{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T11:14:31Z","timestamp":1783682071178,"version":"3.55.0"},"reference-count":30,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neurology International"],"abstract":"<jats:p>Headache is a frequent and clinically relevant symptom in patients undergoing cranial radiotherapy, most often reflecting treatment-induced structural and inflammatory changes such as cerebral edema or radiation-related brain injury. Differentiating secondary headache from primary disorders, particularly migraine, is essential for appropriate management. This review aims to examine the pathophysiological mechanisms underlying headache following cranial radiotherapy, evaluate current pharmacological and complementary treatment strategies and highlight key aspects of differential diagnosis with migraine. Unlike existing literature that focuses primarily on radiological findings of radiation injury, this review adopts a symptom-driven approach, reframing headache as a critical clinical gateway for the early detection of structural complications. A structured narrative review of the literature was conducted using PubMed\/MEDLINE, Scopus and Google Scholar to identify studies published between 2020 and 2025, focusing on cerebral edema, radiation-related complications, therapeutic approaches and migraine. Relevant clinical trials, systematic reviews and guidelines were included. Cerebral edema consistently emerges as the main mechanism of acute and subacute post-radiotherapy headache, whereas late-onset symptoms are most often linked to radiation necrosis. Corticosteroids remain first-line therapy, while bevacizumab has demonstrated benefit in steroid-refractory cerebral edema and radiation necrosis through inhibition of vascular endothelial growth factor (VEGF), thereby reducing vascular permeability and attenuating peritumoral edema. Its use in the context of cranial radiotherapy requires careful consideration, as the safety of concomitant administration with radiation has not been formally established, and headache itself is among its recognized adverse effects. Evidence for complementary therapies, including Boswellia serrata and plant-based compounds, remains limited. Migraine constitutes a distinct neurovascular disorder requiring careful differentiation from secondary headache in oncological patients. The review emphasizes headache as a clinically relevant indicator of underlying structural complications rather than an isolated symptom. Post-radiotherapy headache should be interpreted as a manifestation of underlying structural pathology. Accurate etiological diagnosis and individualized management are essential. Further research is needed to refine treatment strategies and clarify the role of complementary therapies.<\/jats:p>","DOI":"10.3390\/neurolint18070132","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T09:46:47Z","timestamp":1783676807000},"page":"132","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Headache as a Sentinel Signal After Cranial Radiotherapy: A Symptom-Driven Approach to Pathophysiology and Management"],"prefix":"10.3390","volume":"18","author":[{"given":"Silviu","family":"Lungu\u021b","sequence":"first","affiliation":[{"name":"Francisc I. Rainer Institute of Anthropology, Romanian Academy, 050474 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0208-4052","authenticated-orcid":false,"given":"Suzana","family":"Turcu","sequence":"additional","affiliation":[{"name":"Francisc I. Rainer Institute of Anthropology, Romanian Academy, 050474 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2272-8129","authenticated-orcid":false,"given":"Cristiana","family":"Glavce","sequence":"additional","affiliation":[{"name":"Francisc I. Rainer Institute of Anthropology, Romanian Academy, 050474 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.ijrobp.2005.01.039","article-title":"Molecular targets in radiation-induced blood-brain barrier disruption","volume":"62","author":"Nordal","year":"2005","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1093\/neuonc\/noad038","article-title":"Diagnosis and management of complications from the treatment of primary central nervous system tumors in adults","volume":"25","author":"Weller","year":"2023","journal-title":"Neuro-Oncology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4368","DOI":"10.1002\/cncr.33930","article-title":"Evaluation of headache in patients with cancer","volume":"127","author":"Bernstein","year":"2021","journal-title":"Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S56","DOI":"10.1093\/neuonc\/noad188","article-title":"The dilemma of radiation necrosis from diagnosis to treatment in the management of brain metastases","volume":"26","author":"Mayo","year":"2024","journal-title":"Neuro-Oncology"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Mittelman, L., Duehr, J., Kazmi, J.S., Vargas, L.O., Donahue, N., Chen, J., Leskinen, S., Syed, S.A., Wernicke, A.G., and D\u2019Amico, R.S. (2025). Radiation Necrosis in Neuro-Oncology: Diagnostic Complexity and Precision Radiotherapy Strategies. Cancers, 17.","DOI":"10.3390\/cancers17213542"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Khan, M., Zhao, Z., Arooj, S., Khan, A., Yang, J., and Tang, Y. (2021). Bevacizumab for radiation necrosis following radiotherapy of brain metastatic disease: A systematic review and meta-analysis. BMC Cancer, 21.","DOI":"10.1186\/s12885-021-07889-3"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Liao, G., Khan, M., Zhao, Z., Arooj, S., Yan, M., Li, X., and Tang, Y. (2021). Bevacizumab treatment of radiation-induced brain necrosis: A systematic review. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.593449"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"101732","DOI":"10.1016\/j.adro.2025.101732","article-title":"Boswellia serrata for the Management of Radiation-Induced Cerebral Edema and Necrosis: A Systematic Meta-Narrative Review of Clinical Evidence","volume":"10","author":"Dejonckheere","year":"2025","journal-title":"Adv. Radiat. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3331024241252666","DOI":"10.1177\/03331024241252666","article-title":"International Headache Society global practice recommendations for the acute pharmacological treatment of migraine","volume":"44","author":"Puledda","year":"2024","journal-title":"Cephalalgia Int. J. Headache"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1111\/head.14692","article-title":"Calcitonin gene-related peptide-targeting therapies are a first-line option for the prevention of migraine: An American Headache Society position statement update","volume":"64","author":"Charles","year":"2024","journal-title":"Headache"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1016\/j.ijrobp.2009.06.006","article-title":"Irradiated volume as a predictor of brain radionecrosis after linear accelerator stereotactic radiosurgery","volume":"77","author":"Blonigen","year":"2010","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/1748-717X-6-48","article-title":"Stereotactic radiosurgery for brain metastases: Analysis of outcome and risk of brain radionecrosis","volume":"6","author":"Minniti","year":"2011","journal-title":"Radiat. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1001\/jamaoncol.2020.4630","article-title":"Multi-institutional analysis of prognostic factors and outcomes after hypofractionated stereotactic radiotherapy to the resection cavity in patients with brain metastases","volume":"6","author":"Eitz","year":"2020","journal-title":"JAMA Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Zoto Mustafayev, T., Turna, M., Bolukbasi, Y., Tezcanli, E., Guney, Y., Dincbas, F.O., Atasoy, B.M., Ugurluer, G., Caglar, H.B., and Atalar, B. (2024). Clinical and radiological effects of bevacizumab for the treatment of radionecrosis after stereotactic brain radiotherapy. BMC Cancer, 24.","DOI":"10.1186\/s12885-024-12643-6"},{"key":"ref_15","first-page":"100600","article-title":"Management of initial and recurrent radiation-induced contrast enhancements following radiotherapy for brain metastases: Clinical and radiological impact of bevacizumab and corticosteroids","volume":"39","author":"Meixner","year":"2023","journal-title":"Clin. Transl. Radiat. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1007\/s12017-022-08707-0","article-title":"The biological activity of 3-O-acetyl-11-keto-\u03b2-boswellic acid in nervous system diseases","volume":"24","author":"Gong","year":"2022","journal-title":"Neuromol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1016\/j.ijrobp.2025.02.016","article-title":"Boswellia Serrata for Cerebral Radiation Necrosis After Radiosurgery for Brain Metastases","volume":"122","author":"Upadhyay","year":"2025","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"103076","DOI":"10.1016\/j.ctim.2024.103076","article-title":"Acupuncture for migraine: A systematic review and meta-regression of randomized controlled trials","volume":"86","author":"Yang","year":"2024","journal-title":"Complement. Ther. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1186\/s10194-025-02152-7","article-title":"Migraine-like headache attributed to a causative disorder: Primary migraine or secondary headache with a migraine-like phenotype?","volume":"26","author":"Lebedeva","year":"2025","journal-title":"J. Headache Pain"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Lungu\u021b, E.F., Antal, C., Turcu, S., Varlas, V.N., Filipescu, A.G., Balescu, I., Bacalba\u0219a, N., and Gorecki, G.-P. (2024). Neurasites\u00ae\u2014A standardized plant extract in the treatment and prevention of migraine attacks. J. Clin. Med., 13.","DOI":"10.3390\/jcm13123364"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"American Headache Society (2021). The American Headache Society consensus statement: Update on integrating new migraine treatments into clinical practice. Headache, 61, 1021\u20131039.","DOI":"10.1111\/head.14153"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1111\/j.1468-2982.2006.01184.x","article-title":"SMART: Stroke-Like Migraine Attacks After Radiation Therapy","volume":"26","author":"Black","year":"2006","journal-title":"Cephalalgia"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2298","DOI":"10.3174\/ajnr.A3602","article-title":"Stroke-like migraine attacks after radiation therapy (SMART) syndrome is not always completely reversible: A case series","volume":"34","author":"Black","year":"2013","journal-title":"Am. J. Neuroradiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"100424","DOI":"10.1016\/j.esmoop.2022.100424","article-title":"MRI-based contrast clearance analysis shows high differentiation accuracy between radiation-induced reactions and progressive disease after cranial radiotherapy","volume":"7","author":"Bodensohn","year":"2022","journal-title":"ESMO Open"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1111\/1754-9485.13847","article-title":"Differentiation between radiation necrosis and true tumour progression after radiotherapy to intracranial metastases","volume":"69","author":"Lasocki","year":"2025","journal-title":"J. Med. Imaging Radiat. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.ijrobp.2023.07.015","article-title":"A Systematic Review Informing the Management of Symptomatic Brain Radiation Necrosis After Stereotactic Radiosurgery and International Stereotactic Radiosurgery Society Recommendations","volume":"118","author":"Vellayappan","year":"2024","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11060-024-04650-1","article-title":"Comparative analysis of bevacizumab and LITT for treating radiation necrosis in previously radiated CNS neoplasms: A systematic review and meta-analysis","volume":"168","author":"Gecici","year":"2024","journal-title":"J. Neuro-Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1080\/02656736.2020.1760362","article-title":"Laser interstitial thermal therapy for treatment of cerebral radiation necrosis","volume":"37","author":"Hong","year":"2020","journal-title":"Int. J. Hyperth."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1007\/s11060-021-03790-y","article-title":"The effect of surgery on radiation necrosis in irradiated brain metastases: Extent of resection and long-term clinical and radiographic outcomes","volume":"153","author":"Newman","year":"2021","journal-title":"J. Neuro-Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"804","DOI":"10.3171\/2017.11.JNS171273","article-title":"Laser ablation after stereotactic radiosurgery: A multicenter prospective study in patients with metastatic brain tumors and radiation necrosis","volume":"130","author":"Ahluwalia","year":"2019","journal-title":"J. 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