The hypersensitivity to intravenous contrast media has been broadly classified as immediate reactions (IR) and non-immediate reactions (NIR). The immediate reactions occur within 1 h and can be IgE mediated or non-IgE mediated [1, 6]. Non-immediate reaction occurs within hours or even days and has T-cell involvement and lymphocyte proliferation. Since this patient developed an allergic reaction within 1 h of contrast instillation, he had an immediate reaction. It was associated with urticaria, flushing, bronchoconstriction, and hypotension, suggesting anaphylaxis. The incidence of immediate hypersensitivity reaction to nonionic contrast lies between 0.01 and 0.04% in severe cases and up to 3% in mild cases. Risk factors include previous history of reaction to contrast media, history of asthma and atopy, heart diseases, renal diseases, thyroid abnormalities, medications like metformin, and beta blockers and in the elderly (greater chance of severe reaction) [7].

Usually, the brain does not suffer from allergic reactions since IgE cannot cross the blood-brain barrier even though mast cells (MC) are present in the brain. But a majority of contrast medium allergies happen even in the absence of previous exposure and are non-IgE mediated. Symptoms are due to release of inflammatory mediators from mast cells either directly by non-specific binding of contrast media particles to membrane receptors or indirectly by complement-kinin activation (C5a) [2].

There are case reports in the literature on contrast medium hypersensitivity causing Kounis syndrome (KS) [8, 9]. There are three variants of Kounis syndrome—vasospastic allergic angina, allergic myocardial infarction due to plaque rupture, and stent thrombosis with occluding thrombus infiltrated by eosinophils and mast cells [4]. Similarly, vasospasm causing symptoms in other organs like transient ischemic attacks (TIA) in patients of known mast cell activation disorders and allergic reactions causing abdominal symptoms due to vasospasm of splanchnic artery or embolism causing bowel ischemia has also been described [5, 10]. But anaphylactic reaction to contrast medium resulting in multi-territorial cerebral infarction has not been reported before to the best of our knowledge.

When activated by C5a complement, mast cells switch from a profibrinolytic phenotype in the resting state to a prothrombotic phenotype by expressing plasminogen activator inhibitor 1 (PAI-1) [11]. Prothrombotic mechanisms include triggering platelet activation and aggregation by PAF, activation of factor XII by heparin, activation of fibrinogen, factors XII and XIII by proteases like tryptase and chymase, secretion of vWF and factor VIII, and promoting the expression and release of tissue factor and plasminogen activator inhibitor into circulation. Mast cells also produce extracellular traps, the presence of which has been reported in coronary thrombi formation. A case series had pointed out the risk of anaphylaxis in causing secondary thrombosis, and it is highest in the first 72 h [12]. The patient also had severe anemia, probably due to chronic blood loss in the form of hematuria. Chronic blood loss can also stimulate erythrocytes and platelets, resulting in thrombocytosis as well [13, 14].

PAF cause a decrease in myocardial contractility, which result in reduced cardiac output. There is also loss of intravascular component due to increased vascular permeability and vasodilation in the systemic circulation. The anaphylactic mediators—histamine, chymase, and leukotrienes, along with PAF, can induce cerebral artery spasm too. Hence, the reduction in cerebral blood flow due to anaphylactic shock is greater than that due to mere arterial hypotension [15].

This patient was diagnosed with a noninvasive bladder cancer later which caused the hematuria in this patient. But the association with thromboembolism is negligible in noninvasive bladder cancer. The risk increases only in muscle-invasive bladder cancer (up to 6%) and up to twofold times if the patient has undergone radical cystectomy [16].

Thus, a prothrombotic environment with acute reduction in cerebral blood flow due to anaphylaxis is hypothesized to be the causative factor behind stroke in our patient and makes this a unique case.