Seizure freedom as an outcome in epilepsy treatment clinical trials.

Seizure freedom is recognized as the goal of epilepsy treatment by patients, families, and in treatment guidelines and is associated with notably improved quality of life. However, many studies of epilepsy treatments (including antiseizure medications/antiepileptic drugs, neurostimulation, and dietary therapies) fail to report data on seizure freedom. Even among studies that include this outcome, methods for defining and analyzing seizure freedom vary considerably. Thus, the available data are often difficult to interpret and comparisons between studies are particularly challenging. Although these issues had been identified over a decade ago, there remains a lack of clarity and standardized methods used in analyzing and reporting seizure freedom outcomes in studies of epilepsy treatments. In addition, it remains unclear whether short-term seizure freedom outcomes from pivotal clinical trials are predictive of longer-term seizure freedom outcomes for patients with treatment-refractory epilepsy. Ultimately, the limitations of the available data lead to the potential for misinterpretation and misunderstanding of seizure freedom outcomes associated with the spectrum of available treatments when examining treatment options for patients. Clearly defined outcome analyses of seizure freedom attainment and duration are essential in future clinical studies of treatment for seizures to guide treatment selection and modification for patients.

Epilepsy through the eyes of the media: A paradox of positive reporting and challenges of access to advanced neurotechnology.

OBJECTIVE: Media coverage of disorders and medical advancements can impact public perception regarding the riskiness, effectiveness, and accessibility of treatment options. We studied that coverage for epilepsy with a focus on surgical interventions and emerging neurotechnologies. METHODS: Epilepsy-related English language articles published through 2019 were retrieved from online International news media with a circulation of 80,000 or above. We used directed content analysis of news articles to code content into a priori categories both to identify salient themes and to characterize their valence. RESULTS: One hundred forty-six unique articles matched our search terms. Overall, there was a steady increase in epilepsy reporting over time, with a majority of articles published with a positive tone. Neuromodulation was the focus of over 50% of all the articles in the time points analyzed. Vagus nerve stimulation (VNS) and deep-brain stimulation (DBS) were discussed more prominently than other types of neurotechnological interventions; VNS was the neurotechnological focus in 39% of the pediatric articles; resective surgery was the focus in 34% of adult articles. Access, support, and epilepsy literacy were the central themes in the context of ethical, legal, and social issues. SIGNIFICANCE: News media can influence the trust that the public places in science and medicine, and by extension, influences health policy. As innovations in neurotechnology for epilepsy emerge, understanding of individual and societal values is essential to their beneficial evolution and translation to care.

Deep brain stimulation for cerebral palsy: where are we now?

Cerebral palsy (CP) is a complex disorder and children frequently have multiple impairments. Dystonia is a particularly frustrating impairment that interferes with rehabilitation and function and is difficult to treat. Of the available treatments, deep brain stimulation (DBS) has emerged as an option with the potential for large effect size in a subgroup of children. While brain stimulation has been used in CP for more than 40 years, modern devices and targeting methods are improving both the safety and efficacy of the procedure. Successful use of DBS depends on appropriate selection of patients, identification of effective neuroanatomical targets in each patient, careful neurosurgical procedure, and detailed follow-up evaluation and programming. The use of functional neurosurgery for neuromodulation in CP remains a technology in its infancy, but improving experience and knowledge are likely to make this one of the safest and most effective interventions for children with moderate-to-severe motor disorders. This review summarizes the current procedures for patient and target selection, and surgical implantation of DBS electrodes for CP. The history of DBS and future directions when used in secondary dystonia are also examined. WHAT THIS PAPER ADDS: Selection of candidates for deep brain stimulation (DBS) requires understanding of dystonia in cerebral palsy . DBS could become a first-line treatment option in some children.

ESTIMULACIÓN CEREBRAL PROFUNDA PARA LA PARÁLISIS CEREBRAL: ¿DÓNDE ESTAMOS AHORA?: La parálisis cerebral (PC) es un trastorno complejo y los niños con frecuencia tienen discapacidades múltiples. La distonía es un deterioro particularmente frustrante que interfiere con la rehabilitación y la función y es difícil de tratar. De los tratamientos disponibles, la estimulación cerebral profunda (DBS, por sus siglas en inglés - deep brain stimulation) ha surgido como una opción con el potencial de un gran tamaño de efecto en un subgrupo de niños. Si bien la estimulación cerebral se ha utilizado en PC durante más de 40 años, los dispositivos modernos y los métodos de detección están mejorando tanto la seguridad como la eficacia del procedimiento. El uso exitoso de la DBS depende de la selección apropiada de los pacientes, la identificación de objetivos neuroanatómicos efectivos en cada paciente, el procedimiento neuroquirúrgico cuidadoso y la evaluación y programación de seguimiento detalladas. El uso de la neurocirugía funcional para la neuromodulación en la PC sigue siendo una tecnología en su infancia, pero es probable que la mejora de la experiencia y los conocimientos hagan de esta una de las intervenciones más seguras y efectivas para los niños con trastornos motores de moderados a graves. Esta revisión resume los procedimientos actuales para la selección de pacientes y objetivos, y la implantación quirúrgica de electrodos DBS para PC. La historia de DBS y las direcciones futuras cuando se utilizan en la distonía secundaria también se examinan.

ESTIMULAÇÃO CEREBRAL PROFUNDA PARA PARALISIA CEREBRAL: ONDE ESTAMOS AGORA?: Paralisia cerebral (PC) é uma desordem complexa e crianças frequentemente apresentam múltiplas deficiências. A distonia é uma deficiência particularmente frustrante que interfere com a reabilitação e função, e é difícil de tratar. Dentre dos tratamentos disponíveis, a estimulação cerebral profunda (ECP) emergiu como uma opção com potencial de grande tamanho de efeito em um subgrupo de crianças. Embora a estimulação cerebral seja usada em PC há mais de 40 anos, dispositivos modernos e métodos de identificação de áreas alvo tem melhorado tanto a segurança quanto a eficácia do procedimento. O uso bem sucedido da ECP depende da seleção apropriada dos pacientes, identificação dos alvos neuroanatômicos efetivos para cada paciente, procedimento neurocirúrgico cuidadoso, e avaliação e programação detalhadas no acompanhamento. O uso de neurocirurgia funcional para neuromodulação em PC ainda é uma tecnologia iniciante, mas a crescente experiência e conhecimento provavelmente farão dela uma das mais seguras e efetivas intervenções para crianças com transtornos motores de moderados a severos. Esta revisão sintetiza os procedimentos atuais para seleção de pacientes e alvos, e a implantação cirúrgica de eletrodos de ECP para PC. A história da ECP e direções futuras, quando usados em distonia secundária, também são examinados.

Deep Brain Stimulation Results in Greater Symptomatic Improvement in Tourette Syndrome than Conservative Measures: A Meta-Analysis.

INTRODUCTION: Deep brain stimulation (DBS) has emerged as a safe and effective therapy for refractory Tourette syndrome (TS). Recent studies have identified several neural targets as effective in reducing TS symptoms with DBS, but, to our knowledge, none has compared the effectiveness of DBS with conservative therapy. METHODS: A literature review was performed to identify studies investigating adult patient outcomes reported as Yale Global Tic Severity Scale (YGTSS) scores after DBS surgery, pharmacotherapy, and psychotherapy. Data were pooled using a random-effects model of inverse variance-weighted meta-analysis (n = 168 for DBS, n = 131 for medications, and n = 154 for behavioral therapy). RESULTS: DBS resulted in a significantly greater reduction in YGTSS total score (49.9 ± 17.5%) than pharmacotherapy (22.5 ± 15.2%, p = 0.001) or psychotherapy (20.0 ± 11.3%, p < 0.001), with a complication (adverse effect) rate of 0.15/case, 1.13/case, and 0.60/case, respectively. CONCLUSION: Our data suggest that adult patients with refractory TS undergoing DBS experience greater symptomatic improvement with surprisingly low morbidity than can be obtained with pharmacotherapy or psychotherapy.

Pulse Width and Implantable Pulse Generator Longevity in Pallidal Deep Brain Stimulation for Dystonia: A Population-Based Comparative Effectiveness Study.

INTRODUCTION: A wide range of pulse widths (PWs) has been used in globus pallidus internus (GPi) deep brain stimulation (DBS) for dystonia. However, no specific PW has demonstrated clinical superiority, and the paradigm may differ among DBS centers. OBJECTIVE: To investigate how different paradigms of PWs in GPi DBS for dystonia affect implantable pulse generator (IPG) longevities and energy consumption. METHODS: Thirty-nine patients with dystonia treated with bilateral GPi DBS at 2 Swedish DBS centers from 2005 to 2015 were included. Different PW paradigms were used at the 2 centers, 60-90 µs (short PWs) and 450 µs (long PW), respectively. The frequency of IPG replacements, pulse effective voltage (PEV), IPG model, pre-/postoperative imaging, and clinical outcome based on the clinical global impression (CGI) scale were collected from the medical charts and compared between the 2 groups. RESULTS: The average IPG longevity was extended for the short PWs (1,129 ± 50 days) compared to the long PW (925 ± 32 days; χ2 = 12.31, p = 0.0005, log-rank test). IPG longevity correlated inversely with PEV (Pearson's r = -0.667, p < 0.0001). IPG longevities did not differ between Kinetra® and Activa® PC in the short (p = 0.319) or long PW group (p = 0.858). Electrode distances to the central sensorimotor region of the GPi did not differ between the short or long PW groups (p = 0.595). Pre- and postoperative CGI did not differ between groups. CONCLUSIONS: Short PWs were associated with decreased energy consumption and increased IPG longevity. These effects were not dependent on the IPG model or the anatomic location of the electrodes. PWs did not correlate with symptom severities or clinical outcomes. The results suggest that the use of short PWs might be more energy efficient and could therefore be preferred initially when programming patients with GPi DBS for dystonia.

Symptomatic Pneumocephalus after Deep Brain Stimulation Surgery: Report of 2 Cases.

BACKGROUND: Symptomatic pneumocephalus is an uncommon complication of cranial surgery. Reports of symptomatic pneumocephalus in deep brain stimulation (DBS) surgery are lacking, due to the rarity of this condition. The -authors describe 2 patients who experienced clinically significant intraparenchymal pneumocephalus as a consequence of DBS surgery and report their clinical presentations, treatments, and outcomes. Cases Descriptions: The first patient was a 69-year-old woman with Parkinson disease and the second was a 73-year-old woman with medically refractory essential tremor. Both patients underwent DBS implantation and developed focal neurological deficits in the days after surgery. In each case, immediate postoperative head computed tomography scans showed extra-axial pneumocephalus which redistributed on subsequent imaging along the dorsal length of the lead. For each patient, a second surgery was carried out to evacuate the pneumocephalus without lead removal. Clinical symptoms and radiological signs of intracranial air were resolved on the last follow-up. CONCLUSION: Symptomatic intraparenchymal pneumocephalus is a rare complication of DBS surgery which can be treated with surgical evacuation.

Subthalamic Gamma Knife Radiosurgery in Parkinson's Disease: A Cautionary Tale.

INTRODUCTION: Deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) has been shown to reliably improve several symptoms of Parkinson's disease (PD) in appropriately selected patients. Various factors may preclude patients from undergoing DBS and for them, non-invasive lesion-based therapies such as focused ultrasound and Gamma Knife (GK) radiosurgery may present a safer alternative. MATERIALS AND METHODS: Based on preliminary positive reports of STN GK for PD, we conducted a prospective, open-label, single-center, pilot study in PD patients deemed potential candidates for unilateral DBS based on their disease characteristics, but contraindicated due to age >74, an irreversible bleeding diathesis, or significant comorbid medical disease. Stereotactic MRI-guided GK radiosurgery was performed using a single 110- or 120-Gy dose targeting the STN contralateral to the more symptomatic extremity. Clinical follow-up and imaging assessed the safety and efficacy of the procedure over a 12-month period. RESULTS: Four PD patients with medication-refractory tremors and disabling dyskinesias underwent unilateral STN GK radiosurgery. Contraindications to DBS included high-risk comorbid cardiovas-cular disease in 3 patients and an irreversible bleeding diathesis in 1. There were no immediate post-procedural adverse events. One patient who underwent left STN GK radiosurgery developed right hemiparesis and dysarthria 7 months post-procedure followed by hospitalization at 9 months for bacterial endocarditis and liver failure from which he died. The remaining 3 patients were free of adverse events up to 12 months post-procedure and experienced a reduction in contralateral rigidity, bradykinesia, and tremor. Upon extended follow-up, 2 patients developed subacute worsening of gait. One died at 16 months due to complications of a fall whereas the other saw no change in gait up to 42 months post-procedure. All 3 patients with adverse events demonstrated a hyper-response in the targeted area on follow-up neuroimaging. DISCUSSION/CONCLUSION: Despite the potential for clinical improvement, our results suggest that unilateral STN GK radiosurgery should be approached cautiously in medically frail PD patients who may be at higher risk of GK hyper-response and neurologic complications.

Screening for Platelet Dysfunction and Use of Prophylactic Tranexamic Acid in Patients Undergoing Deep Brain Stimulation: A Retrospective Analysis of Incidence and Outcome of Intracranial Hemorrhage.

INTRODUCTION: The rate of intracranial hemorrhage (ICH) after deep brain stimulation (DBS) is between 1.5 and 6.1%, with prolonged deficits occurring in 0.4-2.5% of the patients. This retrospective study investigates whether the prophylactic administration of tranexamic acid (TA) to patients with abnormal platelet function detected preoperatively by platelet function analyzer (PFA) lowered the risk for an ICH event. METHODS: We performed a systematic review of the medical records of 485 consecutively admitted patients who underwent bilateral DBS surgery in a single-center university hospital setting between 2009 and 2018. The cohort was split into two groups. In one group, preoperative PFA screening was performed (n = 156, patients recruited from 2014 to 2018), and TA was administered if platelet function was abnormal. No preoperative PFA was performed in the second group (n = 359, patients recruited from 2009 to 2013). Both cohorts were analyzed for the occurrence of ICH, defined by (i) detection of ICH in routine postoperative magnetic resonance/computed tomography imaging or (ii) in non-routine imaging for the onset of new neurological symptoms. RESULTS: Fourteen of the 156 screened patients (9%) showed reproducible PFA-100 closure abnormalities (3 with von Willebrand disease, 11 with no identifiable cause of platelet dysfunction). Two of the 156 patients (1.3%) in this cohort revealed an ICH on imaging, 1 of whom (0.6%) exhibited a prolonged neurological deficit as a result of ICH. In the cohort without platelet testing, 11 of the 329 patients (3.3%) demonstrated ICH on imaging, of whom 5 (1.5%) suffered from a prolonged neurological deficit. CONCLUSION: In this retrospective study, the screening and the administration of TA appeared to lower the risk of an ICH by 1.8%. One patient with von Willebrand disease suffered an ICH despite TA treatment. A prospective study is needed to clarify the impact of platelet testing and TA administration on the of incidence ICH.

Dystonia and Parkinson's disease: What is the relationship?

Dystonia and Parkinson's disease are closely linked disorders sharing many pathophysiological overlaps. Dystonia can be seen in 30% or more of the patients suffering with PD and sometimes can precede the overt parkinsonism. The response of early dystonia to the introduction of dopamine replacement therapy (levodopa, dopamine agonists) is variable; dystonia commonly occurs in PD patients following levodopa initiation. Similarly, parkinsonism is commonly seen in patients with mutations in various DYT genes including those involved in the dopamine synthesis pathway. Pharmacological blockade of dopamine receptors can cause both tardive dystonia and parkinsonism and these movement disorders syndromes can occur in many other neurodegenerative, genetic, toxic and metabolic diseases. Pallidotomy in the past and currently deep brain stimulation largely involving the GPi are effective treatment options for both dystonia and parkinsonism. However, the physiological mechanisms underlying the response of these two different movement disorder syndromes are poorly understood. Interestingly, DBS for PD can cause dystonia such as blepharospasm and bilateral pallidal DBS for dystonia can result in features of parkinsonism. Advances in our understanding of these responses may provide better explanations for the relationship between dystonia and Parkinson's disease.

Pallidal and thalamic neural oscillatory patterns in tourette's syndrome.

OBJECTIVE: Aberrant oscillatory activity has been hypothesized to play a role in the pathophysiology of Tourette's syndrome (TS). Deep brain stimulation (DBS) has recently been established as an effective treatment for severe TS. Modulation of symptom-specific oscillations may underlie the mechanism of action of DBS and could be used for adaptive neuromodulation to improve therapeutic efficacy. The objective of this study was to demonstrate a pathophysiological association of pallidal and thalamic local field potentials (LFPs) with TS. METHODS: Nine medication-refractory TS patients were included in the study. Intracerebral LFPs were recorded simultaneously from bilateral pallidal and thalamic DBS electrodes. Spectral and temporal dynamics of pallidal and thalamic oscillations were characterized and correlated with preoperative Yale Global Tic Severity Scale (YGTSS) scores. RESULTS: Peaks of activity in the theta (3-12Hz) and beta (13-35Hz) were present in pallidal and thalamic recordings from all patients (3 women/6 men; mean age, 29.8 years) and coupled through coherence across targets. Presence of prolonged theta bursts in both targets was associated with preoperative motor tic severity. Total preoperative YGTSS scores (mean, 38.1) were correlated with pallidal and thalamic LFP activity using multivariable linear regression (R² = 0.96; p = 0.02). INTERPRETATION: Our findings suggest that pallidothalamic oscillations may be implicated in the pathophysiology of TS. Furthermore, our results highlight the utility of multisite and -spectral oscillatory features in severely affected patients for future identification and clinical use of oscillatory physiomarkers for adaptive stimulation in TS. Ann Neurol 2018;84:505-514.