Pituitary apoplexy associated with COVID-19 infection: review and a case report

Abstract Pituitary apoplexy (PA) is a clinical syndrome caused by a hemorrhage and/or infarction in a pituitary adenoma due to a diverse group of pathophysiological mechanisms. The clinical spectrum consists of severe headaches, visual disturbances, cranial nerve involvement and hormonal deficiencies. There have been a growing number of case reports of pituitary apoplexy with a possible association with Coronavirus disease 2019 (COVID-19) recently. The aim of this paper is to review and analyze the possible connection between pituitary apoplexy and the novel coronavirus SARS-CoV-2. The literature review was conducted by searching the term ‘COVID-19 pituitary apoplexy’ in the PubMed database. Seventeen results were screened. We identified 12 cases of patients with pituitary apoplexy with a possible connection to COVID-19. The pathophysiological mechanisms include infarction and acute hemorrhage. COVID-19 could contribute to pituitary apoplexy due to a series of predisposing factors, like hemodynamic instability, increase in intracranial pressure, coagulopathy, endothelial dysfunction and hypercoagulative state. The possible association between COVID-19 and pituitary apoplexy is still debatable. Finally, we report a case of a 63-year-old female presenting with pituitary apoplexy with an onset of symptoms 15 days after initial positive polymerase chain reaction (PCR) testing for SARS-CoV-2. The patient was hospitalized for COVID-19 due to associated pneumonia for 12 days. Three days after discharge from the hospital, the patient developed a severe onset headache. Magnetic resonance imaging revealed a pituitary macroadenoma with pituitary apoplexy. In the presented case, the most probable reason for the pituitary apoplexy is infarction and not acute hemorrhage.


Introduction
Coronavirus disease 2019 (COVID-19) is best known for causing respiratory pathology, but it can also result in various extrapulmonary manifestations. In the course of the ongoing pandemic, reports have appeared of multiple symptoms and complications due to SARS-CoV-2 infection. The neurological complications recognized as possible consequences of COVID-19 include ischemic strokes, intracerebral hemorrhage, encephalopathy, meningoencephalitis, Guillain-Barré syndrome and others [1]. Pituitary apoplexy (PA) is a clinical syndrome caused by a hemorrhage and/or infarction in a pituitary adenoma due to a diverse group of pathophysiological mechanisms. The clinical spectrum consists of severe headaches, visual disturbances, cranial nerve involvement and hormonal deficiencies [2].
Since the beginning of the COVID-19 pandemic, researchers have been trying to identify possible manifestations and complications from the infection with the novel virus. There are a growing number of case reports of pituitary apoplexy with a possible association with COVID-19 [3][4][5][6][7][8][9][10][11][12]. COVID-19 and pituitary apoplexy have overlapping symptoms like headaches and general tiredness, resulting in misdiagnosis of this condition in patients with COVID-19, while pituitary apoplexy can be life-threatening in some cases. Authors approach with caution the possibility to establish a direct connection between the two entities.
The possible association between COVID-19 and pituitary apoplexy is still debatable. There are only a few reported cases, which are diverse in their clinical presentation and clinical behavior. While the clinical course of the reported cases is well documented, there is limited data on the primary reason for the pituitary apoplexy (infarction or acute hemorrhage).
The aim of the present review is to summarize and analyze the possible connection between pituitary apoplexy and the novel coronavirus. Although the accumulated data so far are insufficient to support a direct connection between these two conditions, there is a series of published papers reporting on cases of pituitary apoplexy in patients with COVID-19. Possible pathophysiological mechanisms have been discussed, but there is a lack of clear evidence for establishing a reliable causal connection between them. The present review attempts to identify the possible pathophysiological mechanisms that might have led to pituitary apoplexy in these patients. In addition, we report a case of pituitary apoplexy and concurrent COVID-19 in a patient treated in our neurosurgical department and comment on the outcomes in this particular case.

Methods
We screened the literature using the term 'COVID-19 pituitary apoplexy' . Seventeen results in PubMed, all manuscripts published between December 2019 and July 2021 were screened. Inclusion criteria consisted of identifying patients with pituitary apoplexy in existing adenomas associated with COVID-19. We identified 11 papers that reported on 13 patients with possible pituitary apoplexy association with COVID-19. We excluded one case report on a pediatric patient diagnosed with a suprasellar nongerminomatous germ cell tumor. In addition to this, we report a case of a 63-year-old female presenting with pituitary apoplexy with an onset of symptoms 15 days after initial positive polymerase chain reaction (PCR) testing for SARS-CoV-2.

Case report
We present a 63-year-old female with a sudden severe headache located behind the eyes with an onset of symptoms 15 days after initial positive PCR testing for SARS-CoV-2. The patient met the criteria for moderate COVID-19 and was hospitalized for COVID-19 due to associated pneumonia for 12 days. During her hospital stay, her SpO 2 levels stayed above 94%. No anticoagulant therapy was administered during that time. The patient was not prescribed any anticoagulant or antiplatelet treatment after leaving the hospital. Three days after being discharged from the hospital, the patient developed a sudden-onset severe headache. In addition to this, the patient reported nausea, vomiting and a brief loss of consciousness on that day. No other relevant symptoms were recognized at that time. Due to the persistence of the headache, magnetic resonance imaging was performed 11 days after the initial presentation of symptoms. It revealed a heterogeneous lesion with dimensions in the sagittal plane of 39/34.6 mm. The pre-contrast T1 weighted image (T1WI) showed low signal sellar and suprasellar mass with dispersed areas of an isointense signal. Post-contrast T1WI showed enhancement of these areas and rim enhancement. The T2 weighted image (T2WI) sequence of the MRI was hypertensive in necrotic regions of the mass ( Figure 1). These characteristics of the MRI are consistent with non-hemorrhagic apoplexy in the pituitary macroadenoma. A meningioma was identified as a side finding arising from the anterior clinoid process with sagittal dimensions of 15.8/9.3 mm ( Figure 2). The endocrinological laboratory tests showed central hypothyroidism and low serum cortisol levels. The visual field test showed partial bitemporal hemianopsia, and the patient had no visual acuity disorders.
The patient was scheduled for a transnasal transsphenoidal endoscopic adenomectomy. Surgical management was postponed due to the absence of a progressing severe neurological deficit in order for the patient to recover from COVID-19 fully. At admission into our neurosurgery department, the patient had a negative PCR test for SARS-CoV-2. Intraoperative observation, after opening the dura mater, found areas of small hemorrhagic infarctions of the pituitary adenoma and liquefied parts of the tumor. There was no evidence of previous severe hemorrhage, which was consistent with the imaging data. A specimen was taken for histopathological examination. The pathology report described the histological findings as a chromophobe pituitary adenoma with apoplexy. Subsequently, a second specimen was sent to the laboratory for PCR testing for SARS-CoV-2, proving negative. After the surgery, there was complete resolution of the headaches. The patient fully recovered with no visible evidence of a residual tumor on the control MRI three mounts after the surgery (Figure 3). The patient developed partial hypopituitarism (hypocortisolism, hypothyroidism, hyposomatotropism and hypogonadism) and required prednisone and levothyroxine supplementation.

Review and discussion
Healthcare workers and researchers are facing unforeseen challenges due to the COVID-19 pandemic. The novel virus proves to cause a complex infectious disease with varying clinical presentation and complications. For the last year and a half, the medical community has focused on comprehending the diverse  nature of the illness. One of those challenges was to identify the possible consequences of the SARS-CoV-2 infection.
The present review identified ten articles that reported 12 patients with a pituitary apoplexy possibly associated with COVID-19 [3][4][5][6][7][8][9][10][11][12]. All the known cases are presented in Table 1. Patients' age varied from 27 to 75 years of age. The course of COVID-19 was evaluated as severe in two patients, of which one died due to respiratory failure [10]. In the reported cases, the onset of symptoms of pituitary apoplexy ranged from three days before to six weeks after the onset of COVID-19symptoms. While the clinical course of the patients is well documented, there is a brief description of the possible pathophysiological mechanism of the onset of pituitary apoplexy. We extracted data from those papers that combined clinical data and imaging studies in order to derive the possible mechanism of the pituitary apoplexy in each patient. Hemorrhage was identified as the probable reason for the pituitary apoplexy in eight out of 12 patients. Predominant hemorrhage and partial infarction were recognized in four of the cases.

Possible entry mechanism and pathophysiology
Viruses can invade the central nervous system (CNS) by two major routes: hematogenous or neuronal retrograde dissemination [13]. In the first scenario, SARS-CoV-2 can bind to ACE2 expressed in the capillary endothelium of the blood brain barrier to migrate into the CNS [13]. Infected monocytes and macrophages with SARS-CoV-2 can also pass through the blood-brain barrier [13].
The second possible mechanism for entry in the CNS is through axonal transport from the peripheral parts of the cranial nerves to the CNS, which can explain symptoms associated with COVID-19 as anosmia. Olfactory receptor neurons have dendrites in the nasal cavity and extend axons through the cribriform plate into the olfactory bulb of the brain [13].
Coronavirus entry into host cells is mediated by the viral transmembrane spike (S) glycoprotein binding the metallopeptidase angiotensin-converting enzyme 2 (ACE2) [14]. Researchers have found that the cellular transmembrane serine protease 2 (TMPRSS2) also plays a part in the entry mechanism of SARS-CoV-2-by priming the spike protein [15].
There are several cell types in the brain that express angiotensin-converting enzyme-2 (ACE2), the main SARS-CoV-2 receptor, and other related proteins. However, it is still not clear whether the observed neurological manifestations are attributed to virus invasion into the brain or just comorbidities caused by dysregulation of systemic factors.
Neurological involvement in COVID-19 might be associated with ACE2 expression on the cerebral vascular endothelium neurons and glial cells [16]. ACE2 messenger ribonucleic acid (mRNA) expression was also found in pituitary gland cells [16]. Although the expression levels of ACE2 receptors in the pituitary gland were lower than other tissues, the pituitary gland might be a possible target for SARS-CoV-2 [16]. In addition to this, a previous study from 2004 showed the presence of SARS-CoV in the pituitary gland in patients who died from SARS [17]. Researchers still consider the neurotropism of SARS-CoV-2 a topic of dispute. The S protein of SARS-CoV-2 shows up to 20-fold higher affinity to the ACE2 receptor than that of SARS-CoV-1 [18].
Dysregulated immune response like the cytokine storm in many severe COVID-19 patients can cause breakdown of the blood-brain barrier. Cytokines  facilitate the formation of thrombosis, leading to possible damage to the CNS. Infected immune cells like circulating monocytes, B lymphocytes, and CD4 + T lymphocytes can invade the blood-brain barrier [19].
Some of the possible factors that could account for the various neurological disorders in patients with SARS-CoV-2 infection are coagulopathy, endothelial dysfunction and hypercoagulative state [1]. In the setting of a pandemic, pituitary apoplexy manifested only with a headache could be misdiagnosed as a symptom of COVID-19.
The pathophysiology of pituitary apoplexy is complicated. Pituitary apoplexy is caused by hemorrhage and/or infarction of the pituitary adenoma. Several triggering factors for pituitary apoplexy have been described: reductions in blood flow; acute increase in blood flow; pituitary gland stimulation; and coagulation disturbances; glucose deprivation [2].
COVID-19 could contribute a series of factors that predispose to pituitary apoplexy. One of the possible contributing factors is hemodynamic instability, leading to reduced blood flow to the pituitary adenoma. Other factors might include the sudden increase in intracranial pressure due to the severe coughing from COVID-19, leading to hypoperfusion of the pituitary adenoma [10]. COVID-19, being an acute viral systemic illness, can lead to increased stimulation of the pituitary gland, which is a precipitating factor for pituitary apoplexy [20].
Another precipitating factor for pituitary apoplexy is hypertension [20]. In the case reported here, the patient had a history of arterial hypertension grade one, and the condition was well controlled. During the hospitalization for COVID-19, the arterial blood pressure values were normal.
Admission of anticoagulants during an active COVID-19, as well as thrombocytopenia, could contribute to a pituitary apoplexy event. In our case, the patient had not received any anticoagulation therapy and did not have thrombocytopenia. There were no other known predisposing factors for pituitary apoplexy in this patient other than hypertension. In the presented case, the most probable reason for the pituitary apoplexy is infarction and not acute hemorrhage. One of the proposed mechanisms for non-hemorrhagic pituitary apoplexy is the possible ischemia caused by the decreased blood flow to the adenoma due to the compression of the hypophyseal vessels by the macroadenoma. In addition to this, the presence of microemboli in an ongoing COVID-19 disease might lead to infarction of the pituitary adenoma [21]. Pituitary apoplexy caused by acute hemorrhage is associated with more severe clinical presentation in comparison to infarction. The absence of visual disturbances and cranial nerve involvement might lead to misdiagnosis of pituitary apoplexy.
Despite the reported cases of pituitary apoplexies in the literature, the possible connection with COVID-19 is still debatable. There is no clear evidence and a concrete pathophysiological mechanism that can be attributed to the event of pituitary apoplexy. The sequence of events is also essential for establishing an association between SARS-CoV-2 infection and pituitary apoplexy. Most of the reported patients in the literature experienced pituitary apoplexy in close proximity to the onset of the COVID-19 symptoms. The case reported in this study was diagnosed 15 days after the onset of COVID-19 symptoms, confirmed with magnetic imaging 11 days after the first reported symptom of pituitary apoplexy. The accumulated data up to this moment cannot exclude the possibility of a direct connection between the two entities. Further investigation should be carried out to prove the association between COVID-19 and pituitary apoplexy.

Conclusions
Managing pituitary apoplexy may be challenging, especially against the backdrop of a pandemic. The reported case of pituitary apoplexy in close proximity to SARS-CoV-2 infection contributes to the already existing reports of a possible association between COVID-19 and pituitary apoplexy. Various factors and pathophysiological mechanisms should be taken into consideration in order to establish a more reliable connection. Reported cases suggest that both mechanisms, infarction and acute hemorrhage, may lead to pituitary apoplexy, which can be induced by different factors associated with COVID-19. In the presented case, the possible cause for the pituitary apoplexy is infarction and not acute hemorrhage.

Data availability statement
The authors confirm that the data supporting the findings of this study are available within the article.

Disclosure statement
The authors have no conflicts of interest to declare.