Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial.

BACKGROUND: Long-term loss of arm function after ischaemic stroke is common and might be improved by vagus nerve stimulation paired with rehabilitation. We aimed to determine whether this strategy is a safe and effective treatment for improving arm function after stroke. METHODS: In this pivotal, randomised, triple-blind, sham-controlled trial, done in 19 stroke rehabilitation services in the UK and the USA, participants with moderate-to-severe arm weakness, at least 9 months after ischaemic stroke, were randomly assigned (1:1) to either rehabilitation paired with active vagus nerve stimulation (VNS group) or rehabilitation paired with sham stimulation (control group). Randomisation was done by ResearchPoint Global (Austin, TX, USA) using SAS PROC PLAN (SAS Institute Software, Cary, NC, USA), with stratification by region (USA vs UK), age (≤30 years vs >30 years), and baseline Fugl-Meyer Assessment-Upper Extremity (FMA-UE) score (20-35 vs 36-50). Participants, outcomes assessors, and treating therapists were masked to group assignment. All participants were implanted with a vagus nerve stimulation device. The VNS group received 0·8 mA, 100 µs, 30 Hz stimulation pulses, lasting 0·5 s. The control group received 0 mA pulses. Participants received 6 weeks of in-clinic therapy (three times per week; total of 18 sessions) followed by a home exercise programme. The primary outcome was the change in impairment measured by the FMA-UE score on the first day after completion of in-clinic therapy. FMA-UE response rates were also assessed at 90 days after in-clinic therapy (secondary endpoint). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT03131960. FINDINGS: Between Oct 2, 2017, and Sept 12, 2019, 108 participants were randomly assigned to treatment (53 to the VNS group and 55 to the control group). 106 completed the study (one patient for each group did not complete the study). On the first day after completion of in-clinic therapy, the mean FMA-UE score increased by 5·0 points (SD 4·4) in the VNS group and by 2·4 points (3·8) in the control group (between group difference 2·6, 95% CI 1·0-4·2, p=0·0014). 90 days after in-clinic therapy, a clinically meaningful response on the FMA-UE score was achieved in 23 (47%) of 53 patients in the VNS group versus 13 (24%) of 55 patients in the control group (between group difference 24%, 6-41; p=0·0098). There was one serious adverse event related to surgery (vocal cord paresis) in the control group. INTERPRETATION: Vagus nerve stimulation paired with rehabilitation is a novel potential treatment option for people with long-term moderate-to-severe arm impairment after ischaemic stroke. FUNDING: MicroTransponder.

Surgical Neuromodulation of Tinnitus: A Review of Current Therapies and Future Applications.

INTRODUCTION: Tinnitus is the conscious perception of an auditory sensation in the absence of external stimulus. Proposed theories are based on neuroplastic changes that occur due to sensory deprivation. The authors review the relevant literature on functional imaging and neuromodulation of tinnitus and describe potential targets for deep brain stimulation (DBS). MATERIALS AND METHODS: A MEDLINE keyword and Medical Subject Heading term literature search was performed using PubMed for tinnitus, neuromodulation, DBS, transcranial magnetic stimulation, epidural electrode stimulation, intradural electrode stimulation, functional imaging, and connectivity. Data from these reports were extracted and reviewed. RESULTS: Multiple imaging studies are employed to understand the pathophysiology of tinnitus. Abnormal regions and altered connectivity implicated in tinnitus include auditory pathway and limbic structures. Neuromodulation attempts to correct this hyperexcitable state by disrupting these aberrant oscillations and returning activity to baseline. Applied treatment modalities include transcranial magnetic stimulation, epidural/intradural electrode stimulation, and DBS. More recently, modulation of autonomic pathways through vagus nerve stimulation and paired auditory sounds has demonstrated tinnitus improvement via plasticity changes. CONCLUSIONS: DBS shows much promise as a therapeutic option for tinnitus. Stimulation of the auditory pathway, particularly the medial geniculate body, could counteract thalamocortical dysrhythmias and reduce gamma activity implicated in the tinnitus percept. Stimulation of the limbic pathway could decrease attention to and perception of tinnitus. Additional studies, focusing on the involvement of thalamic and limbic structures in the pathophysiology of tinnitus, are needed to support the use of DBS.

History and Future of Spinal Cord Stimulation.

Spinal cord stimulation (SCS) is a surgical treatment for chronic neuropathic pain refractory to medical management. An SCS system comprised one or more leads implanted in the epidural space, typically connected to an implantable pulse generator. This review discusses the history, indications, surgical technique, technological advances, and future directions of SCS.

Healthcare disparities in deep brain stimulation access and utilization: a systematic review.

OBJECTIVE: Since FDA approval of deep brain stimulation (DBS) for essential tremor over 2 decades ago, indications and utilization of this modality have rapidly expanded worldwide. However, certain patient populations are known to be underrepresented among those undergoing DBS for various indications. METHODS: A systematic search was conducted using PubMed and Embase for disparities related to DBS care. Any retrospective or prospective study addressing inequalities related to DBS were included for qualitative analysis. Additionally, all clinical trials and DBS studies with at least 100 patients were also included to evaluate for demographic disparities in the DBS literature. RESULTS: Of the 5192 screened articles, 43 were included. The authors found that female gender, minority race, geographic barriers, low socioeconomic status, and the presence of multiple comorbidities are all linked to the underutilization of DBS. Analysis of demographic data from large-scale DBS studies and clinical trials revealed that females and Black patients continue to be underrepresented in the DBS literature and among those receiving DBS therapy. CONCLUSIONS: As the indications and utilization continue to grow, addressing healthcare disparities related to DBS has become increasingly important. The authors suggest that increasing patient and provider education, expanding the role of telemedicine within DBS care, and improving support services for DBS patients may improve access and utilization.

Vagus Nerve Stimulation Paired With Rehabilitation for Upper Limb Motor Impairment and Function After Chronic Ischemic Stroke: Subgroup Analysis of the Randomized, Blinded, Pivotal, VNS-REHAB Device Trial.

BACKGROUND: Vagus Nerve Stimulation (VNS) paired with rehabilitation improved upper extremity impairment and function in a recent pivotal, randomized, triple-blind, sham-controlled trial in people with chronic arm weakness after stroke. OBJECTIVE: We aimed to determine whether treatment effects varied across candidate subgroups, such as younger age or less injury. METHODS: Participants were randomized to receive rehabilitation paired with active VNS or rehabilitation paired with sham stimulation (Control). The primary outcome was the change in impairment measured by the Fugl-Meyer Assessment Upper Extremity (FMA-UE) score on the first day after completion of 6-weeks in-clinic therapy. We explored the effect of VNS treatment by sex, age (≥62 years), time from stroke (>2 years), severity (baseline FMA-UE score >34), paretic side of body, country of enrollment (USA vs UK) and presence of cortical involvement of the index infarction. We assessed whether there was any interaction with treatment. FINDINGS: The primary outcome increased by 5.0 points (SD 4.4) in the VNS group and by 2.4 points (SD 3.8) in the Control group (P = .001, between group difference 2.6, 95% CI 1.03-4.2). The between group difference was similar across all subgroups and there were no significant treatment interactions. There was no important difference in rates of adverse events across subgroups. CONCLUSION: The response was similar across subgroups examined. The findings suggest that the effects of paired VNS observed in the VNS-REHAB trial are likely to be consistent in wide range of stroke survivors with moderate to severe upper extremity impairment.

Evaluation of DBS Timeline in Movement Disorders: A Comparison Between Genders.

BACKGROUND: Deep brain stimulation (DBS) is a pivotal surgical treatment for movement disorders. However, men and women have had differing opinions and referral experiences related to DBS, leading us to assess whether a gender disparity exists in the interval from a movement disorder diagnosis to DBS usage. METHODS: We performed a single-center, retrospective cohort study of 105 patients who had undergone DBS surgery for either Parkinson disease (PD) or essential tremor (ET). We compared gender differences in the median interval between the diagnosis date, DBS consultation date, and DBS surgery dates. Additionally, the patient demographics, baseline clinical characteristics, and DBS outcomes were compared between men and women. RESULTS: We found no significant differences between genders in the interval from the diagnosis to DBS surgery for ET or PD. At the DBS consultation for ET, the women had had significantly greater disease severity compared with the men (P = 0.029). The baseline motor impairment without medication was similar between the men and women with PD. However, female patients with PD had experienced a significantly greater reduction compared with male patients in baseline motor impairment with medication versus without medication (P = 0.042). No minority populations were represented within the female ET and PD subgroups. CONCLUSIONS: Our study detected no gender differences in the DBS implantation timeline but alluded to a gender-specific discrepancy in DBS referral for ET. The female patients did not have a shorter duration from the ET diagnosis to DBS, despite experiencing significantly greater baseline ET severity compared with their male counterparts. Furthermore, the women with ET more often used Medicaid insurance and were without minority representation.

Closed-Loop Systems in Neuromodulation: Electrophysiology and Wearables.

Most currently available neuromodulation techniques for pain work through an open-loop system. The distance between the epidural space and the target of the stimulation in a dynamic body can change because of physiologic conditions. The closed-loop system in spinal cord neuromodulation consists of an integrated system that records real-time electrophysiological activity in the form of evoked compound action potentials and uses it in a feedback mechanism to adjust stimulus output. Wearables represent newly developed technologies that have gained traction in recent years. Their application in pain management is still developing but promising.

Emerging Trends in Neuromodulation for Treatment of Drug-Resistant Epilepsy.

Epilepsy is a neurological disorder that affects more than 70 million people globally. A considerable proportion of epilepsy is resistant to anti-epileptic drugs (AED). For patients with drug-resistant epilepsy (DRE), who are not eligible for resective or ablative surgery, neuromodulation has been a palliative option. Since the approval of vagus nerve stimulation (VNS) in 1997, expansion to include other modalities, such as deep brain stimulation (DBS) and responsive neurostimulation (RNS), has led to improved seizure control in this population. In this article, we discuss the current updates and emerging trends on neuromodulation for epilepsy.

Jamestown Canyon Virus (JCV) Encephalitis Mimicking Acute Stroke in Michigan: A Case Report and Review of the Literature.

Jamestown canyon virus (JCV) is an arbovirus and is an under-recognized cause of mosquito-borne viral encephalitis. In this report we present a patient who presented with focal neurological deficits. Patient was initially evaluated for stroke. However, leptomeningeal enhancement on MRI and CSF studies were concerning for viral encephalitis. Brain biopsy and CSF sample from surgical site was positive for JCV IgM antibodies. Patients presenting with concern for viral encephalitis in endemic areas should undergo antibody testing for JCV to guide appropriate treatment.

Speaker Gender Representation at the North American Neuromodulation Society Annual Meeting (2017-2021): Have We Made Progress in Closing the Gender Gap?

Background: Speaker gender representation at medical conferences is a significant site of gender disparity. Our primary objective was to quantify the proportion of female speakers and compare plenary session opportunities by gender at the North American Neuromodulation Society (NANS) Annual Conference. Methods: Data from the 2017-2021 NANS Annual Conference presentations were abstracted. Primary outcomes included gender composition of speaker slots, gender composition of individual speakers, and comparison of plenary speaker slots by gender. Secondary outcomes included comparisons of session size, age, professional degree, and number of presentations per speaker based on gender. Results: Gender composition of annual speaker slots was (% slots presented by women): 2017:14.6%; 2018:20.5%; 2019:23.5%; 2020:21.0%; 2021:41.4%. Annual gender composition of individual speakers was (% women): 2017:18.7%; 2018:20.6%; 2019:24.6%; 2020:24.9%; 2021:33.8%. Of all speaker slots, the percentage of plenary slots did not differ based on gender, with 11.4% presented by female speakers versus 11.2% presented by male speakers (OR 1.0, 95% CI 0.7-1.5, P=0.893). Compared to male speaker slots, there was an association of lower age (43.9±5.6 vs 50.8±8.9, P<0.001), lower odds of holding a single doctorate degree (OR 0.3, 95% CI 0.2-0.5, P<0.001), and lower odds of holding a dual MD/PhD or DO/PhD degree (OR 0.3, 95% CI 0.1-0.5, P<0.001) in female speaker slots. Compared to male speakers, there was an association of higher number of presentations per female speaker at the 2021 NANS Annual Meeting (2.48±1.60 vs 1.79±1.30, P=0.008). Conclusion: Although the volume of female speaker slots and individual speakers trailed behind their male counterparts, female speaker representation steadily increased at each subsequent annual NANS meeting. We identified no difference in plenary session slots based on gender.

Vagus nerve stimulation paired with rehabilitation for stroke: Implantation experience from the VNS-REHAB trial.

OBJECTIVE: Vagus Nerve Stimulation (VNS) paired with rehabilitation delivered by the Vivistim® Paired VNS™ System was approved by the FDA in 2021 to improve motor deficits in chronic ischemic stroke survivors with moderate to severe arm and hand impairment. Vagus nerve stimulators have previously been implanted in over 125,000 patients for treatment-resistant epilepsy and the surgical procedure is generally well-tolerated and safe. In this report, we describe the Vivistim implantation procedure, perioperative management, and complications for chronic stroke survivors enrolled in the pivotal trial. METHODS: The pivotal, multisite, randomized, triple-blind, sham-controlled trial (VNS-REHAB) enrolled 108 participants. All participants were implanted with the VNS device in an outpatient procedure. Thrombolytic agents were temporarily discontinued during the perioperative period. Participants were discharged within 48 hrs and started rehabilitation therapy approximately 10 days after the Procedure. RESULTS: The rate of surgery-related adverse events was lower than previously reported for VNS implantation for epilepsy and depression. One participant had vocal cord paresis that eventually resolved. There were no serious adverse events related to device stimulation. Over 90% of participants were taking antiplatelet drugs (APD) or anticoagulants and no adverse events or serious adverse events were reported as a result of withholding these medications during the perioperative period. CONCLUSIONS: This study is the largest, randomized, controlled trial in which a VNS device was implanted in chronic stroke survivors. Results support the use of the Vivistim System in chronic stroke survivors, with a safety profile similar to VNS implantations for epilepsy and depression.

B-cell lymphoma of the brainstem with central neurogenic hyperventilation.

Non-Hodgkin's lymphoma of the brainstem is a rare entity. Central Neurogenic Hyperventilation (CNH), an associated manifestation of this disease, is an even rarer event. We report a case of an immunocompetent individual who presented to us with tachypnea and facial nerve palsy. Neuroimaging showed a Cerebellopontine angle tumour which on histopathology showed feature consistent with a Non-Hodgkin's B-Cell Lymphoma. The patient went on to develop severe respiratory alkalosis with findings consistent with CNH. Chemotherapy with Methotrexate was started and high dose Dexamethasone was added to the regimen a month later. Radiologically, the tumour size decreased by 50% but the patient's clinical condition deteriorated. He eventually expired due to cardiopulmonary arrest. Some common clinical presentations of this disease and various diagnostic modalities and treatment options available to such patients are discussed.

Experience From 211 Transcortical Selective Amygdalohippocampectomy Procedures: Relevant Surgical Anatomy and Review of the Literature.

BACKGROUND: Selective amygdalohippocampectomy (SelAH) is designed to treat medically refractory mesial temporal lobe epilepsy with reduced morbidity compared to standard anterior temporal lobectomy. At our institution, we perform SelAH via a transcortical approach via small corticectomy in the middle temporal gyrus. OBJECTIVE: To discuss the surgical anatomy and nuances of SelAH, share our institutional experience, and perform a review of literature. METHODS: Institutional experience was recorded by collecting demographic and outcome data from 1999 to 2017 under an Institutional Review Board protocol in a prospective manner using a REDCap database. RESULTS: A total of 211 SelAH procedures were performed at our institution between 1999 and 2017. Of these patients, 54% (113/211) were females. The average age at surgery was 39.4 yr. Two-year Engel outcome data were available for 168 patients, of which 73% (123/168) had Engel I outcomes. Engel II outcomes were reported in 16.6% (28/168), III in 4.7% (8/168), and IV in 5.3% (9/168). Our review of literature showed that this is comparable to the seizure freedom rates reported by other groups. We then reviewed our surgical methodology based on operative reports and created illustrations of the surgical anatomy of temporal lobe approach. These illustrations were compared with postoperative magnetic resonance imaging to provide a better 3D understanding of the complex architecture of mesial temporal structures. CONCLUSION: SelAH is a minimally invasive, safe, and effective approach for the treatment of medically refractory epilepsy with good surgical outcomes and low morbidity. We feel that mastering the complex anatomy of this approach helps achieve successful outcomes.

Craniocerebral aspergillosis: a review of advances in diagnosis and management.

Craniocerebral aspergillosis is a rare but dangerous central nervous system infection. The infection has a spectrum of presenting features, mostly affecting immunocompromised individuals. The incidence appears to be on the rise that has been especially observed in the immunocompetent population. A high index of suspicion, a comprehensive understanding of the infectious process and advanced laboratory and radiological diagnostic techniques, allow early diagnosis. Surgery, followed by systemic antifungal medications, remains the cornerstone of management. Early administration of empirical anti-fungal agents along with immunomodulators may further improve prognosis. Immunocompetent patients tend to have better outcomes as compared to those who are immunocompromised. Patients with intradural disease carry the worst prognosis.

Concurrent Placement of Bilateral Suboccipital and Supraorbital Nerve Stimulators Using On-Q* Tunneler: Technical Note.

BACKGROUND: Stimulation of the occipital and supraorbital nerves is used to treat chronic migraine refractory to medical management. Placement of cranial leads is often challenging due to the rigid Touhy needle included in the kit for its placement. OBJECTIVE: To report the first case of concurrent placement of bilateral supraorbital (SNS) and occipital nerve stimulators (ONS) from a unilateral approach using the On-Q* Tunneler, (Halyard Health, Alpharetta, Georgia) a flexible, blunt tipped plastic tunneler with a tear-away sheath. METHODS: We present the case of a 49-yr-old female with debilitating daily holocephalic headaches who underwent placement of SNS and ONS through a cervical and left temporal incision at an outside hospital. She presented to our institution with purulent drainage from the temporal incision and the system was removed. We describe an alternative approach to bilateral SNS and ONS placement with a soft flexible tunneling device, which facilitated placement of the entire system through a right temporal incision, thereby avoiding her previously infected surgical sites. RESULTS: The patient reported complete resolution of her daily headaches and was able to resume her activities as a full-time student. CONCLUSION: The flexibility of the On-Q tunneler device (Halyard Health) allows the placement of bilateral SNS and ONS from a unilateral incision, thereby minimizing the cosmetic effect and infectious risk of this procedure.

Novel Technique for Insertion of Cervical Spinal Cord Stimulator Percutaneous Leads: Technical Note and Institutional Experience.

OBJECTIVE: Cervical spinal cord stimulation is a safe and effective treatment for chronic axial neck pain and upper limb neuropathic pain. We report our novel institutional experience with performing cervical spinal cord stimulation trials with patients placed in an upright sitting position. This allows easy access to the cervical epidural space and has the added benefit of unobstructed access to the airway. METHODS: We retrospectively reviewed data for patients who had undergone cervical spinal cord stimulation trial procedures in an upright, sitting position at the Vanderbilt University Medical Center. Demographic information including age, gender, preoperative diagnosis, progression to permanent implant after a successful trial, and operative time in minutes was collected. RESULTS: A detailed description of the technique for implantation of cervical spinal cord stimulator trial leads in an upright sitting position is described. A total of 29 patients were implanted; 16 (55%) were female. Mean operative time was 78 minutes from incision to closing. The majority of patients (25/29; 86%) had successful trials and proceeded to permanent implant. No complications occurred, and the procedure was well tolerated by all patients. CONCLUSIONS: Cervical spinal cord stimulation trials performed in an upright, sitting position allow for easy epidural access and an unobstructed airway with reasonable setup time.

Use of social media to assess the effectiveness of vagal nerve stimulation in Dravet syndrome: A caregiver's perspective.

BACKGROUND: Dravet syndrome (DS) is a rare genetic epilepsy syndrome which is particularly pharmacoresistant. Vagus nerve stimulation (VNS) is commonly used in the treatment of DS as an adjunct to medical therapy. A meaningful assessment of post-surgical outcomes with VNS is difficult given the rarity of the condition. OBJECTIVE: In a novel approach, we used social media to contact patients with DS to gather data on post-surgical seizure reduction and overall satisfaction with VNS. METHODS: A survey consisting of 10 questions was posted to a social media webpage for a DS support group moderated by the Dravet Syndrome Foundation. The results were analyzed and percentages reported using the integrated SurveyMonkey analytical software. RESULTS: 49 responses were received. We found that 28.5% of patients had a >50% reduction in seizure frequency after VNS placement, 55.8% felt that VNS therapy had helped to reduce seizure frequency, and 83.7% felt that seizure severity had improved. Of the respondents, 75% felt that they would undergo VNS implantation again for similar outcomes. CONCLUSIONS: We employed the novel technique of using social media to gather the largest set of self-reported outcomes of VNS therapy for Dravet syndrome. As corroborated by prior studies of VNS effectiveness in Dravet syndrome, there is significant albeit limited improvement in seizure control. Our study shows that despite this limitation, it is still considered a useful treatment adjunct from a caregiver's perspective.

Ictal Cardiac Ryhthym Abnormalities.

Cardiac rhythm abnormalities in the context of epilepsy are a well-known phenomenon. However, they are under-recognized and often missed. The pathophysiology of these events is unclear. Bradycardia and asystole are preceded by seizure onset suggesting ictal propagation into the cortex impacting cardiac autonomic function, and the insula and amygdala being possible culprits. Sudden unexpected death in epilepsy (SUDEP) refers to the unanticipated death of a patient with epilepsy not related to status epilepticus, trauma, drowning, or suicide. Frequent refractory generalized tonic-clonic seizures, anti-epileptic polytherapy, and prolonged duration of epilepsy are some of the commonly identified risk factors for SUDEP. However, the most consistent risk factor out of these is an increased frequency of generalized tonic-clonic seizures (GTC). Prevention of SUDEP is extremely important in patients with chronic, generalized epilepsy. Since increased frequency of GTCS is the most consistently reported risk factor for SUDEP, effective seizure control is the most important preventive strategy.