Health-Related Quality of Life in Adults With Classical Infratentorial Superficial Siderosis: A Cross-sectional Study.

BACKGROUND AND OBJECTIVES: Infratentorial superficial siderosis (iSS) is a rare but disabling neurological condition characterised by progressive hearing loss, balance and mobility problems. The functional decline in these neurological domains with iSS progression is likely to adversely impact health-related quality of life (HRQoL). We studied HRQoL of adults with iSS using two common generic HRQoL measures (Health Utilities Index Mark III (HUI3) and EuroQoL EQ5D (5 Level) to determine the most impacted domains and evaluate the association between HRQoL scores and disease duration. METHODS: This observational study was an anonymous online survey. Following institutional Research Ethics Committee approval, we contacted dedicated international organisations, charities and patient-groups identified through online searches, social media and collaborative networks, to distribute the study information and study link, inviting their members diagnosed with iSS to participate. Participation required access to a digital device connected to the internet, confirmation of eligibility (aged ≥18 years and previously diagnosed with iSS) and informed consent to participate in the survey, which included study-specific questions (demographics, iSS, hearing) and HRQoL questionnaires. Survey responses were captured by the Research Electronic Data Capture (REDCap) survey software and analysed using the SPSS statistical package. Linear regression analysis was performed to investigate the association between HRQoL scores and disease duration. RESULTS: Of fifty participants,60% were male; the median (interquartile range, IQR) age was 60 (15) years. The median (IQR) multi-attribute scores for HUI3 and EQ5D were 0.36 (0.53) and 0.64 (0.33), respectively. The most frequently affected domains (moderate or worse category) were hearing (64%), and pain (48%) for HUI3, and mobility (54%) and pain (50%) for EQ5D. There was a weak association between disease duration and multi-attribute scores for HUI3 (R=0.353; adjusted R2=0.096; b=-0.008; p=0.047) but not EQ5D. DISCUSSION: Our findings demonstrate low HRQoL scores which capture low functional status in several domains typically affected in iSS, suggesting that iSS has a major adverse impact on quality of life in multiple functional domains. Measures of HRQoL in iSS should be included in clinical and research settings, including treatment trials.

Olfactory dysfunction is common in classical infratentorial superficial siderosis of the central nervous system.

BACKGROUND: Established features of classical infratentorial superficial siderosis (iSS) include hearing loss, impaired balance, myelopathy and, less commonly, cognitive compromise. Olfactory function may be affected but dedicated studies are lacking. This study aimed to assess the prevalence of olfactory dysfunction in iSS and correlate it with auditory and cognitive functions. METHODS: Ten participants with iSS completed the University of Pennsylvania Smell Identification Test (UPSIT). The scores were compared with population norms; regression analysis was performed to evaluate associations between the scores and hearing thresholds (3-frequency average, 3FA) or the number of cognitive domains impaired. Imaging was reviewed for haemosiderin distribution and to exclude other causes of olfactory and hearing dysfunction. RESULTS: Eight of ten participants were male; the mean (standard deviation, SD) age was 52.5 (14.5) years. Olfactory hypofunction was identified in all participants and in six (60%) was moderate or completely absent. The mean UPSIT score of 25.5 (7.8) was significantly worse than population norms (difference in means - 10.0; 95% CI - 15.6 to - 4.4). Linear regression identified an association between UPSIT and hearing thresholds (R = 0.75; p = 0.013). The score decreases by 0.157 units (95% CI - 0.31 to - 0.002; p = 0.048) per unit increase in 3FA, after adjusting for hearing loss risk factors. There was no statistically significant association between UPSIT and cognitive function (R = 0.383; p = 0.397). CONCLUSION: We report a high prevalence of olfactory dysfunction in iSS, the severity of which correlated with hearing loss. Olfaction appears to be a core feature of the iSS clinical syndrome that should be assessed routinely.

Classical infratentorial superficial siderosis of the central nervous system: pathophysiology, clinical features and management.

The term superficial siderosis (SS) is derived from the Greek word 'sideros', meaning iron. It includes two subtypes, distinguished by their anatomical distribution, causes and clinical features: 'classical' infratentorial SS (iSS, which sometimes also affects supratentorial regions) and cortical SS (cSS, which affects only supratentorial regions). This paper considers iSS, a potentially disabling disorder usually associated with very slow persistent or intermittent subarachnoid bleeding from a dural defect, and characterised by progressive hearing and vestibular impairment, ataxia, myelopathy and cognitive dysfunction. The causal dural defect-most often spinal but sometimes in the posterior fossa-typically follows trauma or neurosurgery occurring decades before diagnosis. Increasing recognition of iSS with paramagnetic-sensitive MRI is leading to an unmet clinical need. Given the diagnostic challenges and complex neurological impairments in iSS, we have developed a multidisciplinary approach involving key teams. We discuss pathophysiology, diagnosis and management of iSS, including a proposed clinical care pathway.

Targeted detection and repair of a spinal dural defect associated with successful biochemical resolution of subarachnoid bleeding in classical infratentorial superficial siderosis.

BACKGROUND AND IMPORTANCE  : Classical infratentorial superficial siderosis (iSS) is characterised by repeated insidious bleeding into the subarachnoid space, leading to haemosiderin deposition within the subpial layers of the brainstem, cerebellum and spinal cord, sometimes with supratentorial involvement. Although nearly always associated with a dural defect (usually from previous trauma or neurosurgery) there is little evidence to support definitive investigation and management strategies. Here, we present a novel investigation strategy to identify a dural defect and subsequent successful surgical repair with biochemical resolution of subarachnoid bleeding. CLINICAL PRESENTATION: A 55-year-old gentleman presented with a 15-year progressive history of sensorineural deafness, followed by a slowly worsening gait ataxia. He had previously sustained cranio-spinal trauma. On examination there were features of myelopathy and ataxia. MRI demonstrated classical iSS, affecting cerebellum and cerebral cortices, with a cervicothoracic epidural CSF collection. Lumbar puncture (LP) revealed elevated ferritin 413 ng/mL and red cell count of 4160. Reverse CT myelography, a novel technique involving contrast injection into the collection, delineated a dural defect at the T9/T10 level that was not present on conventional myelography. Following surgical repair, repeat LP twelve months later demonstrated biochemical improvement (ferritin 18 ng/mL, red cells < 1). There was no further neurological deterioration in symptoms during eighteen months follow-up. CONCLUSION: We show the value of a rational targeted investigation pathway in identifying a surgically reparable dural defect underlying classical iSS. We also provide proof of concept that surgical repair can facilitate biochemical resolution of subarachnoid bleeding and might prevent progression of neurological disability.

Neuropsychological and neuroimaging characteristics of classical superficial siderosis.

OBJECTIVE: To define the neuropsychological and neuroimaging characteristics of classical infratentorial superficial siderosis (iSS), a rare but disabling disorder defined by hemosiderin deposition affecting the superficial layers of the cerebellum, brainstem and spinal cord, usually associated with a slowly progressive neurological syndrome of deafness, ataxia and myelopathy. METHODS: We present the detailed neuropsychological and neuroimaging findings in 16 patients with iSS (mean age 57 years; 6 female). RESULTS: Cognitive impairment was present in 8/16 (50%) of patients: executive dysfunction was the most prevalent (44%), followed by impairment of visual recognition memory (27%); other cognitive domains were largely spared. Disease symptom duration was significantly correlated with the number of cognitive domains impaired (r = 0.59, p = 0.011). Mood disorders were also common (anxiety 62%, depression 38%, both 69%) but not associated with disease symptom duration. MRI findings revealed siderosis was not only in infratentorial brain regions, but also in characteristic widespread symmetrical supratentorial brain regions, independent of disease duration and degree of cognitive impairment. The presence of small vessel disease markers was very low and did not account for the cognitive impairment observed. CONCLUSION: Neuropsychological disturbances are common in iSS and need to be routinely investigated. The lack of association between the anatomical extent of hemosiderin and cognitive impairment or disease duration suggests that hemosiderin itself is not directly neurotoxic. Additional biomarkers of iSS disease severity and progression are needed for future research and clinical trials.

Case Report: Auditory Neuropathy and Central Auditory Processing Deficits in a Neuro-Otological Case-Study of Infratentorial Superficial Siderosis.

Hearing and balance impairment are the most frequently reported features of infratentorial (classical) superficial siderosis (iSS). There are few comprehensive descriptions of audiovestibular function in iSS and therefore limited understanding of the affected segment(s) of the audiovestibular pathway. In addition, monitoring disease progression and response to treatment is challenging and currently mainly guided by subjective patient reports and magnetic resonance imaging. To the best of our knowledge, there have been no previous reports assessing central auditory function in iSS. We describe such findings in a patient with iSS in an attempt to precisely localize the site of the audiovestibular dysfunction, determine its severity and functional impact. We confirm the presence of (asymmetrical) auditory neuropathy and identify central auditory processing deficits, suggesting involvement of the central auditory pathway beyond the brainstem. We correlate the audiological and vestibular findings with self-report measures and the siderosis appearances on brain magnetic resonance images.

Outcomes of endoscopic orbital decompression for graves' ophthalmopathy.

BACKGROUND/AIMS: We assess outcomes of endoscopic orbital decompression for Graves' ophthalmopathy. METHODS: A review of endoscopic orbital decompressions of the medial and partial inferior wall between July 2004 and July 2017 was carried out. Outcome was assessed by comparing pre- and post-operative measurements of exophthalmometry and visual acuity. Results were evaluated by repeated measures analysis of variance. RESULTS: A total of 41 orbits in 25 patients underwent endoscopic orbital decompression for Graves' ophthalmopathy in the time period; however, six orbits in three patients had insufficient data for inclusion. Eleven patients required concurrent septoplasty to allow access. Measurements were taken at a mean of 11 days, 32 days, and 95 days post-operatively. Reduction in mean proptosis was 2.81 mm at 1-month post-decompression and 3.26 mm at 3 months. There was no significant difference between those treated for compressive optic neuropathy compared with those treated for cosmetic reasons. Colour vision by Ishihara plate improved significantly by a mean score of 2.67 post-operatively. Using LogMAR conversion for visual acuity, measured by a best-corrected Snellen chart, improvement of 0.18 was achieved at 1-month post-decompression, equivalent to approximately two lines on the Snellen chart. There was minimal (0.04) further improvement at 3 months. The improvement in visual acuity was greater in cases treated for compressive optic neuropathy than cosmesis, but this did not reach statistical significance (p = 0.06). Three cases required revision surgery. Diplopia disimproved or developed in four cases and squint surgery was required in three cases. CONCLUSIONS: Endoscopic orbital decompression offers an effective, safe and minimally invasive treatment for Graves' ophthalmopathy. There is a trend towards continued improvement in outcomes over the course of 3 months post-operatively.

The impossible gallbladder: aspiration as an alternative to conversion.

BACKGROUND: Laparoscopic cholecystectomy is the standard of care for symptomatic gallstone disease but when laparoscopic removal proves impossible the standard advice is to convert to open surgery. This jettisons the advantages of laparoscopy for a procedure which surgeons no longer perform routinely, so it may no longer be the safest practice. We hypothesised that gallbladder aspiration would be a safer alternative when laparoscopic removal is impossible. METHODS: A retrospective analysis was performed of all laparoscopic cholecystectomies attempted under one surgeon's care over 19 years, and the outcomes of gallbladder aspiration were compared with the standard conversion-to-open procedure within the same institution. RESULTS: Of 757 laparoscopic cholecystectomies attempted, 714 (94.3%) were successful, while 40 (5.3%) were impossible laparoscopically and underwent gallbladder aspiration. Interval cholecystectomy was later performed in 34/40 (85%). Only 3/757 (0.4%) were converted to open. No aspiration-related complications occurred and excessive bile leakage from the gallbladder was not observed. During this time 1209 laparoscopic cholecystectomies were attempted by other surgeons in the institution of which 55 (4.55%) were converted to open and 22 (40%) had procedure-associated complications. There was a significant difference in the mean (± SEM) post-operative hospital stay between laparoscopic gallbladder aspiration [3.12 (± 0.558) days] and institutional conversion-to-open cholecystectomy [9.38 (± 1.04) days] (p < 0.001), with attendant cost savings. CONCLUSION: Laparoscopic gallbladder aspiration is a safe alternative to conversion when inflammation makes cholecystectomy impossible laparoscopically, especially in the sickest patients and for surgeons with limited open surgery experience. This approach minimises morbidity and permits laparoscopic cholecystectomy in the majority after a suitable interval or referral of predicted difficult cases to specialist hepatobiliary centres.

Impact of positive margins on outcomes of oropharyngeal squamous cell carcinoma according to p16 status.

BACKGROUND: Currently, positive surgical margins in head and neck cancer are considered to be an indicator for postoperative chemoradiotherapy (CRT) over radiotherapy (RT) alone. However, there are less data regarding the impact of margin status on human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (SCC). METHODS: We performed a retrospective review of 55 patients with oropharyngeal SCC undergoing primary surgical treatment. The impact of margin status on disease-specific survival (DSS) was studied according to p16 status. RESULTS: Twenty-one patients had positive margins. Adjuvant treatment in these cases was CRT (n = 6), RT alone (n = 14), and none (n = 1). Among p16-negative patients, positive margins and dysplasia at margins predicted significantly worse DSS. Among patients with p16-positive disease, margin status had no impact on DSS. CONCLUSION: Patients with p16-positive oropharyngeal SCC and positive margins after excision maintain a low risk of recurrence despite most receiving RT alone as adjuvant treatment. These findings raise questions regarding the additional benefit of postoperative CRT in this group.

Gastroesophageal Mucosal Injury after Cholecystectomy: An Indication for Surveillance?

BACKGROUND: Cholecystectomy alters bile release dynamics from pulsatile meal-stimulated to continuous, and results in retrograde duodeno-gastric bile reflux (DGR). Bile is implicated in mucosal injury after gastric surgery, but whether cholecystectomy causes esophagogastric mucosal inflammation, therefore increasing the risk of metaplasia, is unclear. STUDY DESIGN: This study examined whether cholecystectomy-induced DGR promotes chronic inflammatory mucosal changes of the stomach and/or the esophagogastric junction (EGJ). Four groups of patients were studied and compared with controls. A group of patients was studied before and 1 year after cholecystectomy; 2 further groups were studied long-term post-cholecystectomy (LTPC) at 5 to 10 years and 10 to 20 years. All underwent abdominal ultrasound and upper gastrointestinal endoscopy with gastric antral and EGJ biopsies, noting the presence of gastric bile pooling. Biopsy specimens were stained for Ki67 and p53 overexpression, and the bile reflux index (BRI) was calculated. RESULTS: At endoscopy, bile pooling was observed in 9 of 26 (34.6%) controls, in 8 of 25 (32%) patients pre-cholecystectomy, in 15 of 25 (60%) 1 year post-cholecystectomy patients (p = 0.047), and 23 of 29 (79.3%) LTPC patients (p = 0.001). Bile reflux index positivity at the EGJ increased from 19% of controls through 41% of LTPC patients (p = 0.032). Ki67 was overexpressed at the EGJ in 19% of controls, but in 62% of LTPC patients (p = 0.044); p53 was overexpressed at the EGJ in 19% of controls compared with 66% of LTPC patients (p = 0.001). CONCLUSIONS: Duodeno-gastric bile reflux was more common in patients with gallstones than in controls, and its incidence doubled after cholecystectomy. This was associated with inflammatory changes in the gastric antrum and the EGJ, evident in most LTPC patients. Ki67 and p53 overexpression at the EGJ suggests cellular damage attributable to chronic bile exposure post-cholecystectomy, increasing the likelihood of dysplasia. Further studies are required to determine whether DGR-mediated esophageal mucosal injury is reversible or avoidable, and whether surveillance endoscopy is indicated after cholecystectomy.

Association of Extracapsular Spread With Survival According to Human Papillomavirus Status in Oropharynx Squamous Cell Carcinoma and Carcinoma of Unknown Primary Site.

IMPORTANCE: The presence of extracapsular spread (ECS) of metastatic nodes is considered a poor prognosticator in head and neck cancer, with postoperative chemoradiation therapy often recommended over radiation therapy alone in such cases. However, there is less clarity regarding the effect of ECS on human papillomavirus-associated oropharynx squamous cell carcinoma (OPSCC) or carcinoma of unknown primary site (CUP). OBJECTIVE: To investigate the association of ECS according to human papillomavirus status in OPSCC and CUP with survival. DESIGN, SETTING, AND PARTICIPANTS: This investigation was a retrospective cohort study performed between August 1998 and March 2015 at an academic teaching hospital. Participants were 83 patients with OPSCC (n = 62) or CUP (n = 21) undergoing neck dissection as part of initial treatment. MAIN OUTCOME AND MEASURES: Human papillomavirus status was determined by p16 immunohistochemistry. The presence of ECS was extrapolated from pathology reports, and the extent of ECS was determined by rereview of original pathology slides. Disease-specific survival (DSS) and recurrence-free survival (RFS) were assessed. RESULTS: Among 83 patients (71 male), there were 45 p16-positive and 38 p16-negative tumors. Fifty-one patients had ECS, which was graded as extensive in 43 cases. The median follow-up was 31 months for all patients and 50 months for surviving patients. Among the entire cohort, adverse predictors of RFS were p16-negative status (hazard ratio [HR], 9.4; 95% CI, 3.3-27.2) and ECS (HR, 6.5; 95% CI, 2.0-21.6). Adverse predictors of DSS were p16-negative status (HR, 16.8; 95% CI, 3.9-71.2) and ECS (HR, 8.3; 95% CI, 2.0-35.3). Among p16-negative patients, ECS was significantly associated with worse RFS (HR, 9.7; 95% CI, 1.3-72.3) and DSS (HR, 8.7; 95% CI, 1.1-62.7). In contrast, among p16-positive patients, ECS had no effect on RFS (HR, 1.1; 95% CI, 0.2-7.8) or DSS (HR, 1.2; 95% CI, 0.1-18.7). CONCLUSIONS AND RELEVANCE: The presence of ECS appears to be associated with survival in OPSCC and CUP according to p16 status. Our findings raise questions regarding the benefits of postoperative chemoradiation therapy in p16-positive patients with ECS.