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Spaceflight-associated neuro-ocular syndrome (SANS) involves unilateral or bilateral optic disc edema, widening of the optic nerve sheath, and posterior globe flattening. Owing to posterior globe flattening, it is hypothesized that microgravity causes a disproportionate change in intracranial pressure (ICP) relative to intraocular pressure. Countermeasures capable of reducing ICP include thigh cuffs and breathing against inspiratory resistance. Owing to the coupling of central venous pressure (CVP) and intracranial pressure, we hypothesized that both ICP and CVP will be reduced during both countermeasures. In four male participants (32 ± 13 yr) who were previously implanted with Ommaya reservoirs for treatment of unrelated clinical conditions, ICP was measured invasively through these ports. Subjects were healthy at the time of testing. CVP was measured invasively by a peripherally inserted central catheter. Participants breathed through an impedance threshold device (ITD, -7 cmH 2 O) to generate negative intrathoracic pressure for 5 min, and subsequently, wore bilateral thigh cuffs inflated to 30 mmHg for 2 min. Breathing through an ITD reduced both CVP (6 ± 2 vs. 3 ± 1 mmHg; P = 0.02) and ICP (16 ± 3 vs. 12 ± 1 mmHg; P = 0.04) compared to baseline, a result that was not observed during the free breathing condition (CVP, 6 ± 2 vs. 6 ± 2 mmHg, P = 0.87; ICP, 15 ± 3 vs. 15 ± 4 mmHg, P = 0.68). Inflation of the thigh cuffs to 30 mmHg caused no meaningful reduction in CVP in all four individuals (5 ± 4 vs. 5 ± 4 mmHg; P = 0.1), coincident with minimal reduction in ICP (15 ± 3 vs. 14 ± 4 mmHg; P = 0.13). The application of inspiratory resistance breathing resulted in reductions in both ICP and CVP, likely due to intrathoracic unloading. NEW & NOTEWORTHY Spaceflight causes pathological changes in the eye that may be due to the absence of gravitational unloading of intracranial pressure (ICP) under microgravity conditions commonly referred to as spaceflight-associated neuro-ocular syndrome (SANS), whereby countermeasures aimed at lowering ICP are necessary. These data show that impedance threshold breathing acutely reduces ICP via a reduction in central venous pressure (CVP). Whereas, acute thigh cuff inflation, a popular known spaceflight-associated countermeasure, had little effect on ICP and CVP.

Astronauts have presented with a constellation of visual changes referred to as spaceflight-associated neuro-ocular syndrome (SANS). However, neither have early markers of microgravity-induced optic remodeling been fully identified nor have countermeasures been developed. To identify early markers of SANS, we studied 10 subjects with optical coherence tomography and ultrasonography when upright and supine and again after 24 h of 6° head-down tilt (HDT) bed rest. Upon acute transition from the upright to the supine position, choroid area (2.24 ± 0.53 to 2.28 ± 0.52 mm 2 , P = 0.001) and volume (9.51 ± 2.08 to 9.73 ± 2.08 mm 3 , P = 0.002) increased. After 24 h of HDT bed rest, subfoveal choroidal thickness (372 ± 93 to 381 ± 95 µm, P = 0.02), choroid area (2.25 ± 0.52 to 2.33 ± 0.54 mm 2 , P = 0.08), and volume (9.64 ± 2.03 to 9.82 ± 2.08 mm 3 , P = 0.08) increased relative to the supine position. Subsequently, seven subjects spent 3 days in -6°HDT bed rest to assess whether low-level lower body negative pressure (LBNP) could prevent the observed choroidal engorgement during bed rest. Maintaining the -6° HDT position for 3 days caused choroid area (Δ0.11 mm 2 , P = 0.05) and volume (Δ0.45 mm 3 , P = 0.003) to increase. When participants also spent 8 h daily under -20 mmHg LBNP, choroid volume still increased, but substantially (40%) less than in the control trial (Δ0.27 mm 3 , P = 0.05). Moreover, the increase in choroid area was diminished (Δ0.03 mm 2 , P = 0.13), indicating that low-level LBNP attenuates the choroid expansion associated with 3 days of -6° HDT bed rest. These data suggest that low-level LBNP may be an effective countermeasure for SANS. NEW & NOTEWORTHY Choroid measurements appear to be sensitive to changes in gravitational gradients, as well as periods of head-down tilt (HDT) bed rest, suggesting that they are potential indicators of early ocular remodeling and could serve to evaluate the efficacy of countermeasures for SANS. Eight hours of lower body negative pressure (LBNP) daily attenuates the choroid expansion associated with 3 days of strict -6° HDT bed rest, indicating that LBNP may be an effective countermeasure for SANS.

Key Points: During long-term missions, some astronauts experience structural and functional changes of the eyes and brain which resemble signs/symptoms experienced by patients with intracranial hypertension. Weightlessness prevents the normal cerebral volume and pressure 'unloading' associated with upright postures on Earth, which may be part of the cerebral and ocular pathophysiology. By placing the lower body in a negative pressure device (LBNP) that pulls fluid away from cranial compartments, we simulated effects of gravity and significantly lowered pressure within the brain parenchyma and ventricle compartments. Application of incremental LBNP demonstrated a non-linear dose-response curve, suggesting 20 mmHg LBNP as the optimal level for reducing pressure in the brain without impairing cerebral perfusion pressure. This non-invasive method of reducing pressure in the brain holds potential as a countermeasure in space as well as having treatment potential for patients on Earth with traumatic brain injury or other pathology leading to intracranial hypertension., Abstract: Patients with elevated intracranial pressure (ICP) exhibit neuro-ocular symptoms including headache, papilloedema and loss of vision. Some of these symptoms are also present in astronauts during and after prolonged space-flight where lack of gravitational stress prevents daily lowering of ICP associated with upright posture. Lower body negative pressure (LBNP) simulates the effects of gravity by displacing fluid caudally and we hypothesized that LBNP would lower ICP without compromising cerebral perfusion. Ten cerebrally intact volunteers were included: six ambulatory neurosurgical patients with parenchymal ICP-sensors and four former cancer patients with Ommaya-reservoirs to the frontal horn of a lateral ventricle. We applied LBNP while recording ICP and blood pressure while supine, and during simulated intracranial hypertension by 15° head-down tilt. LBNP from 0 to 50 mmHg at increments of 10 mmHg lowered ICP in a non-linear dose-dependent fashion; when supine (n = 10), ICP was decreased from 15 ± 2 mmHg to 14 ± 4, 12 ± 5, 11 ± 4, 10 ± 3 and 9 ± 4 mmHg, respectively (P < 0.0001). Cerebral perfusion pressure (CPP), calculated as mean arterial blood pressure at midbrain level minus ICP, was unchanged (from 70 ± 12 mmHg to 67 ± 9, 69 ± 10, 70 ± 12, 72 ± 13 and 74 ± 15 mmHg; P = 0.02). A 15° head-down tilt (n = 6) increased ICP to 26 ± 4 mmHg, while application of LBNP lowered ICP (to 21 ± 4, 20 ± 4, 18 ± 4, 17 ± 4 and 17 ± 4 mmHg; P < 0.0001) and increased CPP (P < 0.01). An LBNP of 20 mmHg may be the optimal level to lower ICP without impairing CPP to counteract spaceflight-associated neuro-ocular syndrome in astronauts. Furthermore, LBNP holds clinical potential as a safe, non-invasive method for lowering ICP and improving CPP for patients with pathologically elevated ICP on Earth., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

OBJECTIVE Despite a hemorrhagic presentation, many patients with arteriovenous malformations (AVMs) do not require emergency resection. The timing of definitive management is not standardized in the cerebrovascular community. This study was designed to evaluate the safety of delaying AVM treatment in clinically stable patients with a new hemorrhagic presentation. The authors examined the rate of rehemorrhage or neurological decline in a cohort of patients with ruptured brain AVMs during a period of time posthemorrhage. METHODS Patients presenting to the authors' institution from January 2000 to December 2015 with ruptured brain AVMs treated at least 4 weeks posthemorrhage were included in this analysis. Exclusion criteria were ruptured AVMs that required emergency surgery involving resection of the AVM, prior treatment of AVM at another institution, or treatment of lesions within 4 weeks for other reasons (subacute surgery). The primary outcome measure was time from initial hemorrhage to treatment failure (defined as rehemorrhage or neurological decline as a direct result of the AVM). Patient-days were calculated from the day of initial rupture until the day AVM treatment was initiated or treatment failed. RESULTS Of 102 ruptured AVMs in 102 patients meeting inclusion criteria, 7 (6.9%) failed the treatment paradigm. Six patients (5.8%) had a new hemorrhage within a median of 248 days (interquartile range 33-1364 days). The total "at risk" period was 18,740 patient-days, yielding a rehemorrhage rate of 11.5% per patient-year, or 0.96% per patient-month. Twelve (11.8%) of 102 patients were found to have an associated aneurysm. In this group there was a single (8.3%) new hemorrhage during a total at-risk period of 263 patient-days until the aneurysm was secured, yielding a rehemorrhage risk of 11.4% per patient-month. CONCLUSIONS It is the authors' practice to rehabilitate patients after brain AVM rupture with a plan for elective treatment of the AVM. The present data are useful in that the findings quantify the risk of the authors' treatment strategy. These findings indicate that delaying intervention for at least 4 weeks after the initial hemorrhage subjects the patient to a low (< 1%) risk of rehemorrhage. The authors modified the treatment paradigm when a high-risk feature, such as an associated intracranial aneurysm, was identified.

Background: Deep brain stimulation (DBS) of the subcallosal cingulate white matter has shown promise as an intervention for patients with chronic, unremitting depression. To test the safety and efficacy of DBS for treatment-resistant depression, a prospective, randomised, sham-controlled trial was conducted., Methods: Participants with treatment-resistant depression were implanted with a DBS system targeting bilateral subcallosal cingulate white matter and randomised to 6 months of active or sham DBS, followed by 6 months of open-label subcallosal cingulate DBS. Randomisation was computer generated with a block size of three at each site before the site started the study. The primary outcome was frequency of response (defined as a 40% or greater reduction in depression severity from baseline) averaged over months 4-6 of the double-blind phase. A futility analysis was performed when approximately half of the proposed sample received DBS implantation and completed the double-blind phase. At the conclusion of the 12-month study, a subset of patients were followed up for up to 24 months. The study is registered at ClinicalTrials.gov, number NCT00617162., Findings: Before the futility analysis, 90 participants were randomly assigned to active (n=60) or sham (n=30) stimulation between April 10, 2008, and Nov 21, 2012. Both groups showed improvement, but there was no statistically significant difference in response during the double-blind, sham-controlled phase (12 [20%] patients in the stimulation group vs five [17%] patients in the control group). 28 patients experienced 40 serious adverse events; eight of these (in seven patients) were deemed to be related to the study device or surgery., Interpretation: This study confirmed the safety and feasibility of subcallosal cingulate DBS as a treatment for treatment-resistant depression but did not show statistically significant antidepressant efficacy in a 6-month double-blind, sham-controlled trial. Future studies are needed to investigate factors such as clinical features or electrode placement that might improve efficacy., Funding: Abbott (previously St Jude Medical)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Key Points: Astronauts have recently been discovered to have impaired vision, with a presentation that resembles syndromes of elevated intracranial pressure on Earth. Gravity has a profound effect on fluid distribution and pressure within the human circulation. In contrast to prevailing theory, we observed that microgravity reduces central venous and intracranial pressure. This being said, intracranial pressure is not reduced to the levels observed in the 90 deg seated upright posture on Earth. Thus, over 24 h in zero gravity, pressure in the brain is slightly above that observed on Earth, which may explain remodelling of the eye in astronauts., Abstract: Astronauts have recently been discovered to have impaired vision, with a presentation that resembles syndromes of elevated intracranial pressure (ICP). This syndrome is considered the most mission-critical medical problem identified in the past decade of manned spaceflight. We recruited five men and three women who had an Ommaya reservoir inserted for the delivery of prophylactic CNS chemotherapy, but were free of their malignant disease for at least 1 year. ICP was assessed by placing a fluid-filled 25 gauge butterfly needle into the Ommaya reservoir. Subjects were studied in the upright and supine position, during acute zero gravity (parabolic flight) and prolonged simulated microgravity (6 deg head-down tilt bedrest). ICP was lower when seated in the 90 deg upright posture compared to lying supine (seated, 4 ± 1 vs. supine, 15 ± 2 mmHg). Whilst lying in the supine posture, central venous pressure (supine, 7 ± 3 vs. microgravity, 4 ± 2 mmHg) and ICP (supine, 17 ± 2 vs. microgravity, 13 ± 2 mmHg) were reduced in acute zero gravity, although not to the levels observed in the 90 deg seated upright posture on Earth. Prolonged periods of simulated microgravity did not cause progressive elevations in ICP (supine, 15 ± 2 vs. 24 h head-down tilt, 15 ± 4 mmHg). Complete removal of gravity does not pathologically elevate ICP but does prevent the normal lowering of ICP when upright. These findings suggest the human brain is protected by the daily circadian cycles in regional ICPs, without which pathology may occur., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

Objective: To develop a process to improve patient outcomes from deep brain stimulation (DBS) surgery for Parkinson disease (PD), essential tremor (ET), and dystonia., Methods: We employed standard quality improvement methodology using the Plan-Do-Study-Act process to improve patient selection, surgical DBS lead implantation, postoperative programming, and ongoing assessment of patient outcomes., Results: The result of this quality improvement process was the development of a neuromodulation network. The key aspect of this program is rigorous patient assessment of both motor and non-motor outcomes tracked longitudinally using a REDCap database. We describe how this information is used to identify problems and to initiate Plan-Do-Study-Act cycles to address them. Preliminary outcomes data is presented for the cohort of PD and ET patients who have received surgery since the creation of the neuromodulation network., Conclusions: Careful outcomes tracking is essential to ensure quality in a complex therapeutic endeavor like DBS surgery for movement disorders. The REDCap database system is well suited to store outcomes data for the purpose of ongoing quality assurance monitoring., Competing Interests: The authors of this manuscript have the following competing interests: R.B. Dewey, III, BS reports no disclosures. P.E. O’Suilleabhain, MD reports grants from AVID. M. Sanghera, PhD reports no disclosures. N. Patel, MD reports grants from Adamas. P. Khemani, MD reports advisory boards with Lundbeck, honoraria from Lundbeck and Dallas School of Neuroscience and Sleep Medicine, and grants from NIH and Once Upon a Time Foundation. L.H. Lacritz, PhD reports advisory boards with Teva, honoraria from Omni hotel, John Peter Smith hospital, and Parkland hospital, and grants from NIH/NIA neurobiology of aging and the State of Texas, Texas Alzheimer's Research and Care Consortium. S. Chitnis, MD, PhD reports consultancies with Teva and Medtronic, advisory boards with Teva, honoraria from Teva, and grants from Teva, Medtronic, NIH, and Allergan. L. Whitworth, MD reports no disclosures. R.B. Dewey, Jr., MD reports consultancies with Teva, Acadia and Impax, advisory boards with Teva, Acadia, Lundbeck and Impax, honoraria from Teva, Acadia, Impax, Merz, US WorldMeds, Lundbeck, and UCB, and grants from NIH. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The number of brain metastases identified on diagnostic magnetic resonance imaging (MRI) is a key factor in consideration of stereotactic radiosurgery (SRS). However, additional lesions are often detected on high-resolution SRS-planning MRI. We investigated pre-treatment clinical characteristics that are associated with finding additional metastases at SRS. Patients treated with SRS for brain metastases between the years of 2009-2014 comprised the study cohort. All patients underwent frame-fixed, 1 mm thick MRI on the day of SRS. Patient, tumor, and treatment characteristics were analyzed for an association with increase in number of metastases identified on SRS-planning MRI. 289 consecutive SRS cases were analyzed. 725 metastases were identified on pre-treatment MRI and 1062 metastases were identified on SRS-planning MRI. An increase in the number of metastases occurred in 34 % of the cases. On univariate analysis, more than four metastases and the diameter of the largest lesion were significantly associated with an increase in number of metastases on SRS-planning MRI. When stratified by the diameter of the largest lesion into <2, 2-3, or ≥3 cm, additional metastases were identified in 37, 29, and 18 %, respectively. While this increase in the number of metastases is largely due to the difference in imaging technique, the number and size of the metastases were also associated with finding additional lesions. These clinical factors may be considered when determining treatment options for brain metastases.

DBS is a typically well-tolerated operation for treatment of Parkinson's disease, dystonia, and essential tremor (ET). Complications related to the surgical procedure and implanted hardware may occur. More commonly reported complications include hemorrhage, seizure, confusion, and infection. In this article, we report on a rare, but important, complication of DBS surgery, a brain cyst formation at the tip of the implanted ventralis intermedius nucleus (VIM) DBS lead in 2 patients who underwent the procedure at 2 different centers. The indication for surgery was debilitating ET, and in both cases, there was development of a delayed-onset neurological deficit associated with an internal capsule/thalamic cystic lesion formation located at the tip of the DBS lead. Case 1 presented within a few months post-DBS, whereas case 2 had a 10-mo delay to onset of symptoms. No clinical and radiological signs of infection were observed and both DBS systems were explanted with uneventful recovery.

Infiltrating astrocytomas and oligoastrocytomas of low to anaplastic grade (WHO grades II and III), in spite of being associated with a wide range of clinical outcomes, can be difficult to subclassify and grade by the current histopathologic criteria. Unlike oligodendrogliomas and anaplastic oligodendrogliomas that can be identified by the 1p/19q codeletion and the more malignant glioblastomas (WHO grade IV astrocytomas) that can be diagnosed solely based on objective features on routine hematoxylin and eosin sections, no such objective criteria exist for the subclassification of grade II-III astrocytomas and oligoastrocytomas (A+OA II-III). In this study, we evaluated the prognostic and predictive value of the stem cell marker nestin in adult A+OA II-III (n = 50) using immunohistochemistry and computer-assisted analysis on tissue microarrays. In addition, the correlation between nestin mRNA level and total survival was analyzed in the NCI Rembrandt database. The results showed that high nestin expression is a strong adverse prognostic factor for total survival (p = 0.0004). The strength of the correlation was comparable to but independent of the isocitrate dehydrogenase 1/2 (IDH 1/2) mutation status. Histopathological grading and subclassification did not correlate significantly with outcome, although the interpretation of this finding is limited by the fact that grade III tumors were treated more aggressively than grade II tumors. These results suggest that nestin level and IDH 1/2 mutation status are strong prognostic features in A+OA II-III and possibly more helpful for treatment planning than routine histopathological variables such as oligodendroglial component (astrocytoma vs. oligoastrocytoma) and WHO grade (grade II vs. III).

Some of the pelvic pain syndromes seem to have features of neurogenic inflammation and neuropathic pain in common. As opposed to being separate disease entities, they may represent a spectrum of clinical presentations of CRPS I of the pelvis. Sacral nerve root stimulation provides good symptomatic relief of pain and voiding dysfunction. The techniques of retrograde root stimulation may offer superior results with fewer complications and lead migrations when compared with other methods. Perhaps neuromodulation should be used earlier in the treatment paradigm for these disorders, before the potentially injurious procedures of hydrodistention, bladder installations, and cystectomies.

While spinal cord stimulation has commonly been carried out using percutaneous leads, these devices have limitations in cervical implants due to problems with positional stimulation and lead migration. Paddle leads, by virtue of their design, are more stable in their apposition to the neural elements; however, mid and lower cervical insertions have been associated with both acute and subacute spinal cord injuries. These complications are likely related to limitations in canal diameter, as paddle leads occupy a greater volume than percutaneous leads. At C1-C2, the space around the spinal cord is more generous, and thus allows greater room for insertion of leads. We report a series of patients treated with a technique for the implantation of a C1-C2 paddle electrode that capitalizes on this anatomy while still meeting the need for paresthetic overlap in patients with upper extremity pain syndromes. While the technique is not novel, it has not yet been popularized (1). This paper is presented to increase implanters' awareness of the method, its safety and utility. Twenty consecutive patients with neuropathic pain syndromes of the upper extremity were implanted using this technique. Surgical implantation of leads was done under a general anesthetic. An upper cervical incision was used, and after performing minimal laminotomies at C1 and C2, the lead was passed rostro-caudally under direct visualization beneath the lamina. Paresthetic overlap of pain segments was achieved in all but one patient. Pre and postoperative VAS scores were compared to evaluate effectiveness of treatment. Eighteen of 20 patients reported a significant benefit from stimulation, with an average of 63 percent reduction in pain scores. The only complication was a malpositioned lead that required reoperation to adjust placement. No patient suffered neurologic sequelae as a result of this procedure. We have found C1-C2 sublaminar insertions of paddle leads to be a safe and effective way of treating neuropathic pain phenomenon involving the upper extremity. To further assess the relative benefit over percutaneous leads, a prospective trial would be required.

Percutaneous retrograde lead insertion for sacral nerve root stimulation is a newly described technique being applied to a variety of pain disorders. The success of the procedure rests in a defined epidural space such that there is unimpeded progression of the lead into the desired location. It is hypothesized that any condition that results in anatomic compromise of the epidural space would prevent the success of the procedure. Two patients with biopsy-proven interstitial cystitis and intractable pain were referred to the senior author for evaluation. Percutaneous retrograde lead insertion for sacral nerve root stimulation was performed on these patients in a standard fashion (1,2). Intraoperative fluoroscopy verified the diagnosis of spina bifida occulta. In one patient, implantation was completed percutaneously, but later two of the leads were found to have been placed intradurally. In another patient, repeated attempts at passing the epidural lead distal to the congenital defect were unsuccessful, and the percutaneous procedure was aborted. In conclusion, we have found that the diagnosis of spina bifida occulta, or any other condition in which the epidural space is anatomically disrupted, is a relative contraindication for this procedure. Preoperative roentograms of the lumbar spine may be helpful in avoiding technical difficulties due to this diagnosis.