OBJECTIVE:This retrospective, single-center, descriptive case series evaluates early adoption of a two-stage spine MRI protocol incorporating high-resolution, three-dimensional mesoscale constructive interference in steady state (meso-CISS) for targeted cerebrospinal fluid (CSF) leak localization. BACKGROUND:Spontaneous intracranial hypotension (SIH) results from CSF leaks at the spinal canal, yet precise localization of dural defects remains challenging. Although fat-saturated heavily T2-weighted magnetic resonance (MR) myelography (HT2-MRM) is sensitive to spinal longitudinal extradural CSF collections (SLECs), it does not reliably localize the leak site. METHODS:Thirty-six consecutive patients with suspected SIH underwent a standardized total spine MRI protocol, including three-dimensional HT2-MRM for SLEC screening at Barnes-Jewish Hospital/Washington University School of Medicine between December 2023 and November 2025. In 11 SLEC-positive cases, meso-CISS was performed for targeted high-resolution leak localization. RESULTS:Among the 10 patients with SIH with interpretable meso-CISS imaging, findings consistent with dural defects were visualized in six (0.5-8 mm in size), with additional supportive features suggestive of dural defects identified in three patients. Compared with HT2-MRM, meso-CISS provided higher spatial detail, allowing clearer delineation of dural defects. CONCLUSION:A two-stage spine MRI protocol incorporating HT2-MRM and meso-CISS may aid in the noninvasive localization of dural defects in SIH. Meso-CISS provides high spatial resolution for visualization of small dural defects and associated pathology. Larger studies are required to clarify how this approach may be incorporated into existing diagnostic workflows for spinal CSF leak localization.

STUDY DESIGN:Prospective cohort study. OBJECTIVE:This study aims to define Substantial Clinical Benefit (SCB) thresholds for PROMIS physical function (PF) and pain interference (PI) in lumbar or thoracolumbar spine surgery population. SUMMARY OF BACKGROUND DATA:Patient-reported outcome measures (PROMs) are widely used in spine surgery to assess treatment efficacy. SCB is a relatively new concept that represents a substantial improvement perceived by the patient. METHODS:This is a prospective study that included adults aged 21-85 years, undergoing lumbar/ thoracolumbar surgery for degenerative spine disease, and reporting at least 3/10 back or leg pain on a numeric rating scale. PROMs including Oswestry Disability Index, PROMIS PF, and PROMIS PI were collected preoperatively and at one year postoperatively. The North American Spine Surgery Patient Satisfaction (NASS) Index was collected one year postoperatively. SCB thresholds of absolute and percentage changes were calculated using anchor-based methods with ODI and NASS index as anchors. ROC analysis was used to determine optimal SCB cutoffs. RESULTS:We included 137 patients. Using a fixed 19-point reduction in ODI as an anchor yielded SCB thresholds of 6.8 and 11.3 points for PROMIS PF and PI respectively. When using a dynamic anchor based on preoperative disability (50% ODI improvement), SCB thresholds were defined as achieving 18 and 27% of maximum possible improvement for PROMIS PF and PI respectively. Using NASS index, thresholds were 11 points or 24% for PROMIS PF, and 11.2 points or 21% for PROMIS PI. ROC values ranged from 0.81 to 0.9, with the dynamic ODI anchor cutoffs demonstrating the best discrimination. CONCLUSION:Our study is the first to define SCB thresholds for PROMIS PF and PROMIS PI using both fixed and dynamic cutoffs based on preoperative disability in lumbar and thoracolumbar patients. These thresholds will help in patient counseling and outcome evaluation for spine surgery research.

Sleep is a major driver of waste clearance from the brain, but the mechanisms underpinning brain cleansing during sleep, which are also important for immunological functions, are poorly understood. Recent mouse work by Hauglund et al. shows how oscillatory surges in norepinephrine (NE) during sleep drive vascular pulsation and cerebrospinal fluid (CSF) movement to cleanse the brain.

The flow of cerebrospinal fluid (CSF) is important for conveying brain-derived macromolecules for signaling and enabling them to be drained from the brain parenchyma. The glymphatic route is the best-characterized means of this CSF flow; however, it does not permit the movement of larger macromolecules. Here, we identify in mice an alternative route whereby intra-CSF-injected macromolecules can traverse from periarterial to perivenous spaces, with transfer occurring at sites of overlap between leptomeningeal perivascular (arteriovenous) spaces dispersed across the surface of the brain's leptomeninges. We show that intra-CSF-injected fluorescent tracers can reach the perivenous space by passing through these arteriovenous perivascular overlaps. These spaces remain functional in a mouse model of amyloidosis and are essential for clearing excess CSF volume. These anatomical structures may support brain function by allowing the drainage of brain-derived macromolecules and the shunting of excess fluid and by aiding the immune surveillance of freshly generated CSF.

Alzheimer's disease (AD) is characterized by the accumulation of extracellular aggregated amyloid beta, resulting from impaired waste clearance. We recently identified new cerebrospinal fluid (CSF) efflux structures termed arachnoid cuff exit (ACE) points and speculated that these may be impacted in AD, leading to impaired waste clearance function. Using 5XFAD mice, we found progressive amyloidosis of bridging veins at ACE points. Indeed, in 5XFAD mice, there is impaired CSF efflux to the dura mater, impaired CSF flow along bridging veins, and impaired blood flow through bridging veins. These observations suggest that ACE point amyloidosis plays a role in waste clearance dysfunction in AD. In postmortem human samples, we also found striking amyloidosis of the bridging veins of individuals with AD. Moreover, in human AD specimens, there was prominent bridging vein structural degeneration, indicating advanced pathology and stronger deficits in humans. We propose that bridging vein amyloidosis is an underrecognized pathophysiological correlate of AD that may impair CSF efflux, intracranial pressure, vascular reactivity, and vascular integrity.

Cervical spinal cord injury (SCI) causes devastating loss of upper limb function and independence. Restoration of upper limb function can have a profound impact on independence and quality of life. In low-cervical SCI (level C5-C8), upper limb function can be restored via reinnervation strategies such as nerve transfer surgery. The translation of recovered upper limb motor function into functional independence in activities of daily living (ADLs), however, remains unknown in low cervical SCI (i.e., tetraplegia). The objective of this study was to evaluate the association of patterns in upper limb motor recovery with functional independence in ADLs. This will then inform prioritization of reinnervation strategies focused to maximize function in patients with tetraplegia. This retrospective study performed a secondary analysis of patients with low cervical (C5-C8) enrolled in the SCI Model Systems (SCIMS) database. Baseline neurological examinations and their association with functional independence in major ADLs-i.e., eating, bladder management, and transfers (bed/wheelchair/chair)-were evaluated. Motor functional recovery was defined as achieving motor strength, in modified research council (MRC) grade, of >= 3 /5 at one year from <= 2/5 at baseline. The association of motor function recovery with functional independence at one-year follow-up was compared in patients with recovered elbow flexion (C5), wrist extension (C6), elbow extension (C7), and finger flexion (C8). A multi-variable logistic regression analysis, adjusting for known factors influencing recovery after SCI, was performed to evaluate the impact of motor function at one year on a composite outcome of functional independence in major ADLs. Composite outcome was defined as functional independence measure score of 6 or higher (complete independence) in at least two domains among eating, bladder management, and transfers. Between 1992 and 2016, 1090 patients with low cervical SCI and complete neurological/functional measures were included. At baseline, 67% of patients had complete SCI and 33% had incomplete SCI. The majority of patients were dependent in eating, bladder management, and transfers. At one-year follow-up, the largest proportion of patients who recovered motor function in finger flexion (C8) and elbow extension (C7) gained independence in eating, bladder management, and transfers. In multi-variable analysis, patients who had recovered finger flexion (C8) or elbow extension (C7) had higher odds of gaining independence in a composite of major ADLs (odds ratio [OR] = 3.13 and OR = 2.87, respectively, p < 0.001). Age 60 years (OR = 0.44, p = 0.01), and complete SCI (OR = 0.43, p = 0.002) were associated with reduced odds of gaining independence in ADLs. After cervical SCI, finger flexion (C8) and elbow extension (C7) recovery translate into greater independence in eating, bladder management, and transfers. These results can be used to design individualized reinnervation plans to reanimate upper limb function and maximize independence in patients with low cervical SCI.

Study Design: A narrative review. Objective: To summarize relevant data from representative studies investigating upper limb restorative therapies for cervical spinal cord injury. Summary of Background Data: Cervical spinal cord injury (SCI) is a debilitating condition resulting in tetraplegia, lifelong disability, and reduced quality of life. Given the dependence of all activities on hand function, patients with tetraplegia rank regaining hand function as one of their highest priorities. Recovery from cervical SCI is heterogeneous and often incomplete; currently, various novel therapies are under investigation to improve neurological function and eventually better quality of life in patients with tetraplegia. Methods: In this article, a narrative literature review was performed to identify treatment options targeting the restoration of function in patients with cervical SCI. Studies were included from available literature based on the availability of clinical data and whether they are applicable to restoration of arm and hand function in patients with cervical SCI. Results: We describe relevant studies including indications and outcomes with a focus on arm and hand function. Different treatment modalities described include nerve transfers, tendon transfers, spinal cord stimulation, functional electrical stimulation, non-invasive brain stimulation, brain-machine interfaces and neuroprosthetics, stem cell therapy, and immunotherapy. As the authors’ institution leads one of the largest clinical trials on nerve transfers for cervical SCI, we also describe how patients undergoing nerve transfers are managed and followed at our center. Conclusions: While complete recovery from cervical spinal cord injury may not be possible, novel therapies aimed at the restoration of upper limb motor function have made significant progress toward the realization of complete recovery.

OBJECTIVE:High cervical spinal cord injury (SCI) results in complete loss of upper-limb function, resulting in debilitating tetraplegia and permanent disability. Spontaneous motor recovery occurs to varying degrees in some patients, particularly in the 1st year postinjury. However, the impact of this upper-limb motor recovery on long-term functional outcomes remains unknown. The objective of this study was to characterize the impact of upper-limb motor recovery on the degree of long-term functional outcomes in order to inform priorities for research interventions that restore upper-limb function in patients with high cervical SCI. METHODS:A prospective cohort of high cervical SCI (C1-4) patients with American Spinal Injury Association Impairment Scale (AIS) grade A-D injury and enrolled in the Spinal Cord Injury Model Systems Database was included. Baseline neurological examinations and functional independence measures (FIMs) in feeding, bladder management, and transfers (bed/wheelchair/chair) were evaluated. Independence was defined as score ≥ 4 in each of the FIM domains at 1-year follow-up. At 1-year follow-up, functional independence was compared among patients who gained recovery (motor grade ≥ 3) in elbow flexors (C5), wrist extensors (C6), elbow extensors (C7), and finger flexors (C8). Multivariable logistic regression evaluated the impact of motor recovery on functional independence in feeding, bladder management, and transfers. RESULTS:Between 1992 and 2016, 405 high cervical SCI patients were included. At baseline, 97% of patients had impaired upper-limb function with total dependence in eating, bladder management, and transfers. At 1 year of follow-up, the largest proportion of patients who gained independence in eating, bladder management, and transfers had recovery in finger flexion (C8) and wrist extension (C6). Elbow flexion (C5) recovery had the lowest translation to functional independence. Patients who achieved elbow extension (C7) were able to transfer independently. On multivariable analysis, patients who gained elbow extension (C7) and finger flexion (C8) were 11 times more likely to gain functional independence (OR 11, 95% CI 2.8-47, p < 0.001) and patients who gained wrist extension (C6) were 7 times more likely to gain functional independence (OR 7.1, 95% CI 1.2-56, p = 0.04). Older age (≥ 60 years) and motor complete SCI (AIS grade A-B) reduced the likelihood of gaining independence. CONCLUSIONS:After high cervical SCI, patients who gained elbow extension (C7) and finger flexion (C8) had significantly greater independence in feeding, bladder management, and transfers than those with recovery in elbow flexion (C5) and wrist extension (C6). Recovery of elbow extension (C7) also increased the capability for independent transfers. This information can be used to set patient expectations and prioritize interventions that restore these upper-limb functions in patients with high cervical SCI.

BACKGROUND CONTEXT: Patients with cervical spine disease suffer from upper limb disabil-ity. At present, no clinical benchmarks exist for clinically meaningful change in the upper limb function following cervical spine surgery. PURPOSE: Primary: to establish clinically meaningful metrics; the minimal clinically important difference (MCID) and substantial clinical benefit (SCB) of upper limb functional improvement in patients following cervical spine surgery. Secondary: to identify the prognostic factors of MCID and SCB of upper limb function following cervical spine surgery. STUDY DESIGN: Retrospective cohort study. PATIENT SAMPLE: Adult patients >= 18 years of age who underwent cervical spine surgery from 2012 to 2016. OUTCOME MEASURES: Patient-reported outcomes: Neck disability index (NDI) and Disabil-ities of Arm, Shoulder, and Hand (DASH). METHODS: MCID was defined as minimal improvement and SCB as substantial improvement in the DASH score at last follow-up. The anchor-based methods (ROC analyses) defined optimal MCID and SCB thresholds with area under curve (AUC) in discriminating improved vs. non-improved patients. The MCID was also calculated by distribution-based methods: half standard -deviation (0.5-SD) and standard error of the mean (SEM) method. A multivariable logistic regres-sion evaluated the impact of baseline factors in achieving the MCID and SCB in DASH following cervical spine surgery. RESULTS: Between 2012 and 2016, 1,046 patients with average age of 5711.3 years, 53% males, underwent cervical spine surgery. Using the ROC analysis, the threshold for MCID was -8 points with AUC of 0.73 (95% CI: 0.67-0.79) and the SCB was -18 points with AUC of 0.88 (95% confidence interval [CI]: 0.85-0.91). The MCID was -11 points by 0.5-SD and -12 points by SEM-method. On multivariable analysis, patients with myelopathy had lower odds of achieving MCID and SCB, whereas older patients and those with >= 6 months duration of symptoms had lower odds of achieving DASH MCID and SCB respectively. CONCLUSIONS: In patients undergoing cervical spine surgery, MCID of -8 points and SCB of -18 points in DASH improvement may be considered clinically significant. These metrics may enable evaluation of minimal and substantial improvement in the upper extremity function follow-ing cervical spine surgery.(c) 2023 Elsevier Inc. All rights reserved.

"Letter to the Editor. Cerebrospinal fluid circulation failure in the pathogenesis of post-craniectomy glymphatic flow impairment" published on 29 Nov 2019 by American Association of Neurological Surgeons.

OBJECTIVE:Cranial neurosurgical procedures can cause changes in brain function. There are many potential explanations, but the effect of simply opening the skull has not been addressed, except for research into syndrome of the trephined. The glymphatic circulation, by which CSF and interstitial fluid circulate through periarterial spaces, brain parenchyma, and perivenous spaces, depends on arterial pulsations to provide the driving force for bulk flow; opening the cranial cavity could dampen this force. The authors hypothesized that a craniectomy, without any other pathological insult, is sufficient to alter brain function due to reduced arterial pulsatility and decreased glymphatic flow. Furthermore, they postulated that glymphatic impairment would produce activation of astrocytes and microglia; with the reestablishment of a closed cranial compartment, the glymphatic impairment, astrocytic/microglial activation, and neurobehavioral decline caused by opening the cranial compartment might be reversed. METHODS:Using two-photon in vivo microscopy, the pulsatility index of cortical vessels was quantified through a thinned murine skull and then again after craniectomy. Glymphatic influx was determined with ex vivo fluorescence microscopy of mice 0, 14, 28, and 56 days following craniectomy or cranioplasty; brain sections were immunohistochemically labeled for GFAP and CD68. Motor and cognitive performance was quantified with rotarod and novel object recognition tests at baseline and 14, 21, and 28 days following craniectomy or cranioplasty. RESULTS:Penetrating arterial pulsatility decreased significantly and bilaterally following unilateral craniectomy, producing immediate and chronic impairment of glymphatic CSF influx in the ipsilateral and contralateral brain parenchyma. Craniectomy-related glymphatic dysfunction was associated with an astrocytic and microglial inflammatory response, as well as with the development of motor and cognitive deficits. Recovery of glymphatic flow preceded reduced gliosis and return of normal neurological function, and cranioplasty accelerated this recovery. CONCLUSIONS:Craniectomy causes glymphatic dysfunction, gliosis, and changes in neurological function in this murine model of syndrome of the trephined.

Cerebrospinal fluid (CSF) flow in rodents has largely been studied using ex vivo quantification of tracers. Techniques such as two-photon microscopy and magnetic resonance imaging (MRI) have enabled in vivo quantification of CSF flow but they are limited by reduced imaging volumes and low spatial resolution, respectively. Recent work has found that CSF enters the brain parenchyma through a network of perivascular spaces surrounding the pial and penetrating arteries of the rodent cortex. This perivascular entry of CSF is a primary driver of the glymphatic system, a pathway implicated in the clearance of toxic metabolic solutes (e.g., amyloid-β). Here, we illustrate a new macroscopic imaging technique that allows real-time, mesoscopic imaging of fluorescent CSF tracers through the intact skull of live mice. This minimally-invasive method facilitates a multitude of experimental designs and enables single or repeated testing of CSF dynamics. Macroscopes have high spatial and temporal resolution and their large gantry and working distance allow for imaging while performing tasks on behavioral devices. This imaging approach has been validated using two-photon imaging and fluorescence measurements obtained from this technique strongly correlate with ex vivo fluorescence and quantification of radio-labeled tracers. In this protocol, we describe how transcranial macroscopic imaging can be used to evaluate glymphatic transport in live mice, offering an accessible alternative to more costly imaging modalities.

Despite the initial promise of immunotherapy for CNS disease, multiple recent clinical trials have failed. This may be due in part to characteristically low penetration of antibodies to cerebrospinal fluid (CSF) and brain parenchyma, resulting in poor target engagement. We here utilized transcranial macroscopic imaging to noninvasively evaluate in vivo delivery pathways of CSF fluorescent tracers. Tracers in CSF proved to be distributed through a brain-wide network of periarterial spaces, previously denoted as the glymphatic system. CSF tracer entry was enhanced approximately 3-fold by increasing plasma osmolality without disruption of the blood-brain barrier. Further, plasma hyperosmolality overrode the inhibition of glymphatic transport that characterizes the awake state and reversed glymphatic suppression in a mouse model of Alzheimer's disease. Plasma hyperosmolality enhanced the delivery of an amyloid-β (Aβ) antibody, obtaining a 5-fold increase in antibody binding to Aβ plaques. Thus, manipulation of glymphatic activity may represent a novel strategy for improving penetration of therapeutic antibodies to the CNS.

The glymphatic system is a brain-wide clearance pathway; its impairment contributes to the accumulation of amyloid-β. Influx of cerebrospinal fluid (CSF) depends upon the expression and perivascular localization of the astroglial water channel aquaporin-4 (AQP4). Prompted by a recent failure to find an effect of Aqp4 knock-out (KO) on CSF and interstitial fluid (ISF) tracer transport, five groups re-examined the importance of AQP4 in glymphatic transport. We concur that CSF influx is higher in wild-type mice than in four different Aqp4 KO lines and in one line that lacks perivascular AQP4 (Snta1 KO). Meta-analysis of all studies demonstrated a significant decrease in tracer transport in KO mice and rats compared to controls. Meta-regression indicated that anesthesia, age, and tracer delivery explain the opposing results. We also report that intrastriatal injections suppress glymphatic function. This validates the role of AQP4 and shows that glymphatic studies must avoid the use of invasive procedures.

The central nervous system (CNS) is unique in being the only organ system lacking lymphatic vessels to assist in the removal of interstitial metabolic waste products. Recent work has led to the discovery of the glymphatic system, a glial-dependent perivascular network that subserves a pseudolymphatic function in the brain. Within the glymphatic pathway, cerebrospinal fluid (CSF) enters the brain via periarterial spaces, passes into the interstitium via perivascular astrocytic aquaporin-4, and then drives the perivenous drainage of interstitial fluid (ISF) and its solute. Here, we review the role of the glymphatic pathway in CNS physiology, the factors known to regulate glymphatic flow, and the pathologic processes in which a breakdown of glymphatic CSF-ISF exchange has been implicated in disease initiation and progression. Important areas of future research, including manipulation of glymphatic activity aiming to improve waste clearance and therapeutic agent delivery, are also discussed.

Recent discoveries of the glymphatic system and of meningeal lymphatic vessels have generated a lot of excitement, along with some degree of skepticism. Here, we summarize the state of the field and point out the gaps of knowledge that should be filled through further research. We discuss the glymphatic system as a system that allows CNS perfusion by the cerebrospinal fluid (CSF) and interstitial fluid (ISF). We also describe the recently characterized meningeal lymphatic vessels and their role in drainage of the brain ISF, CSF, CNS-derived molecules, and immune cells from the CNS and meninges to the peripheral (CNS-draining) lymph nodes. We speculate on the relationship between the two systems and their malfunction that may underlie some neurological diseases. Although much remains to be investigated, these new discoveries have changed our understanding of mechanisms underlying CNS immune privilege and CNS drainage. Future studies should explore the communications between the glymphatic system and meningeal lymphatics in CNS disorders and develop new therapeutic modalities targeting these systems.

Objective: The goal of this study was to investigate how manipulation of the RAA axis, both with angiotensin and common anti-hypertensive pharmacotherapy, influences glymphatic flow. Background: The CNS possesses the astrocyte-dependent perivascular glymphatic pathway to facilitate CSF-ISF exchange and clearance of interstitial wastes. Cerebral arterial pulsations drive glymphatic flow, and cerebrovascular pulsatility is dependent, at least in part, on systemic blood pressure. Renin-angiotensin-aldosterone axis dysregulation is responsible for hypertension, a condition that affects nearly 30[percnt] of the US population and 40[percnt] of individuals globally. Methods: All drugs were administered to the cisterna magna via cannulation at a rate of 1 μL/min for a total volume of 5 μL. Immediately after, 1[percnt] AlexaFluor-555 conjugated bovine serum albumin (BSA-555) was delivered intracisternally at a rate of 2 μL/min for a total volume of 10 μL. 30 minutes following tracer injection, cerebral tissues were collected and processed for ex vivo conventional fluorescence microscopy. Tissue area occupied by fluorophore was quantified, with greater percent areas indicating increased glymphatic influx. Results: Pre-treatment with Angiotensin II (ATII, 1 μM) increased glymphatic influx relative to vehicle-injected controls. Losartan (1 μM), an AT1 receptor inhibitor, was found to decrease glymphatic CSF influx, indicating that ATII acts through the AT1 receptor to increase glymphatic flow. Systemic administration of DSP-4 (50 mg/kg), a neurotoxin known to deplete locus coeruleus norepinephrine, resulted in suppressed glymphatic influx. Co-administration of ATII in DSP-4 treated mice or in mice receiving a norepinephrine inhibitory cocktail (1 μM) resulted in decreased glymphatic influx, suggesting that ATII regulates glymphatic pathway function through a NE-dependent mechanism. Conclusions: Angiotensin II acts via the AT1 receptor to increase glymphatic influx in a norepinephrine-dependent manner. Further study on hemodynamic regulation of glymphatic flow may reveal mechanisms of hypertension-related brain pathology. Disclosure: Dr. Russak has nothing to disclose. Dr. Plog has nothing to disclose. Dr. Vates has nothing to disclose. Dr. Nedergaard has nothing to disclose.