG LI. SIGNIFICANCE: Temporal lobe foci have wide-ranging effects on the distributed language system. In contrast, the effects of a frontal lobe focus appear restricted to anterior rather than posterior language processing areas.

Safety study of 50 Hz repetitive transcranial magnetic stimulation in patients with Parkinson's disease.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) has shown promising results in treating Parkinson's disease (PD), but the best values for rTMS parameters are not established. Fifty Hertz rTMS may be superior to 25 Hz rTMS investigated so far. The objective of this study was to determine if 50 Hz rTMS could be delivered safely in PD patients since current safety limits are exceeded. METHODS: Fifty Hertz rTMS was applied with a circular coil on the primary motor cortex (M1). Stimulation intensity was first tested at 60% rest motor threshold [RMT] and 0.5 s train duration and then increased in 0.5 s steps to 2 s, and by 10% steps to 90% RMT. Multi-channel electromyography (EMG) was recorded to control for signs of increasing time-locked EMG activity including correlates of the spread of excitation and after-discharges, or an increase of M1 excitability. Pre- and post-50 Hz rTMS assessments included EEG, Unified Parkinson Disease Rating Scale (UPDRS), Grooved Pegboard Test, Serial Reaction Time Task (SRTT), Folstein Mini-Mental Status Examination (MMSE) and Verbal Fluency to control for motor and cognitive side effects. RESULTS: Ten PD patients were investigated. Multi-channel EMG showed no signs of increased time-locked EMG activity including correlates of the spread of excitation and after-discharges, or increased M1 excitability in 9 patients. A PD patient with bi-temporal spikes in the pre-testing EEG had clinical and EMG correlates of spread of excitation at 90% RMT, but no seizure activity. Pre- and post-50 Hz assessment showed no changes. No adverse events were observed. Fifty Hertz rTMS was well tolerated except by 1 patient who wished to terminate the study due to facial muscle stimulation. CONCLUSION: Fifty Hertz rTMS at an intensity of 90% RMT for 2 s appears safe in patients with PD, but caution should be taken for patients with paroxysmal EEG activity. For this reason, comprehensive screening should include EEG before higher-frequency rTMS is applied. SIGNIFICANCE: This is the first study to investigate safety of 50 Hz rTMS in humans.

Intractable epilepsy in patients treated for childhood acute lymphocytic leukemia.

PURPOSE: In the 1970s and 80s, standard treatment for childhood acute lymphocytic leukemia (ALL) included both intrathecal methotrexate and whole-brain irradiation. During acute treatment, seizures were not uncommon. The development of intractable epilepsy years after treatment, however, has not been well described in the literature. We describe five patients who were treated for acute lymphocytic leukemia as children, who later developed intractable epilepsy. RESULTS: All of the patients were diagnosed with leukemia before age seven. Treatment included both whole-brain irradiation and intrathecal chemotherapy. All five received intrathecal methotrexate; in addition, two also received intrathecal cytosine arabinoside. The first seizure occurred at a mean of 7.5 years after diagnosis. Four patients have multiple seizure types, and all patients have been on multiple antiepileptic drugs. All five patients are cognitively impaired. CONCLUSIONS: Successful treatment for childhood leukemia may be followed by signs of late cerebral injury including intractable epilepsy. We propose that neurotoxicity resulting from exposure to intrathecal methotrexate and cranial irradiation may have contributed to the intractable epilepsy seen in our five patients.