The Freiburg Registry on SpontanEous IntercrAnial Hypotension (SIH) & Post-duraL Puncture Headache (PDPH)
- Conditions
- CerebroSpinal Fluid (CSF) Leak
- Registration Number
- NCT06711731
- Lead Sponsor
- University Hospital Freiburg
- Brief Summary
Spinal CSF leaks are considered as rare disease. They cause a variety of symptoms, mainly culminating in a chronic headache syndrome. Crucially, yet often disregarded, the disease holds the potential for cure. The multitude of symptoms, and their inconsistency over time are just two of many challenges preventing timely diagnosis and treatment in many patients.
Spinal CSF leaks can occur after intentional or accidental dural puncture (post-dural puncture headache - PDPH) or spontaneously (spontaneous intracranial hypotension - SIH). Awareness is steadily increasing with simultaneous increase of recognized patients. Yet, research and diagnostic is mainly provided by few specialized centers, as e.g. Freiburg. Thus, many observations point towards a large non-diagnosed and non-recognized number of patients, most likely being misdiagnosed and mistreated.
Objective: The aim of the registry is to collect structured information on the frequency, cause, symptoms, diagnostic procedures, treatment options and long-term outcome. With the help of the registry, we would like to contribute to a better understanding and treatment of the diseases.
Methods: Prospective, longitudinal registry on patients with suspected SIH or PDPH, including data on demographics, clinical presentation, diagnostic findings, treatment, at treatment outcome.
- Detailed Description
Spinal CSF leaks have a severe impact on quality of life and health. Symptoms vary from chronic headache syndrome to intracranial bleeding, cognitive decline, and coma. Crucially, yet often disregarded, the disease holds the potential for cure.
Lumbar dural leaks can arise from commonly performed medical interventions such as diagnostic lumbar punctures, spinal anesthesia, spinal infiltrations, or incidental dural punctures during epidural analgesia in obstetric care, resulting in post-dural puncture headache (PDPH).
Additionally, a notable fraction of spinal CSF leaks manifests as spontaneous intracranial hypotension (SIH), which derives from different types of spontaneous leaks along the Spine and remains broadly under-recognized.
The main clinical symptoms of spinal CSF leaks are orthostatic headaches with a most often defined beginning, typically accompanied by hearing impairment and dizziness, worsened by exercise and movement. Additionally, other manifestations are known, such as cognitive decline, bilateral brachial amyotrophy, paradox headache, fatigue, and many more. In patients presenting with spinal CSF leaks, the accurate diagnosis often eludes clinicians, leading to frequent misdiagnoses of chronic migraine, fatigue, or psychiatric conditions. Many patients endure months, if not years, before a diagnosis of a treatable condition is finally established. The heterogeneity of the symptoms can appear inconsistent or even paradoxical, posing diagnostic challenges. The extent of possible long-term deterioration is not recognized.
The reported incidence of PDPH fluctuates considerably, ranging from 2 to 40 per 100 procedures performed. This variance is influenced by patient-related factors (e.g., age, gender, pregnancy status) and procedural factors (e.g., needle size and type). PDPH, according to current criteria, occurs within 5 days after a dural puncture. Nevertheless, there are widely underestimated pitfalls: a dural puncture is not always recognized by the person performing an epidural procedure, symptoms can occur after more than 5 days, and disease courses can be chronic. These facts are widely unknown, leading to largely hidden figures of patients being under or misdiagnosed and, thus, not treated. Moreover, PDPH is primarily observed following unintentional dural puncture during the administration of obstetric anaesthesia and analgesia to parturients.
Spontaneous intracranial hypotension (SIH) can be caused by ventral, lateral, or sacral spinal leaks or by CSF-venous fistulae, which was first described in 2014. An annual incidence rate of \~ 4/100,000 was estimated in 2022. This rate is likely underestimated as it only includes confirmed cases, thus recognized cases within a widely non-recognized entity. Often, patients are neither identified nor directed to the appropriate MRI, which, in numerous instances, could lead to the correct diagnosis. Even when SIH is identified, non-targeted epidural blood patches in the lumbar region are often not administered due to perceived elevated risks. An epidural blood patch might be able to help to heal the leak. At the same time, it must be noted that even long-term improvement does not necessarily indicate closure of the leak and prevention of long-term sequelae, such as superficial siderosis. Invasive diagnostics are not employed to pinpoint the location, and treatment to seal the leak is not consistently pursued. The effects of treatment are often immediate and can be successful even in chronic patients. Evidence shows that leaks are held open by new membranes (Neo-membranes) that prevent spontaneous healing. Thus, the correct localization of such a leak and targeted sealing or close follow-ups should be initiated.
The management approaches for SIH and PDPH significantly deviate from standard pain management strategies employed for other types of headaches. Noteworthy interventions include the application of blood patches and even surgical measures to seal the leak, offering curative solutions. Those enduring chronic spinal CSF leaks experience profound limitations in their health-related quality of life, comparable to those with chronic immunological diseases or cancer. Overlooking the diagnosis and management of spinal CSF leaks may precipitate progressive deterioration, with the potential for persistent sequelae like superficial siderosis, syndromes mimicking frontotemporal dementia (FTD), and chronic subdural hematoma formation.
This registry aims to set ground for standardized, prospective demographic, diagnostic and treatment data assessments, and patient self-reported outcome measures.
Collecting this data is essential to potentially exploring risk factors, understanding outcome predictors, and refining diagnostics. Additionally, standardized data collection will allow the appropriate designing of urgently needed randomized trials.
Aims:
Primary aim:
To describe the proportion of patients diagnosed with SIH or PDPH
Secondary aims:
1. To describe the proportion of different spinal CSF leaks observed per entity
2. To describe the demographics per entity, and per different spinal CSF leak type
3. To describe the clinical spectrum per entity, and per different spinal CSF leak type
4. To describe the imaging features per entity, and per different spinal CSF leak type
5. To describe the outcome of different treatments, and per different spinal CSF leak type
6. To describe the adverse events of different treatments, and per different spinal CSF leak type
7. To explore potential diagnostic markers per entity, and per different spinal CSF leak type
8. To explore risk factors per entity, and per different spinal CSF leak type
9. To evaluate differences between spinal CSF leak types regarding age, sex, BMI, clinical presentation, diagnostic findings
10. To assess the effect of disease duration on imaging findings, and on outcome after persistent closure of a leak
Method:
The registry is prospective, longitudinal and currently monocentric\*. Diagnostic, treatment, and follow-up procedures follow clinical standard operating procedures (SOP) according to the suspected diagnosis and the clinical findings.
Routinely assessed data of the initial diagnostic workup and the individual's disease course with or without treatment will be collected over 2 years per individual. The investigators' semi-annual meetings ensure the achievement of the register's predefined aims.
There are no specific risks or benefits for the patients participating in this registry. Any procedure will be performed according to clinical standards as indicated. There will be no additional visits to the hospital or the ambulatory. There will be no additional imaging performed, especially no additional radiation.
A merely intrinsic benefit might exist for the patient supporting this study and supporting medical research.
As this is an explorative and observational study on rare diseases without formal sample size estimation, we limit the study by time of duration (10 years).
Patients suffering from rare diseases most often face delays in diagnostics and treatments. To underscore this known burden: By an estimated population of 1.74 Mio in the Freiburg area and an incidence rate of SIH of about 5/100.0004, approximately 85 patients should be expected per year stemming from this area. Freiburg is the only center offering adequate diagnostic pipelines for these patients. Despite the increasing awareness, the number of patients diagnosed in the area adjunct to the Freiburg CSF center is within a range of 15 to 20 patients per year, thus still too low compared to the expected number with many patients unrecognized, and or underdiagnosed.
Our current numbers of confirmed SIH treatments range from 100 per year with patients being referred throughout Germany and about 15-20 international patients per year. We expect this rate to rise within the next few years. The number of PDPH patients with a focus on persistent PDPH patients is currently rapidly increasing. We see about 40-60 per year.
Interim-Evaluation of the Registry's primary and secondary descriptive aims will be performed and reported as a step-wise, dynamic approach:
* After each +100 patients with confirmed SIH
* After each +50 patients with confirmed PDPH
The secondary objectives, which involve comparisons, the exploration of diagnostic markers, and risk factors, will be addressed using a dynamic biostatistical model: The analysis will only be conducted after a power analysis deems the observed sample adequate.
Proportions will be presented as a percentage with 95% confidence interval (CI).
The sata of patients with different types of spinal CSF leaks will be summarized using descriptive statistics, i.e. median and quartiles for continuous and absolute and relative frequencies for categorical variables, regarding their clinical, laboratory, and diagnostic findings, and number of diagnostic and therapeutic procedures needed.
Furthermore, the proportion of SIH patients with different spinal CSF leak types
1. will be compared between males and females using a Chi2-Test and a risk difference with 95% CI.
2. Will be presented by age groups (per two decades), and per sex as a percentage with a 95% Wilson confidence interval (CI).
Age, sex, BMI, clinical presentation, and diagnostic findings between different spinal CSF leaks will be compared using the Mann-Whitney-Wilcoxon test and Chi2 test for continuous and categorical variables, respectively.
A multivariable logistic regression for the presence of SIH, PDPH, and chronic PDPH, respectively, will be constructed using the clinical and diagnostic parameters with some evidence for a difference according to the presence of a spinal CSF leak (p \< 0.2). The potential nonlinearity of the age effect is evaluated based on a residual analysis of the regression model. Odds ratios with 95% CI will be reported. Using bootstrapping, we will present a ROC curve and AUC with 95% Due to the exploratory approach,, no correction for multiple testing will be performed.
A multivariable linear regression for imaging findings (especially Bern Score, presence of SLEC, vand olumetries), and for the patient-reported outcomes will be constructed using the clinical and diagnostic parameters at admission with some evidence for a difference (p\<0.2). Adjusted R-squares, Beta-coefficients with 95% CI, standard errors will be reported.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 2000
-
Patients with suspected spinal CSF leak based on one of the following
- History of new orthostatic symptomes with or without prior spinal procedure
- Imaging suggestive for spinal CSF leak
-
Informed consent
a) Symptoms beeing conclusively explained by another known diagnosis
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Primary Diagnosis given after primary workup (yes/no) up to 4 weeks after inclusion * SIH (fulfilling ICHD-3 criteria) - yes/no
* atypical SIH - yes/on
* Asymptomatic SIH (positive imaging signs only) - yes/no
* PDPH (fulfilling ICHD-3-criteria) - yes/no
* persistentPDPH - yes/no
- Secondary Outcome Measures
Name Time Method SIH/PDPH - sex at time of inclusion male female diverse
SIH/PDPH - height at time of inclusion height in meter (m)
SIH/PDPH - weight at time of inclusion kilogram (kg)
SIH/PDPH - modified Ranking scale at time of inclusion range in 0-6, 0 indicating best health
SIH/PDPH - pre-existing Neurological deficits (yes/no) at time of inclusion Neurological deficits due to previously attempted treatments at the time of inclusion
SIH/PDPH - Neurological deficits in routine clinical testing at time of inclusion descriptive
SIH - Montreal cognitive Assessment at time of inclusion range 0-30, 30 indicating best performance
SIH - Trail-making test part B at time of inclusion in minutes needed to fulfill the task
PDPH -BMI at time of inclusion kg/m\^2
SIH/PDPH - Regular use of stimuli > 6 months (yes/no) at time of inclusion Nicotine, Alcohol, Recreational drugs
SIH/PDPH - Headache-Impact-Test (HIT)-6 at time of inclusion Headache-Impact-Test (HIT)-6 range 36 to 78 points, 78 indicating highest impact of headaches.
SIH/PDPH - 5 dimensions /5 levels European Quality of life questionaire (EQ-5D-5L) Index at time of inclusion \<0 to 1, with 1 indicating unimpaired health
SIH/PDPH - Self-Administered Comorbidity Questionaire (SCQ) at time of inclusion 13-item Self-Adminestered Comorbidity Questionaire (SCQ), range 0 to 39, 0 indicating lowest burden
PDPH - Patient'S Global Impression of Change (PIGC) at time of inclusion range 7 - 42, 7 indicating highest improvement
SIH - Opening pressure on lumbar puncture if performed (not recommended in routine), or myelogram up to 4 weeks cmH2O
SIH/PDPH - Total Bern-Score MRI head according to Dobrocky et al. up to 4 weeks range 0 to 9 with 9 indicating highest likelihood of a spinal CSF leak
SIH/PDPH - Subitems Bern-Score MRI head according to Dobrocky et al. up to 4 weeks Meningeal enhancement (yes/no), Subdural fluid (yes/no), Venous Distention (yes/no), Effaced suprasellar distance (yes/no), Effaced mamillopontine distance (yes/no), Effaced prepontine distance (yes/no)
SIH - MRI head - Superficial Siderosis up to 4 weeks (yes/no)
SIH - MRI head - Layered calvarial hyperostosis up to 4 weeks (yes/no)
SIH - Sinus vein thrombosis up to 4 weeks (yes/no)
SIH/PDPH - Volumetry of the CSF-space MRI head & spine up to 4 weeks mm\^3
SIH/PDPH - Volumetry of the CNS MRI head & spine up to 4 weeks mm\^3
SIH/PDPH - Imaging Density score up to 4 weeks Density scores of the intracranial compartments MRI head \& spine
SIH/PDPH - Total radiation dose applied per diagnostic procedure with radiation performed at primary workup Sievert
SIH - Myelography number up to 24 weeks Number of myelographies performed for precise localization
SIH - Type of myelography technique applied (yes/no) up to 4 weeks conventional,digital subtraction, dynamic CT, Cone-beam CT, Photon-counting CT, fluoroscopy, Other (specify)
SIH/PDPH - lumbar infusion test - amplitude at plateau up to 4 weeks after inclusion mmHg
SIH/PDPH - lumbar infusion test - amplitude at tilt up 30° up to 4 weeks after inclusion mmHg
SIH/PDPH - Experience of the local team at time of inclusion Number of patient with suspicion for SIH work-up/year
SIH/PDPH - Patients' demographics at time of inclusion Country, City
SIH - Previously received treatment at time of inclusion (yes/no) at time of inclusion Medical SIH treatment, Other symptomatic treatment, Untargeted lumbar blood patch, Targeted blood patch, Targeted fibrin patch, Endovascular embolization, Minimally invasive surgery, Open surgery - dorsal approach, Open surgery-ventral approach, Open surgery-transforaminal approach, Discectomy, Laminectomy, Stabilization procedures, Surgery, other techniques
SIH/PDPH - age at time of inclusion years
SIH - Adverse events during myelography (yes/no) up to 4 weeks nausea, dizziness/vertigo, emesis, allergic reaction, seizure, treatment intensive care unit (independent of cause))
SIH - Headache before and after myelogram up to 4 weeks in 0-10, 10 numeric rating scale
SIH - Positioning during index myelography that proofs the leak (yes/no) up to 4 weeks prone, lateral decubitus, supine
SIH - myelography that proofs the leak performed applying (yes/no) up to 4 weeks resisted insipration, pressuization, valsalva maneuver
SIH/PDPH - Lumbar Infusiontest - Pressure at baseline up to 4 weeks pressure (mmHg)
SIH/PDPH - Lumbar Infusiontest - Resistence to CSF outflow (Rcsf) up to 4 Weeks mmHg/(ml/min)
SIH/PDPH - Lumbar Infusiontest - Elastance up to 4 weeks Elastance coefficient (1/ml)
SIH/PDPH - Lumbar Infusiontest - Pressure-Volume-Index up to 4 weeks ml
SIH/PDPH - Lumbar Infusiontest - Needle resistance up to 4 weeks SIH/PDPH - PET-CT - Evidence of CSF-loss (yes/no) up to 4 weeks SIH/PDPH - PET-CT if performed - up tp 4 weeks half-life of the tracer o0ver the convexities (minutes)
SIH/PDPH - Laboratory parameters at diagnosis (normal/abnormal) up to 4 weeks after inclusion * complete routine Blood analysis (including: cellcount, electrolytes, coagulation, renal function, thyroid marker) (normal/abnormal)
* complete routine CSF-analysis (including: cell count, protein) (normal/abnormal)SIH - CSF leak types identified by dynamic myelography (yes/no) up to 4 weeks * Ventral dural leak
* Lateral dural leak
* CSF-venous fistula, single
* CSF-venous fistula, multiple
* Sacral dural leak
* CSF-lymphatic fistula
* Dorsal dural leak
* UndefinedSIH - Multiples leaks (yes/no) up to 4 weeks SIH - Level of spinal CSF leak (spinal segment) and side in myelogram up to 4 weeks SIH - In case of surgery: spinal segment and side confirmed? (yes/no) up to 4 weeks SIH/PDPH - Experience of leading interventionalist in SIH-diagnostics/year up to 4 weeks SIH/PDPH - Disease duration at time of therapy up to 4 weeks month
SIH/PDPH - Therapy performed after CSF leak diagnosis (yes/no) up to 4 weeks Untargeted lumbar blood patch, Targeted blood patch, Targeted fibrin patch, Endovascular embolization, Minimally invasive surgery with patching, Minimally invasive surgery with clipping, Minimally invasive surgery with disconnection, Open surgery, dorsal approach, Open surgery, ventral approach, Open surgery, transforaminal approach, Surgery, other techniques, Medical PDPH treatment, Other symptomatic treatment, e.g. infiltration N. occipitalis, Untargeted lumbar platelet-rich fibrin patch
SIH/PDPH - Experience of leading surgeon in SIH/PDPH-surgeries/year up to 4 weeks or longer, depending on the number of surgeries in numbers of SIH/PDPH-surgeries/year
SIH/PDPH - Interventions needed addressing secondary complications of spinal CSF leaks, especially chronic subdural hematoma up to 4 weeks Twist drill craniostomy (yes/no), Burr hole craniostomy (yes/no ), Mini craniotomy (yes/no), Conventional trepanation (yes/no), Use of drains and any form of controlled lavage (saline and or clot lysis) (yes/no,), Embolization of MMA (middle meningeal arteria) (yes/no), Other intervention (yes/no)
PDPH - Event of putative dural puncture up to 4 weeks date
PDPH - Event of putative dural puncture (yes/ no) up to 4 weeks * Diagnostic lumbar puncture
* Diagnostic lumbar puncture with drainage in idiopathic intracranial hypertension
* Diagnostic lumbar puncture with drainage in idiopathic normal-pressure hydrocephalus
* Peridural anesthesia in obstetrics
* Spinal anesthesia in obstetrics
* Peridural anesthesia, other intervention
* Spinal anesthesia, other intervention
* Infiltration
* othersSIH/PDPH - adverse events related to current treatment at discharge (yes/no) up to 4 weeks Rebound hypertension, Persistence/Reoccurrence of the leak, Suture insufficiency, Infect (systemic/local), Bleeding, Sensory deficits, Motor deficits, Gait ataxia, Bladder dysfunction, Bowl dysfunction, Others
PDPH - Lumbar segment of putative dural puncture known (yes/no) up to 4 weeks PDPH - Puncture under imaging guidance up to 4 weeks "location truly known"
PDPH - Duration between (putative) dural puncture until the onset of symptoms up to 4 weeks days
PDPH - Time to first blood patch up to 4 weeks days
PDPH - Number of bloodpatches received before admission up to 4 weeks PDPH - Prior treatments at the time of admission (yes/no) up to 4 weeks Fluids, Caffeine, Bedrest, Medical treatment, Other treatment, e.g., infiltrations, Untargeted lumbar bloodpatch, Surgery
PDPH - Post-dural puncture pseudomeningocele ("arachnoid bleb") up to 4 weeks (yes/no)
PDPH - Spinal Segment location of the "arachnoid bleb" up to 4 weeks PDPH - Identified CSF leak types by dynamics myelography and/or intraoperatively: up to 4 weeks ventral post-dural puncture leak, dorsal post-dural puncture pseudomeningocele ("arachnoid bleb"), dorsal post-dural puncture leak None
PDPH - Intraoperatively Identified membranes (yes/no) up to 4 weeks neo-membranes (pseudo dura), webs, funnels
PDPH - Dinosaur-tail sign (yes/no) at time of inclusion PDPH - specific segment of identified intraoperative membranes (descriptive) up to 4 weeks PDPH - Diagnostic procedures performed (yes/no, number) uo to 4 weeks CT Head, MRI head, MRI spine, Dynamic digital subtraction myelogram, Dynamic CT-myelogram, Photon-counting CT-myelogram, Cone-beam myelogram, Infusion testing, PET-CT, Other (to exclude/confirm alternative diagnosis)
PDPH - CSF leak types identified by dynamic myelography and/or intraoperatively up to 4 weeks ventral post-dural puncture leak, dorsal post-dural puncture pseudomeningocele ("arachnoid bleb"), dorsal post-dural puncture leak, None
PDPH - Volume lumbar bloodpatch up to 4 weeks ml
SIH/PDPH - work capacity at time of inclusion range 0 to 5, 0 indicating full capacity
SIH/PDPH -complaints at time of inclusion * current complaints (descriptively)
* most stressful complaint (descriptively)SIH/PDPH - headache severity at time of inclusion range 0 to 10, 10 indicating most severe pain
SIH/PDPH - maximum duration being continuously upright at time of inclusion hours
SIH/PDPH - Severeness of shoulder- and neck pain at time of inclusion - in 0 to 10, 10 being most severe
SIH/PDPH - severeness of nausea at time of inclusion - in 0 to 10, 10 being most severe
SIH/PDPH - severeness of hearing disturbances and tinnitus at time of inclusion - in 0 to 10, 10 being most severe
SIH/PDPH - severeness of cognitive deficits at time of inclusion - in 0 to 10, 10 being most severe
SIH/PDPH - severeness of visual disturbances at time of inclusion - in 0 to 10, 10 being most severe
SIH/PDPH - . ability to focus and concentrate at time of inclusion rated between 0 to 5, with 5 indicating highest burden
SIH/PDPH - MRI spine: Spinal longitudinal extradural fluid collection (SLEC) (yes/no) up to 4 weeks SIH/PDPH - MRI-spine: DiverTICula (TIC) ≥8mm (yes/no) up to 4 weeks number of TICs ≥8mm
SIH/PDPH - Volumetry of epidural spinal veins at C2 up to 4 weeks mm\^3
SIH/PDPH - MRI spine: Enlarged cervical epidural spinal veins at C2 up to 4 weeks yes/no
SIH/PDPH - Days within the last month at time of inclusion * with headaches
* with pain medication intake in the last monthSIH/PDPH - severeness of dizziness at time of inclusion - in 0 to 10, 10 being most severe
SIH/PDPH - lumbar infusion test - pressure at tilt down up to 4 weeks after inclusion mmHg
SIH/PDPH - lumbar infusion test - pressure at tilt up 10° up to 4 weeks after inclusion mmHg
SIH/PDPH - lumbar infusion test - pressure at tilt up 30° up to 4 weeks after inclusion mmHg
SIH/PDPH - lumbar infusion test - pressure at plateau up to 4 weeks after inclusion mmHg
SIH/PDPH - Laboratory parameters at diagnosis (decriptive) up to 4 weeks after inclusion * Routine Blood analysis
* Abnormal CSF-analysisSIH/PDPH - Lumbar Infusiontest - amplitude at baseline up to 4 weeks mmHg
SIH/PDPH - lumbar infusion test - amplitude at tilt down up to 4 weeks after inclusion mmHg
SIH/PDPH - lumbar infusion test -amplitude at tilt up 10° up to 4 weeks after inclusion mmHg
SIH/PDPH - Results of neuropathological tissue analysis if assessed (descriptive) up to 6 weeks epidural membranes (descriptive) arachnoid funnels (descriptive) diverticula (descriptive) epidural vessels (descriptive)
SIH/PDPH - phase-contrast MRI : CSF-velocity up to 4 weeks cm/s
SIH/PDPH - phase-contrast MRI: Stroke-volume CSF up to 4 weeks ml
SIH/PDPH - phase-contrast MRI: Spinal cord motion up to 4 weeks mm
SIH/PDPH - phase-contrast MRI: Spinal cord velocities up to 4 weeks cm/s
SIH/PDPH - MRI spine: Bud-on-branching sign (yes/no) up to 4 weeks SIH/PDPH - MRI spine: Localized flow-voids in sagittal spine T2 images (yes/no) up to 4 weeks
Related Research Topics
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Trial Locations
- Locations (1)
Medical Center - University of Freiburg, Germany
🇩🇪Freiburg, Germany