[Erdheim-Chester disease presenting with bilateral orbital involvement: Report of three cases]. / La maladie d'Erdheim­Chester révélée par une atteinte orbitaire bilatérale : étude de trois cas.

PURPOSE: To report treatment outcomes of orbital tumors associated with Erdheim-Chester disease and to highlight the importance of systemic work-up in patients presenting with bilateral proptosis. PATIENTS AND METHODS: Three patients with Erdheim-Chester disease, whose initial manifestation was bilateral proptosis, were retrospectively studied. The course of onset, clinical, imaging and histopathological features, systemic associations and response to treatment were reviewed. The main outcome measures were Hertel measurements and orbital tumor regression on imaging studies. RESULTS: All patients presented with bilateral non-pulsatile proptosis resistant to retropulsion and headeache without specific localization. Magnetic resonance imaging studies showed bilateral intraconal orbital tumors. Incisional biopsy of these tumors demonstrated CD68+, CD1a-, and S100- histiocytic infiltrates consistent with the diagnosis of Erdheim-Chester disease. The BRAFV600E mutation was found in all cases. Systemic work-up revealed asymptomatic bony involvement in the lower extremities, perirenal fibrosis, central nervous system and cardiac involvement. All patients initially received pegylated interferon-α2a, which resulted in excellent responses except for the orbital tumors. Two patients were then treated with vemurafenib, which resulted in rapid regression of the orbital lesions. CONCLUSION: Pegylated interferon-α was highly effective in the control of cardiac, perirenal, skeletal and cerebral involvement but not the orbital tumors. The infiltrative orbital lesions of Erdheim-Chester disease would appear more responsive to vemurafenib.

Review: Challenges in the histopathological classification of ganglioglioma and DNT: microscopic agreement studies and a preliminary genotype-phenotype analysis.

Low-grade epilepsy-associated brain tumours (LEAT) are the second most common cause for drug-resistant, focal epilepsy, that is ganglioglioma (GG) and dysembryoplastic neuroepithelial tumours (DNT). However, molecular pathogenesis, risk factors for malignant progression and their frequent association with drug-resistant focal seizures remain poorly understood. This contrasts recent progress in understanding the molecular-genetic basis and targeted treatment options in diffuse gliomas. The Neuropathology Task Force of the International League Against Epilepsy examined available literature to identify common obstacles in diagnosis and research of LEAT. Analysis of 10 published tumour series from epilepsy surgery pointed to poor inter-rater agreement for the histopathology diagnosis. The Task Force tested this hypothesis using a web-based microscopy agreement study. In a series of 30 LEAT, 25 raters from 18 countries agreed in only 40% of cases. Highest discordance in microscopic diagnosis occurred between GG and DNT variants, when oligodendroglial-like cell patterns prevail, or ganglion cells were difficult to discriminate from pre-existing neurons. Suggesting new terminology or major histopathological criteria did not satisfactorily increase the yield of histopathology agreement in four consecutive trials. To this end, the Task Force applied the WHO 2016 strategy of integrating phenotype analysis with molecular-genetic data obtained from panel sequencing and 450k methylation arrays. This strategy was helpful to distinguish DNT from GG variants in all cases. The Task Force recommends, therefore, to further develop diagnostic panels for the integration of phenotype-genotype analysis in order to reliably classify the spectrum of LEAT, carefully characterize clinically meaningful entities and make better use of published literature.

Pseudopapillary pattern in intra-operative squash smear preparations of central nervous system germinomas.

BACKGROUND: Although the morphology of central nervous system (CNS) germ cell tumours is very similar to that of gonadal germ cell tumours, some architectural changes may dominate the microscopic appearance of CNS germinomas leading to misdiagnosis at low-power magnification. METHODS: We report five cases of CNS germinoma demonstrating delicate pseudopapillary fronds on squash smear preparations. RESULTS: The age of the patients ranged from 5 to 21 years (mean 14). Three were female and two male. Three patients presented with symptoms of diabetes insipidus, including polydipsia and polyuria, while absence seizures, meaningless speech, hemiparesia, weight loss, insufficient breast development, amenorrhoea and symptoms of raised intracranial pressure were also encountered depending on the location of the tumours. Tumours were located in the hypophysis in two cases and in the suprasellar region in three. During the intra-operative pathological consultation, evenly distributed pseudopapillary or papillary structures formed the dominant pattern in the squash preparations of all cases. The neoplastic cells were characterized by pale variably vacuolated cytoplasm, pleomorphic nuclei with irregular membranes, and several prominent nucleoli. Variable numbers of small lymphocytes were also found. CONCLUSION: Intracranial germinomas may commonly exhibit a pseudopapillary pattern on squash smears that may cause misdiagnosis as neoplasms with papillary morphology. Careful examination of cellular details is essential in order to reach the correct diagnosis.

Cell death and survival mechanisms are concomitantly active in the hippocampus of patients with mesial temporal sclerosis.

Mesial temporal lobe epilepsy (MTLE) is often characterized pathologically by severe neuronal loss in the hippocampus. In this study we investigated concomitant appearance of the pro-apoptotic and anti-apoptotic mechanisms in injured neurons in epileptic human hippocampi. Postsurgical hippocampal specimens of randomly selected 25 patients with MTLE were studied with standard immunohistochemical techniques to detect the below markers of cell death pathways: truncated Bid - tBid, mitochondrial translocation of Bax (markers of pro-apoptotic Bcl-2 protein activation) and nuclear translocation of AIF (caspase-independent pro-apoptotic pathway). For cell survival pathways, we investigated the expression of c-IAP1, c-IAP2 and Hsp70 (heat shock protein). Immunopositive cells were counted in different regions of the hippocampus. We also verified IAP (inhibitor of apoptosis) expression with Western blotting. The results were statistically compared with hippocampi from non-epileptic autopsy controls. In patient hippocampi, Bax and tBid immunoreactivity were significantly increased and Bax staining was consistent with mitochondrial translocation. AIF was not translocated to the nucleus. c-IAP1 and c-IAP2 were barely detectable in control hippocampi, whereas their expression was dramatically increased in the patients in all hippocampal subfields. Interestingly, these neurons were also positively co-labeled for tBid and translocated Bax. Hsp70 immunreactivity was significantly increased in all surviving neurons in patient hippocampi whereas degenerating neurons failed to express Hsp70. Our findings are consistent with both pro-apoptotic and anti-apoptotic mechanisms being active within the same hippocampal neurons of patients with MTLE, illustrating an ongoing struggle between cell death and survival mechanisms in neurons under stress.

Pineal region tumors in children: a single center experience.

Pineal region tumors are a relatively uncommon, deep-seated heterogeneous group of mass lesions of the brain. Their management is much more complicated in children with cancer, both in terms of survival and sequelae, due to primary location of the tumor and treatment modality. The goal of this retrospective study was to report the presentation, treatment, and outcome of tumors that arose from this region in 24 children treated at our institution between March 1975 and May 2006. In all, 15 (62.5%) of the 24 children were initially treated with partial or complete resection, adjuvant radiotherapy was given to 18 (75%) patients, and chemotherapy was given to 15 (62.5%) of the patients. Overall survival was 44.5%. Although statistically insignificant, the most favorable outcome were obtained in patients with grossly resected tumors (66%) and in children >10 years of age (80%). Long-term sequelae occurred at a high rate in this study due to the primary location of the tumors and treatment modalities, which warrants further investigation.

Gangliocytic paraganglioma of the cauda equina with significant calcification: first description in pediatric age.

A 17-year-old boy was referred with a 2-month history of low back pain and bilateral sciatica and difficulty in ambulation. Neurological examination found mild muscle weakness and diminished deep tendon reflexes in his right leg. Lumbar magnetic resonance imaging revealed an intradural-extramedullary tumor at the level of the L4, exiting through the right L4-L5 intervertebral foramen into the right psoas muscle. After total resection of the tumor, histopathological diagnosis revealed a gangliocytic paraganglioma. There are 184 paraganglioma cases reported at the lumbar region to date, and only 4 of them were in the pediatric age group. This report is the fifth paraganglioma case in the lumbar region and the first gangliocytic paraganglioma case in the pediatric age population.

[Solitary orbital schwannomas: clinical, imaging, and surgical features]. / Schwannomes orbitaires isolés : aspects cliniques, radiologiques et chirurgicaux.

INTRODUCTION: Schwannoma is a rare peripheral nerve tumor of the orbit, the diagnosis of which can only be made with certainty by histopathological examination. We report our experience on the clinical, imaging, and surgical aspects of orbital schwannomas based on our series of six patients. PATIENTS AND METHODS: We retrospectively reviewed the records of six patients managed at our institution for orbital schwannoma. The age, sex, presenting clinical signs and symptoms, pre- and postoperative visual acuities, magnetic resonance imaging (MRI) features, the surgical techniques employed, and the pitfalls encountered were recorded. RESULTS: There were three female and three male patients. The mean age at diagnosis was 39.5 years. Decreased visual acuity and proptosis were the most common presenting signs. MRI studies showed that schwannoma was hypointense on T1- and slightly hyperintense on T2-weighted images. With the exception of degenerated or myxoid parts of the tumor, there was variable enhancement following gadolinium injection. The tumor was totally removed via the transconjunctival approach in five patients and through a subbrow cutaneous incision in one patient. There was no recurrence during a mean follow-up of 2.2 years. CONCLUSION: Most orbital schwannomas, whether intraconal or extraconal, can be safely excised through the transconjunctival approach. Meticulous dissection is mandatory to separate the tumor from its surroundings. Cryoextraction may not be advisable because of the risk of fragmentation of the tumor due to its weak pseudoencapsulation.

Cyclooxygenase-2 (cox-2) expression and angiogenesis in intracranial ependymomas.

AIM: Cyclooxygenase-2 (Cox-2), the inducible key enzyme in the biosynthesis of prostaglandins, appears to play a role in the regulation of progression, invasiveness and angiogenesis of various neoplasms including some glial tumors. Little is known about the role of Cox-2 in angiogenesis and proliferation of ependymomas. We studied Cox-2 expression, Ki-67 labeling index (Ki-67 LI) and microvessel density (MVD) in 30 intracranial ependymomas and analyzed the relationship among these parameters to evaluate their importance in the tumor biology of ependymomas. RESULTS: The mean Ki-67 LI for all tumors ranged from 1 - 50% (mean 9%). Statistically significant difference was present for Ki-67 LI between ependymomas (grade II, WHO) and anaplastic ependymomas (grade III, WHO) (p < 0.001) (mean Ki-67 LI for ependymoma, 2.8%, for anaplastic ependymomas, 15.6%). Anaplastic ependymomas did not demonstrate a greater vascularization than ependymomas, and the MVD values were 84.5 +/- 39.7 for ependymomas, and 90.6 +/- 61.4 for anaplastic ependymomas. Cox-2 immunohistochemical expression was observed in 19 tumors (63%). Although Cox-2 expression was slightly higher in anaplastic ependymomas, it was not statistically significant. No correlation was found between Cox-2 expression and MVD and Ki-67 LI. CONCLUSION: Similar to morphologic and prognostic heterogeneity in ependymomas, Cox-2 expression, MVD and Ki-67 LI also show a great variability. Other factors may be more important for the proliferation and angiogenesis of ependymomas.

Cerebral alveolar echinoccosis mimicking primary brain tumor.

We present a case of cerebral infestation by Echinococcosis multilocularis mimicking an infiltrative primary brain tumor. A heavily calcified mass invading the midbrain enhanced in a cauliflower-like fashion with small peripheral nodules present on MR imaging. Perfusion-weighted MR imaging revealed low relative cerebral blood volume within the calcified lesion and peripheral hyperemia. Single-voxel proton MR spectroscopy with an echo time of 135 milliseconds was normal.

Serial analysis of gene expression in the hippocampus of patients with mesial temporal lobe epilepsy.

Hippocampal sclerosis constitutes the most frequent neuropathological finding in patients with medically intractable mesial temporal lobe epilepsy. Serial analysis of gene expression was used to get a global view of the gene profile in human hippocampus in control condition and in epileptic condition associated with hippocampal sclerosis. Libraries were generated from control hippocampus, obtained by rapid autopsy, and from hippocampal surgical specimens of patients with mesial temporal lobe epilepsy and the classical pattern of hippocampal sclerosis. More than 50,000 tags were analyzed (28,282, control hippocampus; 25,953, hippocampal sclerosis) resulting in 9206 (control hippocampus) and 9599 (hippocampal sclerosis) unique tags (genes), each representing a specific mRNA transcript. Comparison of the two libraries resulted in the identification of 143 transcripts that were differentially expressed. These genes belong to a variety of functional classes, including basic metabolism, transcription regulation, protein synthesis and degradation, signal transduction, structural proteins, regeneration and synaptic plasticity and genes of unknown identity of function. The database generated by this study provides an extensive inventory of genes expressed in human control hippocampus, identifies new high-abundant genes associated with altered hippocampal morphology in patients with mesial temporal lobe epilepsy and serves as a reference for future studies aimed at detecting hippocampal transcriptional responses under various pathological conditions.

[Ciliary body leiomyomas. Three case reports]. / Léiomyome du corps ciliaire. A propos de trois cas.

We present our experience with three patients, two of whom were women, 16, 28 and 44 years of age, presenting with leiomyomas of the ciliary body. Salient clinical features were involvement of the left eye and temporal quadrants in two cases and extension into the anterior chamber in the other. Two patients underwent enucleation and the third had iridocyclochoroidectomy. Immunohistochemical studies showed strong positivity for muscle-specific actin, smooth muscle actin and desmin, whereas staining against vimentin, HMB-45 and S-100 protein was negative. Although there are no specific clinical or imaging signs for intraocular leiomyoma, this tumor should be suspected when pigmented ciliary body tumors are encountered, especially in young female patients.

Neurotrophin receptor immunoreactivity in the hippocampus of patients with mesial temporal lobe epilepsy.

Recent evidence supports a critical role of neurotrophins in the regulation of both neuronal survival and synaptic transmission during epileptogenesis. We have examined the immunohistochemical expression of high- (tyrosine kinase receptors, trk) and low-affinity (p75) neurotrophin receptors (NTRs) in the hippocampal specimens from 18 patients with chronic temporal lobe epilepsy [TLE; 14 patients with hippocampal sclerosis (HS) and four with focal lesions (tumours) not involving the hippocampus proper]. Nonepileptic autopsy brains (n = 6) and surgical specimens from tumour patients without epilepsy (n = 3) were used as controls. Immunoreactivity (IR) for the trk receptors (trkA, trkB, trkC) was detected in normal human brain within the pyramidal neurones of hippocampal cornus ammoni (CA) regions and in the dentate gyrus. There were no detectable differences in the neuronal trk IR patterns in the hippocampus between control and TLE cases with HS, except for a decrease in neuronal density in regions where cell death had occurred (CA1, CA3 and CA4). In contrast, a consistent increase in trkA IR was observed in reactive astrocytes in CA1 and dentate gyrus. The low-affinity p75 neurotrophin receptor (p75(NTR)) was expressed in low levels in postnatal normal hippocampus. In contrast, neuronal p75(NTR) IR was detected in 10/14 cases of HS in spared neurones within the CA and hilar regions of the hippocampus. Double labelling revealed that p75(NTR)-positive neurones also contain trk receptor IR. In six cases with prominent glial activation strong p75(NTR) IR was observed in microglial cells within the sclerotic hippocampus. The present results indicate that changes in NTR expression are still detectable in the hippocampus of patients with chronic TLE and involve both glial and neuronal cells. Reactive astrocytes were immunoreactive for trkA, whereas activated microglia cells were reactive for p75(NTR), suggesting different functions for specific NTRs in the development of reactive gliosis. Moreover, the increased expression of p75(NTR) in hippocampal neurones of TLE patients may critically influence the neuronal survival during the epileptogenic process.

Intracranial Haemorrhage Probably Due to an Angiographically Occult AVM after Carotid Stenting. A Case Report.

SUMMARY: Angiographically occult vascular malformations refer to cerebrovascular malformations that are not demonstrable on technically satisfactory cerebral angiography. Authors herein present a very unusual intracranial bleeding complication related to an angiographically occult vascular malformation after extracranial carotid artery stenting procedure. A 52-year-old male patient admitted to the hospital with 2 episodes of amaurosis fugax in the left eye. Cervical carotid angiography and bilateral carotid Doppler ultrasonography revealed a 98% stenosis of the left internal carotid artery just distal to the bifurcation. Post-stenting control cervical carotid angiography revealed neither any residual stenosis nor a developmental venous anomaly. The patient developed left pupil dilatation with loss of consciousness two hours after the neurovascular intervention. Emergent cranial CT showed acute subdural haematoma, intracerebral and subarachnoid haemorrhage with massive midline shift. He underwent an emergent craniotomy with left temporal lobectomy. Abnormal cortical vascular structures with prominent engorgement were remarkable over the posterior temporal cortex. Histopathological studies confirmed the diagnosis of an occult AVM. Classically, these lesions are not visualized with angiography.Our patient's cerebral angiography and MR investigations were all normal. To our knowledge this is the first case in literature in which intracranial haemorrhage (acute subdural haematoma, intracerebral haematoma, SAH) occurred due to hyperperfusion of angiographically occult vascular malformation.

Cranial infantile myofibromatosis: report of three cases.

BACKGROUND: Infantile myofibromatosis is a proliferative disorder of infancy and early childhood characterized by the development of single or multiple nodular lesions arising from cutaneous or subcutaneous tissue, muscle, bone or visceral organs. In approximately one-third of cases, this myofibroblastic proliferation involves the head and neck region. CASE REPORT: In this paper we report on three cases of cranial infantile myofibromatosis in infants. The clinical presentation and the deceptive histopathological features can make diagnosis difficult. CONCLUSION: The significance of recognizing this entity is stressed, since its indolent clinical behavior might prevent diagnosis.

Cervical tuberculous spondylitis associated with systemic lupus erythematosus.

STUDY DESIGN: A case report of cervical tuberculous spondylitis associated with systemic lupus erythematosus (SLE). Infection is a frequent problem in SLE, especially in patients hospitalised with the complications of the disease. Tuberculous spondylitis very rarely occurs in SLE patients, and cervical involvement has not been previously reported. CASE REPORT: A 54-year-old female patient was admitted to our hospital with a complaint of neck pain radiating to her shoulder of 2 months' duration. The neurological examination was completely normal and radiological investigations revealed narrowing, angulation and destruction of the end plates of the 5th and 6th cervical vertebrae. She has received corticosteroid and colchicine treatment for the diagnosis of SLE during the last 10 years. The anterior cervical approach was used and pyogenic material was debrided from the C5-6 intervertebral space, and an otogenous bone graft with a Smith Robinson type fusion was performed. CONCLUSION: High doses of corticosteroids are implicated as a risk factor for infection in SLE patients. Early diagnosis and appropriate medical and surgical treatment, as well as increased awareness of higher susceptibility to opportunistic infections, such as tuberculous spondylitis, are keystones for decreasing morbidity and mortality in patients with SLE.

Chronic daily administration of selegiline and EGb 761 increases brain's resistance to ischemia in mice.

Brief cerebral ischemia is reported to cause selective neuronal necrosis, apoptotic cell death, silent infarcts and, when recurrent, cognitive decline. Acute administration of selegiline and EGb 761 have been shown to have anti-apoptotic and neuroprotective effects in experimental ischemia. Their daily use is currently advised to slow down cognitive decline in patients with vascular dementia. Hence, unlike previous studies, we studied the neuroprotective action of chronic daily administration of these drugs in Swiss mice subjected to 30-min middle cerebral artery occlusion and 72 h of reperfusion since this model was reported to induce a slowly evolving infarct with profuse apoptotic cell death. Infarct area was evaluated by H&E staining on coronal brain sections and, apoptotic cells were identified by histological criteria, terminal transferase-mediated d-UTP nick-end labeling (TUNEL) and by immunohistochemical detection of caspase-cleaved actin fragments (fractin). Fifty-one mice received daily intraperitoneal injections of 10 mg/kg selegiline (n=18) or 50 mg/kg EGb 761 (n=17) or equal volume of saline (n=16) for 10-14 days before but not on the day of insult. The infarct volume, number of TUNEL- and fractin-positive cells were significantly reduced in treatment groups by 30, 42 and 51% (selegiline) and, 27, 27 and 29% (EGb 761), respectively. These data suggest that prophylactic use of selegiline and EGb 761 could increase the brain's resistance to mild ischemic injury.