The goal of the ONSITE study is to investigate whether an increase Optic nerve sheath diameter (ONSD) may help to predict intracranial hypertension (IH) after stroke. IH is a life-threatening complicaitons of malignant middle cerebral artery (MCA) infarction due to space-occupying brain edema. Patients at risk are monitored based on clinical symptoms, which can be difficult due to comorbidities such as delirium or systemic infections, which can hempen clinical judgement. Readily available, non-invasive methods to monitor ICP in stroke patients could help to earlier diagnose rising ICP and facilitate treatment decisions such as hemicraniectomy. This study investigates whether ONSD with optic nerve sonography (ONS) can detect brain edema after stroke.

Intracranial Hypertension (IH) is a life-threatening complication after ischemic and hemorrhagic stroke. IH develops in ischemic stroke due to brain edema, which may occur in large-vessel occlusion, most common in large middle cerebral artery (MCA) infarcts due to occlusion of the internal carotid artery (ICA) or occlusion of the proximal segment (M1) of the middle cerebral artery. Up to 30% of patients with occlusion of these vessels develop large space-occupying brain edema leading to a serious condition termed "malignant media infarction" leading to rapid neurological deterioration and reduced consciousness. IH usually develops within the first 24-96 hours after stroke; however, the exact time course is not predictable.

IH is a life-threatening emergency that demands immediate medical or surgical action. As it is not possible to predict the course of intracerebral pressure increase in patients at risk, it is necessary to monitor these patients closely. However, clinical observation of neurological symptoms may be hampered, as stroke patients often require pain or anxiolytic medications or suffer from typical comorbidities of stroke, such as infection, cardiac diseases, or delirium, which limit judgment of neurological symptoms. Despite the limitations of clinical symptom prediction for IH, ICP is not routinely monitored in stroke patients as invasive intracranial devices, the current gold standard for ICP monitoring have several drawbacks that limit their routine application. Intracranial ICP monitors require a neurosurgical intervention, which may not always be feasible or contraindicated in several conditions such as coagulopathy and thrombocytopenia. Furthermore, ICP monitors are associated with complications such as hemorrhages (1.1-5.8% of cases), infection (0-15% of cases) or monitor malfunction (6.3-40% of cases).

Because of these limitations, noninvasive methods to measure ICP have been eagerly sought. Se-rial computer tomography (CT) or Magnetic Resonance Imaging (MRI) are applied to detect in-creased ICP in patients at risk. However, imaging is expensive, potential harmful to patients due to radiation or necessity to lie supine and still for a prolonged period and have limited availability. As such, their use is restricted as well. Furthermore there are studies suggesting that CT scans might have a poor sensitivity for detection of IH.

Ultrasonography is an alternative tool to measure ICP non-invasively. Ultrasonography is a low cost, simple bedside tool, widely available in emergency rooms as well as on stroke units. Optic nerve sonography (ONS) to measure the optic nerve sheath diameter (ONSD) has been developed and suggested as an alternative sonographic method to detect IH. ONS utilizes the fact that the optic nerve sheath, which is readily visualized by transorbital ultrasound, is filled with spinal fluid and grows in diameter according to ICP. To perform ONS, the patient is placed in a position 20̊ supine to horizontal. The probe is then placed on the temporal side of the closed eyelid without pressure to avoid any damage to the eye. The position of the probe is then adjusted until the entry of the optic nerve into the globe of the eye is visible. ONSD is measured 3 mm behind the globe, as this position shows the greatest distension of the optic sheath in IH patients and thus has become the standard measurement point.

The method is quickly learned and a trained operator can perform measurement of ONSD in both eyes in less than 4 minutes. In current clinical practice, ONS has been used in intensive care setting to monitor ICP and diagnose brain death in brain trauma patients. ONS is also used in other neurological diseases, such as idiopathic intracranial hypertension. It was shown in several studies, as well as meta-analyses that ONS derived measurements of intracranial hypertension can be performed with good intra- and interobserver reliability. In a meta-analysis, in which ONDS was compared to invasive ICP measurements, ONSD showed good test accuracy with a pooled sensitivity of 90% and pooled specificity of 85%. When compared to CT scan, ONSD showed good accuracy for IH as well, with a sensitivity of 95.6% and specificity of 92.3%. ONSD can also be used to rapidly assess the success of therapeutic interventions. For example, patients with idiopathic intracranial hypertension showed a significantly reduced ONSD directly af-ter lumbar puncture with therapeutic removal of 30-50 ml of cerebrospinal fluid (CSF).

Several studies raised the question of which cut-off value should be used for the ONSD in healthy individuals. Earlier studies that compared ONSD to CT results suggested a upper normal value of 4.5 mm for individuals aged ≤1 year and 5.0 mm for those aged >1 year. More recent studies, however, comparing ONSD to invasive ICP measurements, suggested that a cut-off value of 5.7-6.0mm provided the best accuracy and that values above that cut off should alert the clinician of IH.

Preliminary data from routine evaluation of ONSD in patients with stroke and ICH showed significantly increased ONSD on the side of stroke compared to the contralateral side. The investigators also tested for the feasibility of the method in patients with diagnosed idiopathic intracranial hyper-tension, which were found to have larger ONSD than healthy individuals on both sides. In each patient, 3 individual measurements per eye were averaged.

The goal of this study is to improve stroke patient care by helping to investigate whether ONS is a feasible tool to diagnose IH after stroke, as IH is one of the most troublesome and life-threatening complications of large-vessel ischemic stroke. It is critical that the clinician does not miss rising ICP so that life-saving treatment is not delayed. ONS measurement of ICP is an accurate, widely avail-able and easy to learn method to detect IH and has been successfully used in clinical practice in several fields of neurology. Its value in acute stroke care, however, remains uncertain. The investigators have tested ONS derived ONSD measurements and have confirmed the feasibility to use this parameter. If ONSD thresholds can be established to detect IH early after stroke, it could be further tested in a clinical trial to aid in decision making for hemicraniectomy in stroke patients.

This study aims to investigate the hypothesis that ONS is a feasible method to detect IH in stroke patients. To this end, the primary objective is to observe the changes in ONSD after large-vessel ischemic stroke and in the presence of IH.

The second objective is to derive a cut-off value for ONSD that best predicts the presence of IH in stroke patients and to assess whether this cut-off value would be able to detect IH before clinical changes occur (assessed by the Glasgow Coma Scale (GCS) and/or National Institutes of Health Stroke Scale (NIHSS) in patients at risk). This cut-off value could be the base for a future clinical trial to evaluate the diagnostic performance of this method in stroke patients. In addition, the investigators aim to investigate the predictive value of the ONSD in the clinical outcome after stroke (as derived from the modified Rankin Scale (mRS) and NIHSS after 3 month).

Inclusion Criteria:

• ≥ 18 years of age
• Consent according to the regulations of research in an emergency situation
• For non-Control patients: Acute ischemic stroke within 24 hours of recruitment

Exclusion Criteria:

• Known intracranial space-occupying lesion
• Known history of intracranial hypertension
• Contra-indications on ethical grounds
• Expected or known non-compliance to participate in the observational study, severe drug- or/and alcohol abuse

For non-stroke, non-IH patients we will recruit patients hospitalized at the Department of Neurology, University Hospital of Zurich. Patients within the clinic are screened for inclusion / exclusion criteria. If a patient is considered eligible for the study, he or she will be contacted by a member of the study team.

For stroke patients acute stroke patients admitted to the Department of Neurology, University Hospital of Zurich will be screened for study eligibility. If a patient is considered eligible for the study, he or she will be contacted by a member of the study team after initial emergency care is completed.

Will be decided upon reasonable request