Title pageTitle: Pseudotumor Cerebri Syndrome and Essential Thrombocythemia: A Case ReportAuthors: Yi-Ying Chen, Fang-Tzu Chang, Fu-Yu LinAll authors are affiliated with the Department of Neurology, China Medical University Hospital, Taichung 404, TaiwanCorresponding Author: Fu-Yu LinCorresponding author e-mail address: linfuyu95@gmail.comKeywords: Pseudotumor Cerebri Syndrome, Essential Thrombocythemia, Headache, Increased intracranial pressureData availability statement: all relevant data are included in this manuscript.Funding statement: This study was not supported by any sponsor or funder.Conflict of interest disclosure: The authors have no conflicts of interest to declare.Ethics approval statement: As a single-case report with the patient’s signed consent, no other ethical review was required.Patient consent statement: Written informed consent was obtained from the patient for the publication of this case report.Permission to reproduce material from other sources: not applicable.Clinical trial registration: not applicableManuscript Type: Case ReportAuthor ContributionsYi-Ying Chen : writing - original draftFang-Tzu Chang: writing- review and editingFu-Yu Lin: supervision, validation, writing - original draft, writing- review and editingAdditional Authorship Options :Yi-Ying Chen and Fang-Tzu Chang should be considered joint first authors.Key Clinical Message (KCM)Essential thrombocytosis could be one of the secondary causes of pseudotumor cerebri syndrome (PTCS). Etiology–specific intervention for PTCS is crucial for prognosis.IntroductionPseudotumor cerebri syndrome (PTCS) is characterized by increased intracranial pressure with papilledema, normal brain parenchyma on neuroimaging, and normal cerebrospinal fluid (CSF) composition [1]. Most patients with primary PTCS, also called idiopathic intracranial hypertension, are female, or have obesity or recent weight gain. The underlying pathogenesis remains unclear [2]. However, a survey of identifiable secondary causes of increased intracranial pressure revealed causes, such as venous sinus thrombosis, medications, and systemic or endocrine disorders; these secondary causes should be emphasized for etiology-specific management and improved treatment outcomes [1,2]. Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by the sustained elevation of platelet counts (≥450 × 109/L) and a prevalent Janus kinase 2 (JAK2) mutation. ET increases the risk of thrombotic complications [3]. Currently, ET is not regarded as a secondary cause of PTCS [1,4]. In this paper, we report a case of PTCS with papilledema and ET that was successfully treated with an antiplatelet agent and cytoreductive therapy.Case history / examinationA healthy 26-year-old woman presented with episodic blurry vision for 5 months. Regarding her visual symptoms, the patient suddenly developed transient visual obscuration lasting for approximately 30 seconds each time in either eye. The frequency ranged from once per 2-3 days to 5-10 times per day. She also reported episodic headache, and occasional pulsatile tinnitus. She did not have a history of seizure disorder, vitamin A supplementation, medications for acne, lead exposure, oral contraceptives, and steroid intake or withdrawal.On physical examination, her body mass index was 23.6. She was conscious, cooperative and oriented. Her corrected visual acuity was 20/20 in her right eye, and 20/25 in her left eye. Her papillary responses and intraocular pressure in bilateral eyes were normal. Fundus examination revealed papilledema without spontaneous venous pulsations in both eyes. The examination revealed defects of visual fields at the superior and inferior margins of the left eye. Otherwise, her neurological examination provided unremarkable results.Differential diagnosis, investigations and treatmentIn our case, the main differential diagnosis should be to focus on headache with increased intracranial pressure(IICP). Secondary headache causes, usually more urgent to be treated, should be considered first to keep patients out of danger. Common secondary headache causes include vascular related, such as aneurysm, arteriovenous malformation, cerebral venous thrombosis, reversible cerebral vasoconstriction syndrome; infection related, such as viral/ bacterial/fungus meningitis, meningoencephalitis; inflammation related, such as vasculitis, multiple sclerosis; mass lesion related, such as neoplasm, intracranial hemorrhage, hydrocephalus; drug induced or withdrawal related, such as steroid, retinoic acid use. Primary headache causes also need to be considered, such as migraine, tension type headache. In our case, secondary causes need to be considered first rather than primary cause due to the sign of bilateral papilledema as the hint of IICP.Back to our case, the results of brain magnetic resonance imaging with and without contrast were unremarkable. Lumbar puncture revealed markedly increased opening pressure (34.0 cmH2O). The CSF composition was normal. Brain magnetic resonance venogram revealed several areas of possible dural venous sinus stenosis. However, digital subtraction angiography did not demonstrate definite focal thrombosis or occlusion. Laboratory tests revealed high platelet levels of 860,000/μL. Positive JAK2 V617F gene mutation was identified. Her D-dimer level was within normal limits (244 ng/mL). The survey for autoimmune disorders was all negative.Under the impression of PTCS,initially, we administered acetazolamide and topiramate for controlling her intracranial hypertension. However, her visual symptoms and headache were only partially relieved. With the diagnosis of PTCS, secondary to ET, we administered aspirin and hydroxyurea, which led to the obvious improvement of her symptoms.Outcome and follow-upThe patient was followed up for 3 years, without reoccurrence of PTCS.DiscussionPatients with PTCS are classified into two groups: individuals without clear causes, known as idiopathic intracranial hypertension (IIH), and individuals with recognizable secondary causes. Clinically, the presentations of patients with secondary causes might be indistinguishable from those with IIH. However, identifying the secondary causes of PTCS is crucial for etiology–specific intervention [1]. In the present case, the diagnostic criteria of PTCS were met, without evidence of secondary causes including venous sinus thrombosis. She was initially treated for IIH, without obvious improvement. Her symptoms were close to being resolved after aspirin and cytoreductive therapy were initiated, indicating a potential link between ET and PTCS.In the literature, numerous secondary causes that contribute to PTCS development have been described, including cerebral venous abnormalities (cerebral venous sinus thrombosis, or arteriovenous fistula), medications exposure (vitamin A, tetracycline, or hormones), and medical conditions (sleep apnea, anemia, or renal failure) [1,2,4-6]. ET, a rare myeloproliferative disorder characterized by elevated platelet count, is considered to increase the risk of thrombosis [3]. Therefore, ET is a potential contributor to the development of PTCS. Notably, a study investigated ET patients with headache disorders and ocular ischemic events [7]. However, at present, ET is not considered an independent risk factor for PTCS.The pathogenesis of PTCS remains unclear. The presence of diverse contributing factors suggests that PTCS does not have a single underlying cause, but that PTCS involves multiple pathogenic mechanisms. By contrast, not all patients presenting with contributing factors develop PTCS, indicating its multifactorial nature [6]. Cases with PTCS and ET have been rarely reported. In the majority of the cases, PTCS was secondary to cerebral venous sinus thrombosis. However, no evidence of venous sinus thrombosis was found in some cases with PTCS and ET suggesting that ET is an independent secondary cause of PTCS. A study suggested that these headaches and visual presentations are related to intermittent cerebral venous sinus blockage, resulting from increased platelet counts [8].A recent study suggested that JAK2V617F mutation is linked to the upregulation of pro-thrombotic genes in platelets and neutrophils, enhancing leukocyte adhesion and the release of neutrophil extracellular traps. Endothelial cells with the JAK2V617F mutation secrete increased pro-thrombotic and adhesive proteins, such as von Willebrand factor and P-selectin [9]. A case series examined the JAK2V617F mutation in patients presenting with PTCS associated with cerebral venous sinus thrombosis. Most patients with the mutation had thrombocytosis, and the visual outcomes in these patients were generally poor despite medical and surgical intervention, warranting aggressive management [10].In conclusion, this case report highlights that ET might be a secondary cause of PTCS. Early intervention in patients with PTCS is crucial for preventing permanent visual impairment resulting from ischemic optic neuropathy. The management of PTCS patients with ET involves implementing platelet-lowering therapies, such as hydroxyurea, and antithrombotic therapy. Future studies should be conducted to elucidate the precise pathophysiological mechanisms and to develop targeted therapeutic strategies for this population.References1. Friedman DI, Liu GT, and Digre KB. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology. 2013; 81(13):1159-65.2. Mollan SP, Davies B, and Silver NC, et al. Idiopathic intracranial hypertension: consensus guidelines on management. J Neurol Neurosurg Psychiatry 2018; 89:1088-1100.3. Tefferi A, Vannucchi AM, Barbui T. Essential thrombocythemia: 2024 update on diagnosis, risk stratification, and management. Am J Hematol. 2024; 99(4):697-718.4. Ball AK, Clarke CE. Idiopathic intracranial hypertension. Lancet Neurol. 2006; 5(5):433-42.5. Toscano S, Fermo SL, and Reggio E, et al. An update on idiopathic intracranial hypertension in adults: a look at pathophysiology, diagnostic approach and management. J Neurol. 2021; 268(9):3249-3268.6. Halmagyi GM, Ahmed RM, and Johnston IH. The Pseudotumor cerebri syndrome: a unifying pathophysiological concept for patients with isolated intracranial hypertension with neither mass lesion nor ventriculomegaly. Neuroophthalmology. 2014; 38(5):249–253.7. Michiels JJ, Berneman Z, Gadisseur A, et al. Aspirin-responsive, migraine-like transient cerebral and ocular ischemic attacks and erythromelalgia in JAK2-positive essential thrombocythemia and polycythemia vera. Acta Haematol. 2015;133(1):56-63.8. Trimboli M, Romaniello A, Troisi L, et al. Pseudotumor cerebri syndrome and essential thrombocythaemia: Case report and literature review. J Neurol Sci. 2020; 15;416:117021.9. Reeves BN, Beckman JD. Novel pathophysiological mechanisms of thrombosis in myeloproliferative neoplasms. Curr Hematol Malig Rep. 2021; 16(3): 304–313.10. Zloto O, Lubetsky A, Ben-Bassat Mizrachi I, Kesler A, Quiros PA, Huna-Baron R. Prognostic value of JAK2V617F mutation in pseudotumor cerebri associated with cerebral venous sinus thrombosis. 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