The Clinical Significance of Small Vessel Vasculitis on Temporal Artery Biopsies.

BACKGROUND: Giant cell arteritis (GCA) is the most common type of systemic vasculitis in the elderly. Untreated, it can lead to irreversible blindness. Its diagnosis relies on a temporal artery biopsy (TAB). However, a proportion of patients have small vessel vasculitis (SVV) on biopsy; the prognosis of which remains unclear. The aim of this study is to compare the clinical presentation and long-term outcomes of those with SVV with negative and positive biopsies to determine whether long-term corticosteroid therapy can be avoided in these patients. METHODS: Post hoc analysis of patients with suspected GCA who underwent TAB and fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) scan as part of a prospective GCA and PET cohort. Patients were divided in to 3 groups based on TAB result: positive (inflammation in the main artery wall), negative (no inflammation), and SVV (isolated vasa vasorum or periadventitial SVV). Clinical, serological, and PET/CT data of patients with SVV were compared with those with positive and those with negative biopsies. RESULTS: For the 58 eligible patients recruited between May 2016 and December 2017, 11 had SVV, 12 had positive, and 35 had negative biopsies. Patients with SVV had similar clinical, serological, and PET/CT findings to those with negative biopsies. Compared with those with positive biopsies, patients with SVV had lower erythrocyte sedimentation rate (25 vs 78 mm/hour; P = 0.02), platelet count (296 vs 385 ×109/L; P = 0.03), and a lower median total vascular score on PET/CT scan (1.0 vs 13.5; P = 0.01). Median prednisone dose was lower (4.8 vs 11.7 mg; P = 0.015) and fewer were on steroid-sparing agents (20% vs 67%; P = 0.043) at 6 months. The percentage of patients with a clinical diagnosis of GCA was similar between those with SVV (3/11, 27.3%) and those with negative biopsies (5/35, 14.3%; P = 0.374). CONCLUSIONS: Patients with SVV on TAB had similar clinical features, PET/CT findings, and 6-month outcomes to those with negative biopsies. Small vessel vasculitis can be treated as equivalent to a negative biopsy when being considered for diagnosis and treatment of GCA.

Infiltrative lymphocytic hypophysitis successfully treated with rituximab and mycophenolate mofetil.

SUMMARY: Lymphocytic hypophysitis is a rare neuroendocrine disease characterised by an autoimmune inflammatory disorder of the pituitary gland. We report a 50-year-old woman who presented with headaches and bilateral sixth cranial nerve palsies. MRI of the pituitary revealed extensive fibrosis involving the sellar and extending into both cavernous sinuses causing bilateral occlusion of the internal carotid arteries (ICA). Transphenoidal biopsy confirmed the diagnosis of infiltrative fibrotic lymphocytic hypophysitis. Symptoms resolved with high dose of oral steroids but relapsed on tapering, requiring several treatments of i.v. pulse steroids over 8 months. Rituximab combined with mycophenolate mofetil was required to achieve long-term symptom relief. Serial MRI pituitary imaging showed stabilisation of her disease without reduction in sellar mass or regression of ICA occlusion. The patient's brain remained perfused solely by her posterior circulation. This case demonstrates an unusual presentation of a rare disease and highlights a successful steroid-sparing regimen in a refractory setting. LEARNING POINTS: Lymphocytic hypophysitis is a rare inflammatory disorder of the pituitary gland. In exceptional cases, there is infiltration of the cavernous sinus with subsequent occlusion of the internal carotid arteries. First-line treatment of lymphocytic hypophysitis is high-dose glucocorticoids. Relapse after tapering or discontinuation is common and its use is limited by long-term adverse effects. There is a paucity of data for treatment of refractory lymphocytic hypophysitis. Goals of treatment should include improvement in symptoms, correction of hormonal insufficiencies, reduction in lesion size and prevention of recurrence. Steroid-sparing immunosuppressive drugs such as rituximab and mycophenolate mofetil have been successful in case reports. This therapeutic combination represents a viable alternative treatment for refractory disease.

Lymphocytic Hypophysitis Presenting as Bilateral Abducens Nerve Palsy: A Case Report.

Lymphocytic hypophysitis (LYH) is a neuroendocrine disorder characterised by autoimmune inflammation of the pituitary gland with varying degrees of pituitary dysfunction, visual field defects and ocular motility disturbance. The authors report an interesting case of a 50-year-old woman presenting with intermittent bilateral abduction deficits. Neuroimaging and histopathological findings are presented. To the authors' knowledge, this is the first report of recurrent horizontal binocular diplopia and complete bilateral internal carotid artery occlusion in association with LYH.

Cranial and large vessel activity on positron emission tomography scan at diagnosis and 6 months in giant cell arteritis.

AIM: Positron emission tomography/computed tomography (PET/CT) can detect cranial and large vessel inflammation in giant cell arteritis (GCA). We aimed to determine the change and significance of vascular activity at diagnosis and 6 months. METHOD: Newly diagnosed GCA patients underwent time-of-flight fluorine-18-fluoro-2-deoxyglucose PET/CT from vertex to diaphragm within 72 hours of commencing corticosteroids and were followed for 12 months. A 6 months scan was performed in patients with inflammatory features on biopsy or CT aortitis. Vascular uptake was visually graded by 2 blinded readers across 18 artery segments from 0 (no increased uptake) to 3 (very marked uptake). Scores were summed to give a total vascular score (TVS). RESULTS: We enrolled 21 GCA patients and 15 underwent the serial scan. Twelve (57%) patients experienced a relapse and 5 of these had ischemic features of vision disturbance, jaw or limb claudication. The median TVS fell from 14 (interquartile range [IQR] 4-24) at baseline to 5 (IQR 0-10) at 6 months (P < .01) with reduction in both cranial and large artery scores. While the overall relapse rate was similar between patients with a high (≥10) and low baseline TVS, patients with high scores were numerically more likely to experience an ischemic relapse (33% vs 11%, P = .34). Five out of 15 patients had persistent uptake in at least 1 vessel on the serial PET/CT but none experienced a subsequent relapse. CONCLUSION: Vascular activity decreased in cranial and large arteries between diagnosis and 6 months. Persistent activity did not predict subsequent relapse.

Molecular and clonal evolution in recurrent metastatic gliosarcoma.

We discuss the molecular evolution of gliosarcoma, a mesenchymal type of glioblastoma (GBM), using the case of a 37-yr-old woman who developed two recurrences and an extracranial metastasis. She was initially diagnosed with isocitrate dehydrogenase (IDH) wild-type gliosarcoma in the frontal lobe and treated with surgery followed by concurrent radiotherapy with temozolomide. Five months later the tumor recurred in the left frontal lobe, outside the initially resected area, and was treated with further surgery and radiotherapy. Six months later the patient developed a second left frontal recurrence and was again treated with surgery and radiotherapy. Six weeks later, further recurrence was observed in the brain and bone, and biopsy confirmed metastases in the pelvic bones. To understand the clonal relationships between the four tumor instances and the origin of metastasis, we performed whole-genome sequencing of the intracranial tumors and the tumor located in the right iliac bone. We compared their mutational and copy-number profiles and inferred the clonal phylogeny. The tumors harbored shared alterations in GBM driver genes, including mutations in TP53, NF1, and RB1, and CDKN2A deletion. Whole-genome doubling was identified in the first recurrence and the extracranial metastasis. Comparisons of the metastatic to intracranial tumors highlighted a high similarity in molecular profile but contrasting evidence regarding the origin of the metastasis. Subclonal reconstruction suggested a parallel evolution of the recurrent tumors, and that the metastatic tumor was largely derived from the first recurrence. We conclude that metastasis in glioma can be a late event in tumorigenesis.

Assessment for varicella zoster virus in patients newly suspected of having giant cell arteritis.

OBJECTIVES: There is uncertainty if varicella zoster virus (VZV) triggers GCA. This is based on discordant reports of VZV detection in GCA temporal artery biopsies. We conducted a multimodal evaluation for VZV in the inception Giant Cell Arteritis and PET Scan (GAPS) cohort. METHODS: Consecutive patients who underwent temporal artery biopsy for suspected GCA were clinically reviewed for active and past VZV infection and followed for 6 months. Serum was tested for VZV IgM and IgG. Temporal artery biopsy (TAB) sections were stained for VZV antigen using the VZV Mouse Cocktail Antibody (Cell Marque, Rocklin, CA, USA). A selection of GCA and control tissues were stained with the VZV gE antibody (Santa Cruz Biotechnology, Dallas, TX, USA), which was used in previous studies. RESULTS: A total of 58 patients met inclusion criteria, 12 (21%) had biopsy-positive GCA and 20 had clinically positive GCA. None had herpes zoster at enrolment and only one patient developed a VZV clinical syndrome (zoster ophthalmicus) on follow-up. There was no difference in VZV exposure between GCA and non-GCA patients. None of the 53 patients who had VZV serology collected had positive VZV IgM antibodies. VZV antigen was not convincingly demonstrated in any of the TAB specimens; 57 TABs stained negative and 1 stained equivocally positive. The Santa Cruz Biotechnology VZV antibody exhibited positive staining in a range of negative control tissues, questioning its specificity for VZV antigen. CONCLUSION: The absence of active infection markers argues against VZV reactivation being the trigger for GCA. Non-specific immunohistochemistry staining may account for positive findings in previous studies.

Diagnostic Accuracy of Positron Emission Tomography/Computed Tomography of the Head, Neck, and Chest for Giant Cell Arteritis: A Prospective, Double-Blind, Cross-Sectional Study.

OBJECTIVE: Positron emission tomography/computed tomography (PET/CT) has not been well studied as a first-line test for giant cell arteritis (GCA), due, in part, to historical limitations in visualizing the cranial arteries. The Giant Cell Arteritis and PET Scan (GAPS) study was therefore carried out to assess the accuracy of a newer generation PET/CT of the head, neck, and chest for determining a diagnosis of GCA. METHODS: In the GAPS study cohort, 64 patients with newly suspected GCA underwent time-of-flight PET/CT (1-mm slice thickness from the vertex to diaphragm) within 72 hours of starting glucocorticoids and before undergoing temporal artery biopsy (TAB). Two physicians with experience in PET reviewed the patients' scans in a blinded manner and reported the scans as globally positive or negative for GCA. Tracer uptake was graded across 18 artery segments. The clinical diagnosis was confirmed at 6 months' follow-up. RESULTS: In total, 58 of 64 patients underwent TAB, and 12 (21%) of the biopsies were considered positive for GCA. Twenty-one patients had a clinical diagnosis of GCA. Compared to TAB, the sensitivity of PET/CT for a diagnosis of GCA was 92% (95% confidence interval [95% CI] 62-100%) and specificity was 85% (95% CI 71-94%). The negative predictive value (NPV) was 98% (95% CI 87-100%). Compared to clinical diagnosis, PET/CT had a sensitivity of 71% (95% CI 48-89%) and specificity of 91% (95% CI 78-97%). Interobserver reliability was moderate (κ = 0.65). Among the enrolled patients, 20% had a clinically relevant incidental finding, including 7 with an infection and 5 with a malignancy. Furthermore, 5 (42%) of 12 TAB-positive GCA patients had moderate or marked aortitis. CONCLUSION: The high diagnostic accuracy of this PET/CT protocol would support its use as a first-line test for GCA. The NPV of 98% indicates the particular utility of this test in ruling out the condition in patients considered to be at lower risk of GCA. PET/CT had benefit over TAB in detecting vasculitis mimics and aortitis.

Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy.

OBJECTIVE: To report novel disease and pathology due to HSPB8 mutations in 2 families with autosomal dominant distal neuromuscular disease showing both myofibrillar and rimmed vacuolar myopathy together with neurogenic changes. METHODS: We performed whole-exome sequencing (WES) in tandem with linkage analysis and candidate gene approach as well as targeted next-generation sequencing (tNGS) to identify causative mutations in 2 families with dominant rimmed vacuolar myopathy and a motor neuropathy. Pathogenic variants and familial segregation were confirmed using Sanger sequencing. RESULTS: WES and tNGS identified a heterozygous change in HSPB8 in both families: c.421A > G p.K141E in family 1 and c.151insC p.P173SfsX43 in family 2. Affected patients had a distal myopathy that showed myofibrillar aggregates and rimmed vacuoles combined with a clear neurogenic component both on biopsy and neurophysiologic studies. MRI of lower limb muscles demonstrated diffuse tissue changes early in the disease stage progressing later to fatty replacement typical of a myopathy. CONCLUSION: We expand the understanding of disease mechanisms, tissue involvement, and phenotypic outcome of HSPB8 mutations. HSPB8 is part of the chaperone-assisted selective autophagy (CASA) complex previously only associated with Charcot-Marie-Tooth type 2L (OMIM 60673) and distal hereditary motor neuronopathy type IIa. However, we now demonstrate that patients can develop a myopathy with histologic features of myofibrillar myopathy with aggregates and rimmed vacuoles, similar to the pathology in myopathies due to gene defects in other compounds of the CASA complex such as BAG3 and DNAJB6 after developing the early neurogenic effects.

Differences in the Pathological Diagnosis and Repeat Craniotomy Rates in Cerebral Tumors Undergoing Biopsy or Resection in an Urban Versus Regional Center.

Primary intracranial tumors occur with an incidence of between 2.5 and 6 per 100,000 individuals. They require specialist expertise for investigation and management including input from radiology, pathology, neurosurgery, and oncology. Therefore, most patients with intracranial neoplasia are investigated and managed in larger hospitals. The geographically dispersed population of Australia has facilitated the development of neurosurgical units in regional areas. However, major metropolitan hospitals are over-represented compared with regional centers in most research cohorts. We therefore sought to investigate the spectrum of intracranial neoplasms undergoing biopsy and surgery at a major regional center in Australia and to compare the demographic and pathological features to similar cohorts treated in major metropolitan hospitals.We searched the pathological databases of both a major regional pathology provider and a major metropolitan pathology practice, which provides surgical pathology services for both a large private and a large public neurosurgical hospital, to identify all cerebral tumors undergoing biopsy or resection over a 14-year period (calendar years 2001 and 2014).In all, 3717 cerebral tumors were identified. Among them, 51% were from an urban private hospital, 33% from an urban public hospital, and 16% from a regional public hospital. Overall, one-third of them were neuroepithelial in origin, a quarter metastatic disease, a fifth meningeal, and one-tenth were pituitary adenomas. The regional center treated a higher proportion of metastatic tumors and less meningeal tumors compared with the urban center. Additionally, patients were less likely to undergo a second operation in the regional center (P < 0.001). The differences give an important insight into the burden of neurosurgical disease in regional Australia, and how it differs from that encountered in large metropolitan centers.

The impact of molecular and clinical factors on patient outcome in oligodendroglioma from 20 years' experience at a single centre.

The increased chemosensitivity of oligodendroglial tumours has been associated with loss of heterozygosity (LOH) of the p arm of chromosome 1 and the q arm of chromosome 19 (LOH 1p/19q). Other clinical and molecular factors have also been identified as being prognostic and predictive of treatment outcome. We reviewed 105 patients with oligodendroglioma treated at a single centre over 20 years. Median survival in oligodendroglioma patients with LOH 1p/19q was significantly longer (10.9 vs. 2.0 years). In the anaplastic oligodendroglioma group, univariate analysis demonstrated decreased patient age, presentation with seizures, use of adjuvant chemotherapy and LOH 1p/19q as predictors of improved survival. Multivariate analysis confirmed LOH 1p/19q as a significant predictor of improved survival (hazard ratio, 3.4; p=0.015). Median survival in patients with anaplastic oligodendroglioma with LOH 1p/19q was 15.4 years vs. 1.2 years for those without LOH 1p/19q. This study confirms the utility of LOH 1p/19q as a prognostic marker in oligodendroglioma.

Two Australian families with inclusion-body myopathy, Paget's disease of bone and frontotemporal dementia: novel clinical and genetic findings.

We report the first Australian families with inclusion-body myopathy, Paget's disease of the bone and frontotemporal dementia (IBMPFD). The clinical characteristics of the two pedigrees are described including a previously undescribed phenotypic feature of pyramidal tract dysfunction in one family member. A novel mutation in the valosin-containing protein (VCP) gene (p.Arg155Leu) was found in one family while the other family had a previously reported mutation (p.Leu198Trp). Our findings broaden the phenotypic spectrum of IBMPFD and further emphasise the resemblance to amyotrophic lateral sclerosis in some cases.

Headache of a diagnosis: frontotemporal pain and inflammation associated with osteolysis.

A 62-year-old woman presented with left frontotemporal pain, scalp tenderness and raised levels of inflammatory markers. Temporal arteritis was considered likely, and symptoms resolved with prednisone therapy. This delayed diagnostic bone biopsy until a soft tissue abscess formed, and Pott's puffy tumour associated with Prevotella osteomyelitis of the frontal bone was diagnosed. This case highlights the value of early histopathological examination, and is a reminder of a condition seen frequently in the pre-antibiotic era.

IQGAP1 and IGFBP2: valuable biomarkers for determining prognosis in glioma patients.

Clinical treatment decisions and the survival outcomes of patients with gliomas are directly impacted by accurate tumor classification. New and more reliable prognostic markers are needed to better identify the variable duration of survival among histologically defined glioma grades. Microarray expression analysis and immunohistochemistry were used to identify biomarkers associated with gliomas with more aggressive biologic behaviors. The protein expression of IQGAP1 and IGFBP2, when used in conjunction with the World Health Organization grading system, readily identified and defined a subgroup of patients with grade III gliomas whose prognosis was poor. In addition, in patients with glioblastoma multiforme, in whom IQGAP1 and IGFBP2 were absent, long-term survival of more than 3 years was observed. The use of these markers confirmed a nonuniform distribution of survival in those with World Health Organization grade III and IV tumors. Thus, IQGAP1 and IGFBP2 immunostaining supplements current histologic grading by offering additional prognostic and predictive information.

The presence of necrosis and/or microvascular proliferation does not influence survival of patients with anaplastic oligodendroglial tumours: review of 98 patients.

Accurate prognosis for patients with anaplastic oligodendroglial gliomas is increasingly difficult to make. Characterisation of these tumours remains challenging, increasing proportions of oligodendroglial diagnoses in gliomas are reported, and no WHO 2000 grade IV exists for them, so that highly anaplastic tumours can only be grouped with glioblastoma (GBM) or with grade III oligodendroglioma, which have differing clinical behaviour. Longer survival times reported for patients with glioblastoma containing an oligodendroglial element (GBMO) suggest that a grade IV for oligodendroglial tumours might exist. In patients with anaplastic gliomas containing an oligodendroglial element, we explored whether microvascular proliferation (MVP) and necrosis were associated with shorter survival, sufficient to create a grade IV. Biopsies for 98 patients with anaplastic oligodendroglioma, anaplastic oligoastrocytoma or tumours with an oligodendroglial and GBM element, discharged 1998-2004, were identified from databases at three allied neurosurgery units. Pathology reports were reviewed for the presence of MVP and necrosis. Anaplastic oligoastrocytoma and GBMO were combined to measure the effect of an astrocytic element on survival. For anaplastic oligodendroglioma patients, median survival time was 24 months, while for anaplastic oligoastrocytoma or GBMO patients, it was 9 months. Age 60 or over (P=0.006) and astrocytic element (P=0.01) were the only independent predictors of survival. Patients 60 and over with an astrocytic element had 4.6 times the risk of death of patients under 60 with anaplastic oligodendroglioma.A grade IV cannot be created using necrosis or MVP since neither feature predicted survival after adjustment for age and an astrocytic element. However age and an astrocytic element were strong predictors of poorer survival in patients with anaplastic oligodendroglial tumours.

'Ancient' schwannoma of the orbit.

A 65-year-old woman presented with a 3 month history of right eye discomfort and protrusion. Examination revealed right proptosis with hypoglobus and diplopia in extremes of upgaze. Computed tomographic scanning revealed a large extraconal mass in the superotemporal orbit. The mass was excised through an extended superior skin crease incision. Histopathology revealed a benign tumour of Schwann cell origin showing advanced cystic degeneration, the so-called 'ancient schwannoma'. The authors could find only two previously reported cases of such tumours arising in the orbit.

Delay of hospital discharge secondary to postoperative fever--is it necessary?

Although postoperative fever is common after major gynecologic surgery, the majority of patients have no identifiable infectious or pathologic etiology. Traditional management has been to delay hospital discharge until the patient is afebrile. The authors evaluate the outcome of patients discharged with postoperative fever after major gynecologic surgery. In a retrospective review of 537 women undergoing major gynecologic surgery, 211 (39%) had postoperative fever. The authors identified all patients who were discharged despite having a temperature of 38 degrees C or higher (> or = 100.4 degrees F) in the preceding 12 hours. All outpatient and inpatient records for a period of 30 days were reviewed. Thirty-eight (18%) of 211 patients who were febrile postoperatively were discharged despite having a fever within the preceding 12 hours. One patient was lost to follow-up. Two (5%) of 37 patients had a documented infection (one urinary tract infection and one postoperative wound infection). Four (11%) were readmitted within 30 days for noninfectious causes. None of the patients discharged on oral antibiotics had an antibiotic-related complication. Eighty-four percent of patients discharged with a postoperative fever did not have a documented infectious or pathologic cause for the fever while at home.