Hrev_master [page 42] [Emergency Care Journal 2025; 21:14053] Emergency Care Journal 2025 volume 21:14053 Abstract Bilateral fixed mydriasis is a rare condition that can arise from a variety of causes (neurological, pharmacological, toxic or metabolic, para-infectious/autoimmune conditions, and traumatic injuries). We report a 65-year-old woman presenting to the emer- gency department with bilateral mydriasis and complaining of acute severe headache associated with blurry vision, photophobia, vomiting, and a recent history of fever with respiratory symptoms. All preliminary medical investigations aimed at identifying possi- ble causes of endocranial hypertension as well as intracranial lesions or expansive processes, while focusing on findings consis- tent with meningoencephalitis. The diagnosis of acute bilateral angle-closure glaucoma was established through a wide range of radiological and laboratory exams, and with the help of different consultants. This unusual case highlights two interesting aspects: the importance of a multidisciplinary diagnostic work-up for chal- lenging clinical presentations, and the critical relevance of a re- evaluation diagnostic strategy to avoid clinical mistakes. Introduction Mydriasis is defined as dilation of the pupil, caused by sympa- thetic stimulation of the iris dilator muscle fibres.1 Bilateral fixed mydriasis, whether or not associated with headache and other symptoms, may result from a wide array of causes2 including neu- rological (e.g., brainstem impairment, serotonin syndrome, third cranial nerve palsy), pharmacological (e.g., antidepressants, sym- pathomimetics, anticholinergics, serotonergic agents), toxic or metabolic (e.g., cocaine, lysergic acid diethylamide, MDMA, methanol-induced optic neuropathy, post-anoxic brain damage), para-infectious or autoimmune conditions, traumatic injuries (e.g., direct ocular contusion with iridoplegia, loss of pupillary reflex following brain injury), and other causes (e.g., emotional sympa- thetic overdrive, incidental exposure to mydriatic agents, ophthal- mological disorders, bilateral congenital mydriasis). The main causes of bilateral mydriasis are summarized in Table 1.1-18 Several uncommon aetiologies of bilateral mydriasis have also been reported as isolated clinical findings: i) Sato et al. reviewed a case series of atypical post-infectious and autoimmune causes, includ- ing botulism, syphilis, Guillain-Barré syndrome (a rare post- inflammatory progressive polyradiculopathy), Fisher syndrome (a variant of Guillain-Barré syndrome), and Bickerstaff brainstem encephalitis (a rare inflammatory disorder of the central nervous system);8 ii) Baki et al. described an unusual case of bilateral mydriasis as a presenting symptom of Hodgkin’s lymphoma, likely caused by sympathetic pathway compression around the carotid artery;19 iii) Du et al. reported a rare intraoperative onset of bilat- eral mydriasis during transcatheter aortic valve replacement, trig- gered by air embolism to the basilar artery, detectable by CT imag- ing and resolved with immediate aspiration;20 iv) Kang et al. pre- sented a case of bilateral mydriasis induced by Ma Huang (Ephedra), a traditional herbal remedy containing pseudoephedrine and ephedrine, commonly used as an energy booster and weight- loss aid.4 Correspondence: Roberto De Giorgio, Department of Translational Medicine, St. Anna University Hospital, via A. Moro 8, 44124 Ferrara, Italy. Tel.: +39 0532.236631. E-mail: dgrrrt@unife.it Key words: bilateral mydriasis, endocranial hypertension, angle-clo- sure glaucoma. Conflict of interest: the authors declare no conflict of interest. Contributions: AC, BM, MDS, and MG designed the project and wrote the paper; AC, BM, TB, CB, and FC searched the literature for retrievable papers; MDS, CP, RDG, and MG critically reviewed the paper. All authors have read and agreed to the published version of the manuscript. Funding: RDG is supported by ‘Fondi Ateneo per la Ricerca’ (FAR) and ‘Fondi Incentivazione alla Ricerca’ (FIR) research funds from the University of Ferrara, Ferrara, Italy. Institutional review board statement: not applicable. Informed consent statement: obtained and available on reasonable request. Data availability statement: this research did not produce any dataset to provide. Received: 2 June 2025. Accepted: 19 August 2025. Early view: 11 September 2025. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright: the Author(s), 2025 Licensee PAGEPress, Italy Emergency Care Journal 2025; 21:14053 doi:10.4081/ecj.2025.14053 Publisher's note: all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Acute onset of bilateral mydriasis, headache, and vomiting: a challenging diagnosis Antonella Cianci, Beatrice Marziani, Tommaso Bachechi, Camilla Bandini, Francesca Cuoghi, Michele Domenico Spampinato, Chiara Pesci, Roberto De Giorgio, Matteo Guarino Department of Translational Medicine, St. Anna University Hospital of Ferrara, University of Ferrara; Emergency Department, S. Anna University Hospital of Ferrara, Italy Case Report A 65-year-old woman presented to our Emergency Department (ED) with a sudden onset of severe headache, blurred vision, and vomiting. She was afebrile, fully alert, and reported a recent episode of fever with respiratory symptoms, for which she had self-administered over-the-counter antitussive medication contain- ing dextromethorphan in the preceding days. Her past medical his- tory was unremarkable. On physical examination, bilateral mydri- asis was observed (Figure 1), with poor reactive pupils to light stimulation, but no focal neurological deficits or signs of meningeal irritation. Vital signs were within normal limits, except for a single systolic blood pressure spike of 170 mmHg, which was managed with intravenous labetalol (10 mg). ECG showed no ischemic changes. Arterial blood gas analysis revealed no respira- tory abnormalities (pH 7.46, pCO2 31 mmHg, pO2 62 mmHg, HCO3⁻ 24 mmol/L, lactate 0.7 mmol/L). A contrast-enhanced cra- nial CT scan ruled out acute lesions or intracranial haemorrhage. Chest X-ray showed nonspecific interstitial markings. Blood tests revealed mild leucocytosis and elevated C-reactive protein (15.43 mg/dL), but no electrolyte alterations. Given the constellation of symptoms, an infectious disease specialist was consulted. Lumbar puncture revealed Clear Cerebrospinal Fluid (CSF) with mild pleo- cytosis (57 WBC/mm³, predominantly polymorphonuclear), nor- mal glucose (77 mg/dL), and protein levels (45 mg/dL). A multi- plex PCR panel (FilmArray) tested negative for neurotropic pathogens. Empiric antimicrobial therapy was initiated with intra- venous ceftriaxone (2 g), ampicillin (4 g every 6 hours), and acy- clovir (1 g three times daily). This treatment was subsequently dis- continued once CSF results were confirmed negative. Blood and urine cultures remained sterile. A repeat neurological evaluation was requested. Given the negative CT findings, a cerebral and spinal MRI was recommended. An Artificial Intelligence-based clinical decision support tool suggested considering serotonin syn- drome or dextromethorphan intoxication based on her recent use of this latter drug to sedate cough, although classical features (such as hyperreflexia, clonus, or altered mental status) and laboratory Case Report [Emergency Care Journal 2025; 21:14053] [page 43] Table 1. Differential diagnosis of bilateral mydriasis and relevant pathophysiological mechanisms Aetiology Specific Causes Mechanism / Notes Neurological • Brainstem impairment Disruption of pupillary [2,3] • Serotonergic syndrome • Third cranial nerve palsy Reflex pathways • Ophthalmoplegic migraine Serotonin excess Pharmacological • Antidepressants Direct receptor-mediated pupillary dilation [1,2,4,5] • Sympathomimetics • Anticholinergics • Serotonergic agents Toxic / Metabolic • Cocaine • LSD, MDMA Sympathetic overdrive [2,4,6,7] • Herbal medicine (e.g., Ma Huang) • Methanol-induced optic neuropathy Direct toxicity • Post-anoxic brain damage Optic nerve injury Para-infectious / Autoimmune • Herpes zoster, VZV Post-infectious neuropathies [2,8-13] • Botulism • Syphilis Autoimmune inflammation of CNS pathways • Guillain-Barré syndrome • Fisher syndrome • Bickerstaff brainstem encephalitis • Vogt-Koyanagi-Harada syndrome Traumatic Injuries • Ocular contusion with iridoplegia Disruption of iris innervation or muscle damage [2,14,15] • Brain injury with pupillary reflex loss • Urrets-Zavalia syndrome post-keratoplasty • Postganglionic mydriasis after blow-out fracture repair Ophthalmological Disorders • Bilateral angle-closure glaucoma Pupillary block [2,16] Sudden IOP increase may impair iris function Other Causes • Emotional sympathetic overdrive Functional or structural disruption of [2,17,18] • Malignant glaucoma after cataract surgery (e.g., capsular tension ring) parasympathetic tone or iris anatomy • Congenital bilateral mydriasis CNS, central nervous system; IOP, intra-ocular pressure; LSD, lysergic acid diethylamide; MDMA, 3,4-methylenedioxymethamphetamine; VZV, varicella zoster virus. Figure 1. Acute bilateral angle-closure glaucoma. This image shows a case of bilateral mydriasis, a clinical finding which can arise from a variety of causes. In this case a definitive diagnosis of acute bilateral angle-closure glaucoma was established only fol- lowing the manifestation of overt ocular signs such as conjunctival hyperaemia (evident in this image), corneal oedema, and a signifi- cant elevation in intraocular pressure. signs of organ dysfunction were absent. Approximately 19 hours after admission, the patient developed progressive binocular con- junctival redness, periorbital swelling, and worsening blurred vision. An ophthalmologic consult was obtained. Examination revealed conjunctival hyperaemia, corneal oedema with folds, and narrowing of the anterior chamber. Intraocular pressure measured by tonometry was markedly elevated (57 mmHg), leading to a diagnosis of acute bilateral angle-closure glaucoma. The patient was transferred to the ophthalmology unit following administra- tion of intravenous mannitol (18%, 250 mL) and topical therapy with timolol 0.5%, brimonidine, and pilocarpine eye drops. Emergency treatment in the ED also included oral acetazolamide (250 mg) and intravenous furosemide (40 mg). Two additional boluses of mannitol (18%, 500 mL each) were administered and YAG laser peripheral iridotomy was performed once the corneal oedema had resolved. The patient was discharged in good condi- tion four days after admission. Discussion This report illustrates a rare and challenging case presentation characterized by bilateral Acute Angle-Closure Glaucoma (AACG), an ophthalmologic emergency that typically occurs uni- laterally. Bilateral involvement is uncommon and often mislead- ing, as it can mimic life-threatening neurological or systemic con- ditions.16 In our patient, the initial symptoms (sudden-onset severe headache, vomiting, blurred vision, and bilateral fixed mydriasis) were suggestive of intracranial pathology rather than of a primary ocular disorder. The absence of ocular pain and conjunctival hyper- aemia at presentation further complicated the diagnostic process. Bilateral fixed mydriasis raises concern for several critical dif- ferential diagnoses, including brainstem lesions, elevated intracra- nial pressure, bilateral third cranial nerve palsy, toxic or metabolic encephalopathies, and post-infectious or autoimmune neu- ropathies.2 In this case, the diagnostic approach appropriately pri- oritized urgent neurological and infectious causes. A stepwise exclusion of these possibilities (through neuroimaging, lumbar puncture, and laboratory investigations) was essential, albeit ini- tially inconclusive. Only after the onset of overt ocular signs (i.e., conjunctival hyperaemia, corneal oedema, and elevated intraocular pressure) did the underlying aetiology become evident. The delayed appearance of ophthalmologic features underscores the importance of serial reassessment in evolving clinical scenarios, especially when the initial presentation is non-specific or atypical. Acute angle-closure glaucoma is usually unilateral and associated with ocular pain, photophobia, and visual loss.17 In contrast, bilat- eral AACG is rare and may present predominantly with headache, nausea, vomiting, and even altered mental status, mimicking con- ditions such as intracranial hypertension, subarachnoid bleeding, or serotonin syndrome, particularly when pupillary abnormalities are prominent, as in the reported case.16 Various factors can trigger bilateral AACG, including medica- tions (e.g., decongestants containing sympathomimetics),1,2,4,5 sys- temic diseases such as Vogt-Koyanagi-Harada disease,9 anatomical predispositions like microspherophakia,17 and postoperative com- plications of intraocular procedures, such as cataract surgery with capsular tension ring implantation.14,18 In our case, the recent use of dextromethorphan (a serotonin reuptake inhibitor with mild anticholinergic properties) may have precipitated or worsened angle closure in a predisposed individual. Although serotonin syn- drome was initially considered, the absence of hallmark features such as hyperreflexia, clonus, or organ dysfunction made this diag- nosis unlikely. This case underscores several key clinical mes- sages: i) bilateral mydriasis should not prompt a neurological work-up alone; although rare, ophthalmologic causes must be con- sidered, especially when the clinical picture evolves; ii) bilateral AACG, while uncommon, should be part of the differential diag- nosis in patients presenting with unexplained headache, visual symptoms, and pupillary abnormalities, even in the absence of classic ocular pain; iii) a multidisciplinary approach is essential when initial investigations prove inconclusive and the clinical con- dition continues to evolve; iv) timely ophthalmologic evaluation and appropriate medical and surgical interventions are crucial to prevent irreversible visual impairment. This management strategy is supported by current European and international guidelines, which advocate prompt laser peripheral iridotomy and individual- ized pharmacological treatment based on anterior chamber anato- my, intraocular pressure profile, and patient-specific risk fac- tors.21,22 Conclusions In this case, the final diagnosis of bilateral AACG was achieved through repeated clinical assessments and a multidisci- plinary approach. The initial presentation was misleading, as it lacked classical ocular signs and instead mimicked neurological and infectious conditions. This emphasizes the need to maintain a broad differential diagnosis when faced with non-specific symp- toms, such as bilateral mydriasis, headache, and vomiting. The evolution of the clinical picture, marked by the appearance of ocu- lar signs and elevated intraocular pressure, ultimately guided to the correct diagnosis. 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