Our recent experience in three consecutive patients with pituitary apoplexy who all suffered from concomitant COVID-19 infection raises concern for a potential relationship between these two identities. Although the exact mechanism of PA is not fully understood, it is generally accepted that it occurs as a consequence of an infarction or hemorrhagic infarction of the pituitary gland[10, 11]. From a pathophysiological perspective, SARS-Cov-2 has shown specific tropism to the central nervous system and utilizes angiotensin-converting enzyme 2 (ACE2) receptors on host cells for its internalization[12]. Once in the nervous system, SARS-Cov-2 induces downregulation of ACE2 receptors, which causes imbalance in oxidative stress, vasodilation, neuroinflammation, and thrombogenesis that may contribute to stroke pathophysiology of COVID-19 and hence, the development of PA in patients with pituitary adenomas[11].
Our observations are in line with mounting data pointing to neurologic manifestations in COVID-19 positive patients. There is accumulating evidence to suggest that SARS-CoV-2 targets the nervous system. Reported rates of stroke in patients with COVID-19 infection ranges between 0.9 and 5.7 percent[13, 14], while the incidence of cerebral thrombosis can be as high as 36 %[15]. In another study, of 32 critically ill patients with COVID-19, 8 (25%) had severe central nervous system involvement[16]. Stroke patients with COVID-19 infection were more likely to be younger and have higher admission National Institute of Health Stroke Scale (NIHSS) score[14]. Similarly, intracranial hemorrhage or cerebral microbleeds have been shown in up to 22% of critically ill patients[16]. Therefore, there exists a plausible biological mechanism that explains the possible role of COVID infection as a risk factor for developing PA.
Coexistence of PA and COVID-19 infection has been previously reported[17, 18]. The significance of this correlation is still unclear [17]. Similarly, Chan et al [18] reported another case of a patient with PA who also tested positive for COVID-19 infection, although in this case, pregnancy may have played an important role in the development of the pituitary infarction[19]. Following the Bradford-Hill criteria that assesses epidemiological evidence of causality between a cause and effect[20], what this works adds to the previous knowledge is a more robust strength of the association (largest series to date), consistency of the results (three consecutive patients in one neurosurgery department), and the absence of any relevant factor that predispose to PA (specificity). While several risk factors, including head trauma, intracranial hypertension, radiotherapy, pregnancy, or anticoagulation, have been described as the potential cause of hemorrhagic infarction of the pituitary gland[11, 21], none of these were found in any the three patients presented here. In addition, temporality is another principle to stablish causality that is met in our report of three consecutive cases. Two of our patients had a positive test demonstrating COVID infection within the month prior to admission for PA. The third patient tested positive after respiratory symptoms that were developed 4 days after he was diagnosed with PA. If considering the mean incubation time of SARS-Cov-2 is estimated to be 5 days, we can prompt that our third patient was likely already infected when he experienced symptoms relative to the pituitary infarction.
From the management perspective, it is worthwhile to highlight the importance of monitoring fluid and electrolyte balance and correction of pituitary hormone deficiencies[11]. Once the patient is stabilized, the surgical indication mostly depends on visual status. PA is generally considered a surgical emergency when associated with acute visual dereterioration[10, 11]. Interestingly, some patients have experimented spontaneous visual improvement with conservative management using steroids[22, 23]. We attempted to opt for conservative management in one of our patients (patient #2), given the subacute progression of his visual symptoms. Nevertheless, the lack of visual improvement after a short interval of observation, prompted the need to proceed with surgical resection. The surgical intervention can be carried out through a transsphenoidal or a transcranial route[10, 11]. However, the increased risk of SARS-Covs-2 dissemination to healthcare workers during transsphenoidal surgery due to aerosolization of viral particles has led some centers to favor the transcranial route or even delay the intervention in non-emergent cases[24]. In our case, just in patient #1 we preferred the transcranial approach, given the lack of benefit in a patient with a large adenoma with suprasellar extension.
The present study has several limitations. Most importantly, its descriptive nature and the small selected sample size prevents from extracting definitive conclusions about the true incidence of PA in patients with COVID-19. However, we believe that our study provides relevant preliminary data regarding pituitary apoplexy in patients with COVID-19.