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Purpose/Objective(s) The grade of meningioma has significant implications on the selection of treatment regimens ranging from observation to surgical resection with adjuvant radiation. For most patients, meningiomas are diagnosed radiologically and grade is not determined unless a surgical procedure is completed. We hypothesize that the use of a 3D convolutional neural network (CNN) architecture with two encoding paths will provide auto-classification of grade I and II meningioma using T1-contrast enhancing (T1-CE) and T2-Fluid attenuated inversion recovery (FLAIR) magnetic resonance (MR) images. Materials/Methods Ninety-six consecutive treatment naive patients with pre-operative T1-CE and T2-FLAIR MR images from 2010 to 2019 were evaluated. The patients underwent surgical resection resulting in a diagnosis of grade I or II meningioma. Histopathology was confirmed by a neuropathologist and neuropathology fellow based on current classification guidelines described in the 2016 World Health Organization (WHO) Bluebook. The delineation of meningiomas was completed on both T1-CE and T2-FLAIR MR with the inclusion of surrounding T2-FLAIR hyperintensity. A novel asymmetric 3D CNN architecture was constructed with two encoding paths based on T1-CE and T2-FLAIR MR. Each path used the same 3 × 3 × 3 kernel with different filters to weight the spatial features of each sequence separately. Final model performance was assessed by 10-fold cross-validation. Results Of the 96 patients, 55 (57%) were pathologically classified as grade I and 41 (43%) as grade II meningiomas. Optimization of our model led to a filter weighting of 18:2 between the T1-CE and T2-FLAIR MR image paths with alternative weighting shown in Table 1. Eighty-six (90%) patients were classified correctly and 10 (10%) were misclassified based on their pre-operative MRs with a model sensitivity of 0.85 and specificity of 0.93. Among the misclassified, 4 were grade I, and 6 were grade II. The model was robust to tumor locations and sizes. Conclusion A novel asymmetric CNN with two differently weighted encoding paths was developed for successful automated meningioma grade classification. Our model outperforms CNN using a single path for single or multimodal MR-based classification.

Cushing's disease manifests as symptoms of glucocorticoid excess secondary to the increased secretion of corticotropin by a corticotroph adenoma in the pituitary gland. Unfortunately, magnetic resonance imaging (MRI) performed at conventional clinical field strengths of 1.5 or 3 Tesla has limited sensitivity for the detection of these pituitary tumors, and radiologic uncertainty often necessitates more invasive workup to confirm diagnosis and guide resection. It has been postulated that higher static magnetic field strengths may increase the adenoma detection rate and thus the utility of MRI for this clinical application. In this report, we describe our initial experience using ultra-high field 7 Tesla (7 T) MRI in patients with suspected Cushing's disease and negative or equivocal imaging at conventional field strengths. We performed contrast-enhanced 7 T pituitary MRI in 10 patients with up to three different T1-weighted sequences and correlated the imaging abnormalities identified with results of histologic evaluation in patients who subsequently underwent resection. We found that 7 T MRI enabled the identification of previously undetected areas of focal pituitary hypoenhancement in 9 patients (90%), of which 7 corresponded histologically to corticotroph adenomas. These early findings suggest an important adjunctive role for ultra-high field MR imaging in the noninvasive clinical workup of suspected Cushing's disease.

Silent thyrotropin pituitary adenomas (TSHomas) are defined by absence of hyperthyroidism despite TSH immunopositivity. Data pertaining to clinical and surgical characteristics of silent TSHomas remains limited. We aim to describe the clinical presentation, pathological characteristics, and outcomes in silent TSHoma patients treated at a tertiary pituitary center. We retrospectively identified patients with histologically-proven silent TSHoma who underwent transsphenoidal resection at our center between 2000 and 2016 (n = 1244 total patients). Patients with preoperative hyperthyroidism or thyroidectomy were excluded. Twenty patients with silent TSHomas were included (1.6% of surgically treated PAs), of which 35% were reoperations. Presenting symptoms included vision loss (45%) and headache (40%). Preoperative pituitary dysfunction included hypothyroidism (40%), hypogonadotropic hypogonadism (30%), and panhypopituitarism (15%). Nineteen patients (95%) had macroadenomas (mean diameter 29.9 mm). Extrasellar growth was identified in 17 patients (85%) and 65% had cavernous sinus invasion. Immunostaining for alpha-subunit was positive in 19 patients (95%), and 75% of tumors expressed immunopositivity for hormones other than TSH. Gross total tumor resection was achieved in 9 patients (45%) on follow-up MRI. Major postoperative complications included hydrocephalus (1 patient) and cerebrospinal fluid leak with meningitis (1 patient). Tumor progression and recurrence occurred in 1 patient each (10% total) over the follow-up period (median 18.5 months). Silent TSHomas tend to be large, invasive tumors. In addition to TSH, a majority express immunopositivity for alpha-subunit and gonadotropins, thereby potentially supporting a primitive adenoma lineage and subtype. Despite reoperation in several patients, good overall outcomes with low complication rates were achieved.

Background Rathke cleft cysts (RCCs) are benign sellar and suprasellar lesions commonly presenting as asymptomatic incidental findings. Rarely, RCCs hemorrhage and mimic pituitary apoplexy on presentation. Objective To review a series of hemorrhagic RCCs for physicians encountering this rare presentation. Methods A database review of >1700 transsphenoidal pituitary operations was performed at the USC Pituitary Center to identify patients with pathologically confirmed RCCs presenting with acute symptoms and evidence of hemorrhage at the time of surgery. Surgical treatment involved transsphenoidal RCC fenestration and drainage. Clinical, endocrine, and imaging outcomes were reviewed. Results A total of 119 RCCs were identified, and 6 (5.0%) presented with hemorrhage mimicking pituitary apoplexy. Presenting symptoms included acute onset headaches (5/6), vision loss (2/6), and oculomotor nerve palsy (n = 1). Endocrine disturbances at presentation included pre-existing amenorrhea in all female patients (3/3), hypothyroidism (n = 2), panhypopituitarism (n = 2), and one with profound hyponatremia (Na 116 meq/L). All patients underwent endonasal transsphenoidal fenestration and drainage with no major complications. Over mean follow-up of 38.4 mo, 2/2 patients with vision loss reported improvement, and 2/5 patients with headaches reported improvement. Although all women resumed menses, patients with preoperative hypopituitarism did not experience pituitary axis improvement. Follow-up magnetic resonance imaging showed no instances of RCC recurrence with a mean imaging follow-up of 38.6 mo. Conclusion RCCs occasionally present with hemorrhage and clinical symptoms that may be confused with apoplexy. Outcomes following hemorrhagic RCC treatment are excellent when treated at tertiary pituitary centers. Although hyperprolactinemia often improves following surgery, other pituitary axis deficits typically do not.

BACKGROUND Neuroendocrine prostatic carcinoma (NEPC) is uncommon. The pathogenesis, clinical association, and clinical implications of this disease are still evolving. METHODS Clinicopathologic, immunohistochemical and genomic studies were used to investigate the incidence of NEPC in various clinicopathologic settings and the expression of various biomarkers in NEPC and non-NEPC as well as small cell NEPC. The study included 45 treatment-naive Gleason pattern (GP) 3 and 94 GP 4/5, 43 post-radiation, 60 post-androgen deprivation therapy (ADT), 38 lymph node metastatic and 9 small cell prostatic adenocarcinomas (PCs). RESULTS NEPC was found in 7% GP3, 10% GP4/5, 9% post-radiation, 18% post-ADT, and 5% lymph node metastatic PCs, respectively. Compared with treatment-naive PCs, post-ADT PCs showed significantly increased incidence of NEPC (p

Reducing body myopathy (RBM) is a rare muscle disorder, with marked presence of characteristic intracytoplasmic aggregates in affected muscle fibers. RBM is associated with FHL1 gene mutations. Clinical presentations of RBM have ranged from early fatal to adult onset progressive muscle weakness. We present herein the clinical, electrodiagnostic, and muscle biopsy findings of a 17-year-old female with progressive muscle weakness and contracture. Muscle biopsy showed atrophic fibers that contained menadione nitroblue tetrazolium (NBT) positive reducing bodies. Genetic testing revealed a variant of uncertain significance in the FHL1 gene at a position known to be pathogenic when substituted by other amino acids (p.His123Arg). This variant was later reclassified as pathogenic.

Background Better treatments for glioblastoma (GBM) patients, in particular in the recurrent setting, are urgently needed. Clinical trials performed in Brazil indicated that intranasal delivery of perillyl alcohol (POH) might be effective in this patient group. NEO100, a highly purified version of POH, was current good manufacturing practice (cGMP) manufactured to evaluate the safety and efficacy of this novel approach in a Phase I/IIa clinical trial in the United States. Methods A total of 12 patients with recurrent GBM were enrolled into Phase I of this trial. NEO100 was administered by intranasal delivery using a nebulizer and nasal mask. Dosing was 4 times a day, every day. Four cohorts of 3 patients received the following dosages: 96 mg/dose (384 mg/day), 144 mg/dose (576 mg/day), 192 mg/dose (768 mg/day), and 288 mg/dose (1152 mg/day). Completion of 28 days of treatment was recorded as 1 cycle. Adverse events were documented, and radiographic response via Response Assessment in Neuro-Oncology (RANO) criteria was evaluated every 2 months. Progression-free and overall survival were determined after 6 and 12 months, respectively (progression-free survival-6 [PFS-6], overall survival-12 [OS-12]). Results Intranasal NEO100 was well tolerated at all dose levels and no severe adverse events were reported. PFS-6 was 33%, OS-12 was 55%, and median OS was 15 months. Four patients (33%), all of them with isocitrate dehydrogenase 1 (IDH1)-mutant tumors, survived >24 months. Conclusion Intranasal glioma therapy with NEO100 was well tolerated. It correlated with improved survival when compared to historical controls, pointing to the possibility that this novel intranasal approach could become useful for the treatment of recurrent GBM.

Background Recent large-scale genomic studies have revealed a spectrum of genetic variants associated with specific subtypes of central nervous system (CNS) tumors. The aim of this study was to determine the clinical utility of comprehensive genomic profiling of pediatric, adolescent and young adult (AYA) CNS tumors in a prospective setting, including detection of DNA sequence variants, gene fusions, copy number alterations (CNAs), and loss of heterozygosity. Methods OncoKids, a comprehensive DNA- and RNA-based next-generation sequencing (NGS) panel, in conjunction with chromosomal microarray analysis (CMA) was employed to detect diagnostic, prognostic, and therapeutic markers. NGS was performed on 222 specimens from 212 patients. Clinical CMA data were analyzed in parallel for 66% (146/222) of cases. Results NGS demonstrated clinically significant alterations in 66% (147/222) of cases. Diagnostic markers were identified in 62% (138/222) of cases. Prognostic information and targetable genomic alterations were identified in 22% (49/222) and 18% (41/222) of cases, respectively. Diagnostic or prognostic CNAs were revealed by CMA in 69% (101/146) of cases. Importantly, clinically significant CNAs were detected in 57% (34/60) of cases with noncontributory NGS results. Germline cancer predisposition testing was indicated for 27% (57/212) of patients. Follow-up germline testing was performed for 20 patients which confirmed a germline pathogenic/likely pathogenic variant in 9 cases: TP53 (2), NF1 (2), SMARCB1 (1), NF2 (1), MSH6 (1), PMS2 (1), and a patient with 47,XXY Klinefelter syndrome. Conclusions Our results demonstrate the significant clinical utility of integrating genomic profiling into routine clinical testing for pediatric and AYA patients with CNS tumors.

Abnormally phosphorylated tau, an indicator of Alzheimer’s disease, accumulates in the first decades of life in the locus coeruleus (LC), the brain’s main noradrenaline supply. However, technical challenges in reliable in-vivo assessments have impeded research into the role of the LC in Alzheimer’s disease.We studied participants with or known to be at-risk for mutations in genes causing autosomal-dominant Alzheimer’s disease (ADAD) of early onset, providing a unique window into the pathogenesis of Alzheimer’s largely disentangled from age-related factors. Using high- resolution MRI and tau PET, we revealed lower rostral LC integrity in symptomatic participants. LC integrity was associated with individual differences in tau burden and memory decline. Post- mortem analyses in a separate set of carriers of the same mutation confirmed substantial neuronal loss in the LC.Our findings link LC degeneration to tau burden and memory in Alzheimer’s and highlight a role of the noradrenergic system in this neurodegenerative disease.

OBJECTIVE Silent corticotroph adenomas (SCAs) are a distinct subtype of nonfunctioning pituitary adenomas (NFAs) that demonstrate positive immunohistochemistry for adrenocorticotropic hormone (ACTH) without causing Cushing’s disease. SCAs are hypothesized to exhibit more aggressive behavior than standard NFAs. The authors analyzed their institution’s surgical experience with SCAs in an effort to characterize rates of invasion, postoperative clinical outcomes, and patterns of disease recurrence and progression. The secondary objectives were to define the best treatment strategies in the event of tumor recurrence and progression. METHODS A retrospective analysis of patients treated at the authors’ institution identified 100 patients with SCAs and 841 patients with NFAs of other subtypes who were treated surgically from 2000 to 2019. Patient demographics, tumor characteristics, surgical and neuroimaging data, rates of endocrinopathy, and neurological outcomes were recorded. Cohorts of patients with SCAs and patients with standard NFAs were compared with regard to these characteristics and outcomes. RESULTS The SCA cohort presented with cranial neuropathy (13% vs 5.7%, p = 0.0051) and headache (53% vs 42.3%, p = 0.042) compared to the NFA cohort, despite similar rates of apoplexy. The SCA cohort included a higher proportion of women (SCA 60% vs NFA 45.8%, p = 0.0071) and younger age at presentation (SCA 50.5 ± 13.3 vs NFA 54.6 ± 14.9 years of age, p = 0.0082). Reoperations were comparable between the cohorts (SCA 16% vs NFA 15.7%, p = 0.98). Preoperative pituitary function was comparable between the cohorts with the exception of higher rates of preoperative panhypopituitarism in NFA patients (2% vs 6.1%, respectively; p = 0.0033). The mean tumor diameter in SCA patients was 24 ± 10.8 mm compared to 26 ± 11.3 mm in NFA patients (p = 0.05). Rates of cavernous sinus invasion were higher in the SCA group (56% vs 49.7%), although this result did not reach statistical significance. There were no significant differences in extent of resection, intraoperative CSF leak rates, endocrine or neurological outcomes, or postoperative complications. Ki-67 rates were significantly increased in the SCA cohort (2.88 ± 2.79) compared to the NFA cohort (1.94 ± 1.99) (p = 0.015). Although no differences in overall rates of progression or recurrence were noted, SCAs had a significantly lower progression-free survival (24.5 vs 51.1 months, p = 0.0011). Among the SCA cohort, progression was noted despite the use of adjuvant radiosurgery in 33% (n = 4/12) of treated tumors. Adequate tumor control was not achieved in half (n = 6) of the SCA progression cohort despite radiosurgery or multiple resections. CONCLUSIONS In this study, to the authors’ knowledge the largest surgical series to assess outcomes in SCAs to date, the findings suggest that SCAs are more biologically aggressive tumors than standard NFAs. The progression-free survival duration of patients with SCAs is only about half that of patients with other NFAs. Therefore, close neuroimaging and clinical follow-up are warranted in patients with SCAs, and residual disease should be considered for early postoperative adjuvant radiosurgery, particularly in younger patients.

Objective Comprehensive molecular profiling of radioresistant and cystic vestibular schwannoma (VS) subtypes. Study design Our study utilized whole-exome sequencing (WES), RNA-sequencing (RNAseq), and correlated clinical data from 12 samples (2 samples of solid sporadic subtype, 8 with cystic changes, and 2 previously irradiated). Setting Academic medical center. Patients Patients diagnosed with VS who required surgical treatment. Inclusion: Cystic and radioresistant tumors matched to age and tumor volume, with solid sporadic VS samples as control; Exclusion: NF-2 patients. Intervention(s) WES using custom probes for copy number analysis. A modified version of the Agilent Human Whole Exome sequencing hybrid capture system was used to process samples. Recurrent variants were identified and compared between groups. Leukocyte-derived DNA was utilized as internal control to reduce false-positives. Main outcome measure(s) Analysis of genetic landscape of VS subtypes (naive solid VS, cystic VS, and previously irradiated VS) by performing deep next-generation sequencing. Results WES data achieved a mean coverage of 202X and RNAseq generated an average of 74 million total reads. As a group, 25% of samples had 22q loss. Somatic analysis identified previously reported genes and multiple novel mutations across samples. Differential expression analysis of RNAseq data found significantly mutated genes such as COL6A3, CLMP, ART4, Lumican that were shared by both cystic VS and irradiated VS, but not seen in sporadic VS. Conclusions Using WES we were able to demonstrate that cystic and irradiated samples are subtypes of VS with an increased mutation burden and a unique genetic fingerprint. We identified differences between the genomic and molecular profile of cystic VS and radioresistant VS. Our results help advance the understanding of the pathophysiology of these tumor subtypes and suggest possible molecular targets for novel treatment strategies.

Amyloidosis is a challenging diagnosis in the absence of clinical suspicion. The two patients reported here lacked any symptoms suggestive of amyloidosis. Instead, they presented with sudden, unexplained cardiac arrests that were persistent, treatment refractory, and ultimately fatal. Post-mortem examination unexpectedly revealed evidence of diffuse, systemic amyloidosis throughout multiple organ systems. We bring awareness to this unusual presentation of systemic amyloidosis that portends to poor outcome.

OBJECTIVES/HYPOTHESIS Spontaneous cerebrospinal fluid (CSF) leaks of the skull base are associated with obesity, multiparity, and elevated intracranial pressure. Although spontaneous CSF leaks often present with rhinorrhea, they can be an underdiagnosed cause of chronic aspiration pneumonitis, a complication that has not been previously reported in detail. STUDY DESIGN Retrospective case series. METHODS The authors retrospectively reviewed all patients undergoing surgical repair of CSF fistulae at the University of Southern California between 2011 and 2018 to identify those presenting with pulmonary symptoms including dyspnea, aspiration, chronic cough, and shortness of breath caused by chronic noniatrogenic CSF pneumonitis. RESULTS Symptomatic chronic pneumonitis was evident in six of 20 patients with spontaneous CSF rhinorrhea. Five women (mean body mass index = 36) had CSF leaks arising from the fovea ethmoidalis (n = 4) and lateral sphenoid region (n = 1). One man had a middle fossa floor dehiscence draining through the eustachian tube. All patients had bilateral ground-glass opacities in their lungs on computed tomography imaging that were attributed to spontaneous CSF fistulae arising from noniatrogenic skull base defects, and one patient underwent a biopsy of a lung lesion at another hospital showing chronic bronchiolitis and adjacent peribronchiolar metaplasia. Five patients underwent endoscopic endonasal repair using an autologous fascial graft and pedicled nasoseptal flap, and one underwent craniotomy for repair. All patients underwent successful repair with no complications or evidence of recurrence. Upon repair of the spontaneous CSF leaks, both pneumonitis symptoms and ground-glass opacities on imaging resolved in all six cases. CONCLUSIONS Skull base CSF fistulae should be considered as a reversible cause of chronic pneumonitis that is not alleviated or worsens with standard treatment. LEVEL OF EVIDENCE 4 Laryngoscope, 131:462-466, 2021.

OBJECTIVEGlioblastoma (GBM) is the most prevalent and the most aggressive of primary brain tumors. There is currently no effective treatment for this tumor. The proteasome inhibitor bortezomib is effective for a variety of tumors, but not for GBM. The authors' goal was to demonstrate that bortezomib can be effective in the orthotopic GBM murine model if the appropriate method of drug delivery is used. In this study the Alzet mini-osmotic pump was used to bring the drug directly to the tumor in the brain, circumventing the blood-brain barrier; thus making bortezomib an effective treatment for GBM.METHODSThe 2 human glioma cell lines, U87 and U251, were labeled with luciferase and used in the subcutaneous and intracranial in vivo tumor models. Glioma cells were implanted subcutaneously into the right flank, or intracranially into the frontal cortex of athymic nude mice. Mice bearing intracranial glioma tumors were implanted with an Alzet mini-osmotic pump containing different doses of bortezomib. The Alzet pumps were introduced directly into the tumor bed in the brain. Survival was documented for mice with intracranial tumors.RESULTSGlioma cells were sensitive to bortezomib at nanomolar quantities in vitro. In the subcutaneous in vivo xenograft tumor model, bortezomib given intravenously was effective in reducing tumor progression. However, in the intracranial glioma model, bortezomib given systemically did not affect survival. By sharp contrast, animals treated with bortezomib intracranially at the tumor site exhibited significantly increased survival.CONCLUSIONSBypassing the blood-brain barrier by using the osmotic pump resulted in an increase in the efficacy of bortezomib for the treatment of intracranial tumors. Thus, the intratumoral administration of bortezomib into the cranial cavity is an effective approach for glioma therapy.

Background Atypical pituitary adenomas (APAs) are a subset of pituitary adenomas (PAs) characterized by the 2004 World Health Organization (WHO) guidelines to have higher risk histopathological features than typical PAs. In July 2017, the WHO published an update to their classification of pituitary tumors and abandoned the APA terminology. Objective To assess the prevalence and outcomes of patients diagnosed with APA through a literature review. Focus was placed on variation in the application of the previous WHO criteria and on rates of recurrence. Methods A systematic review of PubMed (2004-July 2017) was performed to identify studies reporting prevalence and clinical characteristics/outcomes of APA. Eight studies were analyzed for prevalence. Six studies reporting histopathological details were analyzed in depth. Results Of the 7105 included patients, 373 (5.2%) met criteria for APA (prevalence range: 3%-15%). Only 2 of 8 studies utilized identical grading criteria, demonstrating a lack of standardized application. Most APAs (84%) were macroadenomas, with 52% invasive on magnetic resonance imaging. Nonfunctional PAs were most common (37%), followed by prolactinomas (23%) and Growth Hormone adenomas (21%). Recurrence/progression occurred in 21% of APA patients (follow-up range 37-75 mo). Only 2 of 8 studies reported an association between APA diagnosis and recurrence/progression. Conclusion Based on diagnostic variability and lack of association with clinical outcomes, refinement of criteria for APA was necessary. The WHO update eliminates the ambiguity in APA diagnosis in favor of criteria that emphasize clinical behavior (invasion, recurrence, and resistance to treatment) and molecular markers. Our review supports abandonment of the previous APA designation due to limited prognostic utility.

Medulloblastoma (MB) is a malignant pediatric brain tumor. Studies have shown heterogeneous cells amongst the tumor bulk which mirror normal neural cells in various neurodevelopmental stages. To discern exploited mechanisms promoting MB leptomeningeal disease, we drew conclusions from developmental neurobiology. In normal differentiation, the metabolic phenotype in proliferating neural progenitor cells evolves from a glycolysis-dependent to an oxidative phosphorylation-reliant energetic profile in quiescent differentiated neurons. Cancer cells mirror this evolution, which also grants them the capability to utilize alternative nutrients in the microenvironment as an energy source. Considering metastatic cells are typically in a dormant state and primarily utilize oxidative phosphorylation, we hypothesized metastatic MB cells emulate a quiescent neuron-like cellular profile to survive in the cerebrospinal fluid and form leptomeningeal metastases. To examine this, we query the expression of GABA catabolic enzyme GABA transaminase (ABAT) in MB. GABA is found in the cerebellar and leptomeningeal microenvironments, and is utilized by metastatic cancer cells in the CNS as an energy source. We correlate an increase in ABAT expression with neurodevelopment and show heterogeneous expression of this protein in primary MB tumors. MB cells with increased expression of ABAT were slower-dividing, expressed a genetic and metabolic phenotype reminiscent of quiescent neuron-like cells, and had increased capability to metabolize GABA. Conversely, lower expression of ABAT was associated with an increased proliferation rate and correlated with a progenitor-like cellular profile. Transplantation of MB cells into the leptomeningeal compartment decreased proliferative capacity and enhanced ABAT expression. Xenograft models showed MB cells with ABAT knockdown had increased growth in the cerebellar microenvironment. Conversely, MB cells with ABAT overexpression transplanted into the cerebrospinal fluid formed leptomeningeal metastases whereas ABAT knockdown cells could not. These results suggest ABAT expression in MB cells can be modulated by the tumor microenvironment and is required to form leptomeningeal metastases.

A 31 year-old man with HIV and pulmonary tuberculosis (TB) status-post RIPE regimen presented with cough and throbbing headaches. Laboratory results were remarkable for a CD4 count of 2 kcells/L and a viral load of 2.7 million copies/mL. MRI of the brain reported multiple lobulated and cystic intracranial lesions associated with the dura that had thick rinds of enhancement. CT of the chest, abdomen and pelvis demonstrated axillary and inguinal lymphadenopathy, a mass within the right pelvis thought to represent necrotic lymph nodes, prominence of the right psoas muscle, a cystic nodule in the liver, and a right adrenal lesion. The patient was started on dexamethasone, RIPE therapy, and empiric antimicrobial therapy. He subsequently underwent stealth-guided brain biopsy and open craniotomy. Pathology returned a tissue diagnosis of an AIDS related EBV-associated smooth muscle tumor (EBV-SMT) best categorized as a malignant myopericytoma. Following surgery, the patient began additional anti-retroviral therapy for HIV and was discharged. Despite treatment, three to four months following discharge the patient's symptoms progressed and he was found to have developed a severe bilateral homonymous hemianopsia. Repeat MRI demonstrated tumor growth and the patient subsequently received whole brain radiation along with sirolimus and pomalidomide. Approximately two months following radiation therapy the patient had increasing headaches along with nausea and vomiting. Repeat MRI was consistent with radiation arrested tumor growth but did not show any decrease in size of his intracranial lesions. Therapy with bevacizumab was initiated and he had marked improvement of his visual field deficits. The patient has since completed 20 cycles of treatment with bevacizumab and is currently 17 months post his initial diagnosis. Repeat imaging has demonstrated decreasing size of his lesions and no new lesions have developed.

BACKGROUND Limited data exist pertaining to outcomes following surgery for recurrent Rathke's cleft cysts (RCC). OBJECTIVE To determine treatment outcomes in patients undergoing reoperation for recurrent or residual RCCs. METHODS A retrospective analysis of 112 consecutive RCC operations in 109 patients between 1995 and 2017 was conducted. RESULTS Eighteen patients underwent 21 RCC reoperations with a mean follow-up of 58 mo. Patient symptoms prior to reoperation included headaches (14, 66.7%) and vision loss (12, 57.1%). Thirteen of 18 patients (72.2%) required hormone supplementation prior to reoperation including 5 with diabetes insipidus (DI). Mean RCC diameter was 16 mm and 76% had suprasellar extension. Compared to index RCC cases, intraoperative cerebrospinal fluid leak repair was more common in reoperation cases (15/21, 71% vs 43/91, 47%, P = .05). There was 1 carotid artery injury without neurological sequelae, and 2 postoperative cerebrospinal fluid (CSF) leaks (9.5%). Rates of transient hyponatremia (3/10, 30% vs 4/91, 4.4%, P = .04) and transient DI (5/10, 50% vs 17/91, 18.7%, P = .04) were higher in the reoperation vs index group. Improved headaches and vision were reported in 4/12 (33%) and 8/12 (61.5%) of RCC reoperation patients, respectively. Two patients developed new permanent DI. A higher proportion of reoperation patients had RCC squamous metaplasia (24% vs 5.4%, P = .02) or wall inflammation (42.9% vs 2.2%, P

BACKGROUND AND IMPORTANCE Infectious intracranial aneurysms are a rare subset of intracranial aneurysms caused by bacterial, fungal, or viral sources. Intracranial aneurysms of fungal etiology carry a high mortality risk and typically occur in immunocompromised patients via direct extension of skull base infections, or more rarely, after intracranial surgery. CLINICAL PRESENTATION We present the case of a 27-yr-old female with systemic lupus erythematous and primary pulmonary mucormycosis, who suffered a subarachnoid hemorrhage from a ruptured fusiform distal middle cerebral artery aneurysm. Despite undergoing a successful extracranial-to-intracranial bypass and aneurysm excision, the patient ultimately died following progressive disseminated infection and a secondary intracranial hemorrhage of unknown etiology. Pathological examination of the excised artery confirmed Mucor infection. CONCLUSION To the best of our knowledge, this case represents one of the first mycotic cerebral aneurysms from mucormycosis in a patient without an underlying skull base infection or previous intracranial surgery. Despite optimal surgical management, clinical outcomes for mycotic cerebral aneurysms are largely dependent on the success of medical therapies at controlling systemic disease.

Purpose: The aim of this study was to describe a 34-year-old male with hereditary bilateral retinoblastoma treated with radiotherapy as a child who developed 4 distinct tumors within the radiation field. Methods: A 34-year-old male with bilateral retinoblastoma status postradiation therapy and recurrence requiring enucleation presented with left-eye visual acuity changes. Magnetic resonance imaging demonstrated a left orbital mass and a right parasellar complex lobulated mass (right sphenoid and right cavernous sinus). Two weeks later, the patient underwent excision of the orbital mass and biopsy of an upper-lid nodule. This was followed by craniotomy for removal of the complex mass. Results: Histology revealed 4 distinct tumors, including an undifferentiated pleomorphic sarcoma (left orbit), a radiation-induced meningioma (right sphenoid), a schwannoma (right cavernous sinus), and a basal-cell carcinoma (left lid). Conclusion: Although occurrence of a second neoplasm is a well-known outcome following radiation treatment in patients with hereditary retinoblastoma, the diagnosis of 4 additional neoplasms is rare. Pleomorphic sarcoma, radiation-induced meningioma, and schwannoma are uncommon tumors and not well represented in the literature describing irradiated retinoblastoma patients. Secondary malignancies are a leading cause of early death in retinoblastoma survivors, and long-term follow-up is crucial for patient care.

Congenital leukemia is rarely encountered in clinical practice, even in tertiary children's hospitals. Leukemia may cause significant coagulopathy, putting the patient at risk of intracranial hemorrhage. In this case, the authors present a female infant with a unique mixed phenotypic congenital acute myeloid leukemia showing mixed-lineage leukemia (MLL) rearrangement and severe coagulopathy resulting in a large subdural hematoma. Despite the fatal outcome in this case, neurosurgical treatment of patients with acute myeloid leukemia should be considered if coagulopathy and the clinical scenario allow.

B RIEF R EPORT Whipple’s Disease Masquerades as Dementia With Lewy Bodies Kyle Hurth, MD, PhD,* Rawan Tarawneh, MD, wz Nupur Ghoshal, MD, PhD, wz Tammie L.S. Benzinger, MD, PhD, wzy David B. Clifford, MD, y Michael Geschwind, MD, PhD,8 John C. Morris, MD, wz James E. Galvin, MD, z Robert E. Schmidt, MD, PhD,* and Nigel J. Cairns, PhD, FRCPath* wz (Alzheimer Dis Assoc Disord 2015;29:85–89) Key Words: Whipple’s disease, bacterial infection, dementia with Lewy bodies Received for publication March 25, 2013; accepted July 1, 2013. From the *Department of Pathology and Immunology, Division of Neuropathology; wCharles F. and Joanne Knight Alzheimer’s Disease Research Center; zDepartment of Neurology; yMallinck- rodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO; 8Department of Neurology, University of California, San Francisco, CA; and zComprehensive Center on Brain Aging, New York University Langone School of Medicine, New York, NY. K.H., R.T., and N.G. contributed equally. Supported by grants from the National Institute on Aging of the National Institutes of Health (P50-AG05681, P01-AG03991), the Hope Center for Neurological Disorders, the Buchanan Fund, the Charles F. & Joanne Knight Alzheimer’s Disease Research Center, and the Barnes- Jewish Hospital Foundation. A summary of these data were presented at the 2012 Annual Meeting of the American Association of Neuropathologists. N.G. has participated or is currently participating in clinical trials of anti-dementia drugs sponsored by Elan/Janssen, Eli Lilly and Company, Wyeth, Pfizer, Novartis, and Bristol-Myers Squibb. T.L.S.B. declares an interest as a consultant for Biomedical Sys- tems, ICON Medical Imaging, Eli Lilly Advisory Board, and Avid Radiopharmaceuticals. D.B.C. serves on Data Safety Boards for Amgen, Biogen, GlaxoSmithKline, Millennium, Genzyme, Genentech, and Pfizer. He has been a consultant to Brinker, Biddle, Reath [Progressive Multifocal Leukoencephalopathy (PML) Consortium], Genentech, Genzyme, Bristol-Myers Squibb, Millen- nium, Biogen Idec, and Pfizer. He has received research support from the Alzheimer’s Association, Biogen Idec, Eli Lilly, Roche and Pfizer. He has received speaking fees from Biogen, University of Kentucky, ECTRIMS, and CMSC/ACTRIMS. J.C.M. declares an interest as a consultant for: Eisai, Elan/Janssen Alzheimer Immu- notherapy Program, GlaxoSmithKline, Novartis, Otsuka Pharma- ceuticals, Pfizer/Wyeth, Eli Lilly, AstraZeneca, Bristol-Myers Squibb, Genentech, Merck, and Schering Plough; support form NIH/NIA; speaking fees: Dickinson address at Ohio Wesleyan, ABA Soriano Lectureship, Morrell Lecture (Chicago), Eisai (South Korea), Bial Neurology Forum (Portugal); royalties from: Black- well Medical, Taylor and Francis. J.E.G. serves on a scientific advisory board for the American Federation for Aging Research and on the Board of Directors and the Scientific Advisory Council for the Lewy Body Dementia Association; he serves on speakers’ bureaus for Pfizer Inc., Eisai Inc., Novartis, and Forest Labo- ratories Inc.; has served as a consultant for Novartis, Forest Lab- oratories Inc., Pfizer Inc., Eisai Inc., Janssen, and Medivation Inc.; he has received license fee payments for AD8 dementia screening test (copyrighted): license agreements between Washington Uni- versity and Pfizer Inc., Eisai Inc., and Novartis; and receives research support from Novartis, Eli Lilly and Company, Elan Corporation, Wyeth, Bristol-Myers Squibb, the NIH/NIA, and the Alzheimer Association. The remaining authors declare no conflicts of interest. Reprints: Nigel J. Cairns, PhD, FRCPath, Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, MO 63110 (e-mail: cairns@wustl.edu). Copyright r 2013 Wolters Kluwer Health, Inc. All rights reserved. Alzheimer Dis Assoc Disord CASE HISTORY Dr George Whipple first described the disease which bears his name in 1907. 1 He described a 36-year-old male physician who presented with a 5- to 6-year history of insidious symptoms including cough, recurrent attacks of arthritis, gradual weight loss, and asthenia. By the end of his life, skin changes, diarrhea, abdominal swelling, and mesenteric adenopathy were prominent. Pathologic examination showed macrophages and fat vacuoles in the small bowel and inflammation and macrophages within pleura, peritoneum, and the aortic valve. Silver staining demonstrated rod- shaped structures. Electron microscopy has revealed that these aggregates consist of networks of membranous structures and bacillary bodies of the bacterium Tropheryma whipplei. 2,3 Bacterial DNA sequencing and antibodies to T. whipplei may now be used to confirm the diagnosis. We report a 49-year-old white man with a 4-year history of progressive cognitive and behavioral impairment, parkinsonism, cognitive fluctuation, altered sleep-wake cycles, myoclonus, visual hallucinations, and subsequent death. His past medical history included hypertension, chronic obstructive pulmonary disease, smoking, alcohol use, and cadaveric growth hormone replacement for delayed puberty as a child. There was no family history of dementia or movement disorder. He worked as a painter and was frequently exposed to solvents. He was in his usual state of health until approximately 2 years before initial evaluation. At that time, behavioral disturbances were noted by the family from whom he was estranged. He was described as depressed and severely withdrawn. Approximately 12 to 16 months into his course, he became forgetful of recent events and conversations and repeated himself. He had increasingly odd behavior including sleeping during the day and being awake at night, wandering outside inappropriately dressed, and confabulating. His cognition fluctuated from staring spells to deep sleep from which he was difficult to arouse. At other times he was alert and fully oriented without recollection of prior events. He began to have well-formed visual hallucinations that he described as “brightly-colored pets” or “small people” and occur- red during periods of lucidity. Eighteen months after onset, he was evaluated at an outside hospital for pneumonia, confusion, and agitation. He had notable parkinsonism and myoclonus of the left upper extremity. Imaging and diagnostic studies were unrevealing. Valproic acid partially improved his myoclonic movements. He was also treated with intravenous thiamine given his prior alcohol use and presentation concerning for Wernicke-Korsakoff syndrome. Small doses of risperidone and olanzapine produced generalized rigidity and drowsiness. He had one unexplained syncopal episode during his admission. Between episodes, he was alert and fully oriented and was discharged to a skilled nursing facility. Sporadic Creutzfeldt-Jakob disease was considered because of the rapid cognitive decline and a history of treatment with cadaveric growth hormone extract led to the suspicion of iatrogenic Creutzfeldt-Jakob disease. However, the absence of periodic sharp wave complexes in the context of mildly left predominant Volume 29, Number 1, January–March 2015 www.alzheimerjournal.com

To the Editor: Tophaceous gout of the axial skeleton is an unusual presentation. Most cases occur in men with a history of severe polyarticular gout1. In reported cases, patients have usually presented with symptoms including neck and back pain, radiculopathy, myelopathy, and cauda equina syndrome2,3. To our knowledge, this is the first reported case of spinal gout presenting with acute paraplegia. A 34-year-old man with a history of morbid obesity, diabetes mellitus, and renal insufficiency presented with acute onset of motor and sensory loss below the level of his nipples. He awoke early that morning noting leg weakness. While walking to the bathroom, he fell, after which he lost sensation in his legs and was unable to urinate. He had no history of fevers or prior neuromuscular symptoms. His medications on admission included loperimide, aripiprazole, zolpidem, trazodone, and simvastatin. He had been treated intermittently for gout with allopurinol, most recently reinstituted 9 days prior to his fall. On examination, the patient was morbidly obese, with body mass index of 69.5. Vital …

Introduction Langerhans cell histiocytosis is a rare disease within the adult population, with very few cases reported as solitary hypophyseal lesions in adults. Of the reported cases, most have been treated successfully with surgery, radiotherapy, and/or chemotherapy. Radiotherapy has been thought to be curative at the relatively low dose of 20Gy. Here we report a case of recurrent hypophyseal Langerhans cell histiocytosis 9 months after radiotherapy with an interval period of symptomatic and radiographic response to therapy. Case presentation A 50-year-old Caucasian woman who had headaches, memory difficulties, and diabetes insipidus was found to have a 2.5cm suprasellar mass. Langerhans cell histiocytosis was diagnosed following stereotactic brain biopsy. Further workup revealed no other lesions. Initial radiation treatment succeeded in shrinking the tumor and relieving clinical symptoms temporarily; however, growth and recurrence of clinical symptoms was noted at 9 months. Re-irradiation was well tolerated and the patient had no acute side effects. Conclusion Isolated hypophyseal involvement by Langerhans cell histiocytosis in adults is a unique presentation of a rare disease. Although radiotherapy doses as low as 20Gy have been reported to offer control, this case demonstrates that higher doses may be warranted to ensure tumor control. With modern imaging and radiotherapy techniques higher doses should offer little increased more durable risk to surrounding critical structures.