Pituitary Apoplexy Secondary to Thrombocytopenia due to Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Report of a Rare Case and Literature Review

Kaveh Abri Aghdam; Zahra-Alsadat Abtahi; Seyed Ali Sonbolestan; Mostafa Soltan Sanjari

doi:10.4103/joco.joco_321_21

CASE REPORT

Year : 2022 | Volume : 34 | Issue : 3 | Page : 364-368

Pituitary Apoplexy Secondary to Thrombocytopenia due to Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Report of a Rare Case and Literature Review

Kaveh Abri Aghdam¹, Zahra-Alsadat Abtahi¹, Seyed Ali Sonbolestan², Mostafa Soltan Sanjari¹
¹ Eye Research Center, Eye Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
² Department of Oculo-Facial Plastic and Reconstructive Surgery, Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran

Date of Submission	04-Nov-2021
Date of Decision	25-Mar-2022
Date of Acceptance	05-Apr-2022
Date of Web Publication	30-Nov-2022

Correspondence Address:
Zahra-Alsadat Abtahi
Eye Research Center, Eye Department, The Five Senses Health Institute, Rassoul Akram Hospital, Sattarkhan-Niyayesh St. 1449614535, Tehran
Iran

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/joco.joco_321_21

Abstract

Purpose: To report a 16-year-old female patient with pituitary apoplexy in the setting of coronavirus disease 2019 (COVID-19) infection-related thrombocytopenia in the absence of preexisting pituitary macroadenoma.
Methods: The patient had been admitted because of respiratory complications of COVID-19 infection and developed thrombocytopenia, intense headache, and symptoms of cavernous sinus syndrome.
Results: Urgent magnetic resonance imaging of the brain depicted a pituitary apoplexy.
Conclusion: This case indicated that thrombocytopenia due to COVID-19 could be a predisposing factor for pituitary apoplexy in the absence of underlying pituitary disease.

Keywords: Coronavirus disease 2019, Pituitary apoplexy, Severe acute respiratory syndrome coronavirus 2, Thrombocytopenia

How to cite this article:
Aghdam KA, Abtahi ZA, Sonbolestan SA, Sanjari MS. Pituitary Apoplexy Secondary to Thrombocytopenia due to Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Report of a Rare Case and Literature Review. J Curr Ophthalmol 2022;34:364-8

How to cite this URL:
Aghdam KA, Abtahi ZA, Sonbolestan SA, Sanjari MS. Pituitary Apoplexy Secondary to Thrombocytopenia due to Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Report of a Rare Case and Literature Review. J Curr Ophthalmol [serial online] 2022 [cited 2023 Jun 9];34:364-8. Available from: http://www.jcurrophthalmol.org/text.asp?2022/34/3/364/362459

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coronavirus disease 2019 (COVID-19)-related disease is a febrile respiratory disease with various extrapulmonary manifestations including different direct and indirect neurological problems. This infection, in some cases, could cause coagulation-related abnormalities, especially thrombotic events and inflammatory reactions, but spontaneous bleeding was reported infrequently in this situation.¹

Pituitary apoplexy is a rare condition due to hemorrhage or infarction of the pituitary gland that usually occurs secondary to pituitary macroadenoma (2%–12%). Characteristic features include the abrupt onset of headaches, cranial nerve palsies, and hypopituitarism. These neurological presentations are often due to a rapid increase in pituitary gland volume within the restricted space of sella turcica.² Here, we present a case of pituitary apoplexy in the setting of COVID-19-associated thrombocytopenia without any pituitary gland-related risk factor.

Case Report

A 16-year-old female who had been admitted because of respiratory complications of COVID-19 infection was introduced to the neuro-ophthalmology clinic complaining of sharp, retro-orbital headache, diplopia, left eyelid swelling, and mild ptosis having started a day earlier. The patient had a history of upper respiratory tract infection symptoms 10 days before consulting and was confirmed positive for COVID-19 by a nasopharyngeal polymerase chain reaction swab test. Her past medical history was unremarkable. The vital signs were within normal limits. The ophthalmic examination revealed proptosis and chemosis at first glance. Visual acuity was 20/20 in both eyes, and color vision was also normal. Pupillary examination depicted anisocoria with the left pupil 5.5 mm in diameter and minimal reaction. The right pupil was 3.5 mm in diameter and reactive to light. No relative afferent pupillary defect was detected. Ocular motility examination was normal on the right side. Partial ophthalmoplegia due to the limitation of adduction, supraduction, infraduction, and abduction of the left eye suggested the involvement of the third and sixth cranial nerves on the left side [Figure 1]. The corneal and facial sensations were normal on both sides. Slit-lamp examination disclosed no abnormal finding in the right eye, but a superior subconjunctival hemorrhage and upper lid swelling and ptosis in the left eye were evident. The results of Goldmann applanation tonometry and funduscopic examination were normal in both eyes. Urgent magnetic resonance (MR) imaging of the brain was obtained, which revealed blood collection within the sellar region without compression of the optic chiasm. MR venography of the brain revealed no abnormality [Figure 2]. MR angiography of the brain was also unremarkable. Laboratory evaluation demonstrated thrombocytopenia (platelet count: 40000/μL) and elevated inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), which has been previously reported in COVID-19 infection.^[3] During admission, the platelet count decreased dramatically to 25000 and then after about 1 week to 10000/μL, so additional tests were requested. Antithrombotic therapy was administered initially at the time of admission and then discontinued after the development of thrombocytopenia. Two peripheral blood smears were evaluated for the presence of schistocytes and other abnormal cells, but no morphologic abnormalities were found. Furthermore, the ADAMTS13 test results for the diagnosis of congenital or acquired thrombotic thrombocytopenic purpura were negative.

Figure 1: Partial left ophthalmoplegia and ptosis

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Figure 2: Unremarkable magnetic resonance (MR) venogram of the brain, with no evidence of venous sinus thrombosis (a). Coronal T2-weighted brain MR image depicts an asymmetrically expanded left cavernous sinus (blue arrow) (b). Precontrast sagittal T1-weighted brain MR image shows signal hyperintensity due to blood collection within the pituitary gland (red arrow) (c). Precontrast sagittal T1-weighted brain MR image demonstrates an approximately 15 mm × 20 mm sellar lesion without compression of the optic chiasm (green circle) (d)

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After consulting with neurologists, the patient was transferred to the intensive care unit. Three days later, she experienced chest pain and shortness of breath. The body temperature increased to 38.5°C, and the respiratory rate was 30/min. Gradually, her level of consciousness decreased. A spiral computed tomography scan of the chest demonstrated massive pulmonary thromboembolism. Unfortunately, she passed away after 2 days.

Written informed consent was obtained from the patient's parents for participation in the study and publication of this report and related photos.

Discussion

Pituitary apoplexy usually happens in the 5^th–6^th decades of life. Some of its known predisposing factors include trauma or head injury, coagulopathy, hypertension, pregnancy, or postpartum situation, major surgical interventions, anticoagulant therapy, and increased intracranial pressure.⁴

The increased tendency to bleeding in COVID-19 patients could be explained by systemic or local mechanisms.

Systemically, thrombocytopenia could be a result of the COVID-19 infection itself.^[5],[6] The incidence of thrombocytopenia on admission in COVID-19 patients (platelet count <150 × 10^[9]/L) is 36.2%.^[7] It has been generally believed that thrombocytopenia is suggestive of disease severity, so a progressive decline in platelet count is meaningfully associated with increased mortality.^[8] Some proposed mechanisms for thrombocytopenia are (1) direct infection of bone marrow cells by the virus and destruction and inhibition of platelet synthesis (because of a potential defect in hematopoietic microenvironment caused by systemic inflammation or cytokine storm, e.g., elevated interleukin-6 in SARS-CoV-2 infection)^[9],[10], (2) platelet destruction by the immune system activity (cross-reaction of antiviral antibodies with platelet integrin GP IIb/IIIa)^[11], and (3) platelet aggregation in the lungs as microthrombi and thrombi causing platelet consumption.

Moreover, thrombocytopenia has been reported in the setting of several other infectious or hematologic diseases (such as Dengue hemorrhagic fever, idiopathic thrombocytopenic purpura, drug-induced thrombocytopenia, and hemolysis-elevated liver enzymes-low platelet [HELLP] syndrome), as the main cause of pituitary apoplexy.^[5],[6]

Platelet dysfunction and prolongation of prothrombin time/activated partial thromboplastin time can cause coagulopathies in the setting of COVID-19 infection and lead to bleeding tendencies. In general, COVID-19-associated coagulopathy appears as a hypercoagulable state more than a bleeding state; nevertheless, spontaneous hemorrhage could be in association with thrombosis in these patients.¹² In our patient, pituitary apoplexy occurred in combination with the thrombotic event of pulmonary thromboembolism with an interval of several days. This patient developed progressive thrombocytopenia, but thrombotic thrombocytopenic purpura, which may occur in the setting of COVID-19 infection, was ruled out.

Cerebrovascular hemorrhagic events are the most common type of hemorrhagic complication of COVID-19. Documented the presence of the virus in the cerebrospinal fluid could be a local possible mechanism of the bleeding tendency in the central nervous system (CNS). Several hypothetical routes facilitate the viral entry: nasal epithelium and olfactory pathway, direct entry from the cerebral circulation after crossing the blood–brain barrier, and angiotensin-converting enzyme inhibitor receptors on CNS cells, which simplify the adhesion of virus to cells.^[12],[13] Proposed mechanisms of hemorrhage in the pituitary region after the entrance of COVID-19 to CNS are (1) the fragility of the vasculature in the pituitary region that predisposes this location to hemorrhagic infarcts^[2] and (2) infectious stress state itself, which could promote the stimulation of the pituitary gland, and in turn, may increase pituitary blood demand leading to apoplexy.^[6]

Another important issue about this case was the third and sixth cranial nerve palsies that may occur due to the compression of the cavernous sinus resulting from the mass effect of apoplexy. Cranial nerve compressions within or outside the cavernous sinuses are two possible reported mechanisms for this complication. Direct compression of the cranial nerve III (because of its same horizontal plane as the pituitary gland) or cranial nerve VI involvement (at the level of Dorello's Canal) outside the cavernous sinus is possible.^[14] Orbital apex syndrome should also be kept in mind in cases of multiple cranial nerve palsies and proptosis or chemosis, but brain imaging did not demonstrate the involvement of orbital apex in this case.

[Table 1] shows, as far as we know, all previously reported cases of pituitary apoplexy in the setting of COVID-19 infection. Of the 13 patients with this complication, 5 were female. The most common predisposing factor was underlying pituitary macroadenoma. Four cases were under the age of 40 years. Headache and vision problems were the most common symptoms. All except two patients, who died due to pulmonary complications of COVID-19, recovered and were discharged. Contrary to our case, the only previously reported case of pituitary apoplexy in the setting of COVID-19-related thrombocytopenia had pituitary macroadenoma.^{[15],[16],[17],[18],[19],[20],[21]} Our case developed pituitary apoplexy without any pituitary gland-related risk factor.

Table 1: Previously reported cases of pituitary apoplexy in association with Coronavirus disease 2019 infection

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In conclusion, the COVID-19 pandemic is a rapidly developing infectious situation throughout the world that is associated with several endocrine and neurological disorders. This case could be considered a very rare manifestation of COVID-19 and could be added to the list of previously reported cases of SARS-CoV-2 infection and pituitary apoplexy.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given her consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal patient identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	LaRoy M, McGuire M. Pituitary apoplexy in the setting of COVID-19 infection. Am J Emerg Med 2021;47:329.e1-329.e2.
2.	Chan JL, Gregory KD, Smithson SS, Naqvi M, Mamelak AN. Pituitary apoplexy associated with acute COVID-19 infection and pregnancy. Pituitary 2020;23:716-20.
3.	Solomon IH, Normandin E, Bhattacharyya S, Mukerji SS, Keller K, Ali AS, et al. Neuropathological features of Covid-19. N Engl J Med 2020;383:989-92.
4.	Ranabir S, Baruah MP. Pituitary apoplexy. Indian J Endocrinol Metab 2011;15 Suppl 3:S188-96.
5.	Xu P, Zhou Q, Xu J. Mechanism of thrombocytopenia in COVID-19 patients. Ann Hematol 2020;99:1205-8.
6.	Tan SK, Seow CJ, Tan E, Chau YP, Dalan R. Pituitary apoplexy secondary to thrombocytopenia due to dengue hemorrhagic fever: A case report and review of the literature. Endocr Pract 2014;20:e58-64.
7.	Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;382:1708-20.
8.	Yang X, Yang Q, Wang Y, Wu Y, Xu J, Yu Y, et al. Thrombocytopenia and its association with mortality in patients with COVID-19. J Thromb Haemost 2020;18:1469-72.
9.	Liao D, Zhou F, Luo L, Xu M, Wang H, Xia J, et al. Haematological characteristics and risk factors in the classification and prognosis evaluation of COVID-19: A retrospective cohort study. Lancet Haematol 2020;7:e671-8.
10.	Valletta S, Thomas A, Meng Y, Ren X, Drissen R, Sengül H, et al. Micro-environmental sensing by bone marrow stroma identifies IL-6 and TGFβ1 as regulators of hematopoietic ageing. Nat Commun 2020;11:4075.
11.	Amgalan A, Othman M. Exploring possible mechanisms for COVID-19 induced thrombocytopenia: Unanswered questions. J Thromb Haemost 2020;18:1514-6.
12.	Bordes SJ, Phang-Lyn S, Najera E, Borghei-Razavi H, Adada B. Pituitary apoplexy attributed to COVID-19 infection in the absence of an underlying macroadenoma or other identifiable cause. Cureus 2021;13:e13315.
13.	Sharifi-Razavi A, Karimi N, Rouhani N. COVID-19 and intracerebral haemorrhage: Causative or coincidental? New Microbes New Infect 2020;35:100669.
14.	Kobayashi H, Kawabori M, Terasaka S, Murata J, Houkin K. A possible mechanism of isolated oculomotor nerve palsy by apoplexy of pituitary adenoma without cavernous sinus invasion: A report of two cases. Acta Neurochir (Wien) 2011;153:2453-6.
15.	Ghosh R, Roy D, Roy D, Mandal A, Dutta A, Naga D, et al. A Rare case of SARS-CoV-2 infection associated with pituitary apoplexy without comorbidities. J Endocr Soc 2021;5:bvaa203.
16.	Solorio-Pineda S, Almendárez-Sánchez CA, Tafur-Grandett AA, Ramos-Martínez GA, Huato-Reyes R, Ruiz-Flores MI, et al. Pituitary macroadenoma apoplexy in a severe acute respiratory syndrome-coronavirus-2-positive testing: Causal or casual? Surg Neurol Int 2020;11:304.
17.	Martinez-Perez R, Kortz MW, Carroll BW, Duran D, Neill JS, Luzardo GD, et al. Coronavirus disease 2019 and pituitary apoplexy: A single-center case series and review of the literature. World Neurosurg 2021;152:e678-87.
18.	Yazbeck M, Abi Fadel E, Berjaoui C, Abadjian G, Akiki B. Surgical intervention for two patients suffering from pituitary apoplexy associated with Covid-19. Arch Clin Med Case Rep 2021;5:665-71.
19.	Lesniak C, Hu K, Akula M, Zin K, Ong R, Holland S, et al. Abstract# 1000905: Pituitary apoplexy presenting in a COVID-19 positive patient as ophthalmoplegia. Endocr Pract 2021;27:S115.
20.	Liew SY, Seese R, Shames A, Majumdar K. Apoplexy in a previously undiagnosed pituitary macroadenoma in the setting of recent COVID-19 infection. BMJ Case Rep 2021;14:e243607.
21.	Kamel WA, Najibullah M, Saleh MS, Azab WA. Coronavirus disease 2019 infection and pituitary apoplexy: A causal relation or just a coincidence? A case report and review of the literature. Surg Neurol Int 2021;12:317.