Abstract

Background: Pituitary apoplexy (PA) is a rare, life-threatening clinical syndrome that occurs in response to acute ischemic infarction or hemorrhage of a pituitary adenoma. We report two cases of sudden neurologic and visual decline in patients with pituitary region masses in coronavirus disease (COVID)-positive patients with a focus on potential pathophysiological mechanisms and a safe approach to treatment.

Case Description: Case one is a 58-year-old male presenting with sudden-onset headache and visual disturbance. He was febrile and tested positive for COVID-19. Magnetic resonance imaging (MRI) revealed a large sellarsuprasellar mass with intratumoral hemorrhagic components. He underwent endoscopic endonasal resection with subsequent improvement in vision and oculomotor function. Pathology was consistent with hemorrhagic pituitary adenoma. Case two is a 15-year-old male presenting with sudden-onset severe headache and acute visual loss. He also tested positive for COVID-19. MRI revealed a sellar-suprasellar mass with a regional mass effect. He underwent endoscopic endonasal resection with improvement in vision over time. Pathology was consistent with craniopharyngioma. There was no evidence of intraoperative COVID-19 transmission among members of the surgical team, who were monitored for 2 weeks after surgery.

Conclusion: PA in the setting of severe acute respiratory syndrome coronavirus 2 infection should be considered in the differential diagnosis of a COVID-positive patient presenting with acute severe headache, visual loss, and/or ophthalmoplegia; we discuss proposed mechanisms related to inflammation, coagulability, and hypoxia. The absence of intraoperative COVID-19 transmission during transsphenoidal resection performed in an emergency setting suggests that the risk of exposure may be attenuated with safety precautions.

Keywords: Apoplexy, Coronavirus disease 2019, Pituitary, Severe acute respiratory syndrome coronavirus 2, Transsphenoidal

INTRODUCTION

Pituitary apoplexy (PA) is a rare and life-threatening clinical syndrome that occurs in response to acute ischemic infarction or hemorrhage of a pituitary lesion with rapid expansion of sellar contents.[ 4 ] The incidence of PA ranges from 2% to 12% in patients with pituitary adenomas. Patients typically present with severe, acute-onset headaches, visual impairment, extraocular palsy, altered mental status, and hormonal or electrolyte disturbances.[ 4 , 8 , 13 ] Other pituitary region tumors, such as craniopharyngiomas, may also present with bleeding or enlargement that is associated with sudden visual deficits. In such clinical scenarios, endoscopic endonasal transsphenoidal surgery may be urgently offered and has been associated with favorable neurologic and endocrinologic outcomes.[ 19 , 35 , 41 ]

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is largely recognized as a severe respiratory viral syndrome. However, COVID-19 is also known to be associated with systemic alterations, such as pro-inflammatory and hypercoagulable states, that likely contribute to neurological complications, such as stroke.[ 1 , 15 , 23 , 39 ] We hypothesize that COVID-19 may be a risk factor for PA. The goal of this report is to demonstrate a possible relationship between COVID-19 and hemorrhagic complications of pituitary region tumors and to highlight the safety of an endoscopic endonasal approach for emergently treating such tumors in patients with concomitant COVID-19 infection.

CASE DESCRIPTION

Case 1

A 58-year-old male with no past medical history presented with sudden onset of headache, nausea, vomiting, and decreased visual acuity on the day of admission. He had no upper respiratory symptoms. He had not received vaccination against COVID-19 and was not receiving any COVID-19 treatments. He was febrile to 101.3°F with otherwise stable vital signs. On examination, he was confused and intermittently followed commands. Examination of the right eye revealed complete ophthalmoplegia with a visual acuity of 20/400. The left eye had reduced visual acuity and was only able to finger count; however, extraocular movement was intact. On confrontation, the patient was noted to have bitemporal hemianopsia. There were no other neurologic deficits noted on examination. A computed tomography (CT) scan of the head showed a sellar/suprasellar mixed-density mass with osseous remodeling of the sella turcica and hyperdensity within portions of the mass consistent with blood products [ Figure 1a ]. Magnetic resonance imaging (MRI) of the brain with and without contrast showed a contrast-enhancing 5.0 × 3.3 × 2.5 cm mass with a heterogeneous signal with extension to the margins of the cavernous sinus and compression of the optic apparatus [ Figures 1b and c]. Endocrine laboratories showed central hypothyroidism. The patient also tested positive for COVID-19; his fibrinogen (465 mg/dL, normal <400 mg/dL), D-dimer (2,087.00 ng/mL, normal <500 ng/mL), and C-reactive protein (5.50 mg/dL, normal <0.50 mg/dL) were elevated. The patient’s presentation was most consistent with PA. Due to his acute onset of vision decline and cranial neuropathies, an endoscopic endonasal transsphenoidal approach was recommended for rapid debulking and maximal safe resection of the presumed pituitary macroadenoma for tissue diagnosis and relief of mass effect. The surgery was performed jointly by neurosurgery and ENT. To reduce the COVID-19 exposure risk, the number of health-care workers in the room during surgery was limited. Powered air-purifying respirators (PAPRs) were used by all surgeons, and the remainder of the staff used eye protection and N-95 masks. In addition, a high-efficiency particulate air filter was placed in the room. Drilling was limited as much as possible. A cerebrospinal fluid (CSF) leak was encountered, and the dural defect was repaired using a dural substitute, nasoseptal flap, and nasal packing. The patient tolerated the procedure well. Pathology was consistent with gonadotroph adenoma with hemorrhagic necrosis. At 10-month follow-up, his third and sixth cranial nerve palsies had resolved. Visual acuity improved to 20/30 in the left eye and 20/200 in the right eye. He was maintained on levothyroxine and hydrocortisone. *At 3.5 year follow-up, he is no longer on hormone replacement therapy. Post-operative MRI shows no evidence of residual or recurrent tumor [ Figure 1d ].

Figure 1:

(a) Non-contrast head CT shows a predominantly hyperdense mass in the sellar/suprasellar region representing intratumoral density and/or blood products. (b, c) Coronal and sagittal T1-weighted MRI with contrast show a 5 cm heterogeneous mass with intratumoral blood products and significant compression of the optic apparatus. *(d) Postoperative MRI shows no evidence of residual or recurrence.

Case 2

A 15-year-old male with a history of hypothyroidism and adrenal insufficiency status post transsphenoidal resection of a reported pituitary macroadenoma in another country 5 years prior presented with a sudden decline in visual acuity. Per the report, the patient had a residual tumor that was followed with surveillance imaging and had not received any adjuvant therapy. Baseline visual deficits following his prior surgery included the ability only to see shadows in the left eye and a 40% visual field cut in the right eye. In the current presentation, the patient reported a progressive decline in visual acuity over 3 days, followed by a sudden onset of severe headache, which awoke him from sleep and complete loss of vision. He also noted new polyuria and polydipsia. He had no upper respiratory symptoms and was afebrile. He had not received a vaccination against COVID-19 and was not receiving any COVID-19 treatments. On examination, the patient had complete bilateral loss of vision without evidence of papilledema; he was otherwise neurologically intact. Head CT demonstrated a partially hemorrhagic suprasellar mass with cystic and solid components without calcifications. MRI showed a 3.8 × 2.6 × 2.3 cm heterogenous sellar/suprasellar mass with marked regional mass effect and compression of the optic apparatus [ Figures 2a and b]. Endocrine laboratories showed low thyroxine, follicle stimulation hormone, luteinizing hormone, and prolactin. He also tested positive for COVID-19. The patient’s presentation was most consistent with an apoplexy-like event in the setting of likely residual or recurrent tumor. Due to his acute onset of vision decline, an endoscopic endonasal transsphenoidal approach was recommended for rapid debulking and maximal safe resection of the pituitary macroadenoma for tissue diagnosis and relief of mass effect. He received a stress dose of hydrocortisone and underwent surgery under similar precautions as in Case 1. Intraoperatively, sellar contents were noted to extrude under pressure. In the suprasellar region, a 30° endoscope revealed an atretic right optic nerve. It also showed a remaining adherent portion of the tumor and cyst wall in the right suprasellar region that was not aggressively resected due to concern for injury to surrounding structures. CSF was encountered, and closure consisted of a dural substitute, nasoseptal flap, and nasal packing. The patient developed CSF rhinorrhea postoperatively and was treated with nasoseptal flap revision and lumbar drainage. The final pathology was consistent with papillary craniopharyngioma, calling into question the initial diagnosis of pituitary macroadenoma. His immediate postoperative MRI showed resection of the sellar/suprasellar mass with a small residual cystic component and peripheral rim of contrast enhancement within the right aspect of the suprasellar cistern extending toward the region of the inferior right frontal lobe [ Figures 2c and d]. He developed diabetes insipidus and was treated with desmopressin. He was treated with adjuvant photon radiation treatment. At an 8-month follow-up, he reported improvement in his left eye visual acuity with the ability to read enlarged print. Surveillance MRI showed a significant reduction in the size of the small right suprasellar cystic residual component with no other recurrence [ Figures 2e and f]. He was maintained on desmopressin, levothyroxine, and hydrocortisone.

Figure 2:

(a, b) Preoperative coronal and sagittal T1-weighted MRI with contrast show a 3.8 cm predominantly solid sellar and predominantly cystic suprasellar mass. (c, d) Immediate postoperative MRI shows resection of the mass with small cystic residual with peripheral enhancement in the right suprasellar region. (e, f) MRI with contrast at most recent follow-up following radiation therapy shows no recurrence and decreased size of residual tumor.

DISCUSSION

We report two cases of pituitary region tumors in COVID-positive patients who underwent an emergency transsphenoidal approach for resection. The purpose of this report is to raise awareness of a potential association between COVID-19 and PA or apoplexy-like events in other pituitary region tumors and to demonstrate that the two conditions may be managed safely through an endoscopic endonasal transsphenoidal approach with respect to both the patient and the treating medical team.

Understanding of the pathogenesis of PA is evolving and multifactorial. Several mechanisms relate to reduced blood supply and subsequent infarction with a susceptibility to hemorrhage. Rapid tumor growth may outstrip normal blood supply and lead to compression of the superior hypophyseal artery against the diaphragmatic notch, further limiting blood supply.[ 6 , 27 , 30 ] In addition, tumors may have reduced blood vessel density, poor perfusion, and a higher metabolic demand when compared to normal pituitary tissue.[ 29 ] These factors may predispose to ischemic events, as seen in PA. At the same time, ischemic tissue may be prone to hemorrhage, and increased intra-sellar pressure and inherent fragility of tumor vessels may further increase bleeding risk.[ 30 , 39 ] Although less common, several reports exist of acute hemorrhage or hemorrhagic infarction in the setting of craniopharyngioma, which may be mistaken for PA.[ 17 , 28 ] Although the term PA is typically reserved for pituitary adenomas, some authors have applied apoplexy to such cases of craniopharyngioma and other tumors in the region of the sella.[ 11 ]

Multiple features of the COVID-19 virus provide plausible mechanisms that may contribute to a role in apoplexy or acute hemorrhage of a parasellar mass. COVID-19 virus accesses host cells using an angiotensin-converting enzyme 2 receptor, which is found in neurons and glial cells.[ 2 , 3 , 39 ] Proposed routes for viral entry into the brain include the olfactory bulb and circumventricular organs where the blood–brain barrier is lacking.[ 1 , 39 ] In further support of neurotropism, COVID-19 is associated with a range of neurological symptoms, and it has been isolated in CSF samples.[ 22 ] COVID-19 virus is associated with a hypercoagulable state, including elevated fibrinogen and D-dimer levels, as seen in Case 1.[ 25 , 38 ] In a multinational observational study of 17,799 hospitalized patients with COVID-19, 156 patients, or approximately 1% of the sample, had a stroke.[ 32 ] A COVID-related predisposition to thrombosis may increase the likelihood of tumor infarction and possible hemorrhage, as seen in apoplexy, especially in the setting of infection-induced thrombocytopenia and platelet dysfunction.[ 7 ] Other viruses, such as orthohantavirus and dengue, are associated with hemorrhage, possibly through immune-mediated hypophysitis or increased stimulation of the pituitary gland in an infectious state.[ 15 , 16 ] Finally, other studies have shown an association between viral infection and direct damage to the pituitary vasculature.[ 5 , 34 ]

Additional support for a relationship between COVID and PA relates to the interplay between hypoxia and ischemia. Patients with severe COVID-19 often develop pneumonia and acute respiratory distress syndrome, resulting in diffuse alveolar damage and hypoxemia.[ 9 , 37 ] In a retrospective cohort study of 140 patients with COVID, hypoxia was positively associated with inflammatory markers such as C-reactive protein and D-dimer levels.[ 24 ] These findings are consistent with postmortem histopathological brain examinations of COVID-19 patients that show evidence of hypoxic injury and inflammation.[ 24 , 26 , 33 ] Severe inflammation with neurologic involvement has also been reported in pediatric patients with COVID-19.[ 18 , 20 ] The crosstalk between hypoxia, inflammation, and coagulation is well established and demonstrated by classical signaling pathways. For example, it is known that hypoxia leads to the expression of hypoxia-inducible factors 1 and 2, which results in the nuclear translocation of nuclear factor kappa B, a transcription factor responsible for inducing various pro-inflammatory genes.[ 12 ] In addition, hypoxia promotes coagulation by activating the expression of tissue factors and inhibits thrombolysis by upregulating plasminogen activator inhibitor-1.[ 1 ] Thus, hypoxemia, inflammation, and hypercoagulability, in the context of an already compromised hypophyseal vasculature, may further predispose patients with sellar/suprasellar lesions to PA.[ 29 ]

The occurrence of acute hemorrhagic or hemorrhagic infarct of a pituitary region mass in the setting of a COVID-positive diagnosis can make management more challenging. Procedures that involve the nasal mucosa, where SARS-CoV-2 is known to colonize, raise safety concerns related to airway management and disease transmission. Zhu et al. reported a case performed early during the COVID-19 pandemic where a COVID-19 patient underwent a transsphenoidal pituitary adenoma resection that led to 14 cases of postoperative COVID-19 transmission among the medical staff.[ 40 ] In June 2020, The Pituitary Society Professional Education Committee put forth recommendations for pituitary surgery that included guidelines for COVID-19 testing and systematically triaging candidates for transsphenoidal surgery based on severity of presentation.[ 14 ] Although the timing of intervention for PA varies, our report is novel in that it is the first to report safe intervention in the emergency setting in an effort to reduce significant mass effects and provide an opportunity for improvement in vision function. In other reports of COVID and PA, patients were taken to the operating room at delayed time points ranging from 5 days to 2 weeks.[ 10 , 21 , 31 , 38 ] It is also the first, to our knowledge, to report the endoscopic endonasal treatment of a craniopharyngioma in a pediatric patient with SARS-CoV-2.

We report the safe use of the transsphenoidal technique in two COVID-positive patients. The transsphenoidal approach was used because it was felt to be associated with improved visualization and decreased operative time when compared to an open cranial approach. An endonasal approach using a speculum and microscope was considered; however, the use of surgical loupes or an operating microscope for an extended period while wearing a face shield and N95 would have likely been cumbersome to the surgeon. Due to the known aerosolizing capabilities of microdebriders, electrocautery, and especially high-speed drills, attempts were made to minimize any unneeded debridement of the nasal mucosa and to rarely use any powered instrumentation to minimize the risk of viral exposure.[ 36 ] Additional interventions to reduce risk included minimizing OR personnel, especially at the time of intubation, the presence of two High efficiency particulate air (HEPA) filters, and donning of PAPRs by all team members. Of note, multiple medical team members in the OR had only received the first of two scheduled vaccination doses at the time of surgery. COVID was not transmitted from the patient to the OR occupants, followed by a 2-week surveillance period after the surgeries. Both patients were kept under strict COVID precautions during their hospital admissions. Postoperative MRI was deferred in Case 1 to reduce the possible risk of transmission, as it was not deemed absolutely critical to patient care. Limitations of this report include a small sample size, symptomatic monitoring of health-care personnel in the postoperative period rather than formal COVID testing, and insufficient data to determine a causal relationship between COVID-19 pathophysiology and PA.

CONCLUSION

For a COVID-positive patient presenting with acute severe headache, vision loss, and/or ophthalmoplegia, acute hemorrhage or hemorrhagic infarction of a sellar or suprasellar mass should be considered. The association between SARS-CoV-2 infection and hemorrhagic complications of pituitary region tumors may relate to mechanisms such as inflammation, coagulability, and hypoxia. Transsphenoidal surgery in the sellar or suprasellar region performed in an emergency setting in a COVID-positive patient was not associated with virus transmission when the appropriate safety precautions were taken.

Ethical approval

Institutional Review Board approval is not required.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

Disclaimer

The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management. The information contained in this article should not be considered to be medical advice; patients should consult their own physicians for advice as to their specific medical needs.

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