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.