Spontaneous intracranial hypotension - a spinal disease. / Spontane intrakranielle Hypotension ­ eine spinale Erkrankung.

Spontaneous intracranial hypotension (SIH) remains an underdiagnosed condition despite increasing awareness due to recent scientific advances. Diagnosis can be delayed by the broad clinical presentation and imaging pitfalls. This results in a high degree of physical impairment for patients, including social and psychological sequelae as well as long-term damage in the case of delayed diagnosis and treatment.The study is based on a selective literature search on PubMed including articles from 1990 to 2023 and the authors' clinical experience from working in a CSF center.SIH mostly affects middle-aged women, with the primary symptom being position-dependent orthostatic headache. In addition, there is a broad spectrum of possible symptoms that can overlap with other clinical conditions and therefore complicate the diagnosis. The causative spinal CSF loss can be divided into three main types: ventral (type 1) or lateral (type 2) dural leak and CSF-venous fistula (type 3). The diagnosis can be made using a two-stage workup. As a first step, noninvasive MRI of the head and spine provides indicators of the presence of SIH. The second step using focused myelography can identify the exact location of the cerebrospinal fluid leak and enable targeted therapy (surgical or interventional). Intrathecal pressure measurement or intrathecal injection of gadolinium is no longer necessary for primary diagnosis. Serious complications in the course of the disease can include space-occupying subdural hematomas, superficial siderosis, and symptoms of brain sagging, which can lead to misinterpretations. Treatment consists of closing the dural leak or the cerebrospinal fluid fistula. Despite successful treatment, a relapse can occur, which highlights the importance of follow-up MRI examinations and emphasizes the chronic nature of the disease. This paper provides an overview of the diagnostic workup of patients with suspected SIH and new developments in imaging and therapy. · SIH is an underdiagnosed condition with a wide range of possible symptoms.. · The first diagnostic step using MRI provides indications of the presence of SIH.. · The second diagnostic step using (dynamic) myelography can identify the CSF leak.. · Collaboration with a CSF center is advisable for further diagnosis and treatment.. · Prompt detection and treatment of SIH improves the outcome.. · Zander C, Wolf K, El Rahal A et al. Spontaneous intracranial hypotension - a spinal disease. Fortschr Röntgenstr 2024; DOI 10.1055/a-2318-8994.

Clinical severity of aneurysmal subarachnoid hemorrhage over time: systematic review.

The incidence of aneurysmal subarachnoid hemorrhage (aSAH) is well studied. Yet, little is known about the trend of aSAH severity. This systematic review aims to analyze the distribution of aSAH severity over time. We performed a systematic review of the literature according to the PRISMA-P guidelines. We included studies from January 1968 up to December 2022. Studies were included if they either reported the severity of aSAH as single increments of the corresponding 5-point scale or as a binary measure (good grade 1-3, poor grade 4-5) on the Hunt and Hess (HH) or World Federation of Neurosurgical Societies (WFNS) scale. Studies with fewer than 50 patients, (systematic) reviews, and studies including non-aSAH patients were excluded. A total of 2465 publications were identified, of which 214 met the inclusion and exclusion criteria. In total, 102,845 patients with an aSAH were included. Over the last five decades the number of good-grade HH (0.741 fold, p = 0.004) and WFNS (0.749 fold, p < 0.001) has decreased. Vice versa, an increase in number of poor grade HH (2.427 fold, p = 0.004), WFNS (2.289 fold, p < 0.001), as well as HH grade 5 (6.737 fold, p = 0.010), WFNS grade 4 (1.235 fold, p = 0.008) and WFNS grade 5 (8.322 fold, p = 0.031) was observed. This systematic review shows a worldwide 2-3 fold increase of poor grade aSAH patients and an 6-8 fold increase of grade 5 patients, over the last 50 years. Whether this evolution is due to more severe hemorrhage, improvements in neuro-intensive care and prehospital management, or to a change in grading behavior is unknown. This study strongly emphasizes the necessity for an improved grading system to differentiate grade 4 and grade 5 patients for meaningful clinical decision- making.

Dexamethasone in Patients with Glioblastoma: A Systematic Review and Meta-Analysis.

OBJECTIVE: Glioblastomas are the most common primary central nervous system (CNS) tumors. Although modern management strategies have modestly improved overall survival, the prognosis remains dismal, with treatment side effects often impinging on the clinical course. Glioblastomas cause neurological dysfunction by infiltrating CNS tissue and via perifocal oedema formation. The administration of steroids such as dexamethasone is thought to alleviate symptoms by reducing oedema. However, despite its widespread use, the evidence for the administration of dexamethasone is limited and conflicting. Therefore, we aimed to review the current evidence concerning the use and outcomes of dexamethasone in patients with glioblastoma. METHODS: We performed a systematic review and meta-analysis according to the PRISMA-P guidelines. We performed a restricted search using the keywords "Dexamethasone" and "Glioblastoma" on PubMed, Web of Science, Cochrane Library, and Academic Search Premier. We included studies reporting on overall survival (OS) and progression-free survival (PFS) in glioblastoma patients receiving higher or lower dexamethasone doses. The risk of bias was assessed using ROBINS-I. We performed a meta-analysis using a random effects model for OS and PFS. RESULTS: Twenty-two retrospective studies were included. Higher doses of dexamethasone were associated with poorer OS (hazard ratio 1.62, confidence interval 1.40-1.88) and PFS (1.49, 1.23-1.81). OS remained worse even when studies corrected for clinical status (1.52, 1.38-1.67). CONCLUSION: Despite the widespread use of dexamethasone in glioblastoma patients, its use is correlated with worse long-term outcomes. Consequently, Dexamethasone administration should be restricted to selected symptomatic patients. Future prospective studies are crucial to confirm these findings.

Impact of Spinal CSF Leaks on Quality of Life and Mental Health and Long-Term Reversal by Surgical Closure.

Background and Objectives: Spontaneous intracranial hypotension (SIH) caused by a spinal CSF leak is a multisymptom syndrome, which can dramatically affect physical and mental health. However, systematic data on health-related quality of life (HRQoL) and mental health are scarce. We hypothesized that surgical treatment leads to significant and sustained improvements in HRQoL and mental health in patients with SIH. Methods: In this single-center cohort study, we prospectively collected HRQoL and mental health data in patients undergoing surgical closure of a spinal CSF leak from September 2020 to November 2022. EuroQoL (EQ-5D-5L), including the health state index (EQ-Index) and the visual analog scale (EQ-VAS), measured HRQoL. The 21-item version of the Depression Anxiety Stress Scales (DASS-21) measured symptoms of mental health. Follow-ups were performed 3 and 6 months postoperatively. Primary outcome was the change in EQ-Index, EQ-VAS, and DASS-21 subscales. Secondary outcome was the impact of baseline depression symptoms on HRQoL outcomes following surgery. Results: Seventy-four patients were included. EQ-VAS improved from 40 (interquartile range [IQR] 30-60) preoperatively to 70 (IQR 55-85) at 3 months and to 72 (IQR 60-88) at 6 months postoperatively (p < 0.001, respectively). EQ-Index increased from 0.683 (IQR 0.374-0.799) to 0.877 (0.740-0.943) at 3 months and to 0.907 (0.780-0.956) at 6 months postoperatively (p < 0.001, respectively). Depression, anxiety, and stress significantly improved after surgery. Preoperative depressive symptoms did not affect the HRQoL outcome. Discussion: The severe impact of a spinal CSF leak on HRQoL and mental health significantly improved after closure of the leak. Higher levels of depressive symptoms do not predict worse outcomes and should not discourage invasive treatment. Further systematic evaluation of outcomes, with special regard to quality of life, is needed, as it allows a comparison of symptom burden between SIH and more familiar diseases as well as a comparison of different treatment modalities in future studies.

Don't delay, but don't despair: symptom duration, comorbidity and outcome after closure of spinal cerebrospinal fluid leaks.

OBJECTIVE: Microsurgical sealing of spinal cerebrospinal fluid (CSF) leaks is a viable treatment option in spontaneous intracranial hypotension (SIH). Several factors may influence the outcome, with symptom duration probably the most modifiable variable. METHODS: Patients with closure of spinal CSF leaks between September 2020 and March 2023 and a follow-up period of 6 months were included in this retrospective single-center study. Pre- and postoperative scores for impact of headaches (Headache Impact Test, HIT-6) and quality of life (QoL, EQ-5D-5L) were systematically collected. Multiple regression modelling and subgroup analyses for different symptom durations and comorbidities were performed for these outcomes. RESULTS: One hundred patients (61% female, median age 43.5 years) were included. Six months postoperatively, there was significant improvement in headache impact (HIT-6: 66 (IQR 62-69) to 52 (IQR 40-61, p < 0.001) and QoL (EQ-5D-5L VAS: 40 (IQR 30-60) to 79 (IQR 60-90); EQ-5D-5L Index: 0.67 (IQR 0.35-0.8) to 0.91 (IQR 0.8-0.94, p < 0.001, respectively). Subgroup analysis for a symptom duration above (74%) and below 90 days (26%) and comorbidity, as well as multiple regression analysis, revealed a trend in favor of early treatment and lower comorbidity. However, even after a prolonged symptom duration, improvements were significant. CONCLUSION: As patients with shorter symptom duration show a trend for a better outcome, our results promote a timely diagnosis and treatment in SIH patients. However, a significant postoperative improvement can still be expected even after a prolonged symptom duration.

Surgical closure of spinal cerebrospinal fluid leaks improves symptoms in patients with superficial siderosis.

BACKGROUND AND PURPOSE: Spinal cerebrospinal fluid (CSF) leaks may cause a myriad of symptoms, most common being orthostatic headache. In addition, ventral spinal CSF leaks are a possible etiology of superficial siderosis (SS), a rare condition characterized by hemosiderin deposits in the central nervous system (CNS). The classical presentation of SS involves ataxia, bilateral hearing loss, and myelopathy. Unfortunately, treatment options are scarce. This study was undertaken to evaluate whether microsurgical closure of CSF leaks can prevent further clinical deterioration or improve symptoms of SS. METHODS: This cohort study was conducted using data from a prospectively maintained database in two large spontaneous intracranial hypotension (SIH) referral centers in Germany and Switzerland of patients who meet the modified International Classification of Headache Disorders, 3rd edition criteria for SIH. Patients with spinal CSF leaks were screened for the presence of idiopathic infratentorial symmetric SS of the CNS. RESULTS: Twelve patients were included. The median latency between the onset of orthostatic headaches and symptoms attributed to SS was 9.5 years. After surgical closure of the underlying spinal CSF leak, symptoms attributed to SS improved in seven patients and remained stable in three. Patients who presented within 1 year after the onset of SS symptoms improved, but those who presented in 8-12 years did not improve. We could show a significant association between patients with spinal longitudinal extrathecal collections and SS. CONCLUSIONS: Long-standing untreated ventral spinal CSF leaks can lead to SS of the CNS, and microsurgical sealing of spinal CSF leaks might stop progression and improve symptoms in patients with SS in a time-dependent manner.

Distinct Pattern of Membrane Formation With Spinal Cerebrospinal Fluid Leaks in Spontaneous Intracranial Hypotension.

BACKGROUND AND OBJECTIVES: To systematically describe pertinent, intraoperative anatomic findings encountered when approaching spinal cerebrospinal fluid (CSF) leaks and CSF-venous fistulas in spontaneous intracranial hypotension (SIH). METHODS: In a retrospective study, we included surgically treated patients suffering from SIH at our institution from April 2018 to March 2022. Anatomic, intraoperative data were extracted from operative notes and supplemented with data from surgical videos and images. Prominent anatomic features were compared among different types of CSF leaks. RESULTS: The study cohort consists of 120 patients with a mean age of 45.2 years. We found four distinct patterns of spinal membranes specifically associated with different types of CSF leaks: (i) thick, dorsal membranes, which were hypervascular and may mimic the dura (pseudodura); (ii) thin, lateral membranes encapsulating a ventral epidural CSF compartment (confining the spinal longitudinal extradural CSF collection); (iii) ventral membranes constituting a transdural funnel-like CSF channel; and (iv) lateral membranes forming spinal cysts/meningeal diverticulae associated with lateral CSF leaks. The latter three types resemble a layer of arachnoid herniated through the dural defect. CONCLUSION: We describe four distinct spinal (neo-)membranes in association with spinal CSF leaks. Formation of these membranes, or emergence by herniation of arachnoid through a dural defect, constitutes a specific pathoanatomic feature of patients with SIH and CSF leaks. Recognition of these membranes is of paramount importance for diagnosis and treatment of patients with spinal CSF leaks.

Direct comparison of digital subtraction myelography versus CT myelography in lateral decubitus position: evaluation of diagnostic yield for cerebrospinal fluid-venous fistulas.

BACKGROUND: Cerebrospinal fluid (CSF)-venous fistulas (CVFs) are increasingly identified as a cause of spontaneous intracranial hypotension (SIH). Lateral decubitus digital subtraction myelography (LD-DSM) and CT myelography (LD-CTM) are mainly used for detection, but the most sensitive method is yet unknown. OBJECTIVE: To compare LD-DSM with LD-CTM for diagnostic yield of CVFs. METHODS: Patients with SIH diagnosed with a CVF between January 2021 and December 2022 in which the area of CVF(s) was covered by both diagnostic modalities were included. LD-CTM immediately followed LD-DSM without repositioning the spinal needle, and the second half of the contrast agent was injected at the CT scanner. Patients were awake or mildly sedated. Retrospectively, two neuroradiologists evaluated data independently and blinded for the presence of CVF. RESULTS: Twenty patients underwent a total of 27 combined LD-DSM/LD-CTM examinations (4/20 with follow-up and 3/20 with bilateral examinations). Both raters identified significantly more CVFs with LD-CTM than with LD-DSM (rater 1: 39 vs 9, P<0.001; rater 2: 42 vs 12, P<0.001). Inter-rater agreement was substantial for LD-DSM (κ=0.732) and LD-CTM (κ=0.655). The results remained significant after considering the senior rating for cases of disagreement (39 vs 10; P<0.001), and no CVF detected on LD-DSM was missed on LD-CTM. CONCLUSION: In this study, LD-CTM has a higher diagnostic yield for the detection of CVFs than LD-DSM and should supplement LD-DSM, but further studies are needed. LD-CTM can be easily acquired in awake or mildly sedated patients with the second half of contrast injected just before CT scanning, or it may be considered as a stand-alone investigation.

Incidence, therapy, and outcome in the management of chronic subdural hematoma in Switzerland: a population-based multicenter cohort study.

Background: Chronic subdural hematoma (cSDH) is a disease affecting mainly elderly individuals. The reported incidence ranges from 2.0/100,000 to 58 per 100,000 person-years when only considering patients who are over 70 years old, with an overall incidence of 8.2-14.0 per 100,000 persons. Due to an estimated doubling of the population above 65 years old between 2000 and 2030, cSDH will become an even more significant concern. To gain an overview of cSDH hospital admission rates, treatment, and outcome, we performed this multicenter national cohort study of patients requiring surgical treatment of cSDH. Methods: A multicenter cohort study included patients treated in 2013 in a Swiss center accredited for residency. Demographics, medical history, symptoms, and medication were recorded. Imaging at admission was evaluated, and therapy was divided into burr hole craniostomy (BHC), twist drill craniostomy (TDC), and craniotomy. Patients' outcomes were dichotomized into good (mRS, 0-3) and poor (mRS, 4-6) outcomes. A two-sided t-test for unpaired variables was performed, while a chi-square test was performed for categorical variables, and a p-value of <0.05 was considered to be statistically significant. Results: A total of 663 patients were included. The median age was 76 years, and the overall incidence rate was 8.2/100,000. With age, the incidence rate increased to 64.2/100,000 in patients aged 80-89 years. The most prevalent symptoms were gait disturbance in 362 (58.6%) of patients, headache in 286 (46.4%), and focal neurological deficits in 252 (40.7%). CSDH distribution was unilateral in 478 (72.1%) patients, while 185 presented a bilateral hematoma with no difference in the outcome. BHC was the most performed procedure for 758 (97.3%) evacuations. CSDH recurrence was noted in 104 patients (20.1%). A good outcome was seen in almost 81% of patients. Factors associated with poor outcomes were age, GCS and mRS on admission, and the occurrence of multiple deficits present at the diagnosis of the cSDH. Conclusion: As the first multicenter national cohort-based study analyzing the disease burden of cSDH, our study reveals that the hospital admission rate of cSDH was 8.2/100,000, while with age, it rose to 64.2/100,000. A good outcome was seen in 81% of patients, who maintained the same quality of life as before the surgery. However, the mortality rate was 4%.

Recovery and long-term outcome after neurosurgical closure of spinal CSF leaks in patients with spontaneous intracranial hypotension.

INTRODUCTION: Spontaneous intracranial hypotension due to a spinal cerebrospinal fluid leak causes orthostatic headaches and impacts quality of life. Successful closure rates are often reported, whereas data on long-term outcome are still scarce. METHODS: Between April 2020 and December 2022 surgically treated patients completed the Headache Impact Test-6 prior to surgery and at 14 days, three months, six months, and 12 months postoperatively. In addition to the Headache Impact Test-6 score, we extracted data related to orthostatic symptoms. RESULTS: Eighty patients were included. Median Headache Impact Test-6 score preoperatively was 65 (IQR 61-69), indicating severe and disabling impact of headaches. At three months headache impact significantly improved to 49 (IQR 44-58) (p < 0.001) and remained stable up to 12 months (48, IQR 40-56), indicating little to no impact of headaches on quality of life. The need to lie down "always" or "very often" was reduced from 79% to 23% three months postoperatively (p < 0.001). CONCLUSIONS: Surgical closure of spinal CSF leaks significantly improves the impact of headaches in the long term. At least three months should be expected for recovery. Despite permanent closure of the CSF-leak, a quarter of patients still have relevant long-term impairment, indicating the need for further research on its cause and possible treatment.

Sacral Dural Tears as a Cause of Spontaneous Intracranial Hypotension.

PURPOSE: Dural tears at the level of the cervical, thoracic, and lumbar spine cause spontaneous intracranial hypotension (SIH) in patients with a spinal longitudinal extradural CSF collection (SLEC); however, sacral dural tears have rarely been reported so far. This study focuses on sacral dural tears as a cause of SIH. METHODS: Retrospective data from SIH patients with confirmed sacral dural tears studied between October 2020 and November 2022 were analyzed with respect to demographic, clinical and imaging features. Digital subtraction myelography (DSM) and lumbar epidural blood patch (EBP) were modified by placing the patient in reversed Trendelenburg position. RESULTS: Of the SIH patients, 9 (all women; mean age, 38.5 years; mean body mass index, BMI, 22.9) out of 149 had a sacral dural leak (6%) that occurred spontaneously in 7/9, while 2/9 were likely associated with minor trauma. None had a sacral fracture. The mean SIH score was 6.8. All patients showed SLEC on heavily T2-weighted MR myelography (T2-MRM), 4/9 exclusively sacral and 5/9 with partial or complete involvement of the remaining spine. 4/9 had none, but 5/9 had meningeal sacral cysts, 2/5 had large cysts/ectasia. Confirmation of the sacral origin of the leak was provided in 4/9 by T2-MRM, in 2/9 by DSM and 3/9 by CT myelography (CTM) whereas 0/9 revealed the exact site of leak within the sacrum. CONCLUSION: Sacral dural tears should be considered as a possible cause for SIH. It is concluded to implement T2-MRM covering the entire sacrum in the standard MRI protocol and propose EBP in the reverse Trendelenburg position as a therapeutic approach.

Parkinson's disease may disrupt overlapping subthalamic nucleus and pallidal motor networks.

There is an ongoing debate about differential clinical outcome and associated adverse effects of deep brain stimulation (DBS) in Parkinson's disease (PD) targeting the subthalamic nucleus (STN) or the globus pallidus pars interna (GPi). Given that functional connectivity profiles suggest beneficial DBS effects within a common network, the empirical evidence about the underlying anatomical circuitry is still scarce. Therefore, we investigate the STN and GPi-associated structural covariance brain patterns in PD patients and healthy controls. We estimate GPi's and STN's whole-brain structural covariance from magnetic resonance imaging (MRI) in a normative mid- to old-age community-dwelling cohort (n = 1184) across maps of grey matter volume, magnetization transfer (MT) saturation, longitudinal relaxation rate (R1), effective transversal relaxation rate (R2*) and effective proton density (PD*). We compare these with the structural covariance estimates in patients with idiopathic PD (n = 32) followed by validation using a reduced size controls' cohort (n = 32). In the normative data set, we observed overlapping spatially distributed cortical and subcortical covariance patterns across maps confined to basal ganglia, thalamus, motor, and premotor cortical areas. Only the subcortical and midline motor cortical areas were confirmed in the reduced size cohort. These findings contrasted with the absence of structural covariance with cortical areas in the PD cohort. We interpret with caution the differential covariance maps of overlapping STN and GPi networks in patients with PD and healthy controls as correlates of motor network disruption. Our study provides face validity to the proposed extension of the currently existing structural covariance methods based on morphometry features to multiparameter MRI sensitive to brain tissue microstructure.

Intraoperative Visualization of Flow in Direct Cerebrospinal Fluid-Venous Fistulas Using Intrathecal Fluorescein.

BACKGROUND: Cerebrospinal fluid-venous fistulas (CVFs) are a rare cause of spontaneous intracranial hypotension. Intraoperatively, CVFs are not readily identifiable and difficult to differentiate from normal veins. OBJECTIVE: To assess the utility of intrathecal fluorescein injection intraoperatively to visualize and identify the CVF. METHODS: We report a case series of patients treated surgically for a CVF. After surgical exposure, we injected intrathecal fluorescein (5-10 mg) through a lumbar catheter, which we placed immediately before surgery. RESULTS: Four patients with spontaneous intracranial hypotension with a suspected CVF underwent surgical ligation with adjunctive intrathecal fluorescein application. Intraoperative fluorescein injection confirmed the presence of a CVF in 3 cases. In 2 cases, we observed rapid fluorescein filling of a single epidural vein constituting the CVF. Other epidural vessels did not fill with fluorescein. In 1 case, fluorescein helped to identify a residual CVF after previous incomplete embolization. In the fourth case, no CVF was found intraoperatively. By contrast, a meningeal nerve root diverticulum was visualized, wrapped, and clipped. CONCLUSION: We demonstrate for the first time the direct intraoperative visualization of CVF using intrathecal fluorescein. CVF can be identified intraoperatively using fluorescein dye, which can be a valuable adjunct for the surgeon confronted with this disease.

Quality of Life After Poor-Grade Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Poor-grade aneurysmal subarachnoid hemorrhage (aSAH) is associated with high mortality and poor disability outcome. Data on quality of life (QoL) among survivors are scarce because patients with poor-grade aSAH are underrepresented in clinical studies reporting on QoL after aSAH. OBJECTIVE: To provide prospective QoL data on survivors of poor-grade aSAH to aid clinical decision making and counseling of relatives. METHODS: The herniation World Federation of Neurosurgical Societies scale study was a prospective observational multicenter study in patients with poor-grade (World Federation of Neurosurgical Societies grades 4 & 5) aSAH. We collected data during a structured telephone interview 6 and 12 months after ictus. QoL was measured using the EuroQoL - 5 Dimensions - 3 Levels (EQ-5D-3L) questionnaire, with 0 representing a health state equivalent to death and 1 to perfect health. Disability outcome for favorable and unfavorable outcomes was measured with the modified Rankin Scale. RESULTS: Two hundred-fifty patients were enrolled, of whom 237 were included in the analysis after 6 months and 223 after 12 months. After 6 months, 118 (49.8%) patients were alive, and after 12 months, 104 (46.6%) patients were alive. Of those, 95 (80.5%) and 89 (85.6%) reached a favorable outcome with mean EQ-5D-3L index values of 0.85 (±0.18) and 0.86 (±0.18). After 6 and 12 months, 23 (19.5%) and 15 (14.4%) of those alive had an unfavorable outcome with mean EQ-5D-3L index values of 0.27 (±0.25) and 0.19 (±0.14). CONCLUSION: Despite high initial mortality, the proportion of poor-grade aSAH survivors with good QoL is reasonably large. Only a minority of survivors reports poor QoL and requires permanent care.

Herniation World Federation of Neurosurgical Societies Scale Improves Prediction of Outcome in Patients With Poor-Grade Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Favorable outcomes are seen in up to 50% of patients with World Federation of Neurosurgical Societies (WFNS) grade V aneurysmal subarachnoid hemorrhage. Therefore, the usefulness of the current WFNS grading system for identifying the worst scenarios for clinical studies and for making treatment decisions is limited. We previously modified the WFNS scale by requiring positive signs of brain stem dysfunction to assign grade V. This study aimed to validate the new herniation WFNS grading system in an independent prospective cohort. METHODS: We conducted an international prospective multicentre study in poor-grade aneurysmal subarachnoid hemorrhage patients comparing the WFNS classification with a modified version-the herniation WFNS scale (hWFNS). Here, only patients who showed positive signs of brain stem dysfunction (posturing, anisocoric, or bilateral dilated pupils) were assigned hWFNS grade V. Outcome was assessed by modified Rankin Scale score 6 months after hemorrhage. The primary end point was the difference in specificity of the WFNS and hWFNS grading with respect to poor outcomes (modified Rankin Scale score 4-6). RESULTS: Of the 250 patients included, 237 reached the primary end point. Comparing the WFNS and hWFNS scale after neurological resuscitation, the specificity to predict poor outcome increased from 0.19 (WFNS) to 0.93 (hWFNS) (McNemar, P<0.001) whereas the sensitivity decreased from 0.88 to 0.37 (P<0.001), and the positive predictive value from 61.9 to 88.3 (weighted generalized score statistic, P<0.001). For mortality, the specificity increased from 0.19 to 0.93 (McNemar, P<0.001), and the positive predictive value from 52.5 to 86.7 (weighted generalized score statistic, P<0.001). CONCLUSIONS: The identification of objective positive signs of brain stem dysfunction significantly improves the specificity and positive predictive value with respect to poor outcome in grade V patients. Therefore, a simple modification-presence of brain stem signs is required for grade V-should be added to the WFNS classification. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT02304328.

Hydrocephalus Shunting in Supratentorial Glioblastoma: Functional Outcomes and Management.

BACKGROUND: Glioblastoma is the most common and the most challenging to treat adult primary central nervous system tumor. Although modern management strategies modestly improved the overall survival, the prognosis remains dismal associated with poor life quality and the clinical course often dotted by treatment side effects and cognitive decline. Functional deterioration might be caused by obstructive or communicating hydrocephalus but due to poor overall prognosis surgical treatment options are often limited and its optimal management strategies remain elusive. We aimed to investigate risk factors, treatment options and outcomes for tumor-associated hydrocephalus in a contemporary 10 years cohort of glioblastoma patients. METHODS: We reviewed electronic health records of 1800 glioblastoma patients operated at the Department of Neurosurgery, Medical Center - University of Freiburg from 2009 to 2019. Demographics, clinical characteristics and radiological features were analyzed. Univariate analysis for nominal variables was performed either by Fisher's exact test or Chi-square test, as appropriate. RESULTS: We identified 39 glioblastoma patients with symptomatic communicating hydrocephalus treated by ventricular shunting (incidence 2.1%). Opening of the ventricular system during a previous tumor resection was associated with symptomatic hydrocephalus (p<0.05). There was also a trend toward location (frontal and temporal) and larger tumor volume. Number of craniotomies before shunting was not considered as a risk factor. Shunting improved hydrocephalus symptoms in 95% of the patients and Karnofsky Performance Score (KPS) could be restored after shunting. Of note, 75% of the patients had a post-shunting oncological treatment such as radiotherapy or chemotherapy, most prevalently chemotherapy. Infection (7.7%) and over- or under drainage (17.9%) were the most common complications requiring shunt revision in ten patients (25.6%), No peritoneal metastasis was found. The median overall survival (OS) was 385 days and the median post shunting survival was 135 days. CONCLUSION: Ventricular system opening was identified as a risk factor for communicating hydrocephalus in glioblastoma patients. Although glioblastoma treatment remains challenging, shunting improved hydrocephalus-related functional status and may be considered even in a palliative setting for symptom relief.

Syndrome of the trephined: clinical spectrum, risk factors, and impact of cranioplasty on neurologic recovery in a prospective cohort.

Syndrome of the trephined (SoT) is an underrecognized complication after decompressive craniectomy. We aimed to investigate SoT incidence, clinical spectrum, risk factors, and the impact of the cranioplasty on neurologic recovery. Patients undergoing a large craniectomy (> 80 cm2) and cranioplasty were prospectively evaluated using modified Rankin score (mRS), cognitive (attention/processing speed, executive function, language, visuospatial), motor (Motricity Index, Jamar dynamometer, postural score, gait assessment), and radiologic evaluation within four days before and after a cranioplasty. The primary outcome was SoT, diagnosed when a neurologic improvement was observed after the cranioplasty. The secondary outcome was a good neurologic outcome (mRS 0-3) 4 days and 90 days after the cranioplasty. Logistic regression models were used to evaluate the risk factors for SoT and the impact of cranioplasty timing on neurologic recovery. We enrolled 40 patients with a large craniectomy; 26 (65%) developed SoT and improved after the cranioplasty. Brain trauma, hemorrhagic lesions, and shifting of brain structures were associated with SoT. After cranioplasty, a shift towards a good outcome was observed within 4 days (p = 0.025) and persisted at 90 days (p = 0.005). Increasing delay to cranioplasty was associated with decreased odds of improvement when adjusting for age and baseline disability (odds ratio 0.96; 95% CI, 0.93-0.99, p = 0.012). In conclusion, SoT is frequent after craniectomy and interferes with neurologic recovery. High suspicion of SoT should be exercised in patients who fail to progress or have a previous trauma, hemorrhage, or shifting of brain structures. Performing the cranioplasty earlier was associated with improved and quantifiable neurologic recovery. Graphical abstract.

Stimulated Raman histology in the neurosurgical workflow of a major European neurosurgical center - part A.

Histopathological diagnosis is the current standard for the classification of brain and spine tumors. Raman spectroscopy has been reported to allow fast and easy intraoperative tissue analysis. Here, we report data on the intraoperative implementation of a stimulated Raman histology (SRH) as an innovative strategy offering intraoperative near real-time histopathological analysis. A total of 429 SRH images from 108 patients were generated and analyzed by using a Raman imaging system (Invenio Imaging Inc.). We aimed at establishing a dedicated workflow for SRH serving as an intraoperative diagnostic, research, and quality control tool in the neurosurgical operating room (OR). First experiences with this novel imaging modality were reported and analyzed suggesting process optimization regarding tissue collection, preparation, and imaging. The Raman imaging system was rapidly integrated into the surgical workflow of a large neurosurgical center. Within a few minutes of connecting the device, the first high-quality images could be acquired in a "plug-and-play" manner. We did not encounter relevant obstacles and the learning curve was steep. However, certain prerequisites regarding quality and acquisition of tissue samples, data processing and interpretation, and high throughput adaptions must be considered. Intraoperative SRH can easily be integrated into the workflow of neurosurgical tumor resection. Considering few process optimizations that can be implemented rapidly, high-quality images can be obtained near real time. Hence, we propose SRH as a complementary tool for the diagnosis of tumor entity, analysis of tumor infiltration zones, online quality and safety control and as a research tool in the neurosurgical OR.

Neuropathological interpretation of stimulated Raman histology images of brain and spine tumors: part B.

Intraoperative histopathological examinations are routinely performed to provide neurosurgeons with information about the entity of tumor tissue. Here, we quantified the neuropathological interpretability of stimulated Raman histology (SRH) acquired using a Raman laser imaging system in a routine clinical setting without any specialized training or prior experience. Stimulated Raman scattering microscopy was performed on 117 samples of pathological tissue from 73 cases of brain and spine tumor surgeries. A board-certified neuropathologist - novice in the interpretation of SRH - assessed image quality by scoring subjective tumor infiltration and stated a diagnosis based on the SRH images. The diagnostic accuracy was determined by comparison to frozen hematoxylin-eosin (H&E)-stained sections and the ground truth defined as the definitive neuropathological diagnosis. The overall SRH imaging quality was rated high with the detection of tumor cells classified as inconclusive in only 4.2% of all images. The accuracy of neuropathological diagnosis based on SRH images was 87.7% and was non-inferior to the current standard of fast frozen H&E-stained sections (87.3 vs. 88.9%, p = 0.783). We found a substantial diagnostic correlation between SRH-based neuropathological diagnosis and H&E-stained frozen sections (κ = 0.8). The interpretability of intraoperative SRH imaging was demonstrated to be equivalent to the current standard method of H&E-stained frozen sections. Further research using this label-free innovative alternative vs. conventional staining is required to determine to which extent SRH-based intraoperative decision-making can be streamlined in order to facilitate the advancement of surgical neurooncology.

Combining H-FABP and GFAP increases the capacity to differentiate between CT-positive and CT-negative patients with mild traumatic brain injury.

Mild traumatic brain injury (mTBI) patients may have trauma-induced brain lesions detectable using CT scans. However, most patients will be CT-negative. There is thus a need for an additional tool to detect patients at risk. Single blood biomarkers, such as S100B and GFAP, have been widely studied in mTBI patients, but to date, none seems to perform well enough. In many different diseases, combining several biomarkers into panels has become increasingly interesting for diagnoses and to enhance classification performance. The present study evaluated 13 proteins individually-H-FABP, MMP-1, MMP-3, MMP-9, VCAM, ICAM, SAA, CRP, GSTP, NKDA, PRDX1, DJ-1 and IL-10-for their capacity to differentiate between patients with and without a brain lesion according to CT results. The best performing proteins were then compared and combined with the S100B and GFAP proteins into a CT-scan triage panel. Patients diagnosed with mTBI, with a Glasgow Coma Scale score of 15 and one additional clinical symptom were enrolled at three different European sites. A blood sample was collected at hospital admission, and a CT scan was performed. Patients were divided into two two-centre cohorts and further dichotomised into CT-positive and CT-negative groups for statistical analysis. Single markers and panels were evaluated using Cohort 1. Four proteins-H-FABP, IL-10, S100B and GFAP-showed significantly higher levels in CT-positive patients. The best-performing biomarker was H-FABP, with a specificity of 32% (95% CI 23-40) and sensitivity reaching 100%. The best-performing two-marker panel for Cohort 1, subsequently validated in Cohort 2, was a combination of H-FABP and GFAP, enhancing specificity to 46% (95% CI 36-55). When adding IL-10 to this panel, specificity reached 52% (95% CI 43-61) with 100% sensitivity. These results showed that proteins combined into panels could be used to efficiently classify CT-positive and CT-negative mTBI patients.