In this pediatric case of suprasellar pilocytic astrocytoma with the PAI-1 4G/4G genotype, we emphasize the importance of early diagnosis and patient management of symptomatic cerebral vasospasm, a rare complication following endoscopic transsphenoidal surgery.
In our case, to alleviate pressure on the hypothalamic region and address hydrocephalus, we initially performed resection using a transcranial anterior interhemispheric approach. Subsequently, we employed an endoscopic endonasal transsphenoidal surgical approach to resect remaining tumor areas in the sellar and parasellar regions, aiming to alleviate compression on the optic nerve and chiasm.
Ceylan et al. [1] proposed an algorithm in their published study, recommending observation for asymptomatic patients, while suggesting extensive surgical resection followed by observation for symptomatic cases showing progression. In cases where biopsy or partial resection is planned, adjuvant therapy is prioritized in the subsequent steps.
While a 10-year survival rate exceeding 90% has been reported, overall survival is lower for tumors located in the hypothalamic/optic chiasm region and in cases where complete surgical resection is not attainable [2]. The primary treatment approach is gross total resection (GTR). Radiation therapy or chemotherapy is administered only in cases of tumor recurrence after GTR, when subtotal resection leads to neurological deficits, or if there is evidence of growth in radiological follow-ups [3]. In adjuvant therapy, particularly in pediatric cases, chemotherapy is preferred to minimize the potential toxicity of radiotherapy at young ages. However, a definitive consensus on the timing of radiotherapy versus chemotherapy administration has not yet been reached [4].
In our case, a BRAF-KIAA1549 fusion was identified, confirming the diagnosis of pilocytic astrocytoma [5]. These tumors have low recurrence rates, and survival durations are prolonged without recurrence [6]. While first-generation BRAF inhibitors are effective for BRAFV600E, in tumors with BRAF-KIAA1549 fusion, they may lead to paradoxical activation of the RAS/MAPK pathway, resulting in tumor progression [7]. Therefore, second-generation BRAF inhibitors that do not induce paradoxical activation have been developed [8]. Additionally, studies have shown that MEK inhibitors are effective in cases with BRAF-KIAA1549 fusion [9, 10]. These treatment options are recommended for refractory or progressive tumors. In our pediatric case, tumor progression was not observed, and adjuvant therapy was not administered.
The pathophysiology of vasospasm and associated delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage has been well studied [11]. It has been reported in literature reviews to have an approximate mortality rate of about 30% [12]. However, vasospasm developing after an endoscopic transsphenoidal approach has been reported with limited case examples in the literatüre [13].
In pediatric patients, angiographic vasospasm occurs at a similar rate as in adults, but clinically, it is lower due to collateral circulation [14]. However, vasospasm secondary to extensive endoscopic transsphenoidal surgery is rare, and various pathophysiological models have been proposed to explain this pathological condition [15]. One of these models involves leakage of blood into the subarachnoid space. Hemoglobin products such as oxyhemoglobin and methemoglobin interact with the vascular wall, leading to decreased nitric oxide production, resulting in continuous vasoconstriction and, consequently, ischemia [16]. Another model suggests that arteries surrounded by tumors are more susceptible to vasospasm due to compression and local effects of tumor-related factors, leading to impaired vascular tone regulation [17]. Additionally, large-volume tumors with hypothalamic involvement may lead to spasmogenic substance release, contributing to ischemic damage [13]. In our case, resection of the mass extending into the third ventricle could potentially impact the hypothalamic area and adjacent vascular structures (Fig. 1G-I). Reported cases in the literature indicate a higher frequency of affected anterior circulation, especially the ACA, proximal MCA, and supraklinoid ICA, with less frequent involvement of the posterior circulation (proximal posterior cerebral artery, basilar artery) [18].
PAI-1 is a serine protease inhibitor that targets tissue plasminogen activator (tPA) and urokinase (uPA), thereby reducing fibrinolytic activity and leading to fibrin buildup [19, 20]. The 4G/4G genotype is associated with higher PAI-1 levels compared to other genotypes [21]. Elevated PAI-1 activity results in reduced plasminogen activation, leading to weak fibrinolysis and an increased risk of thrombotic events like cardiovascular and cerebrovascular diseases, recurrent miscarriages, and preeclampsia [22]. Vergouwen et al. [23] found a significant link between the 4G allele in the PAI-1 gene and cerebral ischemia following aneurysmal subarachnoid hemorrhage (aSAH). While vasospasm is a significant factor in cerebral ischemia, not all vasospasm patients experience it. Microthrombi formation may determine the occurrence of cerebral ischemia in vasospasm patients, and PAI-1 levels may play a role in their formation and dissolution. The presence of the 4G/4G genotype in our case suggests a predisposition to postoperative cerebral vasospasm and ischemia. We did not find a reported case of cerebral vasospasm and ischemia following endoscopic transsphenoidal surgery in a patient with the PAI-1 4G/4G polymorphism in the literature.
In managing these cases, it is recommended to include oral nimodipine as a calcium antagonist and to control hypertension to enhance cerebral perfusion [24]. It has been shown that nimodipine reduces the risk of cerebral ischemia [25]. One of the effects of nimodipine is to decrease PAI-1 levels in the plasma, thereby increasing fibrinolytic activity [26]. This can help prevent adverse outcomes from cerebral ischemia associated with increased PAI-1 levels [23]. In our case, oral nimodipine treatment was initiated promptly after the occurrence of cerebral vasospasm and ischemia. In suitable patients, among the endovascular treatment options, intra-arterial vasodilators, balloon angioplasty, and/or stent treatment options should be considered [27].