Prevention of Vasospasm in SAH Through CSF Treatment
Prevention of Vasospasm in SAH Through CSF Treatment
The pathophysiological mechanisms of aneurysmal subarachnoid haemorrhage (aSAH) involve early
 brain injury (EBI) and delayed cerebral ischemia (DCI).

 Several mechanisms contribute to EBI pathogenesis, including cell death, inflammatory
 response, oxidative stress, excitotoxicity, microcirculatory dysfunction, microthrombosis and
 cortical spreading depolarization. All are suggested to be linked due to common pathogenic
 pathways and direct interaction.

 Despite advances in research of diagnostics and treatment strategies, brain injury remains
 the major cause of death and disability in SAH patients. There is no sufficient treatment of
 SAH and its devastating consequences known so far. Developing and improving diagnostic
 methods to monitor SAH patients and to evaluate efficacy of treatment strategies are
 essential in SAH research. These include neuroimaging, biomarkers, and other parameters such
 as invasive multimodal neuromonitoring and intraoperative electrophysiological monitoring.

 Cerebral vasospasm (CV) - mostly responsible for DCI - can be depicted on angiograms.
 Alltogether, tremendous efforts have been taken to conquer the occurrence and sustainability
 of CV. The mortality of patients suffering aSAH rises up to 50% if the patients' condition is
 critical (Hunt&Hess (HH) Grade 5, WFNS Grade 5, modified Fisher Grade 4).

 Reports of beneficial outcome in patients with pre-existing CSF shunting have been published.
 The hypothesis of early CSF reapplication to the bloodstream, in order to prevent CV seems to
 be positively approved by the mentioned reports. Nevertheless, no data could be found on the
 mechanisms of action in this phenomenon.

 To confirm the presence of interaction of the mechanisms of EBI and evaluate the application
 of CSF, a pilot clinical trial was planned. Due to the lack of validated animal models for
 aSAH it is necessary to perform the trial first-in-human. A pilot (proof of concept) trial -
 is done through inclusion of 10 patients with severe aSAH (≥HH4). According to clinical
 guidelines, these patients receive external ventricular drainages in order to drain CSF and
 lower intracranial pressure. An interim analysis of data will be performed after inclusion
 and treatment of 5 patients. Blood-/CSF-sampling for further analysis will be collected
 before, during and after treatment according to the study protocol.
Aneurysmal subarachnoid haemorrhage (aSAH) is associated with high morbidity and mortality
 with an incidence of 5-9 per 100,000 population. The incidence of aSAH peaks amongst those of
 40-60 years1; aSAH carries a high overall mortality rate of up to 67%2 with only around half
 of the survivors able to live independently. Given the age-related incidence 3 and high
 morbidity and mortality, SAH has a high burden on society . Conventionally following SAH,
 treatment is directed to securing the aneurysm to prevent further re-bleed. In addition to
 the primary brain injury due to the rupture of the aneurysm the occurrence of cerebral
 vasospasm (VS) with narrowing of the brain supplying arteries potentially lading to brain
 ischemia is as well - known and serious complication following aSAH. The development of VS is
 thought to be caused by various factors. Interestingly, this is not an instant phenomenon
 occurring right after the hemorrhagic event. VS develops rather in a time dependent fashion
 with a peak incidence around 7-10 days following from acute event.

 From angiographic studies, it is known that up to 70% of all patients with a aSAH will
 developVS and in about 40% of these it will result in clinical deterioration and in 10-15%
 inpermanent delayed ischemic neurologic deficits (DIND) leading to an increased morbidity 4,
 5 and mortality

 . Based on the fact that VS develops with a time delay, this is thought to provide a
 "therapeutic window" allowing to initiate measures for its prevention. However, in spite of
 intensive experimental and clinical research the investigators still do not have any
 effective treatment for the prevention of VS in patients with aSAH. Many concepts have been
 elaborated in the past, mostly based o sound pharmacologic considerations such as calcium
 antagonists (Nimodipin), antioxidants (Tirilazad) and endothelin antagonists (Clazosentan).
 In clinical trials, however, none of these drugs have shown a therapeutic effect on VS and
 most of them have been abandoned since then. The only exception is the use of oral Nimodipin,
 which is still used showing a marginal effect 6-8.

 In contrast to all previous studies, which were based on the use of specific drugs, the
 present hypothesis is different. It is based on the assumption that the brain is a
 "privileged" organ, where the in- and outflow is regulated by discrete barrier mechanisms
 (e.g. blood-brain- barrier). In the event of aSAH - factors that are thought to play an
 important role in the development of VS are released into the CSF. However, it is not clear
 whether these factors will enter the systemic circulation. This is further supported by the
 clinical observation that in many patients with aSAH, acute disturbances of CSF circulation
 can be seen, often resulting in hydrocephalus. This in return can be treated by CSF flow
 diversion with the use of external ventricular drainage, which is a routine procedure in the
 management of aSAH patients.

 Based on the assumption that those factors responsible for the development of VS are
 contained in the CSF, but do not enter the systemic circulation, it then might make sense to
 use the externally drained CSF for intravenous re-administration and thereby activating a
 systemic response mechanism with in turn could prevent the development of VS.

 The potential therapeutic benefits outweigh any potential risks for patients with aSAH.

 The proposed clinical study involves autologous CSF without any changes made to the liquid.
 The CSF will be taken from the EVD under sterile environment and reinfused intravenously.

 An interval of approximately 21 days will permit a timely review and evaluation of interim
 safety (after 5 patients) and tolerability data collected The potential benefit to patients
 is significant with reduced delayed cerebral infarction (DCI), improved cognition and
 cerebral function. As such, studies in patients with aSAH are warranted, with a view to
 establishing the optimal dose, safety and exploratory efficacy profiles.

 This is a pilot trial involving higher grade (see inclusion criteria) aSAH patients.

 The human brain is protected and enjoying privileged immune status. The blood-brain- barrier
 (BBB) leads to consequent isolation of brain tissue from humoral immunity. The brain is
 experiencing several major changes during rupture of a cerebral aneurysm. First, the
 intracranial pressure increases immediately, caused by the actual bleeding. Second, the
 extravasation of blood disrupts the BBB and several immunogenic molecules travel through the
 spontaneous rupture into the CSF. Additionally, microscopic particles of the vessel wall are
 present in the CSF as a consequence of the wall rupture. Usually, these potentially
 spasmogenic fractions are never encountered by the brain and the external surface of its
 vessels. Interestingly, the perioperative collection of blood in subarachnoid spaces does not
 induce vasospasm.

 The investigators hypothesized that the reported steps were crucial for the formation of
 cerebral vasospasm.

 This study will be conducted in compliance with the protocol and according to Good Clinical
 Practice and applicable regulatory standards. No deviation from the protocol will be
 implemented without the prior review and approval by the relevant ethics and regulatory
 authorities, except where it may be necessary to eliminate an immediate hazard to a research
 subject. In such case, the deviation will be reported to the relevant ethics and regulatory
 authorities as soon as possible.

 Ten patients with an angiographically confirmed aSAH, who in addition are in need of early
 external ventricular drainage (routine procedure), irrespective of the clinical grade on
 admission and in whom definite treatment (clip ligation or interventional treatment) is
 achievable within 72 hours following aSAH.

 Following aneurysm clip ligation, the predetermined amount of CSF (10ml) will be obtained
 under sterile conditions directly from the external ventricular drain and administered in a
 peripheral vein. To reduce the possibility of contamination, the application of CSF will be
 done immediately. In case of extensive intraventricular hemorrhage, causing the aspiration of
 clotted blood while obtaining CSF, the patient needs to be excluded from the trial.

 A number of patients will have an EVD placed for clinical reasons. These patients would
 regularly have CSF sampling ranging from daily to twice weekly.

 In this study, approximately 2 ml CSF will be taken and stored for translational study
 purposes (starting on day of EVD fitting) until day 21 or until the EVD is removed as per
 standard of care.
Inclusion Criteria:

 Age: >18, <90

 -  SAH HH 3 - 5

 -  Cerebral saccular Aneurysm

 -  Digital subtraction angiography prior to aneurysm repair

 -  Aneurysm repair within 72h

 -  Modified Fisher Grade 3+4

 -  Presence of aneurysm needing treatment (clipping or coiling)

 -  Treatment within 24 hours of symptom onset

 -  External ventricular drain (clinical need)

 Exclusion Criteria:

 -  Non-aneurysmal SAH

 -  SAH HH<3

 -  Extensive intraventricular haemorrhage (unable to obtain CSF without massive
 aspiration of clotted blood)

 -  Contraindication for digital subtraction angiography

 -  Aneurysm repair >72h after rupture

 -  Signs of radiographic vasospasm upon diagnosis

 -  Presence of systemic or CSF infection

 -  Contraindication for oral Nimodipin

 -  Pregnancy