Non-invasive biomarkers for spontaneous intracranial hypotension (SIH) through phase-contrast MRI.

BACKGROUND AND OBJECTIVE: Spontaneous intracranial hypotension (SIH) is an underdiagnosed disease. To depict the accurate diagnosis can be demanding; especially the detection of CSF-venous fistulas poses many challenges. Potential dynamic biomarkers have been identified through non-invasive phase-contrast MRI in a limited subset of SIH patients with evidence of spinal longitudinal extradural collection. This study aimed to explore these biomarkers related to spinal cord motion and CSF velocities in a broader SIH cohort. METHODS: A retrospective, monocentric pooled-data analysis was conducted of patients suspected to suffer from SIH who underwent phase-contrast MRI for spinal cord and CSF velocity measurements at segment C2/C3 referred to a tertiary center between February 2022 and June 2023. Velocity ranges (mm/s), total displacement (mm), and further derivatives were assessed and compared to data from the database of 70 healthy controls. RESULTS: In 117 patients, a leak was located (54% ventral leak, 20% lateral leak, 20% CSF-venous fistulas, 6% sacral leaks). SIH patients showed larger spinal cord and CSF velocities than healthy controls: e.g., velocity range 7.6 ± 3 mm/s vs. 5.6 ± 1.4 mm/s, 56 ± 21 mm/s vs. 42 ± 10 mm/s, p < 0.001, respectively. Patients with lateral leaks and CSF-venous fistulas exhibited an exceptionally heightened level of spinal cord motion (e.g., velocity range 8.4 ± 3.3 mm/s; 8.2 ± 3.1 mm/s vs. 5.6 ± 1.4 mm/s, p < 0.001, respectively). CONCLUSION: Phase-contrast MRI might become a valuable tool for SIH diagnosis, especially in patients with CSF-venous fistulas without evidence of spinal extradural fluid collection.

Cerebrospinal fluid biomarkers of superficial siderosis in patients with spontaneous intracranial hypotension.

BACKGROUND AND PURPOSE: Spontaneous intracranial hypotension (SIH) is an important etiology of infratentorial superficial siderosis (iSS) of the central nervous system. However, the prevalence of iSS amongst patients with SIH is unknown and the imaging findings of iSS might represent a late stage of disease. The aim was to identify cerebrospinal fluid (CSF) biomarkers of iSS in patients with SIH. METHODS: Consecutive patients evaluated for SIH at our institution between May 2017 and January 2019 were included. Lumbar CSF samples were analyzed for the presence of ferritin and bilirubin. Magnetic resonance imaging was assessed for the presence of iSS. RESULTS: Twenty-four patients with SIH were included. CSF samples were positive for bilirubin in 2/19 (10.5%). CSF ferritin was elevated in 7/23 (30.4%). Signs of iSS on imaging were present in four patients (16.7%). All patients with imaging signs of iSS demonstrated elevated CSF ferritin. Ferritin level was significantly higher amongst patients demonstrating iSS compared to those without (median 45.0 vs. 11.0 µg/l; p = 0.003). Symptom duration was longer in patients with iSS than in patients without iSS (median 40 months vs. 9 months, p = 0.018). CONCLUSION: Cerebrospinal fluid alterations indicative of iSS are prevalent amongst patients with SIH. It is speculated that a preclinical phase without symptoms or imaging signs but during which elevated biomarkers of the disease are apparent from CSF analysis might exist. It is suggested that measurement of CSF ferritin is incorporated in the work-up of patients with SIH to identify those at risk of developing iSS.

68Ga-DOTA PET for Diagnosis of Spinal Cerebrospinal Fluid Leaks.

Spontaneous intracranial hypotension due to spinal cerebrospinal fluid (CSF) leakage causes substantial disease burden. In many patients, the course is protracted and refractory to conservative treatment, requiring targeted therapy. We propose PET of the CSF space with 68Ga-DOTA as a state-of-the-art approach to radionuclide cisternography (RC) and validate its diagnostic value. Methods: This study is a retrospective analysis of patients with suspected intracranial hypotension due to spinal CSF leaks and who underwent whole-body PET/CT at 1, 3, and 5 h after intrathecal lumbar injection of 68Ga-DOTA. Two independent raters unaware of the clinical data analyzed all scans for direct and indirect RC signs of CSF leakage. Volume-of-interest analysis was performed to assess the biologic half-life of the tracer in the CSF space and the ratio of decay-corrected activity in the CSF space at 5 and 3 h (simplified marker of tracer clearance). Comprehensive stepwise neuroradiologic work-up served as a reference; additional validation was provided by surgical findings and follow-up. Results: Of 40 consecutive patients, 39 patients with a working diagnosis of intracranial hypotension due to a spinal CSF leak (spontaneous, n = 31; postintervention, n = 8) could be analyzed. A spinal CSF leak was verified by the neuroradiologic reference method in 18 of 39 patients. As the only direct and indirect diagnostic signs, extrathecal tracer accumulation at the cervicothoracic junction (67% sensitivity and 90% specificity) and lack of activity over the cerebral convexities (5 h; 94% sensitivity and 67% specificity) revealed a high diagnostic value for spinal CSF leaks. Their combination provided little improvement (71% sensitivity and 95% specificity). Additional quantitative analyses yielded no benefit (94% sensitivity and 53% specificity for biological half-life; 94% sensitivity and 58% specificity for the ratio of total radioactivity within the CSF space at 5 and 3 h). The location of direct signs (extrathecal tracer accumulation) did not correlate with verified sites of spinal CSF leakage. Conclusion: We propose CSF PET with 68Ga-DOTA as a novel, fast, and convenient approach to RC for verification but not localization of spinal CSF leaks with high sensitivity and specificity. CSF PET may fulfill an important gatekeeper function for stratifying patients toward escalation (ruling in) or deescalation (ruling out) of diagnostic and therapeutic measures. Further prospective studies are needed to validate the present results and determine the potential of the methods to reduce the burden to patients.

Detection rate of MR myelography without intrathecal gadolinium in patients with newly diagnosed spontaneous intracranial hypotension.

AIM: To evaluate the detection rate of magnetic resonance (MR) myelography without intrathecal gadolinium for cerebrospinal fluid (CSF) leakage in patients with newly diagnosed spontaneous intracranial hypotension (SIH) and to validate a published scoring system for predicting CSF leakage. MATERIALS AND METHODS: This retrospective, observational, single-institution study included patients with newly diagnosed SIH between March 2015 and April 2021. Patients were included if they (a) had newly diagnosed SIH and (b) underwent initial brain MR imaging and preprocedural MR myelography with two- and three-dimensional turbo spin-echo sequences. Patients who underwent spine surgery or procedures including epidural injection and acupuncture were excluded. The detection rate was defined as the proportion of patients with a true-positive MR myelography result among all patients with confirmed CSF leakage. The interobserver agreement for the MR myelography results between two radiologists was analysed using weighted kappa statistics. RESULTS: A total of 136 patients (mean age, 48 years; 70 women) with suspected SIH were included. Of these patients, 120 (88%, 120/136) were confirmed to have CSF leakage. Of the patients with confirmed CSF leakage, 90 (75%, 90/120) had epidural fluid collection. The detection rate of MR myelography for CSF leakage was 88% (105/120). The interobserver agreement between the two readers for detecting CSF leakage (κ = 0.76) or epidural fluid collection (κ = 0.76) on MR myelography was high. Among 24 patients with normal brain MR imaging results, 16 had CSF leakage (67%, 16/24). CONCLUSIONS: Non-invasive MR myelography without intrathecal gadolinium should be considered to detect CSF leakage in patients with suspected SIH.

Clinical significance of Epstein-Barr virus in the cerebrospinal fluid of immunocompetent patients.

INTRODUCTION: Polymerase chain reaction (PCR)-based testing of cerebrospinal fluid (CSF) samples has greatly facilitated the diagnosis of central nervous system (CNS) infections. However, the clinical significance of Epstein-Barr virus (EBV) DNA in CSF of individuals with suspected CNS infection remains unclear. We wanted to gain a better understanding of EBV as an infectious agent in immunocompetent patients with CNS disorders. METHODS: We identified cases of EBV-associated CNS infections and reviewed their clinical and laboratory characteristics. The study population was drawn from patients with EBV PCR positivity in CSF who visited Pusan National University Hospital between 2010 and 2019. RESULTS: Of the 780 CSF samples examined during the 10-year study period, 42 (5.4 %) were positive for EBV DNA; 9 of the patients (21.4 %) were diagnosed with non-CNS infectious diseases, such as optic neuritis, Guillain-Barré syndrome, and idiopathic intracranial hypotension, and the other 33 cases were classified as CNS infections (22 as encephalitis and 11 as meningitis). Intensive care unit admission (13/33 patients, 39.3 %) and presence of severe neurological sequelae at discharge (8/33 patients, 24.2 %) were relatively frequent. In 10 patients (30.3 %), the following pathogens were detected in CSF in addition to EBV: varicella-zoster virus (n = 3), cytomegalovirus (n = 2), herpes simplex virus 1 (n = 1), herpes simplex virus 2 (n = 1), Streptococcus pneumomiae (n = 2), and Enterococcus faecalis (n = 1). The EBV-only group (n = 23) and the co-infection group (n = 10) did not differ in age, gender, laboratory data, results of brain imaging studies, clinical manifestations, or prognosis; however, the co-infected patients had higher CSF protein levels. CONCLUSION: EBV DNA in CSF is occasionally found in the immunocompetent population; the virus was commonly associated with encephalitis and poor prognosis, and frequently found together with other microbes in CSF.

Intracranial Hypotension and Cerebrospinal Fluid Leak.

Review of the clinical presentation, imaging findings, and management of headache secondary to intracranial hypotension.

Magnetic resonance imaging provides evidence of glymphatic drainage from human brain to cervical lymph nodes.

Pre-clinical research in rodents provides evidence that the central nervous system (CNS) has functional lymphatic vessels. In-vivo observations in humans, however, are not demonstrated. We here show data on CNS lymphatic drainage to cervical lymph nodes in-vivo by magnetic resonance imaging (MRI) enhanced with an intrathecal contrast agent as a cerebrospinal fluid (CSF) tracer. Standardized MRI of the intracranial compartment and the neck were acquired before and up to 24-48 hours following intrathecal contrast agent administration in 19 individuals. Contrast enhancement was radiologically confirmed by signal changes in CSF nearby inferior frontal gyrus, brain parenchyma of inferior frontal gyrus, parahippocampal gyrus, thalamus and pons, and parenchyma of cervical lymph node, and with sagittal sinus and neck muscle serving as reference tissue for cranial and neck MRI acquisitions, respectively. Time series of changes in signal intensity shows that contrast enhancement within CSF precedes glymphatic enhancement and peaks at 4-6 hours following intrathecal injection. Cervical lymph node enhancement coincides in time with peak glymphatic enhancement, with peak after 24 hours. Our findings provide in-vivo evidence of CSF tracer drainage to cervical lymph nodes in humans. The time course of lymph node enhancement coincided with brain glymphatic enhancement rather than with CSF enhancement.

Spontaneous intracranial hypotension is diagnosed by a combination of lipocalin-type prostaglandin D synthase and brain-type transferrin in cerebrospinal fluid.

BACKGROUND: Spontaneous intracranial hypotension (SIH) is caused by cerebrospinal fluid (CSF) leakage. Definitive diagnosis can be difficult by clinical examinations and imaging studies. METHODS: SIH was diagnosed with the following criteria: (i) evidence of CSF leakage by cranial magnetic resonance imaging (MRI) findings of intracranial hypotension and/or low CSF opening pressure; (ii) no recent history of dural puncture. We quantified CSF proteins by ELISA or Western blotting. RESULTS: Comparing with non-SIH patients, SIH patients showed significant increase of brain-derived CSF glycoproteins such as lipocalin-type prostaglandin D synthase (L-PGDS), soluble protein fragments generated from amyloid precursor protein (sAPP) and "brain-type" transferrin (Tf). Serum-derived proteins such as albumin, immunoglobulin G, and serum Tf were also increased. A combination of L-PGDS and brain-type Tf differentiated SIH from non-SIH with sensitivity 94.7% and specificity 72.6%. CONCLUSION: L-PGDS and brain-type Tf can be biomarkers for diagnosing SIH. GENERAL SIGNIFICANCE: L-PGDS and brain-type Tf biosynthesized in the brain appears to be markers for abnormal metabolism of CSF.

Impaired cerebrospinal fluid pressure.

Abnormalities of cerebrospinal fluid (CSF) pressure are relatively common and may lead to a variety of symptoms, with headache usually being the most prominent one. The clinical presentation of alterations in CSF pressure may vary significantly and show a striking similitude to several primary headache syndromes. While an increase in CSF pressure may be of primary or secondary origin, a pathologic decrease of CSF pressure is usually the result of a meningeal rupture with a resulting leakage of CSF. The pathophysiologic mechanisms of idiopathic intracranial hypertension (IIH) remain largely unknown. However recent evidence indicates that an abnormality in CSF outflow and absorption is likely to play a significant role. Treatment usually consists of a combination of weight loss and a pharmacologic approach using carbonic anhydrase inhibitors. Recent results of the first randomized, double-blind, placebo-controlled trial (RCT) with acetazolamide proved its efficacy in reducing headache and visual disturbances. Clinical evidence suggests efficacy for topiramate and furosemide but no RCT has been conducted to date to confirm these results. In contrast to IIH, spontaneous intracranial hypotension frequently remits spontaneously without specific treatment. If necessary, treatment options range from conservative methods to epidural blood or fibrin sealant patches and surgical interventions.

Factors affecting cerebrospinal fluid opening pressure in patients with spontaneous intracranial hypotension.

OBJECTIVE: Spontaneous intracranial hypotension (SIH) is recognized far more commonly than ever before. Though usually characterized by low cerebrospinal fluid (CSF) pressure, some patients with SIH are observed to have normal pressure values. In this study, we aimed to confirm the proportion of patients with normal CSF opening pressure (CSF OP) and explore the factors affecting CSF OP in SIH patients. METHODS: We retrospectively reviewed 206 consecutive SIH patients and analyzed their clinical and imaging variables (including demographic data, body mass index (BMI), duration of symptoms, and brain imaging findings). Univariate and multivariate analyses were performed to identify the potential factors affecting CSF OP. RESULTS: In a total of 114 (55.3%) cases the CSF OP was ≤60 mmH2O (1 mmH2O=9.806 65 Pa), in 90 (43.7%) cases it was between 60 and 200 mmH2O, and in 2 (1.0%) cases it was >200 mmH2O. Univariate analysis showed that the duration of symptoms (P<0.001), BMI (P<0.001), and age (P=0.024) were positively correlated with CSF OP. However, multivariate analysis suggested that only the duration of symptoms (P<0.001) and BMI (P<0.001) were strongly correlated with CSF OP. A relatively high R2 of 0.681 was obtained for the multivariate model. CONCLUSIONS: Our study indicated that in patients without a low CSF OP, a diagnosis of SIH should not be excluded. BMI and the duration of symptoms can influence CSF OP in SIH patients, and other potential factors need further investigation.

Quantitative Measurement of CSF in Patients with Spontaneous Intracranial Hypotension.

BACKGROUND AND PURPOSE: CSF hypovolemia is a core feature of spontaneous intracranial hypotension. Spontaneous intracranial hypotension is characterized by orthostatic headache and radiologic manifestations, including CSF along the neural sleeves, diffuse pachymeningeal enhancement, and/or venous engorgement. However, these characteristics are only qualitative. Quantifying intraspinal CSF volumes could improve spontaneous intracranial hypotension diagnosis and evaluation of hypovolemic statuses in patients with spontaneous intracranial hypotension. The purpose of this study was to compare intraspinal CSF volumes across spontaneous intracranial hypotension stages and to test the clinical applicability of these measures. MATERIALS AND METHODS: A cohort of 23 patients with spontaneous intracranial hypotension and 32 healthy controls was subjected to brain MR imaging and MR myelography with 1.5T imaging. An automatic threshold-based segmentation method was used to calculate intraspinal CSF volumes at initial hospitalization (spontaneous intracranial hypotension-initial), partial improvement (spontaneous intracranial hypotension-intermediate), and complete recovery (spontaneous intracranial hypotension-recovery) stages. RESULTS: The mean intraspinal CSF volumes observed were the following: 95.31 mL for healthy controls, 72.31 mL for spontaneous intracranial hypotension-initial, 81.15 mL for spontaneous intracranial hypotension-intermediate, and 93.74 mL for spontaneous intracranial hypotension-recovery. Increased intraspinal CSF volumes were related to disease recovery (P < .001). The intraspinal CSF volumes of patients before complete recovery were significantly lower than those of healthy controls. With the estimated intradural CSF volumes as a reference, the intraspinal CSF volume percentage was lower in patients with spontaneous intracranial hypotension with venous engorgement than in those without it (P = .058). CONCLUSIONS: With a threshold-based segmentation method, we found that spinal CSF hypovolemia is fundamentally related to spontaneous intracranial hypotension. Intraspinal CSF volumes could be a sensitive parameter for the evaluation of treatment response and follow-up monitoring in patients with spontaneous intracranial hypotension.

Patterns of cerebrospinal fluid (CSF) distribution in patients with spontaneous intracranial hypotension: Assessed with magnetic resonance myelography.

BACKGROUND: Diagnosis of spontaneous intracranial hypotension (SIH) relies on the ability of medical staff to recognize cerebrospinal fluid (CSF) leakage at the spine. However, difficulties with interobserver discrepancy sometimes occurred while reading magnetic resonance myelography (MRM) because clear image definition was lacking. In this study, we tried to determine which pattern of CSF distribution is more reliable for diagnosis of CSF leakage by using MRM. METHODS: From January 2012 to August 2014, 19 SIH patients and 27 healthy controls (HC) were recruited into our study; 10 of the 19 patients were recovered (SIH-R) after treatment. Whole spine MRM was performed using the 3D-SPACE (three-dimensional sampling perfection with application-optimized contrasts using different flip-angle evolutions) sequence, and interpreted by two experienced neuroradiologists. Two 4-point classification systems of CSF distribution were used to evaluate the three-dimensional maximum intensity projection (3D MIP) and the thin-slice axial multiplanar reconstruction (MPR) images, respectively. RESULTS: The interobserver agreement between the two readers interpreting the 3D MIP and thin-slice axial MPR MRM were moderate to good (κ=0.60-0.78). Grade 3 of 3D MIP and Type D of axial MPR MRM were only noticed in the SIH. Overall, Grade 3 of MIP and Type D of MPR showed significant difference (p<0.008) between the SIH and the HC in the whole spine. Type C at the T-spine was more frequently noted in the SIH than in the HC (p<0.038). By using "Grade 3", "Type D", "Type D and Type C at T-spine" as the diagnostic criteria of CSF leakage, the sensitivity, specificity, positive predict value (PPV), and negative predict value (NPV) were all > 70%. CONCLUSION: Grade 3 on 3D MIP and Type D on axial MPR MRM were definite criteria of MRM for localizing CSF leakage, and Type C in the T-spine was a probable leakage sign with high sensitivity and NPV.

Spontaneous intracranial hypotension caused by cervical CSF fistulae mimicking subarachnoid haemorrhage - a case report.

We describe an unusual and rarely documented site of SIH supported by clear radiological evidence: a case of spontaneous cerebrospinal fluid (CSF) fistulae involving the C7 and C8 nerve root sheaths, presenting with sudden onset headache and requiring surgical intervention to seal the leaks. Investigations confirmed the leaks and the typical MRI findings of meningeal enhancement, which were resolved after surgery.

CSF hypotension: A review of its manifestations, investigation and management.

Intracranial cerebrospinal fluid (CSF) hypotension usually arises in the context of known or suspected leak of CSF. This can be spontaneous, or due to central nervous system trauma or dural defects created during lumbar puncture or epidural anaesthesia. Spontaneous intracranial hypotension (SIH) is increasingly being recognised as a cause for orthostatic headache or spontaneous subdural haematoma where no other obvious cause is found. We review CSF physiology, the mechanism of symptom generation in CSF hypotension and the investigation and management of the syndrome. Whilst commonly mild and self-limiting, CSF hypotension may result in life threatening complications and is most often treatable. When the syndrome is severe, prolonged or complicated, epidural blood patching (EBP) is the mainstay of treatment.

[Headhache secondary to intracranial hypotension in a Lumbar Spinal Stenosis Surgery].

Intracraneal hypotension headache is a well known syndrome in neurosurgery practice. In most cases cerebrospinal fluid leaks are caused by medical interventions, such as lumbar puncture, peridural anesthesia and surgical interventions on the spine. Clinical symptoms tipically show orthostatic headache that resolves in supine position, and other symptoms like neck tightness, vertigo and diplopia. RMI diagnostic confirms paquimeningeal enhancement and subdural hygromas. Conservative treatment usually includes bed resting, hydratation and administration of caffeine or glucocorticoids, resolving spontaneously in one to four months. The importance of the diagnosis lies in the differential diagnosis with other causes of headache, as symptomatic limiting factor in the rehabilitation of the patient and the same favorable prognosis.

Imaging Signs in Spontaneous Intracranial Hypotension: Prevalence and Relationship to CSF Pressure.

BACKGROUND AND PURPOSE: Patients with spontaneous intracranial hypotension often exhibit low CSF pressure and changes on brain MR imaging and/or evidence of CSF leak on myelography. We investigated whether individual imaging signs of spontaneous intracranial hypotension correlate with measured CSF pressure and how frequently these 2 markers of spontaneous intracranial hypotension were concordant. MATERIALS AND METHODS: We performed a retrospective, cross-sectional study of 99 subjects with spontaneous intracranial hypotension. Prevalence of brain and myelographic imaging signs of spontaneous intracranial hypotension was recorded. CSF pressure among subjects with or without individual imaging signs was compared by using a 2-tailed t test and ANOVA. Concordance between low CSF pressure (≤6 cm H2O) and imaging was defined as the presence of the sign in a subject with low CSF pressure or absence of the sign when pressure was not low. RESULTS: Dural enhancement, brain sagging, and venous distension sign were present in 83%, 61%, and 75% of subjects, respectively, and myelographic evidence of CSF leak was seen in 55%. Marginal correlations between CSF pressure and brain sagging (P = .046) and the venous distension sign (P = .047) were found. Dural enhancement and myelographic evidence of leak were not significantly correlated with CSF pressure. Rates of concordance between imaging signs and low CSF pressure were generally low, ranging from 39% to 55%. CONCLUSIONS: Brain and myelographic signs of spontaneous intracranial hypotension correlate poorly with CSF pressure. These findings reinforce the need to base the diagnosis of spontaneous intracranial hypotension on multiple diagnostic criteria and suggest the presence of patient-specific variables that influence CSF pressure in these individuals.

Spontaneous intracranial hypotension presenting with coma: a case report and literature review.

Spontaneous intracranial hypotension is characterized by orthostatic headache in the absence of a history of head trauma or lumbar puncture, and diagnosis is confirmed by a specific cerebrospinal fluid pressure and neuroimaging findings. It rarely presents with coma. A 62-year-old man presented with progressive cognitive decline of 2 to 4 weeks' duration. He was diagnosed with spontaneous intracranial hypotension according to cerebrospinal fluid pressure and neuroimaging findings, and treated conservatively.

Usefulness of phase-contrast magnetic resonance imaging for diagnosis and treatment evaluation in patients with SIH.

BACKGROUND: Most diagnostic tools for spontaneous intracranial hypotension (SIH) are either invasive or occasionally inconsistent with the clinical condition. In this study, we examined the cerebrospinal fluid (CSF) dynamics in SIH using phase-contrast magnetic resonance (PC-MR) imaging. MATERIALS AND METHOD: Seventeen SIH patients and 32 healthy individuals, matched by sex and age, were recruited. Each person underwent brain and PC-MR imaging using 3-Tesla MRI. We evaluated the differences in image parameters among patients during the initial and recovery stages against the status of the control group. RESULTS: SIH patients had lower CSF flow-volume, flux, peak velocity, and higher systolic-to-diastolic time ratio, as well as systolic-to-diastolic volume ratio compared to the control group and the conditions when they recovered. The flow time and volume of the diastolic phase markedly increased after treatment. The discriminating power of PC-MR for SIH was good. Diffuse pachymeningeal enhancement and venous engorgement were present when their PC-MR values were lower than the cut-off values for SIH diagnosis. The headache scores correlated with the peak velocity and pituitary volume. CONCLUSION: Noninvasive PC-MR could provide valid parameters for diagnosis and treatment follow-up in SIH patients. It may be more sensitive than conventional brain MRI.