Intracranial Venous Sinus Stenting Improves Headaches and Cognitive Dysfunction Associated with Ehlers-Danlos Syndrome Type III

The most common subtype of Ehlers-Danlos syndrome (EDS) is type III, or
hypermobility type (EDS-HT). A large proportion of this population suffers from
debilitating headaches and cognitive dysfunction of unclear etiology.

The most common subtype of Ehlers-Danlos syndrome (EDS) is type III, or hypermobility type (EDS-HT). A large proportion of this population suffers from debilitating headaches and cognitive dysfunction of unclear etiology. We hypothesize that a subset of these patients has underlying cerebral venous sinus outflow abnormalities contributing to these symptoms, and that outflow optimization with endovascular stenting may ameliorate these symptoms. In this study, consecutive EDS-HT patients presenting with headache and cognitive dysfunction were evaluated with intracranial venous manometry. Patients who were found to have a significant venous sinus pressure gradient and were treated with venous sinus stenting (VSS). A database of these cases was prospectively maintained and retrospectively reviewed for this study. The study cohort comprised 130 patients with EDS-HT, including 74 who underwent VSS. Technical success with resolution of the pressure gradient was achieved in 100%, with a 4% rate of significant procedural complications. Headaches and cognitive dysfunction significantly improved or completely resolved in 77% of patients, were unchanged in 11%, and worsened in 4%. 7% were lost to follow-up. Our results support the hypothesis that intracranial venous outflow abnormalities contribute to the underlying etiology of headache and cognitive symptoms in some patients with EDS-HT. Diagnostic venography with venous manometry is necessary to identify the population of EDS-HT patients who may benefit from VSS. VSS appears to have a favorable risk to benefit profile, and it may be considered as a minimally invasive treatment option for appropriately selected patients with this disorder.

Introduction
Ehlers-Danlos syndrome (EDS) is a heterogeneous group of heritable connective tissue disorders characterized by joint hypermobility, tissue fragility, and skin extensibility [1]. It is estimated to have a prevalence of up to 1 to 3% of the general population [2]. Multiple subtypes have been characterized, the most common being Type III or hypermobility type (EDS-HT). In EDS-HT, the causative genetic mutation or mutations are not well delineated.
Therefore, the diagnosis of EDS-HT is based on clinical assessment and family history, and it is characterized by musculoskeletal and cutaneous manifestations, and frequently affects other systems including cardiac, immune, gastrointestinal, autonomic nervous and central nervous systems (CNS). CNS and spine manifestations associated with EDS-HT include headaches, Chiari I malformation, craniocervical instability, basilar invagination, spondylotic cervical spine disorders, tethered cord, idiopathic intracranial hypertension (IIH), chronic fatigue, and cognitive slowing [1,3]. The abovereported associations have been poorly quantified in the literature to date, and as such, this syndrome requires further and more definitive characterization.
Cognitive dysfunction, described as "brain fog", chronic fatigue, or as subsyndromal delirium (DSM-IV-TR) are common, and can be incapacitating. The neuropathophysiological basis for these symptoms in EDS patients is unclear. Debilitating pressure headaches are another common complaint in patients with EDS-HT.
Headaches in these patients are multifactorial, but in select patients, we hypothesize that headaches are due to venous hypertension, which may be amenable to neurosurgical or neuroendovascular intervention. Recent studies have demonstrated that in the general population without EDS, venous hypertension, in both IIH and non-IIH patients, is a cause of headaches that may be amenable to treatment with endovascular stenting of the dural venous sinuses, albeit with variable results . Borderline venous hypertension, presenting as chronic fatigue syndrome, has also been treated with venous sinus stenting (VSS), but the available data for this application is very limited [4]. In this retrospective cohort study, we evaluate the outcomes of VSS for the treatment of EDS-HT.

Patient Selection and Characteristics
The inclusion criteria of the study were as follows: (1) A diagnosis of EDS type III (EDS-HT), 1) Resolved or significantly improved (residual symptoms not requiring continued intervention or >50% improvement).

Diagnostic Angiography, Venography, and Manometry
Cerebral angiography, venography, and venous manometry was performed under minimal conscious sedation. Cerebral angiography from a transfemoral arterial approach was performed in all cases to exclude a vascular malformation or arteriovenous fistula as an alternative source of increased intracranial pressure.
Cerebral venography and manometry, from a transfemoral venous approach, were performed in the following manner: a guide catheter was positioned into the distal internal jugular vein proximal to the jugular bulb. Next, the superior sagittal sinus was

Clinical and Radiographic Follow-Up
Patents were seen in neurosurgery clinic at three months after VSS, and then annually thereafter. Radiographic follow-up included cerebral angiography, venography, and venous manometry at 3 and 12 months after VSS to assess venous pressure gradient across the stent and patency of stent. Patients were followed with computerized tomography (CT) angiography and venography, with repeat cerebral angiography, venography, and venous manometry as needed for new or worsening neurological symptoms. Secondary

Patient Characteristics
The study cohort comprised 130 patients with EDS-HT who underwent angiographic evaluation. Table 1

Treatment Characteristics and Outcomes
Of the 130 patients who underwent catheter angiography, only one suffered a complication from the procedure (dissection of left vertebral artery) that was felt to be purely technical and avoidable.       (Table 2).

Discussion
EDS-HT is a heritable connective tissue disorder characterized by joint hypermobility, skin extensibility, and tissue fragility [1]. It is recognized as a multisystem disorder affecting the cardiac, immune, gastrointestinal, and nervous systems. Headache is one of the most common complaints in EDS-HT patients. The etiology of headaches in these patients is heterogenous, multifactorial, and associated with migraines, Chiari malformation type I, craniocervical instability, cervical spine disorders, and IIH [1,3]. Our study suggests that a subset of EDS-HT patients may experience headaches related to abnormal cerebral venous outflow, and that this may be amenable to stenting of the intracranial venous sinuses.  VSS has been previously shown to reliably lower ICP and improve headaches in certain patients [7,20,29,34]. Additionally,

Headache and Cognitive Symptoms
we have noticed that chronic fatigue and cognitive slowing that is common amongst this patient population often improves dramatically after VSS. While the mechanism for this is unknown, we hypothesize that these patients have a dysfunctional glymphatic system, and that improving venous outflow may help to restore its function.

Limitations
While the results of this study appear promising, they must be interpreted with caution. The study design is retrospective without a control arm. Invasive techniques are often associated with a high placebo response rate, and the clinical course or natural history of untreated EDS-HT is not well delineated. Consequently, in the absence of a control arm, the degree of improvement in subjective symptoms (e.g., headaches, cognitive disturbances) as a result of treatment versus a placebo effect or the natural course of the EDS-HT is unclear. Moreover, this study was conducted at a single institution that served as a quaternary referral center for local, national and international patients with EDS-HT. As such, its results are subject to the selection, referral, and management biases of the treating physician (senior author KCL). Therefore, it is unknown whether these findings are generalizable to all patients with EDS-HT. Finally, longer follow-up is needed to assess the durability of the treatment effect observed in our study.

Conclusion
The preliminary results of this single-arm, retrospective cohort study support venous outflow abnormalities as a contributing factor to headaches and cognitive disturbances in a subset of patients with EDS-HT. Diagnostic cerebral angiography and venography with venous manometry is both necessary and safe to define the population which may benefit from endovascular treatment with VSS. Restoration of venous outflow with VSS appears to have a favorable risk to benefit profile, and therefore, it may represent a minimally invasive treatment option for appropriately selected EDS-HT patients with severe or progressive symptoms that are refractory to medical management.