Novel Insights from Clinical Practice Pediatr Neurosurg DOI: 10.1159/000503112 Received: May 3, 2019 Accepted after revision: September 3, 2019 Published online: October 21, 2019 Rathke’s Cleft Cyst Apoplexy in Two Teenage Sisters Jaime Martinez Santos a Madison Hannay b Adriana Olar b Ramin Eskandari a a Department of Neurosurgery, Medical University of South Carolina (MUSC), Charleston, SC, USA; b Department of Pathology, Medical University of South Carolina (MUSC), Charleston, SC, USA Established Facts • Headache is the most common presentation of Rathke’s cleft cysts. • Symptomatic Rathke’s cleft cysts are treated with surgery. Novel Insights • Rathke’s cleft cysts can present acutely with a sellar compressive syndrome due to an intracystic overproduction of mucopolysaccharides (with or without hemorrhage). • Spontaneous spillage of the cyst content triggers an inflammatory response that could cause meningitis and even seizures. • Rathke’s cleft cysts can be encountered incidentally in family members or may have a familiar predisposition. Since both sisters presented here developed apoplexy symptoms, we recommend a more frequent follow-up with sequential imaging in patients with a family history of Rathke’s cleft cysts. Abstract Rathke’s cleft cysts (RCC) are sellar-suprasellar cysts that are usually discovered incidentally given their indolent clinical course. When symptoms do arise, the most common clinical presentation is headache, visual field deficits due to visual pathway compression, diplopia due to cavernous sinus compression, chemical meningitis due to spillage of the cyst contents, endocrine dysfunction, and very rarely apoplexy. We present 2 cases of RCC in sisters who developed a sudden © 2019 S. Karger AG, Basel E-Mail karger@karger.com www.karger.com/pne onset of symptoms in a manner similar to pituitary apoplexy. Interestingly, one of them had a very unusual presentation with seizure. We hypothesize that acute symptoms occur due to aggressive intracystic overproduction of mucopolysaccharides (with or without hemorrhage) and a resulting compressive syndrome or local irritation of surrounding structures by spillage of the cyst contents. RCC can be encountered incidentally in family members or may have a familiar predisposition. Since both sisters presented here developed apoplexy symptoms, we propose a more frequent follow-up with sequential imaging in patients with a family history of RCC. Transsphenoidal surgery with evacuation of the cyst contents is the treatment modality of choice, with excellent outcomes. © 2019 S. Karger AG, Basel Ramin Eskandari, MD Department of Neurosurgery, Medical University of South Carolina (MUSC) 96 Jonathan Lucas St. Charleston, SC 29425 (USA) E-Mail Eskandar @ musc.edu Downloaded by: UCSF Library & CKM 132.174.255.215 - 10/24/2019 9:45:32 PM Keywords Rathke’s cleft cyst · Rathke’s pouch cyst · Pituitary tumor · Pituitary apoplexy · Rathke’s cleft cyst apoplexy · Rathke’s pouch cyst apoplexy Introduction Rathke’s cleft cysts (RCC) are sellar-suprasellar cysts that are usually discovered incidentally given their indolent clinical course. When symptoms do arise, the most common clinical presentation of these benign lesions is headache, visual field deficits due to visual pathway compression, diplopia due to cavernous sinus compression, chemical meningitis due to spillage of the cyst contents, endocrine dysfunction, and very rarely apoplexy. We present 2 cases of RCC in sisters who developed a sudden onset of symptoms in a manner similar to pituitary apoplexy. Interestingly, one of them had a very unusual presentation with seizure. The clinical, pathological, and radiologic features of RCC apoplexy are reviewed. Neither subject had a hereditary or acquired coagulopathy. remained stable for 5 years on sequential MRI. She did not have any endocrine or ophthalmological dysfunction or complaints. At 17 years of age, she developed an acute onset of headache, and MRI (Fig. 3c, d) showed that the RCC was significantly enlarged (measuring 16 mm at the largest diameter). Additionally, there were mixed T1 intensities within the cyst suggestive of hemorrhage as well as significant proximity with the optic chiasm but no neural compression. Giving her acute presentation, radiological evidence of cyst enlargement, and possible hemorrhage, she was taken emergently for endonasal endoscopic transsphenoidal decompression, cyst fenestration, and evacuation of cyst contents. Once the pituitary gland was opened sharply, a white-colored very thick proteinaceous fluid was drained out under pressure without evidence of obvious blood products. Postoperatively, neuroimaging (Fig. 3d, e) showed proper sellar decompression with preservation of the pituitary stalk and she had a full recovery without neurologic deficits and with resolution of her headaches. Curiously, she was seizure free for 7 months and overall her seizure frequency diminished significantly, although she continued taking clonazepam and lamotrigine. Case 1 Case 2 The second case is a 17-year-old sister of the previous patient. Her medical history was significant for anxiety, obsessive-compulsive disorder, migraine headache, and childhood complex febrile seizures. She was seizure-free up to age 12 years when her seizure semiology and frequency changed dramatically. New episodes were triggered by postural changes occurring up to 50 times a day. Subjective reports were of a feeling of warmth, a racing heart, dizziness, lightheadedness, and sometimes stiffness, with abnormal muscle contractions. When these episodes escalated to a cluster of generalized tonic-clonic events with abnormal electroencephalography “spike and wave” discharges, a new brain MRI was obtained (Fig. 3a, b). Incidentally noted on these epilepsy images was a 7-mm RCC, which 2 Pediatr Neurosurg DOI: 10.1159/000503112 Discussion RCC are epithelium-lined sellar and suprasellar lesions derived from remnants of an ectodermal evagination of the primitive oral cavity (stomodeum) known as Rathke’s cleft or pouch [1]. The anterior wall of Rathke’s pouch forms the pars distalis and the tuberalis and the posterior wall forms the pars intermedia of the adenohypophysis. Rathke’s cleft is a slit-like virtual space between the pars distalis and the pars tuberalis of the pituitary gland. This virtual space can accumulate mucoid material rich in cholesterol and protein, thus forming RCC. Epidemiology and Natural History Largely asymptomatic, RCC represent less than 1% of the intracranial masses seen in clinical practice [2] and 10% of surgical sellar and suprasellar masses [3]. On the other hand, autopsy studies have found RCC in 4–33% of normal pituitary glands [4]. The mean age at presentation is 40 years [5] and the female-to-male ratio is 3:1. Their natural history has not been fully elucidated, but RCC tend to remain stable in size for many years. In a study by Sanno et al. [4], only 5.3% of the subjects showed an increased size at follow-up (mean follow-up: 26.9 years). There are no previous reports of a familial association or genetic predisposition. Clinical Presentation The most common clinical presentation of RCC is chronic headache [2, 6–8] in a neurologically intact paMartinez Santos/Hannay/Olar/Eskandari Downloaded by: UCSF Library & CKM 132.174.255.215 - 10/24/2019 9:45:32 PM The first case is a 13-year-old female, with an unremarkable past medical history and normal menses, who presented to the emergency department with a sudden onset of headache, nausea, and peripheral vision loss. Her neurological exam revealed incomplete bitemporal hemianopsia with intact visual acuity. MRI with and without contrast (Fig. 1a, b) demonstrated a T1 hyperintense sellar lesion at the pars intermedia of the pituitary gland. Neuroimaging characteristics were highly suggestive of hemorrhagic pituitary adenoma or a hemorrhagic RCC. Her endocrine function and plasma electrolytes were normal. Because of her presenting neurological deficits and imaging findings, she underwent emergent endonasal endoscopic transsphenoidal decompression of the sellar/suprasellar spaces and fenestration of the hemorrhagic cystic mass. Upon opening the sellar floor dura, a white-colored, very thick, proteinaceous fluid mixed with a browncolored liquid consistent with remote hemorrhage blood products was drained under high pressure. A piece of the hemorrhagic lesion’s capsule was sent for histopathology (Fig. 2) which confirmed the diagnosis of RCC. She did well postoperatively (Fig. 1c, d) with immediate resolution of her visual field deficit. b c d Fig. 1. MRI of our first case. a Preoperative sagittal MRI without contrast showing a T1 hyperintense RCC with suprasellar extension. The normal isointense pituitary gland (arrow) is displaced antero-inferiorly and the neurohypophysis (arrowhead) is displaced posteriorly. b Preoperative coronal MRI with gadolinium contrast showing the RCC compressing (arrow) the left optic nerve. c Immediate postoperative sagittal MRI without contrast showing complete drainage of the RCC. Note how the normal pituitary assumed its original position on the floor of the sella turcica. d Immediate postoperative coronal MRI with gadolinium contrast showing complete resection and a preserved pituitary stalk (arrow). tient. Episodic frontal headache could also occur due to an intermittent inflammatory reaction to the mucinous material [9]. Occasionally, symptoms occur due to compression of the surrounding neural structures, such as the optic chiasm superiorly (blurred vision and temporal hemianopsia), cranial nerves of the cavernous sinus laterally (diplopia), or the brainstem posteriorly. Spillage of the cyst contents could cause chemical meningitis presenting as afebrile nausea, vomiting, and meningismus [10]. Compression of the pituitary gland and the hypothalamus could result in endocrinological dysfunction, most commonly amenorrhea [11], but also hyperprolactinemia from the stalk effect (38%), hypothyroidism (21%), and diabetes insipidus (13%) [3]. In extremely rare occasions, symptoms can present abruptly in a manner similar to pituitary apoplexy. Apoplexy, from the ancient Greek word apoplexia meaning “sudden strike,” refers to a sudden episode of neurological dysfunction. Historically, apoplexy had described sudden death preceded by a loss of consciousness. Pituitary apoplexy is an uncommon syndrome seen in only 0.4–16% of pituitary adenomas. Its presentation is almost exclusively in pituitary adenomas and more commonly in actively hormone-secreting pituitary tumors [8, 12]. The pathophysiology for the rapid clinical manifestations includes a sudden increase in intrasellar pressure RCC Apoplexy in Two Teenage Sisters Pediatr Neurosurg DOI: 10.1159/000503112 3 Downloaded by: UCSF Library & CKM 132.174.255.215 - 10/24/2019 9:45:32 PM a b c Fig. 2. Histopathology of our first case. a Stripped ciliated cuboidal epithelium with underlying eosinophilic cyst contents. Hematoxylin and eosin. ×400. b Ciliated epithelium with goblet cells and admixed red blood cells. Hematoxylin and eosin. ×400. c Ciliated epithelium with goblet cells and background acellular mucin. Hematoxylin and eosin. ×400. 4 Pediatr Neurosurg DOI: 10.1159/000503112 due to hemorrhage with compression of the normal pituitary gland and the portal system leading to hypopituitarism – particularly adrenal insufficiency [13]. A sudden increase in intrasellar contents can also lead to compression of the adjacent neurovascular structures, especially the optic chiasm, causing acute peripheral (or total) vision loss [5, 6–8, 14]. To understand the pathophysiology of pituitary tumor apoplexy, it is necessary to study the vascular supply to the gland. The pituitary gland derives its vascularity from both the hypophyseal portal venous system, via long hypothalamic portal veins that start and end in capillaries, and the superior and the inferior hypophyseal arteries [15]. The superior hypophyseal artery descends along the pituitary stalk into the anterior portion of the pituitary gland [15]. Pituitary tumors such as adenomas, on the other hand, receive their blood supply solely from direct arterial feeders rather than the portal system [12]. In addition, these tumors have a diminished angiogenesis [13]. Ischemia and necrosis occur when metabolically active pituitary adenomas outgrow their direct blood supply or due to superior hypophyseal artery compression by an expanding adenoma against the diaphragm sellae. Hemorrhage occurs from incompletely matured terminal fragile arterioles with a fenestrated endothelium, ruptured basement membranes, and often incompletely formed muscular layers. Hemorrhage and ischemia also occur from sudden drops in systemic blood pressure, the Valsalva maneuver, or hypoglycemia. RCC apoplexy is an extremely rare phenomenon and very few cases have been reported in the literature [6–8, 11, 16, 17]. Possible explanations for the sudden onset of symptoms include hemorrhage within the cyst itself or a rapid volume increase from mucopolysaccharide overproduction. The clinical presentation is identical to that of pituitary tumor apoplexy. A sudden severe headache is almost universally present in these patients, but they also present with nausea, visual field deficits, cranial nerve palsies, endocrine disturbances including diabetes insipidus or hypopituitarism [7], an altered mental status, meningitis [10], acute monocular blindness due to optic nerve ischemia [6], or even a large middle cerebral artery stroke [7]. Though quite rare, one report describes a patient with pituitary tumor apoplexy who developed an altered mental status and possibly status epilepticus [18]; however, there is no documentation of clinical seizure or electroencephalographic confirmation because these patients are commonly taken emergently for surgical decompression of the pituitary gland. Although no reports in the Martinez Santos/Hannay/Olar/Eskandari Downloaded by: UCSF Library & CKM 132.174.255.215 - 10/24/2019 9:45:32 PM Color version available online a b c d e f Fig. 3. Brain MRI of our second case. a, b The initial (preoperative) significant enlargement of the RCC and increased T1 hyperintensity when compared with a. e, f Postoperative brain MRI showing proper sella turcica decompression and preservation of the pituitary stalk (arrow). RCC Apoplexy in Two Teenage Sisters Pediatr Neurosurg DOI: 10.1159/000503112 brain MRI of our second case showing a T1 isointense RCC with suprasellar extension. c, d. Brain MRI of the same patient 5 years later upon presentation with an acute onset of headache showing 5 Downloaded by: UCSF Library & CKM 132.174.255.215 - 10/24/2019 9:45:32 PM a 6 Pediatr Neurosurg DOI: 10.1159/000503112 ache and deep ophthalmic pain secondary to RCC apoplexy. That patient also had resolution of symptoms and preserved endocrine function postoperatively. Neuroimaging Brain imaging typically begins with CT scans secondary to the sudden nature of presenting signs and symptoms. In most cases this rules out more ominous diagnoses such as aneurysmal subarachnoid hemorrhage, which could have a similar clinical presentation. In cases of pituitary apoplexy, a head CT shows intrasellar hyperdensity, but this study alone is insufficient and the clinician should keep in mind that the most common hyperdense sellar lesions are meningiomas and aneurysms [17]. Seventy percent of RCC are both intrasellar and suprasellar and like pituitary adenomas can cause bony remodeling, enlargement of the sella, or both in 80% of cases [2]. In order to better characterize these lesions, contrast-enhanced MRI is preferred to further define the lesion’s relationship with nearby critical structures for surgical planning. RCC are noncalcified and nonenhancing T1 hyperintense and usually T2 hyperintense (in 70%) lesions that often have an intracystic void with cerebrospinal fluid signal characteristics [22]. These lesions tend to be oval shaped and displace the pituitary gland inferiorly – having an “egg-in-acup” appearance on sagittal T2-weighted MRI [23]. In cases of RCC apoplexy with hemorrhage, serial MRI shows an expanding mass with a mixed T1 and T2 signal intensity, depending on the age of the hemorrhage [5, 7, 8, 9, 16]. There is also a noticeable increase in T1 intensity [5], useful if there is prior imaging of the patient for comparison. The most sensitive sequence for detecting hemorrhage is gradient echo [17]. Similar to cases of pituitary apoplexy, thickening of the sphenoid mucosa has also been described [17]. Cerebral angiograms show a hypovascular mass [20]. Treatment Surgery is indicated in patients with new or worsening acute pressure symptoms, especially if there is optic apparatus compression. Goals of surgery are rapid decompression of the optic chiasm to protect vision and the sella to preserve pituitary function, and diagnosis of possible pituitary adenoma or RCC. These lesions can be approached through traditional craniotomy or transnasally through the sphenoid sinus using a microscope or an endoscope. An open approach (pterional, orbitozygomatic, subfrontal, or eyebrow) is sometimes used in tumors with significant suprasellar extension, extension lateral toward the optic nerve, third ventricular extension, and those well above the optic chiasm in which an endonasal resection is more chalMartinez Santos/Hannay/Olar/Eskandari Downloaded by: UCSF Library & CKM 132.174.255.215 - 10/24/2019 9:45:32 PM literature document RCC presenting with seizures, one of our patients had febrile seizures during infancy and later developed a seizure disorder diagnosed as complex febrile seizures in the absence of a clear etiology. At first, we were hesitant to consider her incidentally discovered RCC to be a risk factor for progressive seizures. In this case however, an increased seizure frequency coincided with the growth of the RCC. Additionally, her seizures had an interesting autonomic component: tachycardia, sweating, and a feeling of warmth, among others. We think that these symptoms could be explained by intermittent hypothalamic irritation due to the cyst contents or due to direct compression, especially in the face of progressive cyst growth. Unlike patients with pituitary macroadenomas, patients with RCC apoplexy rarely develop endocrine dysfunction [6, 8, 17, 19] other than a mildly elevated prolactin from a stalk effect [7]. In the series of RCC apoplexy in the study of Chaiban et al. [5], only 4 out of 11 patients demonstrated abnormal hypothalamic-pituitary-adrenal function at presentation. Hypogonadism and hypothyroidism were the most common and all but one patient recovered postoperatively. The exact mechanism of RCC apoplexy with hemorrhage into RCC is not clear, but several hypotheses exist. One explanation is accumulation of blood products from repeated minor hemorrhage from thin blood vessels in the cyst wall [20]. Another possibility is bleeding from the hypophyseal portal venous system by compression or shear stress [7]. Some hypotheses allude to the fragility of the cyst’s wall single-layer epithelium to minimal arterial pressure variations [5]. Others propose that the origin of hemorrhage is from thin-walled blood vessels in the inflammatory granulation tissue formed in RCC [21]. We would add that in patients with RCC apoplexy there is an accelerated overproduction of mucopolysaccharides that could lead to an acute compressive syndrome with or without minor intracystic hemorrhage, supporting the idea of a nonhemorrhagic RCC apoplexy as in our second aforementioned case [16]. No cases in the literature determined an inciting predisposing factor such as trauma, anticoagulation, bromocriptine treatment, radiation, or cardiovascular surgery, with wide fluctuations in systemic blood pressure [5]. Pediatric RCC apoplexy is even less widely reported. Bohnstedt et al. [6] presented a 16-year-old female with rapidly progressing monocular blindness who recovered completely after surgical decompression and drainage of previously undiagnosed RCC. Kurisaka et al. [20] presented an 8-year-old female with a sudden onset of head- lenging. The preferred route, however, is with an endonasal endoscopic transsphenoidal approach. Overall, a large majority of these lesions are easily accessible via this route. Upon opening the basal dura and pituitary gland, a mixture of mucinous material and hemorrhagic fluid [6, 7, 11, 17] usually delivers under pressure. In some cases, blood is not readily evident and yellow-tinged fragments (cholesterol crystals) are encountered instead [9, 8, 16]. The goal of surgery is sellar decompression by evacuating the cyst contents and not necessarily removal of the cyst wall given the potential for pituitary dysfunction. The outcomes of surgery are generally excellent even with incomplete cyst aspiration [5, 20]. Thorough cyst curettage with marsupialization is usually safe and recommended to prevent cyst recurrence and rehemorrhage [20]. In most cases, the preoperative endocrine disturbance resolved after surgery [7, 9], but in some reports patients with preoperative panhypopituitarism required longterm hormone replacement [9]. The recurrence of RCC after surgical resection is very rare. Ross et al. [19] followed patients long term (mean follow-up of 62 months) and only 1 out of 43 showed recurrence. Histopathology RCC are lined by cuboidal or columnar epithelium with goblet cells and cilia often noted at high-power magnification (Fig. 2). Lining cells may be seen adjacent to normal pituitary tissue as RCC occur at the junction of the anterior and posterior pituitary gland. Strips of cystlining cells stain positively for cytokeratin markers such as CK7 and CAM 5.2. Cyst contents are composed of eosinophilic, acellular mucinous material resembling col- loid. Squamous metaplasia can be a prominent feature and has been associated with an increased likelihood of cyst recurrence [24]. Though uncommon, xanthogranulomatous changes including cholesterol clefts, macrophages, and infiltrating lymphocytes can occur [11]. Conclusions Patients with RCC can present with a sudden onset of symptoms in a manner similar to pituitary tumor apoplexy. We hypothesize that acute symptoms occur from aggressive intracystic overproduction of mucopolysaccharides (with or without hemorrhage) and a resulting compressive syndrome or local irritation of surrounding structures by spillage of cyst contents. RCC can be encountered incidentally in family members or may have a familiar predisposition. Since both of the sisters presented here developed apoplexy symptoms, we propose a more frequent follow-up with sequential imaging in patients with a family history of RCC. Transsphenoidal surgery with evacuation of cyst contents is the treatment modality of choice, with excellent outcomes. Statement of Ethics The patients presented in this paper and their parents provided informed consent for this publication. Disclosure Statement The authors declare no conflict of interests. References RCC Apoplexy in Two Teenage Sisters 6 Bohnstedt BN, Patel NB, Hagen MC, Fulkerson DH. Acute, monocular vision loss from Rathke’s cleft cyst. J Clin Neurosci. 2012 Jun;19(6):904–6. 7 Ohnishi Y, Fujimoto Y, Iwatsuki K, Yoshimine T. A Case of apoplexy of Rathke’s cleft cyst followed by cerebral infarction. Case Rep Neurol Med. 2015;2015:645370. 8 Yang CX, Feng M, Liu XH, Bao XJ, Deng K, Yao Y, et al. Symptomatic Rathke’s Cleft Cyst with Rapid Enlargement Masquerading as Rathke’s Cleft Cyst Apoplexy. Chin Med J (Engl). 2016 Aug;129(16):2009–10. 9 Kim E. A Rathke’s Cleft Cyst Presenting with Apoplexy. 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