Headache in Patients with Sellar Disease: Clinicomorphological Predictors of Headache and the Outcome of Endoscopic Transsphenoidal Surgery.

Objectives Sellar pathologies are frequently found on imaging performed to investigate headache. However, both headache and incidental sellar lesions are common. Hence, this study prospectively examined headache prevalence, phenotype, and severity in patients with sellar pathologies and the impact of transsphenoidal surgery on headache. Methods Patients undergoing transsphenoidal resection of sellar lesions were consecutively recruited. At baseline, participants were defined as having headache or not and headache phenotype was characterized using validated questionnaires. Headache severity was assessed at baseline and 6 months postoperatively using the Headache Impact Test-6 (HIT-6) and Migraine Disability Assessment Score (MIDAS). Tumor characteristics were defined using radiological, histological, and endocrine factors. Primary outcomes included baseline headache prevalence and severity and headache severity change at 6 months postoperatively. Correlation between headache and radiological, histological, and endocrine characteristics was also of interest. Results Sixty participants (62% female, 47.1 ± 18.6 years) were recruited. Sixty-three percent possessed baseline headache. HIT-6 scores were higher in patients with primary headache risk factors, including younger age (R 2 = -0.417, p = 0.010), smoking history (63.31 ± 7.93 vs 54.44 ± 9.21, p = 0.0060), and family headache history (68.13 ± 7.01 vs 54.94 ± 9.11, p = 0.0030). Headaches were more common in patients with dural invasion (55.70 ± 12.14 vs 47.18 ± 10.15, p = 0.027) and sphenoid sinus invasion (58.87 ± 8.97 vs 51.29 ± 10.97, p = 0.007). Postoperative severity scores improved more with higher baseline headache severity (HIT-6: R 2 = -0.682, p < 0.001, MIDAS: R 2 = -0.880, p < 0.0010) and dural invasion (MIDAS: -53.00 ± 18.68 vs 12.00 ± 17.54, p = 0.0030). Conclusion Headaches in sellar disease are likely primary disorders triggered or exacerbated by sellar pathology. These may respond to surgery, particularly in patients with severe headache and dural invasion.

Magnetic Resonance-Guided Focused Ultrasound for Treatment of Essential Tremor: Ventral Intermediate Nucleus Ablation Alone or Additional Posterior Subthalamic Area Lesioning?

BACKGROUND: Magnetic resonance-guided focused ultrasound (MRgFUS) for treatment of essential tremor (ET) traditionally targets the ventral intermediate (Vim) nucleus. Recent strategies include a secondary lesion to the posterior subthalamic area (PSA). OBJECTIVE: The aim was to compare lesion characteristics, tremor improvement, and adverse events (AE) between patients in whom satisfactory tremor suppression was achieved with lesioning of the Vim alone and patients who required additional lesioning of the PSA. METHODS: Retrospective analysis of data collected from ET patients treated with MRgFUS at St Vincent's Hospital Sydney was performed. Clinical Rating Scale for Tremor (CRST), hand tremor score (HTS), and Quality of Life in Essential Tremor Questionnaire (QUEST) were collected pre- and posttreatment in addition to the prevalence of AEs. The lesion coordinates and overlap with the dentatorubrothalamic tract (DRTT) were evaluated using magnetic resonance imaging. RESULTS: Twenty-one patients were treated in Vim only, and 14 were treated with dual Vim-PSA lesions. Clinical data were available for 29 of the 35 patients (19 single target and 10 dual target). At follow-up (mean: 18.80 months) HTS, CRST, and QUEST in single-target patients improved by 57.97% (P < 0.001), 36.71% (P < 0.001), and 58.26% (P < 0.001), whereas dual-target patients improved by 68.34% (P < 0.001), 35.37% (P < 0.003), and 46.97% (P < 0.005), respectively. The Vim lesion of dual-target patients was further anterior relative to the posterior commissure (PC) (7.84 mm), compared with single-target patients (6.92 mm), with less DRTT involvement (14.85% vs. 23.21%). Dual-target patients exhibited a greater proportion of patients with acute motor AEs (100% vs. 58%); however, motor AE prevalence was similar in both groups at long-term follow-up (33% vs. 38%). CONCLUSION: Posterior placement of lesions targeting the Vim may confer greater tremor suppression. The addition of a PSA lesion, in patients with inadequate tremor control despite Vim lesioning, had a trend toward better long-term tremor suppression; however, this approach was associated with greater prevalence of gait disturbance in the short term.

Consistency is key: influence of skull density ratio distribution on the formation of clinically effective lesions and long-term tremor suppression following treatment with MR-guided focused ultrasound.

OBJECTIVE: Skull density ratio (SDR) influences the permeability of the skull to the ultrasound waves used in magnetic resonance-guided focused ultrasound (MRgFUS) for the treatment of tremor. SDR values vary across the skull and the mean value is known to be predictive of sonication thermal increase. The aim of this investigation was to explore the effects of the SDR distribution on clinical outcomes following treatment with MRgFUS. METHODS: Data from 61 patients with essential or dystonic tremor treated with MRgFUS targeting the ventral intermediate nucleus (Vim) were retrospectively analyzed. Tremor suppression was assessed using the Clinical Rating Scale for Tremor (CRST) and hand tremor score (HTS). Vim ablation volume was measured on the T1-weighted MR image acquired both at 1 day and 12 months after treatment. The numerical distribution of SDR values measured for each element in the ultrasound transducer was quantified by calculating the mean, standard deviation, skewness, entropy, and kurtosis of the SDR histogram. The effect of the SDR metrics on change in CRST and HTS was examined using a linear mixed-effects model. Additionally, the effect of the regional distribution of SDR values was explored in an element-wise analysis between patients with above- and below-average tremor suppression. RESULTS: A significant positive effect was found between SDR kurtosis and improvement in CRST (ß = 0.33, p = 0.004) and HTS (ß = 0.38, p < 0.001). The effect was found to be significant at 1 month posttreatment (CRST: ß = 0.415, p = 0.008; HTS: ß = 0.369, p = 0.016), and at the most recent clinical follow-up (CRST: ß = 0.395, p < 0.001; HTS: ß = 0.386, p < 0.001). One hundred seventy-one significant elements were identified in the element-wise analysis. The mean percentage difference from the mean SDR in these elements was associated with improvement in CRST (ß = 0.27, p < 0.008) and HTS (ß = 0.27, p < 0.015). Higher SDR kurtosis was associated with increased lesion volume at 12 months (p = 0.040) and less reduction in volume relative to the day-1 lesion volume (p = 0.007). CONCLUSIONS: Greater SDR kurtosis was associated with larger, more stable lesions at 12 months posttreatment and increased tremor suppression at long-term follow-up. SDR kurtosis may provide a more meaningful prognostic factor than the mean SDR.

Outcomes of Focused Ultrasound Thalamotomy in Tremor Syndromes.

BACKGROUND: The current literature comparing outcomes after a unilateral magnetic resonance image-guided focused ultrasound (MRgFUS) thalamotomy between tremor syndromes is limited and remains a possible preoperative factor that could help predict the long-term outcomes. OBJECTIVE: The aim was to report on the outcomes between different tremor syndromes after a unilateral MRgFUS thalamotomy. METHODS: A total of 66 patients underwent a unilateral MRgFUS thalamotomy for tremor between November 2018 and May 2020 at St Vincent's Hospital Sydney. Each patient's tremor syndrome was classified prior to treatment. Clinical assessments, including the hand tremor score (HTS) and Quality of Life in Essential Tremor Questionnaire (QUEST), were performed at baseline and predefined intervals to 36 months. RESULTS: A total of 63 patients, comprising 30 essential tremor (ET), 24 dystonic tremor (DT), and 9 Parkinson's disease tremor (PDT) patients, returned for at least one follow-up. In the ET patients, at 24 months there was a 61% improvement in HTS and 50% improvement in QUEST compared to baseline. This is in comparison to PDT patients, where an initial benefit in HTS and QUEST was observed, which waned at each follow-up, remaining significant only up until 12 months. In the DT patients, similar results were observed to the ET patients: at 24 months there was a 61% improvement in HTS and 43% improvement in QUEST compared to baseline. CONCLUSION: These results support the use of unilateral MRgFUS thalamotomy for the treatment of DT, which appears to have a similar expected outcome to patients diagnosed with ET. Patients with PDT should be warned that there is a risk of treatment failure. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Evaluation of the efficacy and safety of MRI-guided focused ultrasound (MRgFUS) for focal hand dystonia: study protocol for an open-label non-randomised clinical trial.

Introduction: MRI-guided focused ultrasound (MRgFUS) thalamotomy provides an exciting development in the field of minimally invasive stereotactic neurosurgery. Current treatment options for focal hand dystonia are limited, with potentially more effective invasive stereotactic interventions, such as deep brain stimulation or lesional therapies, rarely used. The advent of minimally invasive brain lesioning provides a potentially safe and effective treatment approach with a recent pilot study establishing MRgFUS Vo-complex thalamotomy as an effective treatment option for focal hand dystonia. In this study, we undertake an open-label clinical trial to further establish MRgFUS Vo-complex thalamotomy as an effective treatment for focal hand dystonia with greater attention paid to potential motor costs associated with this treatment. To elucidate pathophysiology of dystonia and treatment mechanisms, neurophysiological and MRI analysis will be performed longitudinally to explore the hypothesis that neuroplastic and structural changes that may underlie this treatment benefit. Methods and analysis: A total of 10 participants will be recruited into this open-label clinical trial. All participants will undergo clinical, kinemetric, neurophysiological and radiological testing at baseline, followed by repeated measures at predesignated time points post MRgFUS Vo-complex thalamotomy. Further, to identify any underlying structural or neurophysiological abnormalities present in individuals with focal hand dystonia, 10 age and gender matched control participants will be recruited to undergo comparative investigation. These results will be compared with the intervention participants both at baseline and at 12 months to assess for normalisation of these abnormalities, if present. Ethics and dissemination: This trial was reviewed and approved by the St Vincent's Health Network Sydney Human Research Ethics Committee (2022/ETH00778). Study results will be published in peer-reviewed journals and presented at both national and international conferences. Trial registration number: CTRN12622000775718.

Tremor suppression following treatment with MRgFUS: skull density ratio consistency and degree of posterior dentatorubrothalamic tract lesioning predicts long-term clinical outcomes in essential tremor.

Objectives: Magnetic resonance-guided focussed ultrasound (MRgFUS) is an incisionless ablative procedure, widely used for treatment of Parkinsonian and Essential Tremor (ET). Enhanced understanding of the patient- and treatment-specific factors that influence sustained long-term tremor suppression could help clinicians achieve superior outcomes via improved patient screening and treatment strategy. Methods: We retrospectively analysed data from 31 subjects with ET, treated with MRgFUS at a single centre. Tremor severity was assessed with parts A, B and C of the Clinical Rating Scale for Tremor (CRST) as well as the combined CRST. Tremor in the dominant and non-dominant hand was assessed with Hand Tremor Scores (HTS), derived from the CRST. Pre- and post-treatment imaging data were analysed to determine ablation volume overlap with automated thalamic segmentations, and the dentatorubrothalamic tract (DRTT) and compared with percentage change in CRST and HTS following treatment. Results: Tremor symptoms were significantly reduced following treatment. Combined pre-treatment CRST (mean: 60.7 ± 17.3) and HTS (mean: 19.2 ± 5.7) improved by an average of 45.5 and 62.6%, respectively. Percentage change in CRST was found to be significantly negatively associated with age (ß = -0.375, p = 0.015), and SDR standard deviation (SDRSD; ß = -0.324, p = 0.006), and positively associated with ablation overlap with the posterior DRTT (ß = 0.535, p < 0.001). Percentage HTS improvement in the dominant hand decreased significantly with older age (ß = -0.576, p < 0.01). Conclusion: Our results suggest that increased lesioning of the posterior region of the DRTT could result in greater improvements in combined CRST and non-dominant hand HTS, and that subjects with lower SDR standard deviation tended to experience greater improvement in combined CRST.

Endoscopic Endonasal Biopsy for Diagnosis of Undifferentiated Lesions of the Cavernous Sinus.

BACKGROUND: Radiologically undifferentiated lesions of the cavernous sinus can pose a diagnostic challenge. Although radiotherapy is the mainstay for treatment of cavernous sinus lesions, histologic diagnosis allows access to a wide variety of alternative treatment modalities. The region is considered a high-risk area for open transcranial surgical access, and the endoscopic endonasal approach presents an alternative technique for biopsy. METHODS: A retrospective case series was performed of all patients undergoing endoscopic endonasal biopsy of isolated cavernous sinus lesions at 2 tertiary institutions. The primary outcomes were the percentage of patients in whom a histologic diagnosis was achieved and the proportion of patients in whom therapy differed from radiotherapy alone. Secondary outcomes included preoperative and postoperative 22-item Sino-Nasal Outcome Test symptom scores, as well as perioperative adverse outcomes. RESULTS: Eleven patients underwent endoscopic endonasal biopsy, with a diagnosis achieved in 10 patients. The most common diagnosis was perineural spread of squamous cell carcinoma, followed by perineuroma and single cases of metastatic melanoma, metastatic adenoid cystic carcinoma, mycobacterium lepri infection, neurofibroma, and lymphoma. Six patients had treatments other than radiotherapy, including immunotherapy, antibiotics, corticosteroids, chemotherapy, and observation alone. There was no significant difference in prebiopsy and postbiopsy 22-item Sino-Nasal Outcome Test scores. There was 1 case of epistaxis requiring return to theater for cautery of the sphenopalatine artery and there were no mortalities. CONCLUSIONS: In a limited case series, endoscopic endonasal biopsy was safe and effective in obtaining diagnosis for cavernous sinus lesions and had a significant impact on therapeutic decision making.

Effective Subthalamic Nucleus Deep Brain Stimulation Following MRgFUS for Tremor Dominant Parkinson's Disease.

Background: Whilst MRI guided Focused Ultrasound (MRgFUS) thalamotomy is an effective treatment option for tremor disorders, there are reports of tremor recurrence in patients with tremor dominant Parkinson's disease (PD). The mechanisms for tremor recurrence are unknown but likely relate to the duality of tremor network pathways with ramifications for subsequent treatment options. Cases: We report two cases of tremor dominant PD who experienced tremor recurrence following MRgFUS thalamotomy with subsequent successful subthalamic nucleus deep brain stimulation (DBS). Tremor scores were measured at baseline, 1- and 3-months post MRgFUS and at least 18 months post DBS in both patients. Both cases evidenced immediate improvement in tremor, after MRgFUS, followed by subsequent tremor recurrence. STN DBS resulted in almost complete long-term tremor alleviation in both cases. Conclusions: These cases demonstrate the efficacy and feasibility of STN DBS in patients with tremor dominant PD with tremor recurrence following MRgFUS thalamotomy. We discuss the dualism of tremor outflow pathways that may have implications for single target lesional therapies.

Cerebellar Cortex Stimulation for Acquired Dystonia: A Case Report and Review of Its Role in Modern Surgical Practice.

BACKGROUND: Cerebral palsy (CP) is a common cause of acquired dystonia, which can lead to significant interference with quality of life and societal participation. In the last two decades, the surgical treatment of dystonia has primarily focused on deep brain stimulation targeting the basal ganglia and thalamic circuits. However, stimulation of the basal ganglia has generally been less effective in acquired combined forms of dystonia, including dystonic CP. These limitations, along with growing evidence for the role of the cerebellum in the pathophysiology of dystonia, have led to renewed interest in the cerebellum as a target for therapeutic stimulation in dystonia. Nevertheless, there are very few contemporary studies demonstrating its use. We present the case of a patient with generalized dystonia due to dyskinetic CP who was successfully treated with stimulation of the cerebellar cortex in the modern era. We also review the evidence underpinning targeting of the cerebellum in surgical therapy for dystonia and examine the latest reports of this approach in the surgical literature. SUMMARY: The patient derived significant improvement in the control of her dystonic symptoms, with a reduction in her BFMDRS score from 83 to 25. No complications were observed during more than 3 years of postoperative follow-up. Since the turn of the 21st century, there have been only 7 reports of cerebellar stimulation for dystonia, recruiting a total of 18 patients. These studies have exclusively targeted deep brain structures, making the present report of cortical cerebellar stimulation particularly unique. KEY MESSAGES: In the 21st century, cerebellar stimulation has predominantly been a second-line treatment for dystonia, after the failure of DBS targeting more mainstream loci within the thalamus and globus pallidus. However, there is increasing recognition of the role of the cerebellum in movement disorders, with multiple convergent lines of evidence supporting its involvement in dystonia pathophysiology. The cerebellum is worthy of greater consideration as a target for neurostimulation in dystonia, particularly in cases of acquired etiology.

Current status of intra-cranial stereotactic radiotherapy and stereotactic radiosurgery in Australia and New Zealand: key considerations from a workshop and surveys.

Recently, there has been increased interest worldwide in the use of conventional linear accelerator (linac)-based systems for delivery of stereotactic radiosurgery/radiotherapy (SRS/SRT) contrasting with historical delivery in specialised clinics with dedicated equipment. In order to gain an understanding and define the current status of SRS/SRT delivery in Australia and New Zealand (ANZ) we conducted surveys and provided a single-day workshop. Prior to the workshop ANZ medical physicists were invited to complete two surveys: a departmental survey regarding SRS/SRT practises and equipment; and an individual survey regarding opinions on current and future SRS/SRT practices. At the workshop conclusion, attendees completed a second opinion-based survey. Workshop discussion and survey data were utilised to identify areas of consensus, and areas where a community consensus was unclear. The workshop was held on the 8th Sept 2020 virtually due to pandemic-related travel restrictions and was attended by 238 radiation oncology medical physicists from 39 departments. The departmental survey received 32 responses; a further 89 and 142 responses were received to the pre-workshop and post-workshop surveys respectively. Workshop discussion indicated a consensus that for a department to offer an SRS/SRT service, a minimum case load should be considered depending on availability of training, peer-review, resources and equipment. It was suggested this service may be limited to brain metastases only, with less common indications reserved for departments with comprehensive SRS/SRT programs. Whilst most centres showed consensus with treatment delivery techniques and image guidance, opinions varied on the minimum target diameter and treatment margin that should be applied.

Low but not undetectable early postoperative nadir serum cortisol predicts sustained remission in Cushing's disease.

Objective: Transsphenoidal surgery (TSS) is the first-line treatment for Cushing's disease. The objectives of the study were to determine remission and recurrence rates after TSS for Cushing's disease, identify factors that predict these outcomes, and define the threshold for postoperative morning serum cortisol (MSeC) that most accurately predicts sustained remission. Methods: Records were retrospectively reviewed for consecutive adults undergoing TSS for Cushing's disease at a tertiary centre (1990-2019). Remission was defined as MSeC <138 nmol/L by 6 weeks postoperatively. Recurrence was defined as elevated 24-h urine free cortisol, lack of suppression after dexamethasone or elevated midnight salivary cortisol. Results: In this study, 42 patients (age 47 ± 13 years, 83% female) were assessed with 55 ± 56 months of follow-up. Remission occurred after 77% of primary (n = 30) and 42% of revision operations (n = 12). After primary surgery, remission was associated with lower MSeC nadir (26 ± 36 nmol/L vs 347 ± 220 nmol/L, P < 0.01) and lower adrenocorticotropin nadir (2 ± 3 pmol/L vs 6 ± 3 pmol/L, P = 0.01). Sustained remission 5 years after surgery was predicted by MSeC <92 nmol/L within 2 weeks postoperatively (sensitivity 100% and specificity 100%). After revision surgery, remission was predicted by lower MSeC nadir (70 ± 45 nmol/L vs 408 ± 305 nmol/L, P = 0.03), smaller tumour diameter (3 ± 2 mm vs 15 ± 13 mm, P = 0.05) and absence of cavernous sinus invasion (0% vs 71%, P = 0.03). Recurrence after primary and revision surgery occurred in 17% and 20% of patients respectively. Conclusions: Lower postoperative MSeC nadir strongly predicted remission after both primary and revision surgery. Following primary surgery, an MSeC <92 nmol/L within 2 weeks predicted sustained remission at 5 years. MSeC nadir was the most important prognostic marker following TSS for Cushing's disease.

Predictors of thermal response and lesion size in patients undergoing magnetic resonance-guided focused ultrasound thalamotomy.

Magnetic resonance-guided focused ultrasound (MRgFUS) is being increasingly utilized in the treatment of movement disorders such as essential tremor (ET) and Parkinson's disease (PD). Whilst skull density ratio (SDR) has previously been correlated with achieving lesional temperature rises, other patient factors such as brain and cerebrospinal fluid (CSF) volume have not previously been investigated. We aimed to investigate the effect of brain and CSF volumes on lesional temperature rises, as well as the effect of brain and CSF volumes and SDR on post-treatment lesion sizes. Fifty-four consecutive patients were studied with patient and treatment-related variables collected along with post-treatment lesion sizes. Linear regression analysis identified that SDR alone was associated with lesional temperatures. Both SDR and brain atrophy were associated with post-treatment lesion sizes on linear regression analysis. On multiple linear regression analysis SDR was significantly associated with post-treatment lesion size, and the association between brain atrophy and lesion sizes approached significance, a finding that warrants further investigation.

Assessment of magnetic resonance imaging criteria for the diagnosis of cavernous sinus invasion by pituitary tumors.

Cavernous sinus invasion (CSI) by pituitary tumors is associated with subtotal resection and persistent endocrinopathy. The Knosp classification is a magnetic resonance imaging (MRI) tool used to define CSI in the 2017 World Health Organization Classification. However, alternative criteria may have superior diagnostic performance. This study aimed to assess the diagnostic performance of four MRI criteria, using a combination of endoscopy and day 1 MRI as the reference standard for CSI. A cross-sectional study was conducted including patients treated with endoscopic endonasal transsphenoidal surgery for pituitary macroadenomas, recruited from a tertiary pituitary multidisciplinary center in Sydney, Australia between September 2013, and February 2021. The diagnostic performances of four MRI criteria were assessed: the Knosp criteria, percentage encasement of the internal carotid (PEICA), venous compartment obliteration (VCO), and the Fernandez-Miranda classification. Reference CSI was defined using a combination of intraoperative endoscopy and day 1 MRI. A total of 210 cavernous sinuses (105 patients), were analyzed, (51.7 ±â€¯16.3yrs, 43% female), of which 18% had CSI. CSI was best diagnosed by Knosp ≥ 2 (63% sensitivity and 89% specificity), PEICA ≥ 28% (84% sensitivity and 77% specificity) and VCO of ≥ 3 compartments (65% sensitivity and 89% specificity). CSI was unlikely if any of the following signs were present: Knosp < 1, PEICA < 28%, preservation of the medial or superior compartments or sparing of the superior Fernandez-Miranda compartment (negative predictive value 95%, 95%, 94%, 91% and 92% respectively). In conclusion, alternatives to the Knops criteria including PEICA and VCO can aid CSI diagnosis.

Multidisciplinary Team Care in the Surgical Management of Pituitary Adenoma.

Objective Despite multidisciplinary care being commonly recommended, there remains limited evidence supporting its benefits in pituitary disease management. This study aimed to assess the impact of multidisciplinary care in pituitary surgery. Methods A retrospective cohort study was performed comparing pituitary surgery outcomes among consecutive patients within a quaternary referral center in 5 years before and after introduction of a multidisciplinary team (MDT). Primary outcomes were endocrine (transient diabetes insipidus [DI], syndrome of inappropriate antidiuretic hormone [SIADH], and new hypopituitarism) and surgical (cerebrospinal fluid [CSF] leak, epistaxis, intracranial hemorrhage, and meningitis) complications, length of hospital stay, and intrasellar residual tumor. Results 279 patients (89 pre-MDT vs. 190 post-MDT) were assessed (age 54 ± 17 years, 48% female). Nonfunctioning adenomas were most common (54%). In the post-MDT era, more clinically functioning tumors (42 vs. 28%, p = 0.03) were treated. Transient DI and SIADH occurred less often post-MDT (20 vs. 36%, p < 0.01 and 18 vs. 39%, p < 0.01), as well as new hypothyroidism (5 vs. 15, p < 0.01). Hospital stay was shorter post-MDT (5[3] vs. 7[5] days, p < 0.001) and intrasellar residuals were less common (8 vs. 35%, p < 0.001). Complications were more frequent pre-MDT independent of tumor size, hormone status, and surgical technique (odds ratio [OR] = 2.14 [1.05-4.32], p = 0.04). Conclusion Outcomes of pituitary surgery improved after the introduction of an MDT. Pituitary MDTs may benefit both patients and the health system by improving quality of care and reducing hospital stays.

Optimal management in optic nerve sheath meningioma - A multicentre study and pooled data analysis.

Optic nerve sheath meningiomas (ONSMs) are rare, benign neoplasms of the anterior visual pathway. The optimal modality of radiotherapy for treatment has not yet been established. This is the first study to show significant difference in visual outcomes between radiotherapy subtypes in the management of ONSM. We performed a retrospective analysis of visual outcomes and side effects in ONSM patients treated with radiotherapy at three centres in Sydney, Australia, between 2000 and 2016. 15 patients with ONSM were included, and visual outcomes (visual acuity, visual fields, colour vision, OCT retinal nerve fibre layer thickness and radiological tumour response) and treatment toxicities were assessed. Pooled data analysis of available studies was also performed. Statistical analysis was performed with binomial, two-tailed chi-squared tests and Fisher exact tests. In our cohort a significant majority experienced improved visual field (p = 0.046), stable or improved visual acuity (p = 0.0017) and colour vision (p = 0.015) after fractionated radiotherapy. Pooled analysis with strict inclusion criteria found 3D conformal radiotherapy to offer significantly poorer visual acuity compared to fractionated stereotactic radiotherapy (p = 0.008). When all published studies were included, stereotactic radiosurgery was superior to 3D conformal methods (p = 0.035), and equivalent to other fractionated methods. 3D conformal methods also had significantly higher rates of long-term side effects. These results support the use of fractionated radiotherapy and radiosurgery for ONSM treatment, however 3D conformal methods cannot be recommended.

Outcomes of pituitary surgery for Cushing's disease: a systematic review and meta-analysis.

PURPOSE: Transsphenoidal surgery (TSS) is the first-line treatment for Cushing's disease (CD). This review aimed to synthesize the remission and recurrence rates following TSS for CD and identify predictors of these outcomes. METHODS: Medline (1946-) and Embase (1947-) were searched until 23rd January 2019 for original studies. A meta-analysis was performed of remission and recurrence rates. Studies were excluded if patients had prior radiosurgery/radiotherapy, mixed pathologies or interventions without separated data, follow-up not reported or population size < 20. For recurrence rate syntheses, studies with follow-up < 6 months were excluded. RESULTS: The search produced 2663 studies, of which n = 68 were included, involving 5664 patients. Remission rates after primary and revision TSS were 80% [77-82] and 58% [50-66] at last follow-up. After primary TSS, predictors of remission were micro- v macroadenomas (83% v 68%, p < 0.01), imaging-visible adenomas (81% v 69%, p < 0.01), adenomas confirmed on histopathology (87% v 45%, p < 0.01), absence of cavernous sinus invasion (80% v 30%, p < 0.01), postoperative serum cortisol (MSeC) nadir < 2 µg/dL (< 55 nmol/L; 95% v 46%, p < 0.01) and lower preoperative 24-h urine free cortisol (1250 nmol v 1726 nmol, p < 0.01). For revision TSS, predictors of remission were postoperative MSeC nadir < 2 µg/dL (< 55 nmol/L; 100% v 38%, p < 0.01) and operations for recurrence v persistence (80% v 54%, p < 0.01). Recurrence rates after primary and revision TSS were 18% [14-22] and 28% [16-42]. CONCLUSIONS: TSS is most effective in primary microadenomas, visible on preoperative imaging and without CS invasion, lower preoperative 24-h urine free cortisol and postoperative MSeC nadir < 2 µg/dL (< 55 nmol/L).

Fatal high-grade skull osteosarcoma 30 years following radiotherapy for Cushing's disease.

SUMMARY: Cushing's disease is a rare disorder characterised by excessive cortisol production as a consequence of a corticotroph pituitary tumour. While the primary treatment is surgical resection, post-operative radiation therapy may be used in cases of ongoing inadequate hormonal control or residual or progressive structural disease. Despite improved outcomes, radiotherapy for pituitary tumours is associated with hypopituitarism, visual deficits and, rarely, secondary malignancies. We describe an unusual case of a 67-year-old female with presumed Cushing's disease diagnosed at the age of 37, treated with transsphenoidal resection of a pituitary tumour with post-operative external beam radiotherapy (EBRT), ketoconazole for steroidogenesis inhibition, and finally bilateral adrenalectomy for refractory disease. She presented 30 years after her treatment with a witnessed generalised tonic-clonic seizure. Radiological investigations confirmed an extracranial mass infiltrating through the temporal bone and into brain parenchyma. Due to recurrent generalised seizures, the patient was intubated and commenced on dexamethasone and anti-epileptic therapy. Resection of the tumour revealed a high-grade osteoblastic osteosarcoma. Unfortunately, the patient deteriorated in intensive care and suffered a fatal cardiac arrest following a likely aspiration event. We describe the risk factors, prevalence and treatment of radiation-induced osteosarcoma, an exceedingly rare and late complication of pituitary irradiation. To our knowledge, this is the longest reported latency period between pituitary irradiation and the development of an osteosarcoma of the skull. LEARNING POINTS: Cushing's disease is treated with transsphenoidal resection as first-line therapy, with radiotherapy used in cases of incomplete resection, disease recurrence or persistent hypercortisolism. The most common long-term adverse outcome of pituitary tumour irradiation is hypopituitarism occurring in 30-60% of patients at 10 years, and less commonly, vision loss and oculomotor nerve palsies, radiation-induced brain tumours and sarcomas. Currently proposed characteristics of radiation-induced osteosarcomas include: the finding of a different histological type to the primary tumour, has developed within or adjacent to the path of the radiation beam, and a latency period of at least 3 years. Treatment of osteosarcoma of the skull include complete surgical excision, followed by systemic chemotherapy and/or radiotherapy. Overall prognosis in radiation-induced sarcoma of bone is poor. Newer techniques such as stereotactic radiosurgery may reduce the incidence of radiation-induced malignancies.