This Viewpoint describes the diagnosis and treatment history of normal pressure hydrocephalus and then highlights recent trial results that may serve as a catalyst for renewed scientific and clinical efforts.

Spaceflight-associated neuro-ocular syndrome (SANS) poses a significant risk for astronauts, being linked to intracranial pressure (ICP) changes in microgravity. Investigating ICP in space has been challenging. We evaluated a telemetric lumbar ICP monitoring system that shows promise for investigating microgravity-induced intracranial pressure changes in astronauts. Despite limitations in pulse amplitude analysis and pressure underestimation, the system’s long-term stability and overall performance support its recommendation for SANS research in space.

Adult hydrocephalus comprises 4 pragmatic categories: (1) transition; (2) unrecognized congenital; (3) acquired; and (4) suspected idiopathic normal pressure hydrocephalus. Each of these groups has unique clinical presentations and care needs that require the involvement of adult neurosurgeons for diagnosis and treatment. Patients in all 4 of these categories benefit from longitudinal care for monitoring of their symptoms or assessing response to treatment.

A subset of long-duration spaceflight astronauts at the International Space Station has been documented to develop spaceflight associated neuro-ocular syndrome (SANS). Researchers have sought to understand SANS by quantification of ocular and brain structural changes thought to be associated with weightlessness induced headward fluid shift. Brain tissue shift and cerebrospinal fluid (CSF) redistribution has been observed as measured by MRI on return to Earth, and not fully quantified. To improve the understanding of this phenomenon, we developed and applied automated methods to quantify 3D center of mass shift within the skull of the extra-axial cerebrospinal fluid (eaCSF) and brain after long-duration spaceflight in astronauts (N = 13) and controls not exposed to microgravity (N = 10). 3D center of mass shift of brain tissue and CSF was computed based on registration of an individual skull segmentation at a baseline timepoint versus follow-up. 3D center of mass shift was quantified in the Gx, Gy, and Gz axis defined as -posterior/+anterior, -left/+right, -inferior/+superior, respectively. For astronauts, average MRI follow-up time pre- to post-flight was 697 ± 137 days (average flight duration = 179 ± 59 days with post-flight MRIs collected an average of 2.23 ± 1.64 days after return to Earth). For controls, average MRI follow-up time was 307 ± 19 days. For astronauts, a superior Gz shift in whole brain was present (+ 0.74 ± 0.28 mm, p < 0.0001) with a concomitant inferior Gz shift in eaCSF (-2.45 ± 0.99 mm, p < 0.0001). In the control cohort, brain tissue Gz shift (-0.082 ± 0.048 mm) and eaCSF Gz shift (0.096 ± 0.26 mm) were not statistically significant. Gy shift lacked significance in both controls and astronauts. These findings support that sustained exposure to weightlessness impacts the overall position of fluids and tissues within the skull.

In 1965, Hakim and Adams described 3 patients with normal pressure hydrocephalus who responded to treatment with a ventriculoatrial shunt. Afterward the adoption of shunt treatment without clear diagnostic criteria and surgical techniques resulted in poor outcomes with significant complications. The clinical practice guidelines for the diagnosis and treatment of idiopathic normal pressure hydrocephalus were first published by the Japanese Neurosurgical Society in 2004 and the international guidelines were published in 2005. Both guidelines led to diagnosis and treatment algorithms and significantly improved outcomes, along with decreased surgical risk. These guidelines should be reevaluated and updated on a regular basis.

BACKGROUND:Idiopathic normal-pressure hydrocephalus is a neurologic disorder characterized by impaired gait, balance, cognition, and bladder control in older adults. The disorder is treated with shunt surgery, but the effectiveness of shunting is unclear. METHODS:We conducted a double-blind, randomized, placebo-controlled trial involving participants selected for shunt surgery on the basis of gait-velocity improvement with cerebrospinal fluid (CSF) drainage. Participants were randomly assigned to an open-shunt valve setting (opening pressure, 110 mm of water) or a placebo valve setting (opening pressure, >400 mm of water) of a noninvasively adjustable shunt. The primary outcome was the change in gait velocity 3 months after surgery. Secondary outcomes were the change at 3 months in the Tinetti scale total score (range, 0 to 28; lower scores indicate worse gait and balance), Montreal Cognitive Assessment (MoCA) score (range, 0 to 30; lower scores indicate worse cognition), and Overactive Bladder Questionnaire score (range, 0 to 100; higher scores indicate worse urinary incontinence). RESULTS:A total of 99 participants underwent randomization and received the assigned intervention. At 3 months, gait velocity had increased in the open-shunt group (mean [±SD] change, 0.23±0.23 m per second; assessed in 49 participants) and was unchanged in the placebo group (mean change, 0.03±0.23 m per second; assessed in 49 participants), resulting in a treatment difference of 0.21 m per second (95% confidence interval, 0.12 to 0.31; P<0.001). A significantly greater improvement in the open-shunt group than the placebo group was seen for the Tinetti scale score (mean change, 2.9 points vs. 0.5 points; P = 0.003) but not the MoCA score (1.3 points vs. 0.3 points) or the Overactive Bladder Questionnaire score (-3.3 points vs. -1.5 points). The results regarding adverse events were mixed, with more participants in the placebo group reporting falls (46% vs. 24%), an equal percentage having cerebral bleeding (2% in both groups), and more participants in the open-shunt group having subdural bleeding (12% vs. 2%) and positional headaches (59% vs. 28%). CONCLUSIONS:Among participants with idiopathic normal-pressure hydrocephalus who had a response to temporary CSF drainage, shunting resulted in significant improvements at 3 months in gait velocity and a measure of gait and balance but not in measures of cognition or incontinence. (Funded by the National Institute of Neurological Disorders and Stroke and the Trial Innovation Network; PENS ClinicalTrials.gov number, NCT05081128.).

Idiopathic intracranial hypertension (IIH) is a condition defined by increased intracranial pressure without an identifiable cause and its associated symptoms, most notably headache and vision loss. With an estimated incidence of 0.9 per 100,000 in the general population, IIH is a disease primarily observed in overweight women of childbearing age, with an incidence of 7.9 to 20 per 100,000. Weight loss is essential to controlling symptoms, and adjunctive pharmacologic therapy with acetazolamide and topiramate can provide more immediate benefit. For fulminant or medically refractive cases, surgical treatments in the form of cerebrospinal fluid diversion procedures, venous sinus stenting, and optic nerve sheath fenestration are effective in preventing or halting progression of significant vision loss.

Hydrocephalus is a neurological disorder that impacts approximately 85 per 100,000 individuals worldwide and is associated with motor and cognitive impairments. While many advances in surgical interventions have helped substantially improve the survival rates and quality of life of those affected, there continues to be significant gaps in our understanding of the etiology of this heterogeneous condition as well as its specific neuropsychological and functional challenges across different phases of life. To address these limitations, the Hydrocephalus Association and Rudi Schulte Research Institute organized a workshop titled, "Improving Cognitive and Psychological Outcomes in Hydrocephalus", composed of top academics in the fields of hydrocephalus, cognition, and neuropsychology, as well as individuals with hydrocephalus or their caregivers. The purpose was to review the available evidence and propose pertinent areas of further research to improve the cognitive functioning, functional status, and quality of life of individuals with hydrocephalus. These topics included cognitive and neuropsychological assessments and daily-life function of children and adults living with hydrocephalus, biomarkers of cognitive function, animal modeling of hydrocephalus, and the longitudinal impact of hydrocephalus treatment. The following paper outlines four primary areas that warrant research: (1) neuropsychological phenotypes, (2) treatment-focused research considerations, (3) translational pre-clinical tools, and (4) establishing pathways for longitudinal care. Through the efforts of this group, the goal of this manuscript is to inspire and direct scientific and clinical inquiry towards these noted research priorities to further improve the lives of individuals with hydrocephalus and their families.

Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT.

OBJECTIVE:The aim of this study was to describe the processes and outcomes associated with patients at five sites in the Adult Hydrocephalus Clinical Research Network (AHCRN) who had undergone evaluation and treatment for suspected idiopathic normal pressure hydrocephalus (iNPH) and had 1-year postoperative follow-up.METHODS:Subjects with possible iNPH who had been prospectively enrolled in the AHCRN registry between November 19, 2014, and December 31, 2018, were evaluated by CSF drainage via either lumbar puncture or external lumbar drainage, consistent with recommendations of the international iNPH guidelines. Standardized clinical evaluations of gait, cognition, urinary symptoms, depression, and functional outcomes were conducted at baseline, before and after CSF drainage, and at 4-month intervals after shunt surgery. Complications of CSF drainage and shunt surgery were recorded.RESULTS:Seventy-four percent (424/570) of patients with possible iNPH had CSF drainage, and 46% of them (193/424) underwent shunt surgery. The mean change in gait velocity with CSF drainage was 0.18 m/sec in patients who underwent shunt surgery versus 0.08 m/sec in patients who did not. For shunt surgery patients, gait velocity increased by 54% from 0.67 m/sec before CSF drainage to 0.96 m/sec 8-12 months after surgery, and 80% of patients had an increase of at least 0.1 m/sec by the first postoperative visit. Evaluation of cognition, urinary symptoms, depression, and functional outcomes also revealed improvement after shunt surgery. Of 193 patients who had undergone shunt surgery, 176 (91%) had no complications and 17 (9%) had 28 complications. Eleven patients (6%) had 14 serious complications that resulted in the need for surgery or an extended hospital stay. The 30-day reoperation rate was 3%.CONCLUSIONS:Using criteria recommended by the international iNPH guidelines, the authors found that evaluation and treatment of iNPH are safe and effective. Testing with CSF drainage and treatment with shunt surgery are associated with a high rate of sustained improvement and a low rate of complications for iNPH in the 1st year after shunt surgery. Patients who had undergone shunt surgery for iNPH experienced improvement in gait, cognitive function, bladder symptoms, depression, and functional outcome measures. Gait velocity, which is an easily measured, objective, continuous variable, should be used as a standard outcome measure to test a patient's response to CSF drainage and shunt surgery in iNPH.

BACKGROUND: Multiple prospective nonrandomized studies have shown 60% to 70% of patients with idiopathic normal pressure hydrocephalus (iNPH) improve with shunt surgery, but multicenter placebo-controlled trial data are necessary to determine its effectiveness. OBJECTIVE: To evaluate the effectiveness of cerebrospinal fluid shunting in iNPH through comparison of open vs placebo shunting groups at 4 months using a pilot study. METHODS: Patients were randomized to a Codman Certas Plus valve (Integra LifeSciences) set at 4 (open shunt group) or 8 (“virtual off”; placebo group). Patients and assessors were blinded to treatment group. The primary outcome measure was 10-m gait velocity. Secondary outcome measures included functional scales for bladder control, activities of daily living, depression, and quality of life. Immediately after 4-month evaluation, all shunts were adjusted in a blinded fashion to an active setting and followed to 12 months after shunting. RESULTS: A total of 18 patients were randomized. At the 4-month evaluation, gait velocity increased by 0.28 ± 0.28 m/s in the open shunt group vs 0.04 ± 0.17 m/s in the placebo group. The estimated treatment difference was 0.22 m/s ([P = .071], 95% CI −0.02 to 0.46). Overactive Bladder Short Form symptom bother questionnaire significantly improved in open shunt vs placebo (P = .007). The 4-month treatment delay did not reduce the subsequent response to active shunting, nor did it increase the adverse advents rate at 12 months. CONCLUSION: This multicenter, randomized pilot study demonstrates the effectiveness, safety, and feasibility of a placebo-controlled trial in iNPH, and found a trend suggesting gait velocity improves more in the open shunt group than in the placebo group.