Endovascular Therapy for Tovorafenib-Induced Reversible Cerebral Vasoconstriction in Pediatrics

Introduction Reversible cerebral vasoconstriction syndrome (RCVS) is a less considered etiology of acute severe headache in the pediatric population. It is classically characterized by thunderclap headache that is recurrent and reversible multifocal cerebral artery narrowing. While it has been linked to vasoactive medication, immunosuppression, and systemic illness, case reports in the field of pediatric hematology‐oncology are rare. No previous cases have linked RCVS with tovorafenib, an oral pan‐RAF inhibitor in clinical investigation for pediatric BRAF V600E‐mutated malignancies. Because RCVS can be imitated by other neurologic disorders and noninvasive vascular testing can be normal, the diagnosis usually necessitates catheter‐based angiography. Intra‐arterial calcium channel blockers have been utilized in endovascular therapy to obtain both diagnostic accuracy and immediate therapeutic benefit. We describe the first documented case of childhood RCVS associated with tovorafenib with successful endovascular diagnosis and intra‐arterial verapamil treatment. Materials and Methods A 12‐year‐old female with multifocal osseous relapsed Langerhans cell histiocytosis (LCH) harboring BRAF V600E mutation started tovorafenib in February 2025. After six cycles, she developed recurrent thunderclap headache that woke her up from sleep, sometimes followed by brief confusion characteristic of postictal states. Tovorafenib was withheld, and she was evaluated via multidisciplinary evaluation. Comparison brain MRI revealed minimal Chiari I malformation and small sphenoid hyperintensity on the left side. Head and neck CT angiogram was normal. EEG, with 2‐hour study during symptomatic attack, revealed no epileptiform discharge. Ophthalmological examination revealed no papilledema. Because of the persistence of thunderclap headache and nonrevealing noninvasive studies, diagnostic cerebral angiography was done. Results Digital subtraction angiography disclosed focal segmental narrowing of the right A3 segment of the anterior cerebral artery characteristic of RCVS. Verapamil (5 mg) was administered intra‐arterially, with resultant immediate angiographic resolution of the vasospasm. Lumbar puncture ruled out infection and inflammation. The patient was switched to oral verapamil with rapid resolution of her thunderclap headaches. Interestingly, tovorafenib was resumed on hospitalization day with continuation of verapamil, and no additional RCVS events were experienced. Discharge on oral verapamil with follow‐up as scheduled in neurology, neurosurgery, and oncology clinics was successful. Conclusion This case highlights the critical importance of endovascular evaluation and treatment of potential pediatric RCVS, especially when vasoconstriction is not detected by noninvasive imaging. In this patient, both therapeutic and diagnostic angiography was in keeping with RCVS and reversible following intra‐arterial verapamil infusion. Temporal correlation of tovorafenib exposure and onset of symptoms, together with angiographic response to calcium channel blockade, is compatible with drug‐related mechanism. One possible explanation would be inhibition of RAF pathway altering vascular smooth muscle or endothelial tone, which predisposes to vasoconstriction. To our knowledge, this is the first description of tovorafenib‐associated RCVS. This presentation underscores the need to heighten awareness of RCVS as an emergent side effect of new targeted therapies in children. Early diagnosis, multidisciplinary assessment, and prompt endovascular therapy will prevent morbidity and enable resumption of potentially life‐extending oncologic therapy. Additional pharmacovigilance and further study are necessary to better clarify the incidence, pathogenesis, and treatment of this new complication.