The HARM (Hyperintense Acute Reperfusion Marker) sign is defined as a hyperintense subarachnoid signal on FLAIR [
1‐
3] post-gadolinium-contrast administration
. It has been attributed to gadolinium contrast leakage into the subpial space due to BBB disruption caused by brain lesions such as ischemic stroke [
4‐
6]. Brain ischemia depletes cellular adenosine triphosphate (ATP), leading to impairment of the sodium-potassium-ATPase. This increases intracellular potassium, lactic acidosis, and extracellular glutamate release [
7]. These alterations favor extracellular matrix degradation, as well as tight junctions and BBB disruption, which may be exacerbated if post-ischemic reperfusion takes place. In such a case, first, there is a hyperemic phase that increases BBB permeability. Immediately after this, swelling of endothelial cells and microvascular obstruction lead to a so-called “no-reflow effect” and to a hypoperfusion stage [
7]. The ensuing brain tissue nutritional deficiency enhances inflammation and oxidative stress (exacerbated by the partially restored oxygen supply), further disrupting BBB integrity [
7]. The resulting increased paracellular permeability can be attributed to a biphasic response. At first, 3–8 h after reperfusion, BBB disruption is mainly due to the aforementioned degradation of the extracellular matrix, inflammation, and oxidative stress. Then, 18–96 h after reperfusion, BBB alterations are associated with vasogenic edema and angiogenesis, which further increase BBB permeability to macromolecules [
7]. These changes not only increase the risk of hemorrhagic transformation but also facilitate gadolinium contrast leakage in the subpial space, thus leading to the HARM sign. This cerebrospinal fluid signal hyperintensity has been reported in prospective studies to appear both close to or far from ischemic lesions [
8,
9], and it usually lasts from about 3 h to 2 days after injection with gadolinium but, in some cases, HARM persists for up to 6 days [
4,
5,
10]. It can be identified in a variety of conditions presenting BBB disruption, including seizures, intracerebral hemorrhages, transient ischemic attacks, and systemic inflammation [
2,
4,
10‐
13]. Cerebral microbleeds are millimetric (< 10 mm) ovoid or rounded spots of hypointense (black) signal drop on SWAN. Like HARM, microbleeds are an MRI finding that should not be neglected, since they are a risk factor for intracerebral hemorrhage (particularly in anticoagulated patients), as well as for ischemic stroke recurrence in patients with brain ischemia [
14]. Again, like HARM, cerebral microbleeds are believed to be associated with BBB disruption, which leads to leakage from capillaries and arterioles of red blood cells. These are phagocyted and degraded by microglial cells, leading to the formation and accumulation of iron products (e.g. hemosiderin). Hemosiderin-laden microglia usually remain in the same cerebral region for the patient’s lifetime, typically next to arterioles affected by microangiopathies [
15]. Therefore, SWAN allows the detection of hemorrhages that may have occurred at any time in the patient’s life. This MRI sequence is usually chosen since it magnifies microbleeds due to the blooming artifact caused by paramagnetic substances, like blood-derived hemosiderin [
14]. Mixed (i.e. lobar and subcortical) patterns of cerebral microbleeds distribution suggest mixed etiologies, while exclusively lobar microbleeds probably indicate cerebral amyloid angiopathy, and subcortical ones are suggestive of hypertension and/or arteriolosclerosis [
14,
15].
This case report highlights first of all the importance of differentiating HARM and subarachnoid hemorrhage. Secondly, it shows an example and timing of the appearance of microbleeds and discusses their pathophysiology. Finally, for the first time, this case report suggests that, in some acute ischemic stroke patients, a relationship between HARM and cerebral microbleeds may exist.