Diagnosis and Treatment of Late Neurological Ischemic Deficit in Patients Suffering From Subarachnoid Hemorrhage.

Aneurysmal subarachnoid hemorrhage (aSAH) is a particular form of hemorrhagic stroke characterized by blood spillage into the intracranial subarachnoid spaces due to the rupture of an aneurysm of a large cerebral arterial vessel of the circle of Willis. It can cause sudden and intense symptoms, such as violent headache, nausea, vomiting, neck stiffness and sensitivity to light, but also loss of consciousness, cardiac arrest and death.

The pre-hospital mortality rate in the literature remains high (22-26%), even if it is lower than in previous decades. However, the number of patients discharged from hospital with permanent disabilities is increasing, especially those of working age (the average age at onset of symptoms is 55 years), contributing significantly to public health costs.

The incidence of aSAH worldwide is approximately 6.1 cases per 100,000 people per year, but there are national differences. In Italy, for example, it is 11.2 (10.5-12.4) cases per 100,000 inhabitants per year.

At the onset of symptoms, once the aneurysmal origin of the cerebral hemorrhage has been confirmed through radiological examinations, it is essential to promptly ensure treatment of the ruptured aneurysm. Early repair of the ruptured aneurysm is recommended within 24 to 72 hours, via endovascular coiling or neurosurgical clipping. This allows to prevent any rebleeding and reduce the risk of cerebral vasospasm, as it reduces the amount of blood distributed in the subarachnoid space. The latter, in fact, represents the main inflammatory stimulus on large cerebral arteries, favoring the vasoconstriction reaction which manifests itself angiographically and/or ultrasonographically in 70% of cases. Cerebral vasospasm is very often clinically silent, since the reduction of the vascular lumen is not sufficient to generate the conditions of discrepancy between the arterial flow of the perfused brain parenchyma and its metabolic demand.

However, in 20-30% of cases a neurological deterioration also occurs, called delayed ischemic neurological deficit or DIND (Delayed Ischemic Neurological Deficit), defined as a focal neurological deterioration (appearance of at least one of the symptoms including hemiparesis, aphasia, hemianopsia or neglect) or global (sudden neurological worsening leading to at least a two-point decrease in the Glasgow Scale or the appearance of anisocoria or pupillary reactivity). DIND is not always immediately evident after securing the aneurysm, and it is necessary to exclude other causes of neurological deterioration, such as hydrocephalus, convulsions, rebleeding and hyponatremia in order to confirm it.

Identifying DIND early is essential to prevent the formation of a true ischemic core in the area affected by vasospasm, i.e. late cerebral ischemia, DCI (Delayed Cerebral Ischemia), defined by radiological criteria: evidence of cerebral infarction on brain computed tomography (CT) scan or brain magnetic resonance imaging (MRI) within 6 weeks of onset of aSAH complicated by vasospasm.

DIND, in fact, is the main preventable cause of unfavorable neurological-functional outcome and DCI in patients with SAH.

Regarding the identification of DIND, it is certainly crucial to carry out a systematic clinical neurological examination on the awake patient. In comatose patients, or in those in whom it is not possible to carry out a sedation window, multimodal instrumental monitoring is certainly helpful. In fact, if the patient is sedated or cannot be awakened, the information deriving from the inspection (pupillary reactivity and isocoria) should be integrated with continuous electroencephalographic monitoring (cEEG) and/or transcranial color Doppler ultrasound (TCD)ccc. Instrumental monitoring is, in fact, fundamental in those patients in whom a suspension of sedation generates an increase in intracranial pressure and consequent reduction in cerebral oxygenation, making clinical neurological evaluation impossible.

The alterations associated with DIND most commonly described during quantitative EEG (qEEG) are decreased alpha/delta ratio and reduced alpha variability. EEG changes may precede clinical deterioration by several hours, and allow for a differential diagnosis with nonconvulsive status epilepticus. Instrumental vasospasm is defined as an average blood flow velocity \> 120 cm/sec detected ultrasonographically via TCD. Instead, clinical vasospasm, i.e. DIND that requires treatment, is diagnosed in case of speed of at least 200 cm/sec, or increased by 50 cm/sec in the last 24 hours, or even if the Lindeegard index is greater of 3 (defined as the ratio of flow velocities between the middle cerebral artery and the ipsilateral distal internal carotid artery, MCA/ICA).

Regarding second-level tests, in sedated or unconscious patients, it is also reasonable to perform screening through repeated imaging tests, such as computed perfusion tomography (CTP), cerebral angiotomography (CTA) and intracranial vessel angiography ( TSA). The use of CTP is increasingly widespread: it detects imminent ischemia by decreasing cerebral perfusion, thus identifying salvageable brain tissue (ischemic penumbra) before irreversible brain damage occurs. This approach, however, involves transporting the critically ill patient to radiology and administering a contrast medium, adding considerable risks. It should also be underlined that, in case of clinical or instrumental suspicion of DIND, in some centers second level tests are used less and less, intervening early with therapy to resolve it.

As with the diagnostic procedure, the therapeutic strategies implemented are also very different from each other, and none has been proven to be more effective than another. They can be more or less invasive, and the main ones are:

* hemodynamic therapy, i.e. permissive hypertension, in which systemic blood pressure is increased to increase cerebral perfusion and ensure that an adequate quantity of blood supplies the brain parenchyma downstream of vasospasm; * local intra-arterial pharmacological therapy, in bolus or continuous infusion, with a vasodilator drug (calcium antagonist/milrinone); * mechanical therapy, whereby action is taken on the muscular wall of the vessel in question by carrying out angioplasty with a transluminal balloon.

Innovative techniques, such as stent retriever angioplasty, which also allows the application of intra-arterial calcium channel antagonists, can be an additional tool in selected patients with refractory vasospasm.

To date, there is no gold standard for diagnosing DIND, evidence on which patients are at greatest risk of developing it and recommendations regarding the most effective treatment to resolve it. Management is delegated to the multidisciplinary department team of each centre.

In conclusion, also in light of the recent guidelines on aSAH, it is urgent to establish how to prevent DCI, identifying the onset of DIND early, both clinically and instrumentally.

With this study the Investoigators aim to determine the incidence of DIND in patients with aSAH, to evaluate the effectiveness of different treatments and to compare the different diagnostic/therapeutic strategies in the participating centers, investigating the impact of DIND on short-term and long-term neurological-functional outcomes.

• Imaging application [Time frame: 12 months]
• Neurological-functional outcome assessment [Time frame: 12 months]
• Invasive monitoring of intracranial pressure [Time frame: 12 months]
• Neurological-functional outcome assessment [Time frame: 12 months]
• Neurological-functional outcome assessment [Time frame: 12 months]