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Review

Pituitary Apoplexy in Patients with Pituitary Neuroendocrine Tumors (PitNET)

by
Ana-Maria Gheorghe
1,†,
Alexandra Ioana Trandafir
1,†,
Nina Ionovici
2,
Mara Carsote
3,*,
Claudiu Nistor
4,*,
Florina Ligia Popa
5 and
Mihaela Stanciu
6
1
Department of Endocrinology, “C.I. Parhon” National Institute of Endocrinology, 011683 Bucharest, Romania
2
Department of Occupational Medicine, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
3
Department of Endocrinology, “Carol Davila” University of Medicine and Pharmacy & “C.I. Parhon” National Institute of Endocrinology, 011683 Bucharest, Romania
4
Department 4—Cardio-Thoracic Pathology, Thoracic Surgery II Discipline, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy & Thoracic Surgery Department, “Carol Davila” Central Emergency University Military Hospital, 013058 Bucharest, Romania
5
Department of Physical Medicine and Rehabilitation, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550024 Sibiu, Romania
6
Department of Endocrinology, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Biomedicines 2023, 11(3), 680; https://doi.org/10.3390/biomedicines11030680
Submission received: 26 January 2023 / Revised: 17 February 2023 / Accepted: 21 February 2023 / Published: 23 February 2023
(This article belongs to the Special Issue Neuroendocrine Neoplasia: From Pathophysiology to Novel Therapeutic Approaches)
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Abstract

:
Various complications of pituitary neuroendocrine tumors (PitNET) are reported, and an intratumor hemorrhage or infarct underlying pituitary apoplexy (PA) represents an uncommon, yet potentially life-threatening, feature, and thus early recognition and prompt intervention are important. Our purpose is to overview PA from clinical presentation to management and outcome. This is a narrative review of the English-language, PubMed-based original articles from 2012 to 2022 concerning PA, with the exception of pregnancy- and COVID-19-associated PA, and non-spontaneous PA (prior specific therapy for PitNET). We identified 194 original papers including 1452 patients with PA (926 males, 525 females, and one transgender male; a male-to-female ratio of 1.76; mean age at PA diagnostic of 50.52 years, the youngest being 9, the oldest being 85). Clinical presentation included severe headache in the majority of cases (but some exceptions are registered, as well); neuro-ophthalmic panel with nausea and vomiting, meningism, and cerebral ischemia; respectively, decreased visual acuity to complete blindness in two cases; visual field defects: hemianopia, cranial nerve palsies manifesting as diplopia in the majority, followed by ptosis and ophthalmoplegia (most frequent cranial nerve affected was the oculomotor nerve, and, rarely, abducens and trochlear); proptosis (N = 2 cases). Risk factors are high blood pressure followed by diabetes mellitus as the main elements. Qualitative analysis also pointed out infections, trauma, hematologic conditions (thrombocytopenia, polycythemia), Takotsubo cardiomyopathy, and T3 thyrotoxicosis. Iatrogenic elements may be classified into three main categories: medication, diagnostic tests and techniques, and surgical procedures. The first group is dominated by anticoagulant and antiplatelet drugs; additionally, at a low level of statistical evidence, we mention androgen deprivation therapy for prostate cancer, chemotherapy, thyroxine therapy, oral contraceptives, and phosphodiesterase 5 inhibitors. The second category includes a dexamethasone suppression test, clomiphene use, combined endocrine stimulation tests, and a regadenoson myocardial perfusion scan. The third category involves major surgery, laparoscopic surgery, coronary artery bypass surgery, mitral valvuloplasty, endonasal surgery, and lumbar fusion surgery in a prone position. PA in PitNETs still represents a challenging condition requiring a multidisciplinary team from first presentation to short- and long-term management. Controversies involve the specific panel of risk factors and adequate protocols with concern to neurosurgical decisions and their timing versus conservative approach. The present decade-based analysis, to our knowledge the largest so far on published cases, confirms a lack of unanimous approach and criteria of intervention, a large panel of circumstantial events, and potential triggers with different levels of statistical significance, in addition to a heterogeneous clinical picture (if any, as seen in subacute PA) and a spectrum of evolution that varies from spontaneous remission and control of PitNET-associated hormonal excess to exitus. Awareness is mandatory. A total of 25 cohorts have been published so far with more than 10 PA cases/studies, whereas the largest cohorts enrolled around 100 patients. Further studies are necessary.

1. Introduction

Various complications have been reported in the relationships of pituitary neuroendocrine tumors (PitNET); an intratumor hemorrhage or infarct/infarction, also named pituitary apoplexy (PA), is a less common feature, yet with a life-threatening potential, thus its importance in early recognition and prompt intervention. Of historical note, hemorrhages associated with pituitary tumors were first described in 1898 by Pearce Bailey, and in 1950 the term “pituitary apoplexy” was introduced by Brougham et al. [1]. PA is a medical emergency presenting as sudden onset headache, loss of vision, ophthalmoplegia, and altered consciousness in relationship with a prior known or unknown pituitary mass, mostly PitNETs (usually a nonfunctioning adenoma, but also, hormonally active tumors with or without previous specific therapy) [1,2,3].
The incidence of PA in the general population varies from 0.2% to 0.6%, and from 2% to 12% in selected subgroups diagnosed with different types of PitNETs [4,5]. Males are affected more frequently than females; even though any age may be involved, most cases are reported within the fifth or sixth decade of life, whereas pediatric incidence remains very low [6,7].
The underlying mechanisms of PA are not completely understood yet. The classical hypothesis states that a rapidly growing tumor exceeds vascular supply [8]. Other potential contributors are vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), pituitary tumor-transforming gene (PTTG), matrix metalloproteinase-2/9 (MMP-2/9) or MMP-9, hypoxia-inducing factor (HIF-1α), a high proliferating index Ki-6 [9,10,11]; and high-mobility group box 1 (HMGB1), a nuclear DNA-binding protein with pro-inflammatory effects [12].
In terms of clinical presentations, sudden headache, often with retro-orbital location, is one of the most common presenting symptoms of PA, with an incidence of 92% up to 100% of the patients [13]. The PA-associated mechanism includes traction of intracranial pain-sensitive structures such as the dura mater, cranial nerves, blood vessels, and meningeal irritation caused by blood and necrotic tissue [14]. Other frequent symptoms are ophthalmological complaints such as visual loss, diplopia, and ophthalmoplegia [15]. Specific hormonal anomalies, caused either by hormonally active PitNETs or by PA-induced or tumor-related hypopituitarism, may also be identified at the moment of PA diagnostic [16]. Arterial hypertension, diabetes mellitus, non-endocrine major surgical procedures, head trauma, infections, and certain drugs targeting the endothelium or clotting profile are PA-associated risk factors [16]. Hemorrhage in prolactinomas is another common scenario, especially under specific medical therapy [17,18]. Cavernous sinus invasion or the presence of a large macroadenoma may also increase the risk of developing PA [18,19]. Socioeconomic factors potentially play a role in the development of PA, yet, not unanimously accepted [20].
The imaging tests used as a diagnostic aid are mostly represented by computed tomography (CT) and magnetic resonance imaging (MRI) [21]. Even though CT is used more often, MRI has a higher sensitivity [22]. The most commonly described MRI signs of PA are “sinus mucosal thickening” and “pituitary ring sign” [23]. Of note, the diagnostic of PA needs to be confirmed by imaging findings and/or associated post-operatory pathological profile after suspicion of PA is raised from a clinical presentation with regard to a neuroendocrine and/or neurologic point of view [21,22,23].
PA management involves a multidisciplinary team, as it is considered a neuroendocrine emergency. The main source of mortality is caused by acute adrenal insufficiency. Therefore, prompt glucocorticoid replacement is crucial [24]. However, the exact protocol still represents a subject of controversy. Early surgery is necessary for patients with severe visual loss since decompression may lead to a better recovery of visual dysfunction [25], but not necessarily to complete hypopituitarism recovery [26]. Other data did not identify any differences regarding the outcome of eye profile and hormonal imbalance when comparing surgical to conservative management [27,28].

Aim

Our purpose is to overview PA as a complication of a pituitary tumor, particularly PitNETs, from clinical presentation to management and outcome.

2. Method

This is a narrative review of the English-language medical literature. Inclusion criteria are the following: clinically relevant papers concerning a PubMed-based search using the keywords “apoplexy”, “hemorrhage”, or “infarction” in association with “pituitary” (alternatively “hyphophyseal”); the timeline of publication is between 2012 and 2022; we included original research, either studies or case reports/series. Exclusion criteria were PA associated with the following circumstances: pregnancy and postpartum period, infection with coronavirus amid the recent COVID-19 pandemic, and non-spontaneous PA meaning PA associated with treatment for a prior known PitNET: neurosurgery, pituitary radiotherapy, and medication for hormonally active PitNETs, for instance, dopamine analogs (cabergoline, bromocriptine) for prolactinomas and somatotropinomas, respectively, somatostatin analogs (octreotide, lanreotide, and pasireotide), and growth hormone (GH) receptor antagonist pegvisomant for somatotroph PitNETs.

3. PitNET Complicated with PA

According to our methodology, we identified 194 original papers that included 165 case reports, 5 case series, 22 retrospective studies, one case–control study, and one prospective study. Overall, 1452 patients with PA were included (926 males, 525 females, and one transgender male). In accordance with medical literature, we found a male predominance (male-to-female ratio of 1.76). The mean age of patients was 50.52 years, the youngest was 9, and the oldest was 85 years [29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222] (please see Table 1) (Figure 1).

3.1. Clinical Presentation in Cases with PA: Neurologic and Ophthalmic Elements

Sudden headache was the most frequent symptom and occurred in more than two-thirds of patients. (Table 1) Headache was severe, often described as the most painful headache episode an individual has ever experienced, and graded, for example, as high as 9 on a scale from 0 to 10, with 10 being the most severe in one study [31]. For practical purposes we point out that headache was absent in some cases; thus, an index of suspicion should be provided by other endocrine and non-endocrine clinical elements [43,86,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216]. For instance, Enatsu et al. reported a 65-year-old woman admitted for a nonfunctioning pituitary adenoma-associated PA who presented third cranial nerve palsy and sudden decrease in visual acuity unaccompanied by headache [196]. Another example is a 65-year-old male who developed PA as a post-operative complication after a coronary artery surgery; he only presented diplopia and third cranial nerve palsy [214]. Other circumstances without headaches involve a comatose status. The case presented by Bhogal et al. involves a 63-year-old man with bradycardia and hypotension due to myxedema coma as part PA-associate hormonal picture [215]. Elsehety et al. reported a 60-year-old woman with vision loss and progression to coma due to an acute stroke as a surrounding event to PA [216].
Other common symptoms include nausea and vomiting, either with a neurological or endocrine component (acute secondary adrenal insufficiency) [25,29,30,33,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,174,176,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,217]. As mentioned, altered consciousness of various degrees up to coma was identified in 24 papers [56,64,70,79,93,97,100,103,111,112,114,122,123,141,151,169,174,177,189,209,210,215,216,218]. Weakness as a distinct clinical element was specified in five clinical cases (as a neurologic or endocrine consequence) [73,147,188,202,217].
Another important clinical finding is meningism, a crucial clue for differentiating between two life-threatening conditions: PA presenting as aseptic meningitis and bacterial meningitis. PA mimics neurological conditions, such as bacterial [30,37,39,59,63,78,83,106,119,168] or aseptic [100,176] meningitis, making differential diagnosis difficult. Both PA and meningitis share a similar clinical presentation with nuchal rigidity [30,59,70,78,83,119,168], positive Kernig and Brudzinski signs [37,78], fever [30,59,78,83], photophobia [39,70,83], and altered states of consciousness [30,83,106,176]. Moreover, laboratory findings consistent with bacterial meningitis, such as neutrophilic pleocytosis [30,39,59,78,119,176], and high protein content [39,59,83,119,176] were also observed in PA. In terms of glucose content of cerebrospinal fluid (CSF), patients presented with normal [59,78,83,119] or high [176] levels in CSF. In spite of findings suggestive of bacterial meningitis, all CSF cultures were sterile [30,39,59,78,83,100,119,176]. In one case, differential diagnosis was particularly difficult [78]. Villar-Taibo et al. presented a patient with clinical presentation (nuchal rigidity, positive Kernig and Brudzinski signs, and fever) and CSF analyses consistent with bacterial meningitis, whose state improved under antibiotics. Following this event, the subject was diagnosed with PA based on MRI findings and pathological examination. The authors hypothesized that meningitis might have led to PA due to vasculitis. However, it remained unclear whether PA mimicked meningitis or if previous meningitis led to PA [78]. Considering that both PA and bacterial meningitis can be life-threatening, prompt differential diagnosis and treatment are essential. Current findings suggest that the presentation of a clinical picture suggestive of meningitis includes differential diagnosis with PA, especially in patients with sterile CSF, knowing that PA may cause aseptic, irritant chemical, bacterial-like meningitis [39].
PA may associate cerebral ischemia through either extrinsic compression or vasospasm, leading to neurological deterioration (mental status changes, motor deficits, speech impairment) in patients who suffered from acute ischemic stroke following PA [79,107,146,199].
PA-associated visual disturbances include decreased visual acuity in most cases [11,25,31,32,33,37,57,70,75,80,93,96,97,98,101,102,105,110,113,120,121,128,135,146,168,177,187,190,196]. Complete blindness was reported in two papers [199,212]. Visual field defects varied from (mostly common) hemianopia [33,39,55,80,126,135,179,187,197] to cranial nerve palsies manifesting as diplopia in the majority of these cases [32,34,35,49,50,58,63,66,68,75,84,85,91,92,114,115,117,127,130,142,147,150,157,163,164,186,191,194,195,207,214] followed by ptosis [34,35,50,59,75,77,79,92,107,146,157,191,199,206] and ophthalmoplegia [47,52,95,140,158,172,190,209]. The most frequent cranial nerve affected was the oculomotor nerve, but rarely, patients also presented with abducens [25,44,77,81,84,85,91,98,113,120,121,123,124,128,142,168,174,182,192,207] and trochlear [25,63,81,84,102,121,123,124,149,168,182,209] nerves palsies. Optic chiasm compression was specified in 18 articles [32,33,46,55,62,63,65,69,80,123,125,169,177,185,186,191,192,218] or, rarely, an invasion of the cavernous sinus [44,63,65,196]. Interestingly, two patients, a 45-year-old male [34] and a 71-year-old female [207] were admitted for PA-associated proptosis.

3.2. PA and Hormonal Imbalance at First Diagnostic

Endocrine features in subjects admitted for PA include PitNETs-associated hormonal excess, even though most patients were nonfunctioning tumors, respectively, tumor- or PA-caused hypopituitarism (as mentioned, we did not include patients with previously recognized and treated PitNETs). In terms of clinical presentation, Cushingoid features (corticotroph PitNET) are reported in 5 studies (less than 0.005% of the patients): two males of 30, respective 33 years [31,186], a cases series of 4 females aged between 26 and 45 years [33], and other two women of 35, respective 47 years [86,161]. Acromegaly (caused by somatotroph or lactosomatotroph PitNET) was recognized in 8 patients (0.005%) aged between 26 and 50 years; a male [86,109,136,148,156,217] to female [38,78] ratio of 6 to 2. One case of gigantism (+5 SD) was reported on a 9-year-old boy with lactosomatotroph PitNET [32]. Hypopituitarism included elements of hypogonadism [127,128,129,131,135] like disturbances of menstrual cycle in women of reproductive age [171,172], etc., but, also, with a more severe potential, hypotension [29,48,83,199,210,213].
Other signs and symptoms at PA presentation include lactotroph PitNET-associated galactorrhea [141,174,183]; hyperthermia [180], pruritic skin rash associated with central adrenal insufficiency-related cortisol deficit [185], hiccups [109], epistaxis [91], hematuria [189], phonophobia [78], visual illusions [45], and symptomatic diabetic ketoacidosis [53,171,172].
In terms of the PitNET stain profile (regardless clinical expression) non-functional type was followed by somatotroph PitNETs [32,38,42,46,53,56,66,76,78,86,92,93,98,100,108,109,121,128,136,141,148,152,156,166,168,169,171,175,192,217], lactotroph PitNETs [66,75,77,90,98,100,113,121,126,128,141,166,168,169,174,175,183,202,206], gonadotroph PitNETs [71,72,77,88,91,98,99,101,105,113,114,128,179,185,187,203,221], corticotroph PitNET [31,33,92,98,100,103,118,121,128,137,144,154,155,168,174,184,186,208,220], lactosomatotroph [32,100,109], and thyrotroph PitNETs [61,92,100,105]. Other pathologic features of pituitary masses complicated with PA include: Crooke cell adenoma [130,161], tumor with switching phenotypes [143], malignant spindle and round-cell tumor [91], Rathke’s cyst [70,194], primitive neuroectodermal tumor [70], craniopharyngioma [70], and pituitary metastasis from squamous cell carcinoma [35], melanoma [55], lung and bronchogenic carcinoma [70,73], respectively, and breast carcinoma [62,187].

3.3. Potential Triggers and Circumstantial Events of PA

Our decade-based analysis showed that high blood pressure may be regarded as the most frequent co-morbidity (or risk factor) followed by diabetes mellitus in individuals admitted for PA. (Table 1) Two cases reported severe, complicated diabetes with diabetic ketoacidosis [53,171,172], and chronic kidney failure [59]. Another endocrine contributor was T3 thyrotoxicosis in one patient [71].
Infectious triggers were also found and include pituitary fungal infection [144], dengue hemorrhagic fever [42,74,77,103,139], varicella [208], and leptospirosis [163]. Of note, Catarino et al. presented the case of a 55-year-old woman who suffered from a corticotroph PitNET-associated PA in relationship to a fungal infection that was surgically treated without anti-fungal treatment [144]. Dengue hemorrhagic fever led to PA in five patients. The underlying mechanism is thrombocytopenia which favors bleeding at the level of PitNET. All patients had pituitary adenomas, with one corticotroph PitNET [103], one somatotroph PitNET [42], and one lactotroph–gonadotroph PitNET [77]. Three patients underwent transsphenoidal surgery (TSS) [42,74,103], one patient was treated conservatively [139], and another patient underwent TSS after initial conservative treatment with cabergoline and dexamethasone due to visual deterioration [77]. The 56-year-old patient introduced by Gohil et al. presented leptospirosis; the proposed mechanisms through which leptospirosis might induce PA include non-inflammatory vasculopathy, as well as platelet dysfunction, rather than thrombocytopenia [163]. An interesting finding was conducted by Humphreys G et al., who analyzed in a prospective study the sphenoid sinus mucosal microbiota characteristics in 10 patients with PA. The authors observed abnormal sinus bacteria like Enterobacteriaceae in patients with PA [105].
Traumatic causes are identified; for instance, head trauma [30,160,204], recent rugby play without an actual head trauma [168], and bodybuilding exercises [106].
Anticoagulation [25,64,66,70,128,135,138,160,166,173,195,198] and antiplatelet therapy [90,94,97,113,141,160,166,169] are the most important iatrogenic elements. For instance, we mention rivaroxaban, enoxaparin, dabigatran etexilate, warfarin, heparin, apixaban, and aspirin. Other vascular and clotting triggers include Takotsubo cardiomyopathy [213], heparin-induced thrombocytopenia [35], thrombocytopenia of other causes [97,208], and polycythemia [108]. Medical treatments in point are further on (at the statistical level of rare case reports): androgen deprivation therapy for prostate cancer [52,88,99,157,168], systemic chemotherapy like bleomycin, etoposide, cisplatin [184], doxorubicin, cyclophosphamide [207], and thyroxine therapy [61].
Oral contraceptives may contribute to PA [54]. Kobayashi et al. presented a 33-year-old female with ischemic PA of a nonfunctioning macroadenoma following the use of oral contraceptives for 1.5 years. The patient fully recovered under conservative treatment with analgesics and hormone replacement with hydrocortisone and thyroxine. The hypercoagulable state induced by estrogens was hypothesized as an underlying mechanism of PA [54]. Additionally, a vardenafil-triggered PA was reported [140]. Uneda et al. reported a 51-year-old male with signs and symptoms of PA (severe headache and oculomotor nerve palsy) the morning after taking vardenafil for erectile dysfunction for the first time in three months. He was diagnosed with apoplexy of a pituitary adenoma based on CT and MRI findings and was surgically treated. Even though the underlying mechanisms remain unclear, possible mechanisms of PA under phosphodiesterase 5 (PDE) inhibitors are hypotension, vasodilation, and antiplatelet effects [140].
Iatrogenic components may include diagnostic tests and procedures: dexamethasone suppression test [118], clomiphene use [66], combined endocrine stimulation tests [43], regadenoson myocardial perfusion scan [153], and MRI scan [46]. Among non-pituitary-surgery-related triggers, we identified major surgery [66,128,132,168,201], laparoscopic surgery [199], coronary artery bypass surgery [34,66,214], mitral valvuloplasty [84], endonasal surgery [127], and lumbar fusion surgery in prone position [80,116]. Interestingly, Naito Y et al. reported a case of PA in a 14-year-old girl with Carney complex who underwent successful resection of a cardiac myxoma, but the day after surgery she experienced headache and visual disturbances requiring urgent surgical decompression for PA [132].
Other therapeutic procedures include the intravitreal injection of vascular endothelial growth factor inhibitor [204], autologous hematopoietic cell transplantation [152], endoscopic retrograde cholangiopancreatography [124], and radiotherapy [113,166].
Two case reports presented individuals with PA caused by exposure to high altitudes (the first case was published in 2012). Both subjects were 29-year-old males without underlying pituitary conditions who ascended slowly to altitudes of over 4500 m. The initial diagnosis was acute mountain sickness in both cases. However, due to low blood pressure and findings of adrenal insufficiency, PA was suspected, and later MRI scans confirmed PA. Neither patient displayed visual disturbances [29,48]. The management included transfer to a lower altitude (as a specific approach in this distinct type of PA) as well as glucocorticoid replacements (100 mg of hydrocortisone every eight hours, the first two days, followed by 7.5 mg of prednisolone daily due to persistent hypocortisolism [29], respective 100 mg of hydrocortisone every six hours followed by full recovery [48].
Of note, two unusual triggers are polysubstance abuse [191] and long restraint in a sitting position [221]. The patient presented by Sun et al., a 49-year-old male, died in custody due to a gonadotroph PitNET-associated PA following restraint in a sitting position for four days [221] (Figure 2).

3.4. PA Management

The management of the patients recognized with PA is summarized in Table 2. Essentially, the subjects were managed surgically (80%) or conservatively. Although the majority are TSSs, five papers introduced patients undergoing craniotomies [36,60,127,159,217]. Craniotomies were necessary for intracranial hemorrhage [36], subarachnoid hemorrhage [60], previous nasal surgery [127], and technical challenges such as cavernous sinus invasion with encasement of the internal carotid artery [159], respectively, encasing of both carotid arteries [217].
Conservative management [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,218,219,220] included vital signs monitoring, hydro-electrolytic balance, glucocorticoid substitution (intravenous hydrocortisone during the first 48 h followed by oral replacement), as well as substitution with levothyroxine and desmopressin (if needed) [123,168]. A management decision was based on the severity of clinical presentation and progression of the neurologic, eye, and hormonal features. The patients analyzed by Marx et al. were treated surgically when they presented severe visual acuity decrease, worsening of ophthalmological symptoms, resistant headache, or altered consciousness [168]. Similar criteria were applied by Almeida et al. and Bujawansa et al. [66,123]. Clinically stable individuals remained under a conservative approach [66,123,168], as well as subjects to contraindications for performing neurosurgery [123] or those refusing it [218].
A few cases under the “wait and see” approach were later referred to TSS due to worsening conditions: hematoma expansion [51] or sudden visual deterioration [77,158].
We identified three clinically relevant studies that compared conservative management versus TSS in terms of evolution [123,160,168]. Almeida et al. found that visual, cranial nerve, and endocrine outcomes are similar between the two subgroups [123]. Cavalli et al. analyzed the clinical presentation, surgical methods, and treatment outcomes of patients with PA. The authors advocated for conservative management in patients without visual impairment and suggested that a tumor with a vertical diameter greater than 35 mm should be referred to neurosurgery in the presence of visual deficits. The only statistical difference between surgically treated patients and patients under conservative treatment was the higher ratio of achieving resolution of visual field defects at the latest follow-up in the group who underwent emergency surgery [160]. Marx et al. found that following surgery, a higher number of patients presented adrenal insufficiency and hypogonadotropic hypogonadism than those who were managed conservatively, but no statistically significant difference was identified in terms of visual acuity and visual field consequences [168]. Bujawansa S et al. suggested conservative treatment as a safe and adequate approach for selected patients (those with mild and non-progressive neuro-ophthalmic defects) [66]. The findings suggest that surgical treatment wields a higher risk of associating endocrine deficiencies [168], but a higher ratio of visual field defects improvement [161], but with similar outcomes in terms of visual acuity [123,160,168].
We mention some isolated reports with uncommon management such as radiotherapy for a subject diagnosed with a null cell tumor and a gonadotroph PitNET [105]; palliative care with dexamethasone and brain radiotherapy for an individual diagnosed with bronchogenic carcinoma metastases-associated PA [73]; transfer to a lower altitude, as prior mentioned, in specific cases with climbing-induced PA [29,48]; for an intraorbital-induced PA, the patient was offered orbital surgery, preceded by embolization through direct puncture techniques combined with a transarterial approach via the right ophthalmic artery [206]. Additionally, functional PitNET continued medical therapy for specific hormonal excess with cabergoline [75,77,168,170,199,218] or somatostatin analogs [76].

3.5. PA-Related Outcome

A large number of patients required hormonal replacement due to PA-associated hypopituitarism manifested as hypocortisolism which is the most important aspect in terms of an immediate life-threatening approach [25,29,30,31,56,65,66,75,80,90,92,123,128,144,163,168,169,208], central hypothyroidism [25,56,65,66,72,75,101,109,123,144,163,168,169,180,184,200], and hypogonadotropic hypogonadism [25,56,65,66,72,109,128,168,169,180,198]. GH deficiency was also reported [109,128,168], whereas spontaneous acromegaly remission was reported in four papers [46,136,156,208] or partial improvement of acromegaly-related GH excess [78]. Long-term therapy with desmopressin for permanent diabetes insipidus was reported, as well as [25,31,55,66,78,90,91,111,112,113,127,128,182]. Microadenomas underlying PA had a better clinical (including endocrine) outcome when compared to macroadenomas which are also associated with a higher rate of multiple hormonal deficiencies [169]. A retrospective study by Ogawa Y et al. found that ischemic rather than hemorrhagic lesions in PA correlated with an increased progression rate [100].
As mentioned, some small studies evaluated the outcome in terms of conservative versus neurosurgical management. A retrospective study (N = 46 patients with PA) showed that individuals with non-severe neuro-ophthalmological deficits were treated conservatively (N = 27), whereas the patients with a pituitary apoplexy score (PAS) ≥4 were treated surgically (N = 19); the only statistically significant difference regarding the outcome was the higher rate of hormonal deficits in the second group [168]. Another study included 49 subjects who were referred for neurosurgery and 18 patients who were conservatively managed and showed similar improvement in visual and cranial nerve palsies [123]. A retrospective study (N = 24 subjects who underwent TSS) showed a complete tumor resection in 87.5% of cases; 94.44% of patients experienced an improvement of visual acuity; diabetes insipidus developed in 16.66% of individuals [174].
The timing of surgery was also taken into consideration by some studies, as a contributor to PA outcome. A study conducted by Rutkowski M et al. (N = 32 patients with acute PA who underwent TSS) included two groups depending on surgery timing: within 72 h of symptom onset and after 72 h; the second group had a statistically significant higher prevalence of hypopituitarism at presentation. However, in terms of hypopituitarism and visual dysfunction recovery, the outcome was similar [121].
The spontaneous resolution of PitNET through PA was reported with a favorable outcome [87,126,154,220]. Ghalaenovi H et al. published the case of a 28-year-old male with spontaneous regression of a nonfunctioning pituitary adenoma over the course of one year with the spontaneous resolution of headache, bitemporal hemianopia, and photophobia [126]. Machado et al. presented a 36-year-old female with spontaneous resolution of a corticotroph PitNET with symptoms remission within 28 months (conservative approach) [220]. Siwakoti et al. introduced a 59-year-old woman with tumor shrinkage and biochemical remission of Cushing’s disease through conservative treatment [154]. Tumor resolution with empty sella following conservative management was reported by Saberifard et al. [87].
Fatal outcome surrounding PA was registered as an early event, for instance, within 48 h [38] or after 5 years since initial TSS [91]. Overall, we identified 14 publications [35,36,38,60,62,90,91,92,100,133,182,187,216,221]. Some of the subjects were comatose at presentation [36,38,60,216], PA causing an intracerebral hemorrhage [36]; similarly, one case of the following is reported: fulminant heparin-induced thrombocytopenia [182]; fatal outcome 12 days following TSS due to sepsis [187]; or 3 months since PA in a patient with breast cancer [62] or leukemia [100]. Interestingly, two studies reported a mortality death of 1.03% (N = 97) [92], respective of 4.6% (N = 87) [90].
Of note, we identified through our analysis a single case of PA in the transgender population: a 46-year-old transgender male under testosterone therapy for 3 years who was admitted for severe headache, central hypocortisolism, and hypothyroidism. IGF-1 (insulin-like growth factor) levels, however, were high. The patient was diagnosed with somatotroph PitNET-associated PA and received surgical treatment with normalization of IGF-1 and improvement of secondary diabetes mellitus. Particularly, testosterone therapy in this situation may mask acromegaly features [76] (please see Table 2).

4. Discussion

4.1. Subentities concerning PA

An unusual case of “pneumo-apoplexy” was described by Singhal A et al.; a 65-year-old female had a PA-associated hemorrhage accompanied by pneumosella and manifested as rhinorrhea as well as classical symptoms of PA including headache and visual loss. The patient needed flap replacement of the nasoseptal defect [137].
“Recurrent” apoplexy was reported by Hosmann A et al. in 4 out of 76 patients (5.3%) after initial neurosurgery. Potential factors include residual post-operatory tumor, cavernous sinus invasion of PitNET, and ophthalmoplegia [128]. However, a recurrent tumor after initial TSS due to PA-PitNET may be found as seen in the general population with PitNET who were previously candidates for neurosurgery [145,168].
Some patients presented “subacute” PA, with little to no symptoms, thus the importance of imaging assessments like MRI scans that point out infarction or hemorrhage [166]. The term “subacute” is used for PA associated with clinical symptoms less severe than fully manifested (or “acute”) PA, thus the importance of awareness since many cases may be under-diagnosed [166,222]. Iqbal F et al. published a retrospective analysis on 55 patients (33 with acute PA and 22 with subacute PA). Severe headache and hyponatremia were more frequent in the acute group whereas the ratio of individuals who were referred to surgery was similar between the two subgroups [166]. Garg M et al. described the case of a 22-year-old female with vision reduction as the single symptom [197]. Klimko A et al. also reported a 41-year-old acromegalic male with subacute PA and panhypopituitarism [148].

4.2. Controversies in PA Domain

PA is an emergency that typically presents a sudden and severe headache and visual symptoms; however, subacute cases or those without headaches should not be missed. The most frequent cause is hemorrhage or ischemia in a nonfunctioning pituitary adenoma, but hormonally active PitNET may embrace a PA scenario. Middle-aged males are affected with the highest frequency, but both pediatric and elderly cases are shown in Table 1. The most common risk factors are high blood pressure, diabetes mellitus, and anticoagulation/antiplatelet therapy; however, at the level of case reports, uncommon conditions are reported as we prior pointed out. (Table 1) Differential diagnosis is sometimes crucial, as PA can mimic a number of conditions including meningitis or temporal arteritis [134]. Controversies around the exact panel of PA contributors still exist since there are still pathogenic elements that remain unclear. Whether the mentioned comorbidities as displayed in Figure 1 are directly connected to PA or are incidental is still a matter of debate.
The optimal treatment approach remains debated, but the main treatment options are TSS or conservative management. Due to possible complications from surgery, as well as a higher rate of pituitary insufficiencies after surgical treatment when compared with conservative management, careful evaluation is necessary. The individual multidisciplinary decision is mandatory. Surgical management should be reserved for patients with visual impairment due to cranial nerve palsies and optic chiasm compression, or patients with other neurological deficits. Conservative treatment is usually an adequate approach for stable patients with mild and stationary visual deficits and without further neurological impairments. When choosing conservative management, the risk of PA recurrence should also be taken into account. (Figure 3).
In terms of outcome, headaches and visual disturbances may resolve following both conservative and surgical treatment. Patients can present different degrees of anterior hypopituitarism and diabetes insipidus. Factors for a worse prognosis may be the presence of a large macroadenoma and an ischemic type of apoplexy. PA is a condition that can lead to a favorable outcome with the remission of symptoms and underlying pituitary disorder in some patients, whereas for others it can be life-threatening and invalidating when fatal cases are reported (as we already mentioned). Specific algorithms of management are still necessary.
To our knowledge, this is the largest analysis of published cases concerning spontaneous PA (outside pregnancy and COVID-19 infection). A timeline of published papers from 2012 to 2022 according to our methodology is displayed below. The largest studies addressing individuals with PA included 109, 97, and 87 subjects, respectively [29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222]. (please see Table 1 and Table 3 and Figure 4)
Abbreviations: N represents the number of patients included in studies with at least 10 subjects with PA per article (of note: in Table 1 we used the term “case series” or “study” according to the original publication; in this figure, we strictly included the original research depending on the number of patients).
Notably, PitNETs terminology and associated concepts massively changed since the WHO 2022 classification. Our 10-year analysis included cases with PA in relationship with different tumors that were diagnosed according to the criteria at that time. Recently, “PitNET” replaced “pituitary adenoma” which, however, is still allowed to be used. Grossly, there are three types of tumors arising from the anterior lobe: PitNET, pituitary blastoma, and craniopharyngioma (two specific subtypes). The modern approach of these tumors massively takes into consideration the role of immunohistochemistry for mainly five elements: PIT1, TPIT, SF-1, GATA3, and ERα in order to profile PitNET subtypes. The major changes are, a part form this new terminology: null cell tumors and unclassified pluri-hormonal tumors as a subtype of PitNETs with negative staining for transcription factors; “metastatic” PitNET replaced “metastatic carcinoma” that should be differentiated from a neuroendocrine carcinoma; immature (formerly “silent”) or mature PIT1-lineage tumor are determined based on PIT1 immunostaining; and mammosomatotroph, acidophil stem cell tumors in addition to mixed somatotroph/lactotroph tumors are distinct types with respect to PIT-1 lineage of PitNET [223,224,225,226] (Figure 5).

4.3. Limitations

We acknowledge that the current review did not follow the PRISMA guidelines for systematic review and may have missed some studies because only PubMed was used for the literature search.

5. Conclusions

PA in PitNETs still represents a challenging condition requiring a multidisciplinary team from first presentation to short- and long-term management. Controversies involve the specific panel of risk factors and adequate protocols with concern to surgical decisions and their timing. The present decade-based analysis, to our knowledge the largest so far on published cases, confirms a lack of unanimous approach and criteria of intervention, a large panel of circumstantial events and potential triggers with different levels of statistical significance, in addition to a heterogeneous clinical picture (if any, as seen in subacute PA) and a spectrum of evolution that varies from spontaneous remission and control of PitNET-associated hormonal excess to exitus. Awareness is mandatory. A total of 25 cohorts have been published so far with more than 10 PA cases/studies, whereas the largest cohorts enrolled around 100 patients. Further studies are necessary.

Author Contributions

Conceptualization, A.-M.G., A.I.T., M.C. and M.S.; methodology, A.-M.G., A.I.T., M.C., C.N. and M.S.; software, A.-M.G., N.I., M.C. and F.L.P.; validation, A.-M.G., A.I.T., M.C. and C.N.; formal analysis, A.I.T., N.I., C.N., F.L.P. and M.S.; investigation, A.-M.G., A.I.T., N.I., M.C. and M.S.; resources, N.I., C.N., F.L.P. and M.S.; data curation, A.-M.G., A.I.T., N.I., M.C., C.N. and M.S.; writing—original draft preparation, A.-M.G. and A.I.T.; writing—review and editing, A.-M.G., A.I.T., M.C. and M.S.; visualization, N.I., M.C., C.N. and F.L.P.; supervision, M.C., C.N. and M.S.; project administration, A.-M.G., A.I.T., M.C. and M.S.; funding acquisition, M.C., C.N. and M.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We thank the patient who provided us with the imaging captures from his own personal records.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

CT computed tomography
CSF cerebrospinal fluid
HIF-1α hypoxia-inducing factor
HMGB1 high-mobility group box 1
HR hormonal replacement
GH growth hormone
IGF-1 insulin-like growth factor
MMP matrix metalloproteinase
MRI magnetic resonance imaging
PA pituitary apoplexy
PAS pituitary apoplexy score
PitNET pituitary neuroendocrine tumor
PDE phosphodiesterase
PTTG pituitary tumor-transforming gene
TNF-α tumor necrosis factor-α
TSS trans-sphenoidal surgery
VEGF vascular endothelial growth factor

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Figure 1. Flowchart according to our methodology.
Figure 1. Flowchart according to our methodology.
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Figure 2. Qualitative analysis of potential contributors to spontaneous PA in PitNETs that are not previously treated (outside pregnancy and coronavirus infections). Abbreviations: T3 = triiodothyronine; T4 = thyroxine.
Figure 2. Qualitative analysis of potential contributors to spontaneous PA in PitNETs that are not previously treated (outside pregnancy and coronavirus infections). Abbreviations: T3 = triiodothyronine; T4 = thyroxine.
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Figure 3. Imaging capture of a pituitary apoplexy. This is a male patient in his late 20s diagnosed with pituitary apoplexy with no prior medical or surgical history. On first presentation as an outpatient (due to severe headache), magnetic resonance imaging (performed as an emergency) shows a pituitary mass of 2.5 cm maximum diameter with inhomogeneous pattern suggesting hemorrhage (yellow arrow) at the level of a pituitary tumor (left). Intravenous contrast computed tomography (10 months since transsphenoidal surgery) shows a tendency to empty sella and no tumor remnants (yellow arrow) at the same level (right). Both captures are coronal plane.
Figure 3. Imaging capture of a pituitary apoplexy. This is a male patient in his late 20s diagnosed with pituitary apoplexy with no prior medical or surgical history. On first presentation as an outpatient (due to severe headache), magnetic resonance imaging (performed as an emergency) shows a pituitary mass of 2.5 cm maximum diameter with inhomogeneous pattern suggesting hemorrhage (yellow arrow) at the level of a pituitary tumor (left). Intravenous contrast computed tomography (10 months since transsphenoidal surgery) shows a tendency to empty sella and no tumor remnants (yellow arrow) at the same level (right). Both captures are coronal plane.
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Figure 4. The timeline of original papers specifically addressing PA according to our methodology: the sample size analysis of original publications (please see references according to Table 1).
Figure 4. The timeline of original papers specifically addressing PA according to our methodology: the sample size analysis of original publications (please see references according to Table 1).
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Figure 5. Integrating hypothalamic–pituitary tumors to new WHO 2022 criteria [223,224,225,226]. PitNET = pituitary neuroendocrine tumors; * well-differentiated adenohypophyseal tumors (formerly pituitary adenomas); ** two specific subtypes.
Figure 5. Integrating hypothalamic–pituitary tumors to new WHO 2022 criteria [223,224,225,226]. PitNET = pituitary neuroendocrine tumors; * well-differentiated adenohypophyseal tumors (formerly pituitary adenomas); ** two specific subtypes.
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Table
Table 1. Original studies published between 2012 and 2022 concerning PA according to our methodology; the cited studies are displayed from 2012 to 2022; the data concern the clinical presentation and potential triggers of PA in addition to underlying pituitary disease (if any) [29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222].
Table 1. Original studies published between 2012 and 2022 concerning PA according to our methodology; the cited studies are displayed from 2012 to 2022; the data concern the clinical presentation and potential triggers of PA in addition to underlying pituitary disease (if any) [29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222].
Author
Reference Number/
Year of Publication		Type of StudyPopulationClinical Presentation at Admission for PAPotential Triggers/Predisposing FactorsUnderlying Pituitary Condition *
Brar
[29] 2012		Case report29-year-old maleHeadache, nausea, non-projectile vomiting, dizziness, hypotension (systolic BP = 86–90 mmHg, diastolic BP = 56–62 mmHg)High altitude (4572 m)*
Cagnin
[30] 2012		Case report80-year-old maleHeadache, nausea, vomiting, drowsiness, neck rigidity, feverHead trauma hypertension*
Chan
[31] 2012		Case report30-year-old maleHeadache, decrease in visual acuity, 3rd cranial nerve palsy
Clinically manifested Cushing disease		 Corticotroph PitNET
Chentli
[32] 2012		Case report9-year-old boyRetro-orbital headache, decrease in visual acuity, diplopia, papillary edema
Gigantism (+5SD)		 Lactosomatotroph PitNET
Choudhry
[33] 2012		Case series4 female patients
(mean age: 41.75 years)		Headache (n = 4), nausea and vomiting (n = 3), decreased visual acuity (n = 4), bitemporal hemianopia (n = 4), 3rd cranial nerve palsy (n = 2), facial numbness/pain (n = 1)
Clinically manifested Cushing disease (n = 4)		DM,
hypertension		Corticotroph PitNET
Enatsu
[196] 2012		Case report65-year-old femaleLeft 3rd cranial nerve palsy, decrease in visual acuity Nonfunctioning pituitary tumor
Komurcu
[34] 2012		Case report45-year-old maleHeadache, bilateral 3rd cranial nerve palsy, proptosis, diplopia, loss of visionCoronary artery bypass surgeryNull cell pituitary adenoma
Kruljac
[35] 2012		Case report77-year-old femaleHeadache, decrease in vision, ptosis, diplopiaHeparin-induced thrombocytopenia, 2DM,
hypertension		Squamous cell carcinoma metastasis in the pituitary
Kurisu
[36] 2012		Case report68-year-old maleHeadache, nausea, vomiting, 3rd cranial nerve palsy, comaHypertensionNonfunctioning pituitary tumor
Liu
[37] 2012		Case report66-year-old maleHeadache, vomiting, decreased visual acuity, right 3rd cranial nerve palsy, meningism Pituitary tumor with hypopituitarism
Mohindra
[38] 2012		Case report40-year-old femaleHeadache, vision loss, coma
Acromegalic features		 Somatotroph PitNET
Paisley
[39] 2012		Case report67-year-old femaleHeadache, vomiting, partial loss of vision, left temporal hemianopia, light sensitivityHypertension*
Tedd
[40] 2012		Case report37-year-old maleHeadache, nausea, vomiting, photophobia, neck stiffness Pituitary tumor
Verma
[41] 2012		Case report36-year-old maleHeadache, fever, loss of vision, 3rd cranial nerve palsy Pituitary tumor
Wildemberg
[42] 2012		Case report40-year-old maleHeadache, vomitingDengue hemorrhagic fever, thrombocytopeniaSomatotroph PitNET
Yamamoto
[43] 2012		Two case reports56-year-old femaleHeadache, vomiting, visual disturbance, left 3rd cranial nerve palsyEndocrine stimulation testsPituitary tumor
73-year-old maleProgressive visual disturbanceEndocrine stimulation testsPituitary tumor
Zoli
[44] 2012		Case report59-year-old femaleHeadache, 6th cranial nerve palsy Pituitary tumor
Chou
[45] 2013		Case report64-year-old femaleHeadache, nausea, vomiting, fever, high BP, visual illusions Pituitary tumor
Cinar
[46] 2013		Case report38-year-old maleHeadache, nausea, vomitingDM, hypertensionSomatotroph PitNET
Delgado-Alvarado
[47] 2013		Case report70-year-old maleHeadache, right total ophthalmoplegia *
Deshwal
2013 [48]		Case report29-year-old maleHeadache, nausea, loss of appetite, fatigue, difficulty sleeping, hypotensionHigh altitude (5200 m)No underlying condition
Fanous
[49] 2013		Case report39-year-old maleHeadache, diplopia Pituitary macroadenoma
Haider
[50] 2013		Case report64-year-old womanHeadache, nausea, diplopia, right ptosisEnoxaparinPituitary macroadenoma
Hojo
[51] 2013		Case report29-year-old maleHeadache, vomiting Lactotroph PitNET
Huang
[52] 2013		Case report77-year-old maleHeadache, nausea, vomiting, ophthalmoplegia, visual field deficitGnRH agonist for prostate cancerPituitary adenoma
Jiang
[53] 2013		Case report49-year-old maleHeadacheDiabetic ketoacidosisSomatotroph PitNET
Kobayashi
[54] 2013		Case report33-year-old femaleHeadache, nausea, malaiseOral contraceptivesNonfunctioning pituitary adenoma
Machado
[220] 2013		Case report36-year-old femaleSpontaneous resolution of cushingoid features under no treatmentHypertensionCorticotroph PitNET
Masui
[55] 2013		Case report68-year-old maleHeadache, fatigue, anorexia, bitemporal hemianopia Pituitary melanoma metastasis
Mir
[56] 2013		Case report55-year-old maleHeadache, vomiting, altered consciousness2DMSomatotroph PitNET
Mohamed
[57] 2013		Case report37-year-old maleHeadache, nausea, vomiting, neck pain, 3rd cranial nerve palsy, left temporal field defect, loss of visual acuity Pituitary adenoma
Ní Chróinín
[58] 2013		Case report75-year-old femaleHeadache, vomiting, diplopia, 3rd cranial nerve palsyHypertension, DMPituitary adenoma
Oh
[59] 2013		Case report42-year-old manHeadache, vomiting, fever, neck stiffness, left eye ptosis, hemianopiaHypertension, chronic renal failurePituitary adenoma
Radhiana
[60] 2013		Case report44-year-old maleHeadache, vomiting, coma Pituitary adenoma
Steinberg
[218] 2013		Case report43-year-old maleVisual loss,
loss of consciousness		DM, hypertensionLactotroph PitNET
Sun
[221] 2013		Case report49-year-old maleExitusLong restrain in sitting positionGonadotroph PitNET
Tutanc
[61] 2013		Case report27-year-old femaleHeadache, vomiting, palpitation, sleep disturbanceThyroxine therapyThyrotrophic PitNET
Uemura
[219] 2013		Case report84-year-old maleRetro-orbital pain, 3rd cranial nerve palsyDM, dabigatran etexilateNonfunctioning pituitary adenoma
Witczak
[62] 2013		Case report67-year-old femalePanhypopituitarism, headache, 3rd cranial nerve palsy Pituitary metastases from breast cancer
Wong
[63] 2013		Case report62-year-old maleHeadache, diplopia, 3rd, 4th, and 5th cranial nerve palsy Pituitary adenoma
Zieliński
[64] 2013		Case report59-year-old femaleHeadache, vomiting, nausea, altered consciousness, visual disturbancesAnticoagulationNonfunctioning pituitary adenoma
Berkenstock
[65] 2014		Case report50-year-old maleHeadache, nausea, vomiting, unilateral loss of vision, diarrhea, polydipsia, polyuriaHypertensionPituitary adenoma
Bujawansa
[66] 2014		Retrospective analysis55 patients
(35 males and 20 females)
Mean age: 58.4 years		Acute headache (n = 48)
Cranial nerve palsy (n = 26): 3rd cranial nerve palsy (n = 16), 6th cranial nerve palsy (n = 50), multiple palsies (n = 5)
Diplopia (n = 21)
Visual field defect (n = 20)
Vomiting (n = 14)
Photophobia (n = 10)
Nausea (n = 9)
Facial pain/trigeminal neuralgia (n = 8)
Collapse (n = 2)		hypertension (n = 11), anticoagulation with warfarin (n = 3), aspirin (n = 2), coronary artery bypass grafting (n = 2), major orthopedic surgery (n = 3), clomiphene (n = 1)Nonfunctioning pituitary adenomas in 45 cases (82%), lactotroph PitNETs in 6 cases (11.5%), somatotroph PitNETs in 4 cases (7.2%), multiple endocrine neoplasia syndrome in 2 cases
Chao
[67] 2014		Case report14-year-old femaleHeadache, nausea, blurred vision Pituitary adenoma
Cho
[68] 2014		Case report40-year-old femaleHeadache, diplopia, hemiparesisHypertension*
Garg
[197] 2014		Case report20-year-old maleVisual impairment, bitemporal hemianopia Pituitary adenoma
Gupta
[69] 2014		Case report62-year-old maleHeadache, 3rd cranial nerve palsy, visual field defects
Acute coronary syndrome, hours after admission to hospital		DMPituitary macroadenoma
Jho
[70] 2014		Retrospective study109 patients (69 males and 40 females)
mean age: 51 years		Headache
Visual acuity/field deficits
Cranial nerve palsies
Vomiting
Altered consciousness
Meningism
Fever		Anticoagulation (n = 9)PitNET (n = 98)
Rathke’s cyst (n = 8)
Primitive neuroectodermal tumor (n = 1)
Craniopharyngioma (n = 1)
Metastatic lung carcinoma (n = 1)
Lee
[71] 2014		Case report58-year-old maleHeadache, visual disturbances, visual field defect, decreased sexual activityT3 thyrotoxicosisGonadotroph PitNET
Maltby
[72] 2014		Case report11-year-old femaleHeadache, vomiting, lethargy, weight loss
Tall stature, central obesity		 Possible gonadotroph PitNET
Man
[73] 2014		Case report52-year-old maleHeadache, left sided weakness Bronchogenic carcinoma metastases
Mishra
[74] 2014		Case report43-year-old maleHeadache, vomiting, loss of vision, bitemporal hemianopia, feverDengue hemorrhagic fever, thrombocytopeniaPituitary adenoma
Mura
[198] 2014		Case report85-year-old male patient3rd cranial nerve palsyLaparoscopic surgery, anticoagulation (dabigatran), hypertensionNonfunctioning pituitary adenoma
Navarro-Bonnet
[75] 2014		Case report30-year-old maleHeadache, decreased visual acuity, diplopia, right ptosis
Within 24 h: confusion, left hemiplegia		 Giant lactotroph PitNET
Rebeiz
[199] 2014		Case report81-year-old femaleStupor, hypotension, bilateral blindnessHypertensionPituitary adenoma
Roerink
[76] 2014		Case report46-year-old transgender maleHeadache, nausea, vomiting, blurred visionDM during testosterone therapySomatotroph PitNET
Tan
[77] 2014		Case report53-year-old maleHeadache, vomiting, left eye ptosis, right 6th cranial nerve palsy, right hemianopia, feverDengue hemorrhagic fever, thrombocytopeniaLactotroph and gonadotroph PitNET
Villar-Taibo
[78] 2014		Case report51-year-old femaleHeadache, nausea, vomiting, photophobia, photophobia
meningeal signs, fever		MeningitisSomatotroph PitNET
Yoshida
[200] 2014		Case report74-year-old femaleAsymptomatic apoplexy, anterior hypopituitarism, hyperthyroidism Pituitary adenoma
Yoshino
[201] 2014		Case report78-year-old maleFever, respiratory distress, polyuriaThoracic surgeryPituitary adenoma
Zhang
[79] 2014		Case report42-year-old maleHeadache, fever, loss of consciousness, visual disturbance Pituitary adenoma
Akakın
[80] 2015		Case report58-year-old maleHeadache, blurred vision, bitemporal hemianopia, lethargyPosterior lumbar fusion surgeryPituitary adenoma
Asaithambi
[81] 2015		Case report54-year-old maleHeadache, visual loss, partial 3rd, 4th, and 6th cranial nerve palsies Pituitary adenoma
Banerjee
[82] 2015		Case report56-year-old femaleHeadache, visual loss, followed by neurological deterioration (unresponsive, fixed and dilated right pupil, decerebrate response to stimuli)Fall from standingPituitary macroadenoma
Fountas
[83] 2015		Case report45-year-old maleHeadache, fever, photophobia, hypotension, confusion Pituitary adenoma
Kasl
[202] 2015		Case report14-year-old femaleUpper limb weakness, mental status changes Lactotroph PitNET
Kasl
[203] 2015		Case report74-year-old femaleUnilateral vision loss, 3rd cranial nerve palsyIntravitreal injection of vascular endothelial growth factor inhibitorGonadotroph PitNET
Kim
[84] 2015		Case report69-year-old maleHeadache, visual field defect, diplopia, 3rd, 4th, and 6th cranial nerve palsyMitral valvuloplastyPituitary adenoma
Man
[85] 2015		Case report82-year-old maleHeadache, diplopia, bilateral 3rd and 6th cranial nerve palsies Pituitary adenoma
Roerink
[86] 2015		Two case reports41-year-old maleNeck pain, acromegalic featuresDMSomatotroph PitNET
47-year-old femaleHeadache, a second episode of headache and visual impairment, Cushingoid featuresDM, hypertensionCorticotroph PitNET
Saberifard
[87] 2015		Case report50-year-old femaleHeadache, vomiting, visual field defect Pituitary adenoma
Sasagawa
[88] 2015		Case report62-year-old maleHeadache, 3rd cranial nerve palsyGnRH agonist for prostate cancerGonadotroph PitNET
Sasaki
[89] 2015		Case report65-year-old maleHeadache, visual impairment, symptoms of adrenal insufficiency Pituitary adenoma
Singh
[90] 2015		Retrospective analysis87 patients (55 males and 30 females)
mean age: 50.9 years		Headache (n = 78, 89.7%)
Cranial nerve palsy (n = 34, 39%)
Visual field defects (n = 30, 34.1%)		Hypertension (n = 34, 39%)
DM (n = 11, 12.6%)
cardiothoracic surgery (n = 2, 2.3%)
anticoagulant therapy (n = 9, 10.3%): heparin (n = 2, 22.2%) or warfarin (n = 7, 77.8%)
antiplatelet drugs (n = 17, 19.5%)		Null cell (n = 18)
Lactotroph PitNET (n = 8)
Teasdale
[91] 2015		Case report72-year-old maleHeadache, nausea, vomiting, visual disturbances
5 years after the initial presentation: headache, vomiting, visual disturbances, diplopia, 3rd and 6th cranial nerve palsy, epistaxis		 Thyreotroph, gonadotroph PitNET
5 years after the initial presentation: malignant spindle and round-cell tumor
Zhu
[92] 2015		Case-control study2021 patients with pituitary tumors, out of which:
97 cases with PA (70 males and 27 females)
mean age: 50.1 ± 13.9 years (PA), randomly matched with 194 controls		Headache (n = 84, 86.6%)
Visual deterioration (n = 60, 61.86%)
Vomiting (n = 39, 40.21%)
Ptosis (n = 25, 25.77%)
Diplopia (n = 6, 6.18%)		Hypertension
DM
(differences between cases and controls were not statistically significant)		Null (non-functional) PitNET (n = 63)
Lactotroph PitNET (n = 7)
Somatotroph PitNET (n = 8)
Corticotroph PitNET (n = 1)
Thyrotroph PitNET (n = 2)
Gonadotroph PitNET (n = 10)
Others (n = 4)
Multiple staining (n = 2)
Zou
[93] 2015		Case report23-year-old maleHeadache, nausea, decreased visual acuity, loss of consciousness, fever Somatotroph PitNET
Choudhury
[94] 2016		Case report75-year-old maleHeadache, nausea, vomiting, photophobiaAntiplatelet drugPituitary adenoma
Doglietto
[95] 2016		Case report76-year-old femaleHeadache, visual disturbances, ophthalmoplegia, 3rd cranial nerve palsyAnticoagulant therapy (dabigatran)Nonfunctioning pituitary adenoma
Gambaracci
[96] 2016		Case report55-year-old femaleHeadache, decreased visual acuity, fever Pituitary adenoma
Giammattei
[97] 2016		Case series8 male patients mean age: 70 yearsHeadache (n = 7)
Nausea and vomiting (n = 4)
Decreased visual acuity (n = 2)
Ophthalmoplegia (n = 6)
Altered consciousness (n = 1)
Photophobia (n = 1)		Anticoagulant (n = 3)
Antiplatelet (n = 1)
Hypertension (n = 5)
DM (n = 2)
Autoimmune hemolytic anemia with thrombocytopenia (n = 1)		Pituitary adenoma
Giritharan
[98] 2016		Case series31 patients (19 males, 12 females), mean age: 55 yearsHeadache (n = 31, 100%)
Nausea/vomiting (n = 17, 55%)
Visual field defect (n = 18, 58%)
Decrease in visual acuity (n = 7, 23%)
Ocular paresis (n = 12, 39%): 3rd cranial nerve (n = 8, 26%), 6th cranial nerve (n = 6, 19%)		Hypertension (n = 5, 16%)
Oral anticoagulation (n = 3, 10%)
Heparin therapy (n = 1, 3%)
Pregnancy (n = 1, 3%)
Previously known adenoma (n = 1, 3%)		Nonfunctioning adenomas (n = 21, 67.74%)
Somatotroph PitNET (n = 2, 6.45%)
Lactotroph PitNET (n = 1, 3.22% )
Gonadotroph PitNET (n = 5, 16.12%)
Corticotroph PitNET (n = 2, 6.45%)
Keane
[99] 2016		Case report67-year-old maleHeadache, 3rd cranial nerve palsyGnRH agonist for prostate cancerGonadotroph PitNET
Ogawa
[100] 2016		Retrospective study43 patients (30 males and 13 females)
mean age: 56.67 years		Headache
Cranial nerve palsies
Aseptic meningitis
Altered consciousness		 Nonfunctioning pituitary adenoma (n = 29)
Lactosomatotroph PitNET (n = 5)
Lactotroph PitNET (n = 4)
Thyrotroph PitNET (n = 3)
Somatotroph PitNET (n = 1)
Corticotroph PitNET (n = 1)
Paschou
[101] 2016		Case report37-year-old maleHeadache, nausea, fever, visual acuity decrease, 3rd cranial nerve palsy, neck stiffness, confusion Gonadotroph PitNET
Sussman
[102] 2016		Case report46-year-old maleHeadache, dizziness, decrease in visual acuity, syncope, 3rd and 4th cranial nerve palsy, hemiparesisAnti-hypertensive drugsPituitary adenoma
Balaparameswara Rao
[103] 2017		Case report45-year-old maleHeadache, vomiting, altered consciousnessDengue hemorrhagic feverCorticotrophic PitNET
Grangeon
[104] 2017		Case report83-year-old maleHeadache (hemicrania)DMPituitary adenoma
Humphreys
[105] 2017		Prospective study10 patients, out of which 5 patients with PA (2 males and 3 females)
mean age: 46 years		Headache (n = 3)
Visual field defect (n = 1)
Decreased visual acuity (n = 1)
Irregular menses (n = 1)
Hyponatremia (n = 1)
Altered consciousness (n = 1)		 Gonadotroph PitNET (n = 3)
Thyrotroph PitNET (n = 1)
Null cell (n = 1)
Ishigaki
[204] 2017		Case report66-year-old maleDelayed 3rd cranial nerve palsyHead trauma, hypertension,
DM		Nonfunctioning pituitary adenoma
Law-Ye
[106] 2017		Case report29-year-old maleHeadache, progression to comaBodybuilding exercisesPituitary adenoma
Pasha
[107] 2017		Case report35-year-old femaleHeadache, vomiting, 3rd cranial nerve palsy, decrease in vision, acute right side motor deficits and speech impairment Pituitary adenoma
Patra
[108] 2017		Case report36-year-old maleHeadachePolycythemiaSomatotroph PitNET
Rais
[205] 2017		Case report86-year-old femaleFunctional declineHypertension, DMPituitary adenoma
Simsek Bagir
[109] 2017		Case report32-year-old maleHeadache, nausea, vomiting, hiccups, acromegalic features Lactosomatotroph PitNET
Souteiro
[110] 2017		Case report77-year-old femaleHeadache, nausea, vomiting, psychomotor impairment, visual acuity lossHypertension,
2DM		Corticotroph PitNET
Waqar
[111]
2017		Retrospective study47 patients with pituitary apoplexy (33 males and 14 females)
mean age: 54 ± 15 years
- patients were compared with 50 surgically treated patients with nonfunctioning pituitary adenomas		Headache (n = 42)
Nausea/vomiting (n = 25)
Visual field defect (n = 26)
Visual acuity defect (n = 18)
Cranial nerve palsy (n = 19)
Altered consciousness (n = 4)		Hypertension (n = 11)
Anticoagulation-antiplatelet therapy (n = 4)		Pituitary adenoma
Zoli
[112] 2017		Retrospective study75 patients (45 males and 30 females)
mean age: 52.4 ± 16.2 years		Headache (n = 75, 100%)
Anterior hypopituitarism (n = 51, 68%)
Visual disturbances (n = 55, 73.4%)
Ophthalmoplegia (n = 38, 50.7%)
Altered consciousness (n = 2, 2.6%)		 Pituitary adenoma
Abbara
[113] 2018		Retrospective study52 patients (25 males and 27 females)
mean age: 46.7 years		Headache (n = 40/43)
Vomiting (n = 22/43)
3rd cranial nerve palsy only (n = 12/35)
6th cranial nerve palsy only (n = 8/35)
3rd and 6th palsy (n = 3/35)
Decreased visual acuity (n = 14/35)
Visual fields defects (n = 13/35)		Hypertension (n = 17)
Intrapartum/puerperal (n = 7)
DM (n = 4)
Antiplatelet or anticoagulant (n = 3)
Dopamine agonists (n = 2)
Radiotherapy (n = 2)
None (n = 24)		Nonfunctioning adenoma or gonadotroph PitNET (n = 47)
Lactotroph PitNET (n = 5)
Bettag
[114] 2018		Case report75-year-old femaleHeadache, diplopia, decreased consciousness Gonadotroph PitNET
Fan
[115] 2018		Case report79-year-old maleHeadache, decreased vision, diplopia, 3rd cranial nerve palsy Pituitary adenoma
Hodgson
[206] 2018		Case report71-year-old femaleProptosis Lactotroph PitNET
Jang
[207] 2018		Case report41-year-old femaleDiplopia, visual disturbances, 6th cranial nerve palsyChemotherapy (doxorubicin and cyclophosphamide)Pituitary macroadenoma
Joo
[116] 2018		Case report73-year-old maleHeadache, 3rd cranial nerve palsyLumbar fusion surgery in prone positionPituitary macroadenoma
Komshian
[117] 2018		Case report56-year-old maleHeadache, diplopia, 3rd cranial nerve palsy Nonfunctioning pituitary adenoma
Kuzu
[118] 2018		Case report30-year-old maleHeadache, 3rd cranial nerve palsyDexamethasone suppression testCorticotroph PitNET
Myla
[119] 2018		Case report59-year-old maleHeadache, stiff neck, nauseaHypertensionNonfunctioning pituitary macroadenoma
Raj
[208] 2018		Case report18-year-old maleVomiting, adrenal insufficiencyVaricella infection, thrombocytopeniaCorticotroph PitNET
Ricciuti
[120] 2018		Case series17 patients (12 males and 5 females)
mean age: 58.76 years		Headache (n = 5)
Vomiting (n = 4)
3rd cranial nerve palsy (n = 10)
6th cranial nerve palsy (n = 4)
Visual acuity deficit (n = 4)
Neck stiffness (n = 1)		Hypertension (n = 3)
Previous radiation therapy (n = 1)
Rutkowski
[121] 2018		Retrospective study32 patients (21 males and 11 females)
mean age: 49 years		Headache (n = 32, 100%)
Nausea/vomiting (n = 10, 31%)
Encephalopathy (n = 6, 19%)
Nuchal rigidity (n = 4, 12%)
Hypopituitarism (n = 28, 88%)
Decrease in visual acuity (n = 31, 97%)
Cranial nerve palsy (3rd, 4th and/or 6th) (n = 16)		 Nonfunctional adenoma (70%)
Clinically hypersecreting adenoma (15%)
Lactotroph PitNET
Somatotroph PitNET
Corticotroph PitNET
Salehi
[209] 2018		Case report78-year-old maleOphthalmoplegia, 3rd and 4th cranial nerves palsy, altered consciousness Pituitary adenoma
Ward
[210] 2018		Case report63-year-old maleFever, hypotension, tachycardia, altered consciousnessClosed head injuryNonfunctioning pituitary adenoma
Yamada
[122] 2018		Case report50-year-old maleHeadache, visual impairments, loss of consciousness *
Almeida
[123] 2019		Retrospective analysis67 patients (41 males and 26 females)
mean age: 57.4 +/− 16.2 years		Headache (n = 60)
Visual deficit (n = 44)
Hypopituitarism (n = 40)
Cranial nerve palsy (n = 32): 3rd (n = 17), 4th (n = 8), 6th (n = 8)
Altered levels of consciousness (n = 10)		 Pituitary adenoma
Crisman
[124] 2019		Case report43-year-old maleHeadache, cranial nerve palsies (3rd, 4th, and 6th)Endoscopic Retrograde CholangiopancreatographyPituitary adenoma
Dupont
[125] 2019		Case report83-year-old femaleHeadache, bilateral vision lossDual anti-aggregationPituitary adenoma
Ghalaenovi
[126] 2019		Case report28-year-old maleResolution of initial symptoms (headache, nausea, photophobia, bitemporal hemianopia at diagnosis of a pituitary macroadenoma) Lactotroph PitNET
Harju
[127] 2019		Case report48-year-old maleHeadache, diplopia, 3rd cranial nerve palsy, visual field defect, feverEndoscopic endonasal surgeryNon-functional macroadenoma
Hosmann
[128] 2019		Retrospective analysis76 patients (53 males and 23 females)
mean age: 53.7 +/−14.3 years		Headache (n = 63, 82.9%)
Nausea/vomiting (n = 26, 34.2%)
Decrease in visual acuity (n = 42, 54.9%)
Visual field deficit (n = 48, 63.3%)
Cranial nerve palsy: 3rd (n = 35, 46.1%), 6th (n = 22, 28.9%)
Altered levels of consciousness (n = 12, 15.8%)		Hypertension (n = 23, 30.3%)
Oral anticoagulation (n = 14, 18.4%)
DM (n = 9, 11.8%)
Extracranial surgery within 24 h before apoplexy (n = 4, 5.3%)		Clinically nonfunctioning PitNETs (81%): gonadotroph PitNET (37.9%), null-cell (29.3%), plurihormonal (8.6%), corticotroph (3.5%), somatotroph (1.7%)
Clinically functioning PitNETs: lactotroph (10.4%), corticotroph (6.9%), somatotroph (1.7%)
Kirigin Biloš
[129] 2019		Case report74-year-old maleHeadache, nausea, vomiting, vertigo, 3rd cranial nerve palsy Pituitary adenoma
Krug
[130] 2019		Case report45-year-old maleHeadache, diplopia Crooke cell adenoma
Mittal
[131] 2019		Case report38-year-old maleHeadache, nausea, 3rd cranial nerve palsy, visual field deficitsDMNonfunctioning pituitary adenoma
Naito
[132] 2019		Case report14-year-old femaleHeadache, visual impairmentCardiac surgeryPituitary adenoma
Nioi
[133] 2019		Case report50-year-old femaleHeadache, visual impairment, vertigo
Hemodynamic collapse after placement of nasogastric tube		TSS, incorrect placement of nasogastric tubePituitary adenoma
Pedro
[134] 2019		Case report79-year-old maleHeadache, photophobia, vomiting Pituitary adenoma
Santos
[135] 2019		Case report74-year-old femaleHeadache, vomiting, decrease in visual acuity, bitemporal hemianopiaSystemic anticoagulation, DMPituitary adenoma
Sanz-Sapera
[136] 2019		Case report50-year-old maleHeadache, acromegalic features Somatotroph PitNET
Singhal
[137] 2019		Case report65-year-old femaleHeadache, vision loss, rhinorrhea Corticotroph PitNET
Swaid
[138] 2019		Case report65-year-old femaleHeadache, 3rd cranial nerve palsyCoronary angiography, anticoagulation (heparin), 2DM, hypertensionPituitary adenoma
Thomas
[139] 2019		Case report85-year-old maleHeadache, 3rd cranial nerve palsyDengue fever-induced thrombocytopeniaPituitary adenoma
Uneda
[140] 2019		Case report51-year-old maleHeadache, 3rd cranial nerve palsies (ophthalmoplegia)Vardenafil therapyPituitary adenoma
Wang
[141] 2019		Case report21 patients (15 males and 6 females), with a mean age of 50.7 ± 15.0 yearsHeadache (n = 21)
Nausea (n = 15)
Vomiting (n = 14)
Visual disturbances:
visual field defects (n = 17)
decreased visual acuity (n = 17)
Cranial nerves palsies (n = 10)
Electrolyte disturbances (n = 12)
Menstrual disturbances and galactorrhea (n = 4/6)
Fever (n = 3)
Altered consciousness (n = 3)		Hypertension (n = 9)
Coagulation disturbances (n = 9)
Diabetes mellitus (n = 4)
Antiplatelet therapy (n = 1)
Chronic renal insufficiency (n = 1)
Atrial fibrillation (n = 1)
Old myocardial infarction (n = 1)		Nonfunctioning pituitary adenoma (n = 18)
Lactotroph PitNET (n = 2)
Somatotroph PitNET (n = 1)
Waqar
[142] 2019		Case report51-year-old maleHeadache, vomiting, diplopia, 6th cranial nerve palsy Nonfunctioning pituitary adenoma
Ahn
[211] 2020		Case report78-year-old maleStupor, hemiparesisHypertensionPituitary adenoma
Brown
[143] 2020		Case report56-year-old male2 episodes of acute-onset headache, vomiting, and a cranial nerve palsy Switching phenotypes
Catarino
[144] 2020		Case report55-year-old femaleHeadache, 3rd cranial nerve palsyDM,
Pituitary fungal infection		Corticotroph PitNET
Eichberg
[145] 2020		Case report46-year-old femaleHeadache, nausea, vomiting, blurred vision Nonfunctioning pituitary adenoma
Elarjani
[146] 2020		Case report31-year-old maleHeadache, hemiparesis, unilateral decreased visual acuity Pituitary adenoma
Franzese
[147] 2020		Case report60-year-old maleHeadache, nausea, weakness, diplopia, 3rd cranial nerve palsyCoronary artery bypass graftingNull cell adenoma
Klimko
[148] 2020		Case report41-year-old maleHeadache, fatigue, weight loss Somatotroph PitNET
Lee
[149] 2020		Case report75-year-old maleHeadache, vomiting, dizziness, 3rd, 4th, and 5th nerve palsiesHypertension, DM, hemodialysisNonfunctioning pituitary adenoma
Marzoughi
[150] 2020		Case report70-year-old maleHeadache, diplopia, 3rd cranial nerve palsyHypertension, DM, anticoagulantPituitary adenoma
Pangal
[151] 2020		Retrospective study50 patients (31 males, 19 females)
mean age: 53 years		Headache (86%)
Vision loss (62%)
Cranial nerve palsy (40%)
Decrease in consciousness (14%)		 Pituitary adenoma
Patel
[152] 2020		Case report60-year-old maleHeadache, nausea, vomiting, monocular vision lossAutologous hematopoietic cell transplantationSomatotroph PitNET
Romano
[212] 2020		Case report65-year-old maleBlindness, hemiparesis, decreased alertness Pituitary macroadenoma
Shetty
[153] 2020		Case report49-year-old femaleHeadache, palpitations, nausea, vomiting, neck stiffnessRegadenoson myocardial perfusion scanNonfunctioning pituitary adenoma
Siwakoti
[154] 2020		Case report59-year-old femaleHeadache, nausea, dizziness Corticotroph PitNET
van Boven
[155] 2020		Case report31-year-old femaleHeadache, nausea, vomiting2DMCorticotroph PitNET
Yang
[213] 2020		Case report70-year-old femaleConfusion, hypotension, fever, chills, cough Pituitary microadenoma
Alam
[156] 2021		Case report40-year-old maleHeadache
acromegalic feats		 Somatotroph PitNET
Aljabri
[157] 2021		Case report74-year-old maleHeadache and vomiting 2 h after goserelin injection, dizziness, diplopiaAndrogen deprivation therapy (goserelin) for prostate cancerPituitary macroadenoma
Alkhaibary
[214] 2021		Case report65-year-old maleDiplopia, 3rd cranial nerve palsyCoronary bypass graft surgeryPituitary adenoma
Ambrose
[158] 2021		Case report84-year-old maleHeadache, bruising 5 days after admission: bilateral ptosis, ophthalmoplegiaImmune thrombocytopeniaPituitary macroadenoma
Bhogal
[215] 2021		Case report63-year-old maleMyxedema coma Pituitary adenoma
Bukhari
[159] 2021		Case report59-year-old maleHeadache, loss of vision, 3rd cranial nerve palsyHypertensionPituitary adenoma
Cavalli
[160] 2021		Retrospective study30 patients (22 males, 8 females) mean age: 54 yearsVisual disturbance (86.7%)
Headache (96%)
Nausea and vomiting (33.3%)		Hypertension (53.8%)
Invasive procedures (30.7%)
Anticoagulation (23%)
Trauma (7.7%)
Antiplatelet therapy (7.7%)		PitNET
de Silva
[161] 2021		Case report35-year-old femaleHeadache, visual loss
Cushingoid features		 Crooke cell tumor
Elsehety
[216] 2021		Case report60-year-old femaleVision loss, vomiting, coma Nonfunctioning pituitary adenoma
Falhammar
[162] 2021		Retrospective study33 patients (18 male and 15 female)
mean age: 46.5 years		Headache (82%)
Visual disturbances (36%)
Nausea (36%)		Antithrombotic therapy n = 7 (21%)PitNET
Gohil
[163] 2021		Case report56-year-old maleHeadache, diplopia, 3rd cranial nerve palsy during hospitalization for leptospirosisLeptospirosisPituitary adenoma
Hanna
[164] 2021		Case report49-year-old maleHeadache, diplopia, 3rd cranial nerve palsy Nonfunctioning pituitary adenoma
Huang
[165] 2021		Case report72-year-old maleHeadache, nausea, vomiting, 3rd cranial nerve palsy Nonfunctioning pituitary adenoma
Iqbal
[166] 2021		Retrospective study55 patients (26 males and 29 females)
mean age: 50 years		Headache
Confusion
Visual field defect
Cranial nerve palsy		Hypertension
Anticoagulation
Antiplatelet
Previous stroke
Radiotherapy		Somatotroph PitNET
Lactotroph PitNET
Komić
[167] 2021		Case report54-year-old maleHeadache, vomiting, photophobia Pituitary adenoma
Marx
[168] 2021		Retrospective study46 patients (29 males and 17 females)
mean age: 47.3 years		Meningism (n = 20)
Headache (n = 38)
Visual acuity decrease (n = 11)
Visual field defect unilateral impairment bitemporal impairment (n = 20)
Cranial nerve palsies: 3rd (n = 19), 4th (n = 6), 6th (n = 13)
Impaired Glasgow Coma Scale ( < 15) (n = 2)		GnRH analogs (n = 2)
Anticoagulant (n = 1)
Cabergoline (n = 2)
Recent major surgery (n = 3)
Recent rugby play without head trauma (n = 1)
Pregnancy (n = 3)		Nonfunctioning adenoma (n = 31)
Corticotroph PitNET (n = 1)
Lactotroph PitNET (n = 12)
Somatotroph PitNET (n = 1)
Nakhleh
[169] 2021		Retrospective study27 patients (14 males and 13 females)
mean age: 40.7  ±  12.5 years		Headache (n = 25)
Visual field defect (n = 9)
Cranial nerve palsy (n = 3)
Altered consciousness (n = 2)		Hypertension (n = 5)
DM (n = 3)
Antiplatelet therapy (n = 3)		Nonfunctioning pituitary adenoma (n = 21)
Lactotroph PitNET (n = 5)
Somatotroph PitNET (n = 1)
Oudghiri
[170] 2021		Case series4 patients (2 males and 2 females)
mean age: 78.25 years		Headache (n = 2)
Vomiting (n = 2)
Visual disturbance (n = 1)
Cranial nerve palsy (n = 3)		Anticoagulant (n = 2)
Hypertension (n = 1)
DM (n = 1)		Nonfunctioning pituitary adenoma
Pan
[171] 2021		Case report44-year-old maleHeadache, vomiting, dizzinessDiabetic ketoacidosis
Acute pancreatitis
Hypertension		Somatotroph PitNET
Pattankar
[172] 2021		Case report20-year-old femaleHeadache, lethargy, altered sensorium
Progressive neurological deterioration: hemiparesis, unilateral ophthalmoplegia		Diabetic ketoacidosisNonfunctioning pituitary adenoma
Pokhrel
[217] 2021		Case report26-year-old maleVision reduction, retro-orbital pain, dizziness, vomiting, right limbs weakness
Acromegalic features		No apparent triggerSomatotroph PitNET
Rosso
[173] 2021		Case report76-year-old femaleHeadache, 3rd cranial nerve palsy2DM
apixaban		Pituitary adenoma
Seaman
[25] 2021		Retrospective study44 patients (24 males and 20 females)
median age: 55 years		Headache (n = 40)
Visual disturbances (n = 30):
visual field disturbances (n = 16), decreased visual acuity (n = 9), cranial nerve palsies: 3rd (n = 18), 4th (n = 6), 5th (n = 1), 6th (n = 6)
Nausea/vomiting (n = 7)
Altered mental status (n = 7)
Hormone-related complains (n = 4)		Hypertension (n = 22)
DM (n = 13)
Anticoagulation (n = 4)		Nonfunctioning adenoma (n = 38)
Functioning PitNET (n = 6)
Sun Z
[174] 2021		Retrospective study24 patients (13 males and 11 females)
mean age: 46.46  ±  14.95 years		Headache (n  =  20, 83.33%)
Nausea and vomiting (n  =  17, 70.83%)
Loss of vision (n  =  18, 75.00%)
Visual field defects (n = 8, 33.33%)
Ophthalmoplegia attributed mainly to 3rd and 6th cranial nerve palsies (n  =  7, 29.17%)
Decreased libido (n  =  2, 8.33%)
Amenorrhea (n  =  2, 8.33%)
Loss of consciousness (n = 1)		 Nonfunctioning adenomas (n = 7)
Lactotroph PitNET (n = 3)
Corticotroph PitNET (n = 1)
Gonadotroph PitNET (n = 1)
Lactocorticotroph PitNET (n = 1)
Teramoto
[175] 2021		Retrospective study45 patients (33 males and 12 females)
mean age: 56 years		Headache (n = 40)
Visual impairment (n = 18)
Ophthalmoplegia (n = 19)
Hypopituitarism (n = 23)		Hypertension (n = 12)
DM (n = 10)
Antithrombotic therapy (n = 7)		Nonfunctioning adenoma (n = 37)
Somatotroph PitNET (n = 5)
Lactotroph PitNET (n = 3)
Tumyan
[176]
2021		Case report67-year-old maleHeadache, nausea, peripheral vision defect, decreased consciousness
within 48 h; 3rd cranial nerve palsy, progressive confusion		DMPituitary adenoma
Van Dong
[177] 2021		Case report38-year-old femaleHeadache, decreased visual acuity, aphasia, hemiparesis, decreased consciousness Pituitary adenoma
Vargas
[178] 2021		Case report53-year-old femaleHeadache, vomiting, 3rd cranial nerve palsy, progressive neurological deterioration Pituitary macroadenoma
Yoshida
[179] 2021		Case report78-year-old maleHeadache, nausea, hemianopia, collapse Gonadotroph PitNET
Zhu JD
[180] 2021		Case report48-year-old maleHeadache, vomiting, 3rd cranial nerve palsy, decreased vision unilaterally
within 48 h: consciousness disturbance, hemiplegia, hyperthermia		 Nonfunctioning pituitary adenoma
Zhu Q
[181] 2021		Retrospective study46 patients (35 males and 11 females)
mean age: 46.78 ± 12.32		Headache (n = 44)
Visual disturbance (n = 41)
Nausea/vomiting (n = 27)
Hypogonadism (n = 39)
Asymptomatic apoplexy (n = 1)		 PitNET
Cross
[182] 2022		Retrospective study59 patients (40 males and 19 females)
median age: 54 years		Headache (n = 59)
Cranial nerve deficits (n = 46): 3rd cranial nerve palsy (n = 26, 44%), 4th cranial nerve palsy (n = 1), 6th cranial nerve paly (n = 12, 20%)
Vision loss (n = 5)		 PitNET
Geyik
[183] 2022		Retrospective study143 patients with pituitary adenoma, out of which 8 patients with PA (4 males and 4 females, mean age: 26.75 years)Headache (n = 7)
Visual disturbances (n = 4)
Amenorrhea and galactorrhea (n = 4)		 Lactotroph PitNET (n = 5)
Nonfunctioning adenoma (n = 3)
Hamrick
[184] 2022		Case report31-year-old maleHeadache, nausea, vision decrease,Systemic chemotherapy (bleomycin, etoposide, cisplatin)Somato- and corticotroph PitNET
Hsu
[185] 2022		Case report53-year-old maleHeadache, fever, pruritic skin rash, abdominal pain, fatigue Gonadotroph PitNET
Liu
[186] 2022		Case report33-year-old maleHeadache, nausea, vomiting, bitemporal hemianopia, diplopia, 3rd cranial nerve palsy, Cushingoid features Corticotroph PitNET
Mills
[187] 2022		Case report65-year-old femaleHeadache, reduced visual acuity, bitemporal hemianopia Metastatic breast carcinoma into gonadotroph PitNET
Oldfield
[188] 2022		Case report57-year-old maleHeadache, thirst, polydipsia, weakness Pituitary adenoma
Puglisi
[189] 2022		Case report81-year-old femaleHeadache, bilateral vision loss, altered consciousness, hematuriaAnticoagulant (acenocoumarol), hypertensionPitNET
Rai
[190] 2022		Case report64-year-old maleHeadache, nausea, vomiting, decreased visual acuity, ophthalmoplegiaHypertension, DM,
polysubstance abuse		Pituitary macroadenoma
Shrestha
[191] 2022		2 case reports56-year-old maleHeadache, 3rd cranial nerve palsy, diplopia, decrease in visionHypertensionPitNET
50-year-old male3rd cranial nerve palsy (ptosis)
Singh A.
[192] 2022		Case report36-year-old maleChronic headache, sudden diplopia, 6th cranial nerve palsy Somatotroph PitNET
Singh V.
[193] 2022		Case report52-year-old femaleHeadache, visual field changes Nonfunctioning pituitary adenoma
Syed
[194] 2022		Case report36-year-old maleHeadache, diplopia, abducens nerve palsy Pituitary adenoma
Viola
[195] 2022		Case report63-year-old maleHeadache, asthenia, diplopia Pituitary adenoma
* there are some reports where imaging findings did not identify an actual pituitary tumor at the moment of PA confirmation. Of note, due to the changes of terminology during the last decade, we used the type of pituitary tumor according to the original papers unless there were clear criteria for what we currently consider PitNET. Abbreviations: BP = blood pressure; DM = diabetes mellitus; 2 DM = type 2 diabetes mellitus; GnRH = gonadotropin-releasing hormone; T3 = triiodothyronine; PA = pituitary apoplexy; n = number of patients (the name of the original article “study” or “series” was used according to the original publication).
Table 2. Management and outcome in patients PitNET–PA [29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222].
Author (Reference)ManagementOutcome
Brar [29]Transfer to a lower altitude
glucocorticoid replacement		Adrenal insufficiency
Cagnin [30]CResolution of neurological symptoms, hypopituitarism
Chan [31]TSS
Hormonal replacement (postoperative hypopituitarism)		3 years follow-up: remission of the pituitary tumor, regression of Cushingoid features, permanent anterior hypopituitarism and central diabetes insipidus
Chentli [32]C2 months follow-up: visual acuity normalized, spontaneous reduction in pituitary tumor (MRI)
Choudhry [33]TSS (n = 4)
Hormonal replacement (postoperative hypopituitarism)		Postoperatively: vision recovery and biochemical remission of Cushing’s disease (n = 4)
6 months follow-up: regression of cushingoid features (n = 4), weight-loss (n = 4), hypertension remission (n = 3), DM resolution (n = 3), DM improvement (n = 1)
40 months follow-up: biochemical remission and postoperative anterior hypopituitarism (n = 4)
Enatsu [196]TSS3rd cranial nerve palsy improved
Complete removal of the mass (MRI)
Endocrine profile recovery
Komurcu [34]TSS4 months follow-up: complete visual recovery
6 months follow-up: complete tumor removal, no recurrence (CT)
Kruljac [35]TSSExitus 1 month later
Kurisu [36]Craniotomy, evacuation of the hemorrhage, tumor resection through anterior interhemispheric approachExitus within 1 month (PA causing intracerebral hemorrhage)
Liu [37]C3 months follow-up: normal pituitary hormones secretion, complete disappearance of pituitary mass (MRI)
Mohindra [38]Ventriculo-peritoneal shuntExitus within 48 h
Paisley [39]TSS
Glucocorticoid replacement		Visual recovery, partial hypopituitarism
Tedd [40]Glucocorticoid replacement
Verma [41]TSS
Glucocorticoid replacement		Clinical improvement
Wildemberg [42]TSS
Yamamoto [43]TSS
Transient desmopressin replacement		Symptoms resolved postoperatively and vision returned
TSSVisual disturbances resolved + No hormonal deficits
Zoli [44]TSS3 months follow-up: radical tumor removal, resolution of neurological symptoms
Chou [45]TSSResolution of visual disturbances
Cinar [46]TSSRemission of acromegaly
Delgado-Alvarado [47]TSSResolution of ophthalmoplegia
Deshwal [48]Transfer to a lower altitude + CFull recovery
Fanous [49]TSSNear complete resolution of visual disturbances
Haider [50]C (+ Dexamethasone)Complete recovery of 3rd cranial nerve function
Hojo [51]Initial C → TSS following hematoma expansionNo visual disturbances
Huang [52]TSSVision improvement
Jiang [53]CPatient refused further treatment
Kobayashi [54]CRecovery without sequela
Machado [220]C28 months follow-up: clinical remission
Masui [55]TSSAnterior pituitary hormonal deficits, diabetes insipidus
Mir [56]TSS
Glucocorticoid replacement		Remission of DM; normalization of GH levels
Central hypothyroidism, hypogonadism, and hypocortisolism
Mohamed [57]TSSPostoperatively: partial improvement of vision and 3rd cranial nerve palsy
Ní Chróinín [58]CClinical improvement
Oh [59]TSSClinical improvement
Radhiana [60]Craniotomy, decompression, tumor excisionExitus
Steinberg [218]Patient refused surgery
C (Cabergoline)		Tumor size decreased, necrotic zone in the pituitary (MRI)
Uemura [219]C (Glucocorticoid, levothyroxine replacement)Resolution of signs and symptoms
Witczak [62]TSSExitus after 3 months (due to breast cancer)
Wong [63]TSSRecovery of nerve palsies
Zieliński [64]C (Glucocorticoid, levothyroxine replacement)Tumor regression (MRI); resolution of ophthalmic and neurological symptoms
Berkenstock [65]TSSResolution of nerve palsy, persistent visual field defects, panhypopituitarism
Bujawansa [66]Pituitary surgery (n = 33, 55%): early emergency surgery (n = 23), delayed elective surgery (n = 18)
conservative (n = 22, 40%)		Complete resolution of visual field defects (65%)
Partial improvement of visual field defects (85%)
Complete resolution of cranial nerve palsies (n = 23)
Partial resolution of cranial nerve palsies (n = 26)
Anterior pituitary deficits (n = 47, 85.5%)
Central adrenal insufficiency (n = 40, 72.7%)
Central hypothyroidism (29 patients, 52.7%)
Severe growth hormone deficiency (n = 21, 38.2%)
Hypogonadism (n = 27 male patients)
Diabetes insipidus (n = 2)
Chao [67]TSSVisual field improvement
Cho [68]CPartial recovery, no endocrine dysfunctions
Garg [197]TSS
Gupta [69]Coronary artery bypass → TSSResolution of nerve palsy, persistent visual field defects
Jho [70]TSS (n = 101)
C (n = 8)		Resolution of symptoms (n = 48)
Improvement of symptoms (n = 12)
Stationary (n = 1)
Lee [71]TSS
Glucocorticoid replacement, anti-thyroid drugs
Maltby [72]CPanhypopituitarism, empty sella
Man [73]Palliative care, dexamethasone, brain radiotherapy
Mishra [74]TSSVisual improvement
Mura [198]ConservativeHypogonadotrophic hypogonadism
Navarro-Bonnet [75]Fronto-temporoparietal craniectomyPostoperatively: hemiplegia, hormonal substitution (prednisone, levothyroxine), cabergoline treatment
6 months follow-up: amelioration of paralysis, normalized prolactin levels, small residual tumor
Rebeiz [199]TSSNo improvement
Roerink [76]C (Hydrocortisone, levothyroxine, lanreotide, scheduled TSS)3 months follow-up: normalized IGF-1 levels
Tan [77]C (Cabergoline, dexamethasone) → TSS due to visual deteriorationHypopituitarism, persistent visual defects, residual tumor
Villar-Taibo [78]C (Hormonal replacement)Resolution of symptoms, improvement of acromegaly signs and symptoms, hypopituitarism, diabetes insipidus
Yoshida [200]TSS
Hormonal replacement		Hypopituitarism, resolution of hyperthyroidism, with subsequent hypothyroidism
Yoshino [201]C (Glucocorticoid replacement)Resolution of pituitary hemorrhage
Zhang [79]TSS
Hormonal replacement		Symptoms improvement
Akakın [80]TSS
Hormonal replacement		Visual defects improvement, no residual tumor
Asaithambi [81]TSSPostoperatively: bitemporal hemianopia, left and right partial 3rd cranial nerve palsy
Banerjee [82]TSSNo improvement
Fountas [83]TSS
Hormonal replacement		Hypopituitarism
Kasl [202]TSSImprovement of neurological symptoms
Kasl [203]TSSRecovery of symptoms
Kim [84]TSSComplete recovery
Man [85]TSSPartial improvement of 3rd cranial nerve palsy
Roerink [86]C
C → elective TSS
Saberifard [87]CEmpty sella
Sasagawa [88]TSSComplete resolution of nerve palsy
Sasaki [89]C
Singh [90]Surgery during acute stage (n = 61, 70.1%)
Delayed surgery (n = 8, 9.2%)
Conservative (n = 18, 20.7%)		Improvement/complete resolution of visual defects in all survivors
HRT with levothyroxine (62.7%) or cortisol (60%)
Diabetes insipidus at 3-month follow-up (23%)
Tumor regrowth (n = 7, 8.6%)
Exitus (n = 4, 4.6%)
Teasdale [91]TSS
5 years after the initial presentation: sphenoidotomy, radiotherapy		Visual improvement, panhypopituitarism
5 years after the initial presentation: exitus
Zhu [92]TSS (n = 93, 95.88%)
Transcranial surgery (n = 4, 4.12%)		Electrolyte disturbance (n = 18, 18.56%)
Diabetes insipidus (n = 69, 71.13%)
Cerebrospinal rhinorrhea (n = 2, 2.06%)
Postoperative hemorrhage (n = 1, 1.03%)
Postoperative infection (n = 1, 1.03%)
Exitus (n = 1, 1.03%)
Zou [93]SurgeryImprovement of symptoms and radiological findings
Choudhury [94]CConsiderable reduction in pituitary tumor
Doglietto [95]TSSRecovery of nerve palsy, complete removal of pituitary adenoma (MRI)
Gambaracci [96]TSS
Giammattei [97]TSS (n = 8)
Hormonal replacement		Hypopituitarism
Giritharan [98]C (n = 11, 35%)
Surgery (n = 20, 65%)		Hormone deficiency (n = 26, 84%)
Resolution of visual disturbances (n = 18, 72%)
Improvement of visual symptoms (n = 6, 24%)
Keane [99]TSSComplete resolution of symptoms
Ogawa [100]TSS (n = 43)Resolution of neurological symptoms (n = 38)
Persistence of nerve palsy (n = 3)
Prolonged visual problems (n = 1)
Exitus due to leukemia (n = 1)
Paschou [101]TSSResolution of symptoms, central hypothyroidism
Sussman [102]TSS6 weeks follow-up: partial recovery of lower limb paresis, persistence of upper limb paresis, full recovery of 3rd and 4th cranial nerve palsies, partial 6th cranial nerve palsy
Balaparameswara Rao [103]TSSImprovement of vision
Anterior hypopituitarism
Grangeon [104]CHeadache resolution
Humphreys [105]TSS (n = 5)
Radiotherapy (n = 2)		Hypopituitarism treated with HR (n = 4)
Ishigaki [204]TSSResolution of nerve palsy
Law-Ye [106]CFull recovery
Pasha [107]TSSRecovery of neurological deficits
Patra [108]CRemission of acromegaly and polycythemia
Rais [205]C
Simsek Bagir [109]TSSRemission of symptoms, central hypothyroidism and hypogonadism, GH deficiency
Souteiro [110]CResolution of hypercortisolism, disappearance of the tumor (MRI)
Waqar [111]TSS (n = 36)
Conservative (n = 11)		Hypopituitarism (n = 45)
Diabetes insipidus (n = 3)
Zoli [112]TSS (n = 75)Anterior hypopituitarism (n = 15, 20%)
Diabetes insipidus (n = 4, 5.3%)
Ophthalmoplegia resolution/improvement (71%)
Visual symptoms improvement (85.5%)
Conscious regain in both patients
Abbara [113]C (n = 33/52)
Surgery (n = 19/52)		Partial resolution of visual symptoms (n = 19/19)
Full resolution of visual symptoms (n = 5/16)
Hypopituitarism: long-term hypocortisolism (n = 27), hypothyroidism (n = 15)
Diabetes insipidus (n = 2)
Bettag [114]TSSPartial improvement of hemiparesis, persistent visual loss
Fan [115]CComplete resolution of visual disturbances after 6 months
Hodgson [206]Embolization, surgical resectionReduction in pain
Jang [207]TSSImprovement of visual disturbances
Joo [116]TSSFull recovery
Kuzu [118]TSSRecovery of symptoms, panhypopituitarism
Myla [119]TSSHormonal replacement
Raj [208]CRemission of central adrenal insufficiency
Ricciuti [120]Surgery (n = 13)
C (n = 4)		Symptoms resolved in up to 6 months
Hormonal substitution (n = 6)
Residual tumor (n = 6)
Rutkowski [121]Surgery (n = 32, 100%)Improvement of visual symptoms (77%)
Resolution of visual symptoms (38%)
Resolution of oculomotor palsies (81%)
Partial hormone recovery following preoperative hypopituitarism 6 (21%) of 28
Salehi [209]TSSComplete recovery
Ward [210]TSS
Hormonal replacement		Stable vision, improved mental status
Yamada [122]CPanhypopituitarism
Almeida [123]Surgery (n = 49)
C (n = 18)		Last follow-up:
Visual status: worsening (n = 1), stationary (n = 3), partial improvement (n = 12), complete recovery (n = 24)
Cranial nerve palsies: partial improvement (n = 9), complete recovery (n = 17)
Hormonal function: hypothyroidism (n = 3), hypocortisolism (n = 11), panhypopituitarism (n = 27), diabetes insipidus (n = 4)
Crisman [124]TSSResolution of cranial nerve palsy
Dupont [125]TSSSlight regain of vision postoperatively
Ghalaenovi [126]Lost during follow-upThe patient experienced spontaneous resolution of initial symptoms
Harju [127]Craniotomy
Glucocorticoid replacement		Persistent visual defects, anosmia, diabetes insipidus
Hosmann [128]TSS (n = 72, 94.7%)
Surgery with sub-frontal approach (n = 4, 5.3%)		Decreased visual acuity (12.3%)
Visual field deficit (35.4%)
Impaired eye movement (14.1%)
Hormonal replacement (72.3%): hypothyroidism (61.3%), hypocortisolism (52.3%), hypogonadism (29.2%), permanent diabetes insipidus (9.2%), GH deficiency (4.6%)
Kirigin Biloš [129]CImprovement of 3rd cranial nerve deficit, diplopia, panhypopituitarism, partial empty sella
Krug [130]TSSRecovery of symptoms
Mittal [131]C → TSS
Naito [132]CResolution of symptoms
Nioi [133] Exitus
Pedro [134]C
Santos
[135]		CResolution of symptoms, hypopituitarism
Sanz-Sapera [136]C (Hormonal replacement)Acromegaly remission
Singhal [137]TSS
Swaid [138]TSS1 month follow-up: persistence of 3rd cranial nerve palsy
Thomas [139]CFull recovery of ptosis
Uneda [140]TSSImprovement of nerve palsy
Wang [141]TSS (n = 21)Hypopituitarism requiring hormonal replacement (n = 6)
Resolution of visual field defects (n = 13), improvement of visual field defects (n = 4)
Resolution of visual acuity (n = 15), improvement of visual acuity (n = 2)
Recovery of crania nerve palsies (n = 10/10)
Residual tumor (n = 4)
Hemiplegia (n = 1)
Waqar [142]TSSResolution of nerve palsy
Ahn [211]TSSNeurological improvement; resolution of ICA stenosis
Brown [143]TSS
Radiotherapy		Lost to follow-up
Catarino [144]TSSClinical improvement
Eichberg [145]C → TSS 4 years later due to tumor recurrenceResolution of symptoms
No hormonal deficits
Elarjani [146]TSSNeurological improvement
Franzese [147]TSSResolution of symptoms
Klimko [148]TSSRemission of acromegalic features
Lee [149]CGradual improvement of headache and nerve palsies
Marzoughi [150]C due to multiple comorbiditiesResolution of diplopia and 3rd cranial nerve palsy, central hypothyroidism
Pangal [151]TSS (n = 50)Headache improvement (87%)
Vision loss improvement (86%)
Resolution of cranial nerve palsy resolved (72%)
Partial improvement of cranial nerve palsy (11%)
Panhypopituitarism persistence (48%)
Development of panhypopituitarism (6%)
Patel [152]Stress dose corticosteroids, TSSResolution of symptoms, vision improvement
Romano [212]TSSVisual and functional improvement
Shetty [153]TSS
Siwakoti [154]C
van Boven [155]C
Yang [213]C
Alam [156]No specific treatmentAcromegaly remission
Aljabri [157]CTumor regression, restart of goserelin treatment without side effects, hormonal substitution (corticosteroids, levothyroxin)
Alkhaibary [214]CVisual acuity and nerve palsy improvement, hypoadrenalism, hypothyroidism
Ambrose [158]C → surgical decompressionMinor neurological improvement
Bhogal [215]CTumor size reduction
Bukhari [159]Fronto-temporoparietal craniotomy for tumor excisionPanhypopituitarism
Cavalli [160]Conservative n = 20 (66.7%) + 8 patients undergoing delayed elective surgery
Emergency surgery n = 10 (33.3%)
Hormonal replacement n = 28 (93.3%)		Resolution of visual acuity defects in 61%
Resolution of visual field defects in 64%
Resolution of cranial nerve palsies in 69%
Poor endocrine outcomes with various degrees of hypopituitarism
de Silva [161]TSSGradual improvement, normalization of cortisol levels
Elsehety [216]TSSExitus
Falhammar [162]Immediate pituitary surgery n = 3
Delayed pituitary surgery n = 8		Visual defect and nerve palsies improved
Hormonal deficits did not regress
3 deaths of unrelated causes during follow-up
Gohil [163]CResolution of visual disturbances and nerve palsy; regression of adenoma
Persistent hypothyroidism and hypocortisolism
Hanna [164]CResolution of symptoms within 4 days
Huang [165]TSSResolution of visual disturbances and nerve palsy
Hormonal replacement therapy
Iqbal [166]TSS (9/33)Deterioration of pituitary function n = 5
Improvement of pituitary function n = 13
Komić [167]C (Hormonal replacement)Resolution of symptoms after conservative treatment
Marx [168]C (n = 27)
TSS (n = 19)		Resolution of visual acuity defects (n = 10/11)
Resolution of visual field defects (n = 16/17)
Resolution of cranial nerve palsies (n = 21/23)
Hormonal deficits: corticotropic (n = 17), thyrotropin (n = 24), gonadotropic (n = 20), somatotropin (n = 6)
Residual tumor (n = 17)
Tumor recurrence (n = 4)
Nakhleh [169]C (n = 10)
TSS (n = 17)		Corticotropic deficiency (n = 13)
Secondary hypothyroidism (n = 8)
Testosterone replacement therapy (n = 7)
Central diabetes insipidus (n = 4)
Cabergoline treatment (n = 2)
Persistence of visual field defect (n = 2)
Persistence of cranial nerve palsy (n = 2)
Oudghiri [170]C (n = 3)
TSS (n = 1)		Resolution of cranial nerve palsy; hormonal replacement therapy
Pan [171]TSSCentral hypothyroidism and hypocortisolism
Pattankar [172]CLeft hemiparesis
Pokhrel [217]Emergency craniotomy and tumor excisionSignificant improvement of neurological and visual disturbances
Rosso [173]TSSResolution of the nerve palsy
Seaman [25]TSS:
within 24 h (n = 34)
within 24–48 h (n = 3)
after 7 days (n = 7)		All cranial nerve palsies were resolved
Visual field disturbances resolved in 13/16 cases
Visual acuity decrease resolved in 6/9 cases
Hormonal deficits (unresolved/acquired):
hypothyroidism (n = 11)
hypocortisolism (n = 6)
hypogonadism (low testosterone) (n = 3)
panhypopituitarism (n = 11)
transient diabetes insipidus (n = 8)
permanent diabetes insipidus (n = 3)
Sun [174]TSSTotal tumor resection (n = 21, 87.50%)
Headache resolution in all patients
Cranial nerve palsies: full recovery (n = 4); improvement (n = 3)
Vision: returned to normal (n = 14); improvement (n = 3); stationary (n = 1)
Resolution of hormonal deficits (n = 5)
Teramoto [175]TSS
Tumyan [176]TSSSignificant improvement of neurological and visual symptoms
Hormonal replacement therapy
Van Dong [177]TSSNo residual tumor; transient central adrenal insufficiency
Improvement of visual and neurological symptoms
Vargas [178] Condition worsened, family withdrew care
Yoshida [179]TSSResidual tumor (MRI); visual acuity improvement
Zhu [180]TSSResolution of neurological symptoms; persistence of visual disturbances
Zhu [181]TSS (n = 45)
C (n = 1)		Decrease visual acuity (n = 7)
Visual field deficit (n = 3)
Resolution of all ocular palsy
Endocrine dysfunction:
hypocortisolism (n = 26)
hypothyroidism (n = 19)
hypogonadism (n = 24)
Cross [182]TSSCranial nerve palsies: resolution (72%), improvement without resolution (16%)
Diabetes insipidus (n = 5)
Exitus due to heparin induced thrombocytopenia (n = 1)
Geyik [183]TSS
Hamrick [184]TSSResolution of visual disturbances, central hypothyroidism
Hsu [185]TSSHypopituitarism; hormone replacement therapy
Liu [186]TSSRemission of hypercortisolism, hypopituitarism, HRT
Mills [187]TSS12 days postoperatively: exitus due to sepsis
Oldfield [188]CNo residual tumor (MRI after 5 months)
Puglisi [189]C
Rai [190]TSSImprovement of visual symptoms
Shrestha [191]TSSResolution of nerve palsy, residual tumor
Singh [192]TSSResolution of 6th cranial nerve palsy; normal IGF-1 levels
Singh [193]TSSRemission of panhypopituitarism, normalization of visual field
Syed [194]CResolution of pituitary adenoma and abducens palsy
Viola [195]CPanhypopituitarism requiring hormonal replacement; resolution of ophthalmologic and neurologic symptoms
Abbreviations: C = conservative approach; CT = computed tomography; DM = diabetes mellitus; GH = growth hormone; IGF-1 = insulin-like growth factors; MRI = magnetic resonance imaging; PA = pituitary apoplexy; TSS = transsphenoidal surgery.
Table
Table 3. Retrospective studies with minimum 10 patients confirmed with PA/study according to our methodology [25,66,70,90,100,111,112,113,120,121,123,128,141,151,160,162,166,168,169,174,181,182,183].
Table 3. Retrospective studies with minimum 10 patients confirmed with PA/study according to our methodology [25,66,70,90,100,111,112,113,120,121,123,128,141,151,160,162,166,168,169,174,181,182,183].
Author
Reference Number/
Year of Publication		PopulationUnderlying Pituitary Condition
Bujawansa
[66] 2014		55 patients
(35 males and 20 females)
Mean age: 58.4 years		Nonfunctioning pituitary adenomas in 45 cases (82%), lactotroph PitNETs in 6 cases (11.5%), somatotroph PitNETs in 4 cases (7.2%), multiple endocrine neoplasia syndrome in 2 cases
Jho
[70] 2014		109 patients (69 males and 40 females)
mean age: 51 years		PitNET (n = 98)
Rathke’s cyst (n = 8)
Primitive neuroectodermal tumor (n = 1)
Craniofaringioma (n = 1)
Metastatic lung carcinoma (n = 1)
Singh
[90] 2015		87 patients (55 males and 30 females)
mean age: 50.9 years		Null cell (n = 18)
Lactotroph PitNET (n = 8)
Ogawa
[100] 2016		43 patients (30 males and 13 females)
mean age: 56.67 years		Nonfunctioning pituitary adenoma (n = 29)
Lactosomatotroph PitNET (n = 5)
Lactotroph PitNET (n = 4)
Thyrotroph PitNET (n = 3)
Somatotroph PitNET (n = 1)
Corticotroph PitNET (n = 1)
Waqar
[111]
2017		47 patients with pituitary apoplexy (33 males and 14 females)
mean age: 54 ± 15 years
Patients were compared with 50 surgically treated patients with nonfunctioning pituitary adenomas		Pituitary adenoma
Zoli
[112] 2017		75 patients (45 males and 30 females)
mean age: 52.4 ± 16.2 years		Pituitary adenoma
Abbara
[113] 2018		52 patients (25 males and 27 females)
mean age: 46.7 years		Nonfunctioning adenoma or gonadotroph PitNET (n = 47)
Lactotroph PitNET (n = 5)
Ricciuti
[120] 2018		17 patients (12 males and 5 females)
mean age: 58.76 years
Rutkowski
[121] 2018		32 patients (21 males and 11 females)
mean age: 49 years		Nonfunctional adenoma (70%)
Clinically hypersecreting adenoma (15%)
Lactotroph PitNET
Somatotroph PitNET
Corticotroph PitNET
Almeida
[123] 2019		67 patients (41 males and 26 females)
mean age: 57.4 +/− 16.2 years		Pituitary adenoma
Hosmann
[128] 2019		76 patients (53 males and 23 females)
mean age: 53.7 +/-14.3 years		Clinically nonfunctioning PitNETs (81%): gonadotroph PitNET (37.9%), null-cell (29.3%), plurihormonal (8.6%), corticotroph (3.5%), somatotroph (1.7%)
Clinically functioning PitNETs: lactotroph (10.4%), corticotroph (6.9%), somatotroph (1.7%)
Wang
[141] 2019		21 patients (15 males and 6 females), with a mean age of 50.7 ± 15.0 yearsNonfunctioning pituitary adenoma (n = 18)
Lactotroph PitNET (n = 2)
Somatotroph PitNET (n = 1)
Pangal
[151] 2020		50 patients (31 males, 19 females)
mean age: 53 years		Pituitary adenoma
Cavalli
[160] 2021		30 patients (22 males, 8 females) mean age: 54 yearsPitNET
Falhammar
[162] 2021		33 patients (18 male and 15 female)
mean age: 46.5 years		PitNET
Iqbal
[166] 2021		55 patients (26 males and 29 females)
mean age: 50 years		Somatotroph PitNET
Lactotroph PitNET
Marx
[168] 2021		46 patients (29 males and 17 females)
mean age: 47.3 years		Nonfunctioning adenoma (n = 31)
Corticotroph PitNET (n = 1)
Lactotroph PitNET (n = 12)
Somatotroph PitNET (n = 1)
Nakhleh
[169] 2021		27 patients (14 males and 13 females)
mean age: 40.7  ±  12.5 years		Nonfunctioning pituitary adenoma (n = 21)
Lactotroph PitNET (n = 5)
Somatotroph PitNET (n = 1)
Seaman
[25] 2021		44 patients (24 males and 20 females)
median age: 55 years		Nonfunctioning adenoma (n = 38)
Functioning PitNET (n = 6)
Sun Z
[174] 2021		24 patients (13 males and 11 females)
mean age: 46.46  ±  14.95 years		Nonfunctioning adenomas (n = 7)
Lactotroph PitNET (n = 3)
Corticotroph PitNET (n = 1)
Gondadotroph PitNET (n = 1)
Lactocorticotroph PitNET (n = 1)
Teramoto
[175] 2021		45 patients (33 males and 12 females)
mean age: 56 years		Nonfunctioning adenoma (n = 37)
Somatotroph PitNET (n = 5)
Lactotroph PitNET (n = 3)
Zhu Q
[181] 2021		46 patients (35 males and 11 females)
mean age:46.78 ± 12.32		PitNET
Cross
[182] 2022		59 patients (40 males and 19 females)
median age: 54 years		PitNET
Geyik
[183] 2022		143 patients with pituitary adenoma, out of which 8 patients with PA (4 males and 4 females, mean age: 26.75 years)Lactotroph PitNET (n = 5)
Nonfunctioning adenoma (n = 3)
Abbreviations: PitNET = pituitary neuroendocrine tumor; PA = pituitary apoplexy; n = number of patients.
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MDPI and ACS Style

Gheorghe, A.-M.; Trandafir, A.I.; Ionovici, N.; Carsote, M.; Nistor, C.; Popa, F.L.; Stanciu, M. Pituitary Apoplexy in Patients with Pituitary Neuroendocrine Tumors (PitNET). Biomedicines 2023, 11, 680. https://doi.org/10.3390/biomedicines11030680

AMA Style

Gheorghe A-M, Trandafir AI, Ionovici N, Carsote M, Nistor C, Popa FL, Stanciu M. Pituitary Apoplexy in Patients with Pituitary Neuroendocrine Tumors (PitNET). Biomedicines. 2023; 11(3):680. https://doi.org/10.3390/biomedicines11030680

Chicago/Turabian Style

Gheorghe, Ana-Maria, Alexandra Ioana Trandafir, Nina Ionovici, Mara Carsote, Claudiu Nistor, Florina Ligia Popa, and Mihaela Stanciu. 2023. "Pituitary Apoplexy in Patients with Pituitary Neuroendocrine Tumors (PitNET)" Biomedicines 11, no. 3: 680. https://doi.org/10.3390/biomedicines11030680

APA Style

Gheorghe, A. -M., Trandafir, A. I., Ionovici, N., Carsote, M., Nistor, C., Popa, F. L., & Stanciu, M. (2023). Pituitary Apoplexy in Patients with Pituitary Neuroendocrine Tumors (PitNET). Biomedicines, 11(3), 680. https://doi.org/10.3390/biomedicines11030680

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