Neuroprotection in Aneurysmal Subarachnoid Hemorrhage - from Laboratory to Clinical Practice

The project is part of a long standing line of research on subarachnoid
hemorrhage (SAH) of neurologists and neurosurgeons in the UMC Utrecht. This
research includes epidemiology, pathogenesis, treatment and prevention of
SAH. The principal investigators have published more than 100 articles on this
subject in the recent years. In this program, clinical and experimental
research is carried out on cerebrovascular disorders with the aim to
characterize pathogenesis, pathophysiology, and therapeutic intervention
strategies. Our project is aimed at improving pharmacological treatment for SAH
and will additionally contribute to a better understanding of
pathophysiological mechanisms of cerebral ischemia and SAH. Studies will be
carried out at the Image Sciences Institute for Biomedical Imaging and the
Rudolf Magnus Institute for Neuroscience. These groups have a joint research
program on cerebral ischemia. MR imaging of cerebral ischemia has been a key
topic of research for many years. The strong link between these groups enables
optimal integration of tools and expertise, thereby allowing direct bridging of
experimental findings to the clinic.

Delayed cerebral ischemia (DCI) is an important cause of death and dependence
after SAH. Vasospasm plays an important role in the pathogenesis of DCI,
because many patients have constricted arteries during the period of DCI, but
vasospasm is not a sufficient factor to explain the occurrence because not all
patients with vasospasm develop DCI. Moreover, treatments aiming to reduce
vasospasm have hardly been successful in improving outcome after SAH. Although
promising drugs have been presented from laboratories all over the world, only
a few have made it to the stage of testing the clinical application, and apart
from nimodipine, none proved to be effective. The main reason probably is that
most of these drugs were developed to reduce vasospasm only.
Our objectives for the clinical part of the study is to prepare the entree in
clinical practice of drugs that proved to be effective in the experimental
setting.

We aim to measure serum concentration of TNF daily in 50 consecutive patients
with SAH to provide more evidence for the relation between serum concentrations
with the occurrence of DCI and subsequent poor outcome. Serum TNF will be
measured at admission and every 2 days up to 21 days after the event, or until
discharge if this occurred within the first 3 weeks.
We will relate the occurrence of DCI to increased TNF before, and during the
DCI onset period (Days 4-21 after SAH) by means of the Cox proportional hazards
model, which yields a crude hazard ratio (HR). HRs will be considered
statistically significant if the 95% confidence interval (CI) did not include
1. We will relate poor
outcome after 3 months to increased TNF before, and during the DCI onset period
by means of the nonparametric Kruskal-Wallis test. This group will be used as
controls in the IFN-β safety study.


Safety study for IFN-β in SAH:

TNF production is inhibited by IFN-β. Consequently, TNF may serve as a
parameter for cerbral damage after SAH and IFN-β action. Three months after the
SAH we assessed functional outcome with the modified Rankin scale, a 6-point
handicap scale that focuses on restrictions in lifestyle, by means of a
telephone interview.


Data analysis and statistics:

The effects of IFN-β treatment will be assessed by comparison of various
outcome measures (e.g., headache, TNF, neurological status, DCI and outcome)
between IFN-β and non-treated group. Statistical comparisons will be performed
using Logistic regression and Cox proportional hazard modelling.

Betaferon 250 microgram (8.0 million IU), contained in 1 ml of the
reconstituted solution, to be injected subcutaneously every other day for 14
days.

Moderate to severe side effects are uncommon and mostly related to extended
administration of study medication. The more common side effects are mild and
exists mainly of flu-like complaints and inflammation or pain at the site of
the injections.