ICAR: endoscopic skull‐base surgery

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Outcome after transsphenoidal surgery for pituitary adenoma : The 2000-2010 Helsinki University Hospital Cohort

Pituitary adenomas are the most common tumors of the sella turcica. Our objectives here were to describe the transitional phase from microscopic to endoscopic surgery for nonfunctional pituitary adenomas (NFPAs), and to outline the health-related quality of life (HRQoL) and its determinants after treatment of different pituitary adenomas in a recent cohort from a single pituitary center. We retrospectively collected the relevant data for a total of 320 patients who had undergone primary surgery for a newly diagnosed pituitary adenoma during 2000-2010 at Helsinki University Hospital. The first part of our study included 185 consecutive patients who had transsphenoidal surgery for NFPA. These patients were divided into two groups based on the surgical approach: microscopic and endoscopic. Surgical and endocrinological outcomes were assessed at the 3-month follow-up. The second part of our study used a cross-sectional design and comprised all pituitary adenoma types. Each patient alive was sent a questionnaire (the 15D) assessing the HRQoL a mean of 7.4 years after the primary transsphenoidal surgery. One hundred functional pituitary adenoma (FPA) and 137 NFPA patients responded. We then compared HRQoL (15D scores) between patients and a large sample of an age- and gender-standardized Finnish general population. Independent factors influencing the overall HRQoL (mean 15D score) were estimated using multivariate analysis. A good short-term surgical outcome could be achieved during the initial phase of transition from microscopic to endoscopic transsphenoidal surgery for NFPA patients. Our first endoscopic single-center consecutive case series showed a trend towards improved tumor control but the operative time was longer than with the microscopic technique.The effect of NFPA surgery on pituitary function (hypopituitarism) in both surgical groups was neutral. Current multimodal treatment protocols with optimized hormonal replacement therapies enabled normal or at least near-normal overall HRQoL to be achieved in the majority of patients with all types of pituitary adenomas. Hormonal remission rate of FPAs was 91%. However, patients with Cushing s disease and NFPA had clinically and statistically significant impairments of some single dimensions compared with the general population. Comorbidities were strong determinants of compromised overall HRQoL in patients treated for pituitary adenomas.Aivolisäkeadenooma on tavallisin sellassa eli kallonpohjan turkinsatulassa esiintyvä kasvain. Tämän tutkimuksen tarkoituksena oli kuvailla siirtymävaihetta mikroskooppisesta endoskooppiseen leikkaustekniikkaan toimimattomien aivolisäkeadenoomien hoidossa. Lisäksi selvitimme terveyteen liittyvää elämänlaatua ja siihen vaikuttavia tekijöitä erityyppisten aivolisäkeadenoomien leikkaushoidon jälkeen. Vuosina 2000-2010 Helsingin yliopistollisessa keskussairaalassa leikattiin 320 uutta aivolisäkeadenoomapotilasta, joiden sairauskertomustiedot kerättiin takautuvasti. Ensimmäisen osatyön 185 potilasta, jaettiin kahteen ryhmään leikkaustekniikan (mikroskooppinen ja endoskooppinen) perusteella. Leikkaushoidon vaikutusta arvioitiin seurantakäynnin yhteydessä 3 kuukautta leikkauksen jälkeen. Toisessa ja kolmannessa osatyössä selvitettiin läpileikkaustutkimuksella erityyppisten aivolisäkeadenoomapotilaiden terveyteen liittyvää elämänlaatua keskimäärin 7.4 vuotta transsfenoidaalisen leikkauksen jälkeen. Elämänlaatukyselyyn (15D) vastasi 100 hormonaalisesti toimivan ja 137 toimimattoman aivolisäkeadenooman vuoksi leikattua potilasta, joiden 15D arvoja verrattiin suureen kaltaistettuun suomalaiseen taustaväestöön. Itsenäisiä elämänlaatua selittäviä tekijöitä arvioitiin monimuuttuja-analyysilla. Toimimattomien aivolisäkeadenoomien hyvät leikkaustulokset voitiin säilyttää mikroskooppisesta endoskooppiseen leikkaustekniikkaan tapahtuvan siirtymävaiheen aikana. Endoskooppisesti leikattujen potilaiden ryhmässä oli suuntaus vähäisempään jäännöskasvaimen määrään, mutta leikkausaika oli pidempi verrattuna mikroskooppisesti leikattuun ryhmään. Leikkauksen vaikutus aivolisäkkeen toimintaan (hypopituitarismiin) oli molemmissa toimenpideryhmissä keskimäärin neutraali. Nykymenetelmin leikatuilla ja hoidetuilla aivolisäkeadenoomapotilailla todettiin lähes normaali elämänlaatu (15D indeksi). Toimivista adenoomista 91 % oli hormonaalisessa remissiossa. Cushingin tauti ja toimimattomat aivolisäkeadenoomat kuitenkin heikensivät joitakin yksittäisiä elämänlaadun ulottuvuuksia taustaväestöön verrattuna. Lisäksi oheissairauksien kertyminen oli merkittävä elämänlaatua heikentävä itsenäinen tekijä aivolisäkeadenoomapotilailla

Haemostasis in endoscopic skull base surgery

The endoscopic approach to the skull base has revolutionised surgery in this region. Neurosurgery involves working around anatomical structures that are uniquely sensitive to damage and manipulation and patients may be left with the potentially devastating consequences of violating these structures. The endoscope allows the surgeon to visualise and reach areas that were previously only accessible with large amounts of destructive dissection. Tumours are able to be removed and aneurysms clipped without the need for large craniotomies and bony drilling. There are, however, drawbacks. The midline endoscopic route takes the surgeon between the carotid arteries. It potentially violates the anterior communicating artery complex and the basilar artery region anterior to the brainstem. These are important arteries that supply critical structures. Damage to these, or diminution of blood flow through them, results in profound neurological dysfunction or death. The rate of damage to the carotid artery with these approaches ranges from 1.1-9% depending on the specific approach and pathology. The carotid artery in this region does not generally lend itself to suturing, clipping or direct closure methods. Currently, the gold standard for repair is the application of crushed muscle patch to stop the bleeding and seal the vessel. The drawbacks to this are that it takes time to harvest and control the bleed (generally requiring 2 surgeons), and that there is a risk of pseudoaneurysm formation post recovery. This thesis describes novel techniques that may replace the muscle patch in order that a single surgeon may have this technique available to them immediately. Aims: To demonstrate the use of fibrin/thrombin/gelatin patches, fibrin/thrombin glues, beta-chitosan patches and self-assembling peptides on a sheep model of carotid artery haemorrhage and quantify the rate of pseudoaneurysm formation. To show the percentage of platelets activated by crushed and uncrushed muscle, chitosan, and fibrin and thrombin patches and gels using flow cytometry to further delineate the mechanism of action of crushed muscle as a haemostatic agent. To quantify the stress response in surgeons training on this sheep vascular haemorrhage model de novo, to quantify its effect on surgeons’ teamwork and communication skills, and determine the effect and value of training on modulation of this stress response.Thesis (Ph.D.) (Research by Publication) -- University of Adelaide, Adelaide Medical School, 201

Le gigantisme hypophysaire

Pituitary gigantism is a rare but important form of overgrowth due to GH/IGF-1 excess. The initial aim of the present research was to design and implement a comprehensive cohort study of the etiology, clinical diagnosis and management of this rare disease. This work describes the findings of an international collaborative study involving the largest pituitary gigantism population described to date (208 patients) from 47 centers across the globe to explore the specific characteristics of these patients and the genetic background of pituitary gigantism. Overall, the work undertaken has permitted us to identify the clinical phenotype and treatment outcomes in patients with pituitary gigantism; these features differ significantly from those in adult somatotropinoma patients with acromegaly. Patients with gigantism presented clear a male predominance (95%) and differ in their presentation based on gender, with females presenting significantly earlier than males. Increased somatic growth in pituitary gigantism is associated with an early onset form of GH/IGF-1 hypersecretion due to pituitary tumors that are highly resistant to treatment. These characteristics point to specific molecular mechanisms in pituitary tumor formation. Until recently, pituitary gigantism has been a well-known disease but poorly understood from genetic point of view. Underlying genetic causes have been studied comprehensively and identified in half of the cases in our large international series. While complex multi-organ syndromes (such as McCune-Albright syndrome (MAS), MEN1 and Carney Complex) counted only for rare cases of pituitary gigantism (7% in total), the most frequent genetic etiologies appear to be those leading to disease isolated to the pituitary, such as AIP mutations (29%) and X-linked acrogigantism syndrome (X-LAG) (10%). The latter is a new genetic form of infant-onset acrogigantism, occurring sporadically and in familial setting, which was described for the first time during the course of this work. X-LAG remains rare and only about 33 genetically confirmed cases have been published to date. X-LAG is a dramatically aggressive disorder affecting children from a very young age (usually during the first year), who are predominantly female (70%). Despite the very young age at disease onset, X-LAG patients develop large pituitary lesions (frequently mixed GH and prolactin secreting adenomas and/or hyperplasia) with extremely elevated hormonal levels. This contributes certainly to excessively rapid somatic growth leading to severe overgrowth. The remarkable phenotype of X-LAG syndrome is underlined by an unusual genetic mechanism; it is due to a microduplication on Xq26.3 including always GPR101 gene, whereas previously described genetic mechanisms in pituitary tumorigenesis are mainly triggered by a point mutation or deletions in a single gene. Additionally, a novel genetic technology (digital droplet PCR (ddPCR)) revealed that males with X-LAG syndrome can be mosaics for the GPR101 duplication, and as few as 16% of duplicated cells could lead to severe overgrowth. Many of the tallest giants in history had a clinical history that exactly mirrors this phenotype. The molecular diagnosis of X-LAG due to a duplication in GPR101 was made using paleogenetic extraction techniques in combination with modern ddPCR on DNA successfully isolated from the century-old remains of the historical case of The Giant Constantin (2.59m) who had autopsy findings of a pituitary adenoma. It can be considered as the tallest genetically proven case of gigantism available. It was also noted that more than 50% of cases remain genetically unexplained. Importantly, these genetic subgroups have statistically significant differences in terms of features at presentation/diagnosis, however all pituitary giants, including the genetically negative group, have aggressive clinical characteristics. Further studies were focused on the association of genetic events, in particular AIP mutations, with the aggressive phenotype of somatotropinomas that are resistant to conventional treatment. The clinical experience in patients with pituitary gigantism that have failed previous therapy with first generation somatostatin analogues, showed the role of other treatment options (pegvisomant, paseriotide) in hormonal and tumoral control in genetically negative and AIP mutated cases. A severe disease burden was highlighted in a comprehensive autopsy and genetic analysis in an adult male patient with a complex clinical profile of MAS including pituitary gigantism. The pathological findings and the presence of GNAS1 mutation in a mosaic state in different endocrine and non-endocrine tissues, combined with the clinical description of this case in the medical records, illustrated the challenges in treatment and consequences of disease activity. Crucially, the results derived from our large pituitary gigantism cohort and our further studies in specific genetically predisposed forms (such as X-LAG, AIP mutation– or MAS– related cases) pointed out that pituitary gigantism is a severe therapeutic challenge, requiring a multimodal treatment approach. However, one of the major findings of our research shows that early recognition and effective management in terms of sustained hormonal control and pituitary tumor shrinkage are essential for limiting the pathological effects on height and multi-organ disease burden.Le gigantisme hypophysaire est une forme rare d’une surcroissance importante due à l'excès de GH et IGF-1. Le but initial de nos travaux était d’organiser une étude complète sur l'étiologie, le diagnostic clinique et la prise en charge de cette maladie rare. Nous décrivons les résultats d'une collaboration internationale impliquant la plus grande population de gigantisme hypophysaire décrite à ce jour (208 patients) de 47 centres à travers le monde pour explorer les caractéristiques spécifiques de ces patients et le contexte génétique du gigantisme hypophysaire. La présentation clinique montre une maladie sévère et invalidante qui affecte généralement la population jeune (enfants, adolescents et jeunes adultes). Dans l'ensemble, ce travail a permis d'identifier le phénotype clinique et les résultats du traitement chez les patients atteints de gigantisme hypophysaire; ces caractéristiques sont différentes de celles bien établies chez les adultes atteints d’acromégalie due à une adénome somatotrope. Les patients atteints de gigantisme présentaient une nette prédominance masculine (95%) et différaient dans leur présentation en fonction du sexe, les femmes se présentant significativement plus tôt que les hommes. Une croissance accrue est associée à une forme précoce d'hypersécrétion de GH / IGF-1 due à des tumeurs hypophysaires très résistantes au traitement. Ces caractéristiques sont les conséquences des mécanismes moléculaires impliqués dans la formation de tumeurs hypophysaires. Jusqu'à très récemment, le gigantisme hypophysaire était une maladie bien connue visuellement, mais mal comprise du point de vue génétique. Les causes génétiques ont été étudiées et révélées dans presque la moitié des cas dans notre grande série internationale. Alors que les syndromes complexes multi-organes (tels que le syndrome de McCune-Albright (MAS), NEM1, et Complex du Carney) ne comptaient que pour de rares cas de gigantisme hypophysaire (7%), les étiologies génétiques les plus fréquentes semblent être celles conduisant à adénomes hypophysaire familiaux isolées (FIPA), comme les mutations AIP (29%) et le syndrome du X-linked acrogigantism (X-LAG) (10%). Ce dernier est une nouvelle forme génétique d'acrogigantisme infantile, apparaissant de façon sporadique et familiale, décrite pour la première fois dans ce travail. L’X-LAG reste une maladie rare et seulement environ 33 cas confirmés génétiquement ont été publiés à ce jour. X-LAG est un maladie extrêmement agressive affectant les enfants dès leur plus jeune âge (généralement au cours de la première année), avec une prédominance chez les femmes (70%). Malgré le jeune âge au début de la maladie, les patients X-LAG développent des grandes lésions hypophysaires (ce sont souvent des adénomes mixtes qui sécrètent de la GH et de la prolactine et/ou une hyperplasie) avec des taux hormonaux extrêmement élevés. Ceci contribue certainement à une croissance excessivement rapide conduisant à une taille finale extrême. Le phénotype remarquable de l’X-LAG est dû à un mécanisme génétique inhabituel; il est dû à une microduplication sur Xq26.3 incluant toujours le gène GPR101, alors que les autres mécanismes génétiques bien décrits précédemment dans la tumorigenèse hypophysaire sont déclenchés par une mutation ponctuelle ou des délétions dans un seul gène. De plus, une nouvelle technologie génétique (digital droplet PCR (ddPCR)) a révélé que les mâles atteints du syndrome X-LAG peuvent être des mosaïques pour la duplication GPR101, et que 16% seulement des cellules dupliquées pourraient conduire à une croissance extrême. Les plus grands géants de l'histoire avaient une présentation clinique qui reflète exactement ce phénotype. Le diagnostic moléculaire de X-LAG dû à une duplication du GPR101 a été fait par la technique paléogénétique en combinaison avec le ddPCR moderne sur l'ADN obtenu à partir du squelette centenaire d'un cas historique du Géant Constantin (2.59m) et qui a eu un adénome hypophysaire selon les résultats d'autopsie. Compte tenu de la description clinique de ce cas dans les archives historiques, il peut être considéré comme le plus grand cas de gigantisme génétiquement prouvé disponible. Plus de 50% des cas restent génétiquement inexpliqués. Les groupes de géants avec des causes génétiques différentes et ceux qui ont été génétiquement négatifs, présentent des caractéristiques distinctes au diagnostic, mais tous les géants hypophysaires, y compris le groupe génétiquement négatif, ont un phénotype agressif. Des études ultérieures se sont concentrées sur l'association d'événements génétiques, en particulier de mutations AIP, avec le phénotype agressif du somatotropinome résistant au traitement conventionnel. L'expérience clinique chez les patients atteints de gigantisme hypophysaire qui n’ont répondu au traitement antérieur avec des analogues du somatostatine de première génération, a montré le rôle d'autres options thérapeutiques (pegvisomant, paseriotide) dans le contrôle hormonal et tumoral dans les cas génétiquement négatifs et AIP mutés. La morbidité sévère a été mise en évidence lors d'une autopsie complète et d'une analyse génétique chez un patient adulte avec un profil clinique complexe de MAS géant. Les résultats pathologiques et la présence de la mutation GNAS1 dans un état mosaïque dans différents tissus endocriniens et non endocriniens, combinés avec la description clinique de ce cas dans le dossier médical, ont illustré les défis du traitement et les conséquences de l'activité de la maladie. Fondamentalement, les résultats de notre grande série de patients atteints du gigantisme hypophysaire et nos études ultérieures dans des formes spécifiques génétiquement prédisposées (comme les cas X-LAG, AIP positifs ou MAS) ont montré que le gigantisme hypophysaire est un challenge thérapeutique nécessitant une approche de traitement multimodal. En plus, nous avons montré qu'une reconnaissance précoce et une prise en charge efficace en termes de contrôle hormonal constant et de diminution du volume de tumeur hypophysaire sont essentielles pour limiter les effets pathologiques sur la taille finale et la charge de morbidité multi-organes

Cerebrospinal Fluid

Cerebrospinal fluid is an essential, clear, and colorless liquid essential for maintaining homeostasis of the brain and neuronal functioning. Its secretion in adults ranges from 400 to 600 ml per day and it is renewed about four or five times daily. Cerebrospinal fluid is mainly reabsorbed from arachnoid granulations. Any disruption in this well-regulated system, such as overproduction, decreased absorption, or obstruction, could lead to hydrocephalus. This book contains essential knowledge about cerebrospinal fluid anatomy and physiology, pathologies related to cerebrospinal fluid, and treatment strategies for cerebrospinal fluid disorders

A follow-up study of the outcome of children post-craniopharyngioma surgery

The management of craniopharyngiomas in childhood remains both complex and controversial. Although histologically benign, this tumour often follows a more malignant course, not only in terms of local disease progression but also in terms of visual, neurological, neuropsychological and endocrine outcome. Seventy-five children diagnosed as having a craniopharyngioma between the ages of 1.0 and 16.4 years and treated from 1973 to early 1994 were studied to investigate the associated morbidity and mortality of this tumour and its treatment and to demonstrate which pre- and intra-operative factors were indicative of a poor outcome as defined by a quantitive assessment of morbidity. All patients had tumour surgery which entailed attempted total excision in 59 cases and subtotal resection or cyst aspiration in 16 cases. Thirty-seven children received radiotherapy, 21 following tumour recurrence. The study involved a review of clinical details and cranial imaging of all patients and a follow-up study assessment of 66 survivors - which included ophthalmological, neurological, psychological and growth and endocrine evaluation. Sixty-three patients underwent magnetic resonance imaging with a 3-dimensional volume acquisition sequence. Predictors of high morbidity included severe hydrocephalus, intra-operative adverse events and young age at presentation. Predictors of increased hypothalamic morbidity included symptoms of hypothalamic disturbance already established at diagnosis, greater height of the tumour in the mid-line, and attempts to remove adherent tumour from the region of the hypothalamus at operation. Large tumour size, young age, and severe hydrocephalus were predictors of tumour recurrence, whereas complete tumour resection (as determined by post-operative neuroimaging) and radiotherapy given electively after subtotal excision were significantly less likely to be associated with recurrent disease. Risk factors for poor cognitive outcome included complications at the time of operation and multiple surgical procedures. Treatment with radiotherapy did not significantly influence intellectual outcome. At follow-up assessment, 15% of all patients were blind, 24% had severe neurological sequelae, 56% had evidence of hypothalamic dysfunction, excluding the endocrinopathies which were almost universal, and 75% of patients had evidence of behavioural or educational difficulties. Although severe hypothalamic syndromes were uncommon (16%), they contributed significantly to morbidity and mortality and the clinical manifestations - particularly post-operative weight gain - correlated well with the extent of hypothalamic damage seen on magnetic resonance imaging. Based on these findings, it is clear that close liaison with a multidisciplinary team is essential, so that the spectra of possible sequelae can be identified early and appropriate support instituted promptly. An individualised, more flexible treatment approach is proposed whereby surgical strategies may be modified in an attempt to provide long-term tumour control with the lowest morbidity

The role of the aryl hydrocarbon receptor interacting protein (AIP) in pituitary tumorigenesis: A novel animal model for investigating the role of AIP during embryogenesis and pituitary tumour formation

Pituitary adenomas (PAs) have a 1:1000 prevalence and carry significant morbidity despite their benign nature. Mutations in the AIP (aryl hydrocarbon receptor interacting protein) gene have been unambiguously associated with higher predisposition for PAs. These tumours pose a challenge in treatment due to delayed diagnosis, increased size, earlier onset, aggressive nature and considerable resistance to therapy. The exact mechanism of the tumour formation due to loss of AIP and the role of AIP in pituitary organogenesis is still unknown. A large-cohort retrospective (225 patients) and prospective (876 patients) clinical study was carried out on the pituitary adenoma patients of a tertiary referral centre in London assessing the prevalence of FIPA (familial isolated pituitary adenomas). 20% of FIPA patients are reported to harbour an AIP mutation, but half of the AIP mutation-positive probands are not aware of a positive family history. This study has shown that active inquiry of family history increases detection of previously unknown family history with nearly 3-fold, enabling the genetic screening of these families for early diagnosis and better customised therapy. The novel, pituitary- specific, biallelic Aip-knockout murine model (AipFlox/Flox; Hesx1Cre/+) generated within this study allowed for the first time to investigate the role of AIP during the embryonic stages. There is phenotypical difference (enlarged anterior lobe, incomplete fusion of the sphenoid bone) in the pituitaries 17.5 dpc AipFlox/Flox; Hesx1Cre/+ embryos when compared with the wildtype of the same embryonic stage, with no difference in cell lineage determination (dpc 15.5). A decrease in growth hormone and prolactin producing cells is described at terminal differentiation (dpc 17.5), which is intriguing because patients harbouring AIP mutations most commonly present with growth hormone and/or prolactin secreting 7 PAs. Further research has since been done efficiently using this model focusing on postnatal tumour formation, which is not part of this thesis. Deregulation of the Hippo signalling components has been increasingly investigated in relation to pituitary tumorigenesis, especially in human hormone secreting PAs, but no study had investigated the role of Hippo signalling in AIP-mediated tumour formation. A bioinformatic-based analysis was performed for the expression of 41 Hippo pathway associated genes in AIP-silenced rat pituitary somatomammotroph GH3 cells, pituitary specific AIP-knockout mice, humans with AIP mutation-positive and AIP mutation-negative familial and sporadic PAs. Both up- and downstream members of the Hippo signalling show significantly altered expression in the different subgroups, which warrants more targeted future studies. Additionally, in the analysed exome and whole genome sequencing of PA patients, variants of several key Hippo pathway components show segregation within families. These data (along with a global phosphorylation analysis) suggest that further studies are needed to investigate the role of Hippo signalling in AIP-mediated tumorigenesis

Biochemical and molecular biological studies of human pituary tumours

Imperial Users onl