The Freiburg Registry on SpontanEous IntercrAnial Hypotension (SIH) & Post-duraL Puncture Headache (PDPH)

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.