Coronavirus disease 2019 infection and pituitary apoplexy: A causal relation or just a coincidence? A case report and review of the literature.

BACKGROUND: Pituitary tumor apoplexy (PA) is an emergency condition caused by hemorrhage or infarction of the preexisting adenoma. Many factors are currently well-known to predispose to PA. However, during the period of coronavirus disease 2019 (COVID-19) pandemic, case reports of PA associated with COVID-19 infection have been sequentially published. To the best of our knowledge, four cases have been reported so far in the English literature. We herein report the fifth case of this association and review the pertinent literature. CASE DESCRIPTION: A 55-year-old male patient with confirmed COVID-19 infection presented by progressive decrease in visual acuity and oculomotor nerve palsy. His medical history is notable for diabetes mellitus, hypertension, and pituitary macroadenoma resection 11 years ago. He was on hormonal replacement therapy for panhypopituitarism that complicated the surgery. Previous magnetic resonance (MR) imaging studies were consistent with enlarging residual pituitary adenoma. During the current hospitalization, computed tomography revealed hyperdensity of the sellar and suprasellar areas. MR imaging revealed PA in a recurrent large adenoma. Endoscopic endonasal transsphenoidal resection was uneventfully undertaken with near total excision of the adenoma and partial improvement of visual loss and oculomotor palsy. Histopathological examination demonstrated classic features of PA. However, his chest condition progressed and he had to be transferred to COVID-19 intensive care unit in the referring hospital where he was intubated and put on mechanical ventilation. One week later, the patient unfortunately passed away due to complications of severe COVID-19 pneumonia.
CONCLUSION: We report the fifth case of PA associated with COVID-19 infection. Based on our patient's clinical findings, review of the other reported cases, as well as the available literature, we put forth a multitude of pathophysiological mechanisms induced by COVID-19 that can possibly lead to the development of PA. In our opinion, the association between both conditions is not just a mere coincidence. Although the histopathological features of PA associated with COVID-19 are similar to PA induced by other etiologies, future research may disclose unique pathological fingerprints of COVID-19 virus that explains its capability of inducing PA. Copyright:

INTRODUCTION

Pituitary tumor-associated hemorrhage was described for the 1st time by Bailey in 1898,[1] but only in 1950, Brougham et al. introduced the term pituitary apoplexy (PA) describing a case series of five patients.[7] The incidence of PA varies from 0.6% to 22% with different diagnostic criteria.[13] Li et al. analyzed 2021 cases of PA and recognized male sex, nonfunctioning adenomas, and the presence of macroadenoma as risk factors for its development.[13] PA has also been reported with pregnancy[18] and with various other conditions including hypertension, diabetes mellitus, and increased intracranial pressure.[6] On the other hand, during the period of coronavirus disease 2019 (COVID-19) pandemic, case reports of PA associated with COVID-19 infection have been sequentially published. To the best of our knowledge, four cases have been reported so far in the English literature.[8,10,19,21] We herein report the fifth case of this association. Although the available information is limited, analyzing the pertinent literature is important to gain further insight on whether the PA is directly caused by COVID-19 infection and to come up with plausible pathophysiological mechanism(s) if any. Such information should also be of help in directing further research.

CASE REPORT

A 55-year-old male patient was presented to a general hospital with fever, myalgia, and persistent cough. Polymerase chain reaction testing for COVID-19 was positive and he was admitted to the hospital due to severe respiratory symptoms. The patient is a known diabetic and hypertensive with a history of a nonfunctioning pituitary macroadenoma for which he underwent an endoscopic endonasal transsphenoidal resection 11 years ago in another hospital. Pituitary tumor recurrence was documented in the available two postoperative magnetic resonance imaging (MRI) studies [Figure 1]. After surgery, the patient was kept on maintenance levothyroxine and hydrocortisone for panhypopituitarism.

Figure 1:

Magnetic resonance imaging (MRI) images of the sella 3 months after the first endoscopic endonasal excision of a large pituitary macroadenoma demonstrating residual tumor (a-d). Residual tumor enlargement is noted in the follow-up MRI done 3 years later (e-h).

Six days after admission, the patient complained of severe headache and acute onset of ptosis and diminution of vision in the left eye. Ophthalmological evaluation revealed complete visual loss in the left eye, a visual acuity of 20/60 in the right eye, left oculomotor nerve palsy with ptosis, and dilated nonreactive pupil. Fundus examination revealed a pale left optic nerve head. Neurological examination was otherwise normal. Computed tomography revealed hyperdensity of the sellar and suprasellar areas. MRI was consistent with PA in a recurrent large pituitary adenoma [Figure 2a and b].

Figure 2:

Magnetic resonance imaging (MRI) images of the current presentation. Preoperative T1-weighted images reveal a large recurrent pituitary macroadenoma with minimal patchy enhancement after gadolinium injection (a and b). Postoperative T1-weighted images with contrast revealed near total excision of the adenoma (c and d).

The patient was transferred to our center and underwent an urgent endoscopic endonasal transsphenoidal surgery through which a near total excision of the tumor was achieved [Figure 2c and d].

The procedure was performed under strict COVID-19 precautions including use of powered air purifying respirators and limited OR personnel. Intraoperative findings were similar to those usually seen in cases of PA and included dark blood mixed with purple-red adenoma tissues of variable consistencies [Figure 3]. It was our observation that the nasal mucosa was pale and separated easily from the underlying bone. We have previously observed such features in two patients who previously tested positive for COVID-19. Histopathological examination demonstrated classic features of PA.

Figure 3:

Intraoperative views during endoscopic endonasal transsphenoidal tumor excision. (a) Bluish discoloration of the dura caused by apoplexy of the underlying tumor is evident at the initial exposure. (b) Dark blood (asterisk) is seen on initial dural opening. (c) View of the necrotic purple adenoma tissue being resected from within the sella. (d) A pituitary ring curette elevates the downward bulging cistern and a pituitary Rongeur is used to excise the superior part of the tumor. (e) The uppermost tumor components (double asterisks) have been separated from the arachnoid of the suprasellar cistern. (f) Final view after tumor resection. Note the fat from previous surgery (arrowheads).

Within the first 3 postoperative days, the patient had some improvement of vision of the left eye so that he was able to perceive hand movement. Ptosis also improved partially. However, his chest condition progressed and he had to be transferred to COVID-19 intensive care unit in the referring hospital where he was intubated and put on mechanical ventilation. One week later, the patient unfortunately passed away due to complications of severe COVID-19 pneumonia.

DISCUSSION

In one large study, male sex, nonfunctioning adenomas, and the presence of macro – rather than microadenoma were recognized as risk factors for the development of PA.[21] PA has also been reported with pregnancy[18] and with various other conditions including hypertension, diabetes mellitus, and increased intracranial pressure.[6] During the period of COVID-19 pandemic, case reports of PA associated with COVID-19 infection have been sequentially published. To the best of our knowledge, four cases have been reported so far in the English literature.[8,10,21] Bray et al. reported a case of pituitary adenoma with possible antecedent apoplexy that was treated with cortisol replacement. The endoscopic endonasal surgery was delayed due to COVID-19 outbreak and the apoplexy resolved spontaneously.[5] This case was excluded from our review because of lacking evidence of COVID-19 infection.

From a clinical standpoint, a broad spectrum of comorbidities and variable outcomes can be observed across these previous reports. Chan et al. have recently reported a case of PA associated with a third-trimester pregnancy complicated by COVID-19, with complete recovery of pupillary defect and visual disturbances with dexamethasone and endoscopic endonasal transsphenoidal surgery.[8] A case of a previously asymptomatic female patient with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection associated with PA and partial recovery with medical treatment was reported by Ghosh et al.[10] In contrast, poor outcome with death of the patient 12 h after presenting with progressive bilateral diminution of vision and left exotropia was reported by Solorio-Pineda et al.[21] The 27-year-old male patient died secondary to pulmonary complications of asymptomatic COVID-19 infection. Patient demographics, clinical findings, treatment modalities, and outcomes of the previously reported cases as well as those of our case are summarized in [Table 1].

Table 1:

Reported cases of pituitary apoplexy associated with COVID-19 infection.

From a pathophysiological point of view, the risk factors for PA can be sorted into the following categories: (1) reduced blood flow of the tumor, as in cases with large adenoma size; (2) acute increase of hypophyseal blood flow, as in cases of trauma, hypertension, diabetes, and increased intracranial pressure; (3) anticoagulated states, caused by anticoagulant, thrombolytic, and antiplatelet therapies; and (4) hormonal stimulation of the pituitary gland and tumor.[3,6]

Viral infections and hypothalamopituitary dysfunction

The COVID-19 virus enters the pneumocyte using the host angiotensin-converting enzyme 2 (ACE2) as a receptor. ACE2 is expressed on the arterial and venous endothelial cells of many organs.[26] Hypothalamic and pituitary tissues express ACE2 and can theoretically be targets for the virus. As a matter of fact, pituitary affection has been described with various viral infections including SARS,[27] orthohantavirus,[2,22] and dengue.[23,27] Biochemical evidence of hypothalamopituitary involvement in SARS was first reported by Leow et al. in 2005. The authors proposed the possibility of a reversible hypophysitis or a direct hypothalamic damage that could have led to a state of hypothalamopituitary dysfunction.[12] On autopsy studies, edema and neuronal degeneration along with identification of SARS genome have been shown in the hypothalamus.[17] With the high frequency of neurological symptoms and HPA involvement in SARS – the cousin of SARS-CoV-2 – one can assume that SARS-CoV-2 may affect the hypothalamic and pituitary tissues as well, either directly or via an immune-mediated hypophysitis.[17] After orthohantavirus infection, foci of hemorrhage were found in the pituitary gland.[24] Ischemic, necrotic, and hemorrhagic damage of the pituitary gland were also detected. Ischemic damage could be caused by hypotension and/or vasospasms, while hemorrhagic damage could be caused by thrombocytopenia, thrombopathy, and other coagulation disorders.[2] Furthermore, the presence of hypophysitis and auto-antibodies postorthohantavirus infection has also been suggested.[2] Although extrapolating the aforementioned data to COVID-19 infection remains speculative, these mechanisms represent potential pathophysiological links between COVID-19 infection and PA that can be validated by future research.

Central nervous system complications of COVID-19

In one study based on data from a UK national database, neurological changes related to COVID-19 have been reported and included cerebral hemorrhage, ischemic strokes, and altered mental status.[25] Cerebrovascular hemorrhage during the active phase of SARS-CoV-2 infection has been reported in many cases with different underlying pathophysiological mechanisms.[4,5,16,20] The neurological changes associated with COVID-19 are multifactorial and are related to endothelial dysfunction, hypoxemia, and the release of inflammatory mediators (cytokine storm).[28] Acute systemic inflammatory response characterized by increased blood coagulation markers, increased inflammatory markers, and thrombocytopenia can induce COVID-19-related coagulopathy state.[9] That being said, it seems logical to postulate that a cause-and-effect relationship might exist between COVID-19 and PA that is based on these mechanisms.

Postulated mechanisms of COVID-19-induced PA

Indeed, there is currently no proof that COVID-19 has a causal effect on the occurrence of PA. Notwithstanding, the close temporal relation of the two conditions and the propensity of COVID-19 infection to induce a multitude of factors that are also well-known precipitants of PA can explain the occurrence of apoplexy in the setting of COVID-19 infection:

Fluctuations in blood pressure associated with hemodynamic instability in COVID-19 infection can lead to reduced blood flow to the pituitary tumor

Hypoperfusion of the pituitary tumor due to transient increases in intracranial pressure caused by coughing, sneezing, or positive pressure ventilation has been reported as a precipitant of apoplexy in patients with pituitary adenomas[20]

Excessive stimulation of the pituitary gland in response to the stress of infection has been postulated to precipitate PA occurring in the setting of an acute systemic illness[4]

In addition, an anticoagulant state whether from administration of anticoagulant medications in the setting of COVID-19 infection, or thrombocytopenia, is another well-identified predisposing factor for PA, which is usually associated with hemorrhage or less likely with infarction of a pituitary tumor[16]

One plausible pathomechanism is that the fragility of the hypophyseal vasculature,[11] renders them more susceptible to the damage caused by the COVID-19-induced endotheliitis and endothelial dysfunction[15]

Diabetes has also been considered a predisposing factor of PA due to associated degenerative changes in the microvasculature,[14] a factor that may have contributed to the occurrence of apoplexy in our patient.

A final point that is worth consideration is that surgery per se could have been implicated in exacerbating the COVID-19 pneumonia in our patient.

CONCLUSION

We report the fifth case of PA associated with COVID-19 infection. Based on our patient’s clinical findings, review of the other reported cases, as well as the available literature, we put forth a multitude of pathophysiological mechanisms induced by COVID-19 that can possibly lead to the development of PA. In our opinion, the association between both conditions is not just a mere coincidence. Although the histopathological features of PA associated with COVID-19 are similar to PA induced by other etiologies, future research may disclose unique pathological fingerprints of COVID-19 virus that explains its capability of inducing PA.