David Muñoz

Primary or metastatic melanocytic tumors in the sellar region are rare and can pose a diagnostic challenge. Here we describe a case of a 74-year-old man who underwent radiological investigations for a transient episode of blurred vision. Based on the clinical and endocrinological findings and MRI results, the patient was assumed to have a clinically non-functioning pituitary macroadenoma, which was followed-up over a 2-year period. He did not have any endocrine symptoms or progressive visual deterioration, and no history of past malignancy, including melanoma. Endocrinological investigation was unremarkable; blood hormone levels were within the normal ranges except for low serum total testosterone and bioavailable testosterone levels without symptoms of hypogonadism. The longitudinal MRI follow-up demonstrated a gradual increase in the size of the tumor over the course of 11 months. For this reason, the patient underwent surgery. Pathologic examination including histology, immunohistochemistry and electron microscopy achieved the correct diagnosis of melanocytic tumor of the sellar region morphologic examination is essential in the diagnosis of melanocytic tumors. Hmb-45 is an important diagnostic biomarker in melanocytic lesions. The use and exploration of miRNA, Ki67 and osteopontin are important in understanding the genesis, progression, and prognosis in treatment of patients with melanocytic tumors.

Five patients had brief simple partial seizures that mimicked panic disorder. The following features assisted diagnosis: Seizures were briefer and more stereotyped than panic attacks; some progressed to typical complex partial seizures; and aphasia and dysmnesia occurred during seizures in some patients. Each patient had one mesial temporal structural lesion. Routine waking EEG was normal in 2 patients. Inadequate response to anti-epileptics necessitated partial temporal lobectomy in 4 patients, 3 of whom remain seizure free.

The brains of most demented patients show at autopsy the lesions of Alzheimer's disease (AD). However, the brains of other demented patients show either no morphological changes or lesions distinct from those of AD. We report clinicopathological studies on two diseases in this latter group. The study of these diseases can improve our understanding of AD. Pick's disease is characterized by dementia, lobar cerebral atrophy, and neuronal cytoplasmic inclusions. Most cases, which we have called "classical", show inclusions made up of straight fibrils that are immunologically cross-reactive with the paired helical filaments of AD. In other "generalized" cases, similar fibrils are coated by granular material and are less reactive with anticytoskeletal antibodies. In contrast to the cytoplasmic localization of the lesions in Pick's disease, it is the cell nucleus that shows abnormalities in neuronal intranuclear hyaline inclusion disease. This disease can pr...

The technique of organotypic tissue culture offers an opportunity to observe in vitro complex interactions among glial cells and neurons, leading to the formation of myelin. In the present and accompanying work a combined ultrastructural, immunocytochemical and autoradiographic approach was used in a detailed study of the process of gliogenesis. Using immunocytochemical and ultrastructural criteria, differentiation along the oligodendroglia cell line is seen to be initiated a few days later than along the astroglial line. The sequence and timing of oligodendroglial differentiation both ultrastructurally and chemically follow those described in vivo. Formation of myelin has been demonstrated only by oligodendrocytes in which there is continuity between the perikaryal plasmalemma and myelin membranes. Oligodendroglial maturation culminated with the formation of light, medium and dark oligodendrocytes. The periodic acid Schiff-positive, glial fibrillary acidic protein (GFAP)-negative process of radial glial cells at explantation become GFAP-positive within 3 days, as described in vivo. Many of the astrocytes appear to have been derived from radial glial cells. Large numbers of dark glial cells, similar to the so-called 'intermediate glial cells', were seen. These were found to be astrocytes whose appearance probably reflected reaction to explantation-induced injury.

Using antibodies generated against the latent membrane protein 1 of Epstein-Barr virus, intense immunoreactivity of Lewy bodies (in PD and dementia with Lewy bodies) and glial cytoplasmic inclusions (in multiple system atrophy) was demonstrated. ELISA and Western blotting techniques confirmed that this immunolabeling was due to cross-reactivity of the antiviral antibody with alpha-synuclein, a neuronal protein implicated in the pathogenesis of PD. This example of cross-reactivity between Epstein-Barr virus and alpha-synuclein may bear implications for further elucidating infectious or autoimmune mechanisms in PD.

Intranuclear filamentous and crystalline inclusion bodies have been described in the nuclei of a variety of cells in both normal and pathological states. The functional significance of these structures remains to be elucidated. Moreover, although the proteinaceous nature of these inclusions has been inferred in some histochemical studies, the identity of their constituent proteins remains to be determined. In the present study, immunohistochemistry was used to investigate the presence of intranuclear inclusions in neurones of the human brain which are intensely immunoreactive for the neuronal cytoskeletal protein class III beta tubulin. The ability to label these structures immunohistochemically was exploited to investigate the topographic pattern of distribution of these inclusions in the human brain. Intranuclear inclusions were rod-shaped, polygonal, or irregular in shape. They were present in neurones and ependymal cells. Intranuclear inclusion-bearing neurones were distributed in an anatomically heterogeneous pattern in the brain. Areas exhibiting relatively high densities of inclusions included the substantia inominata and anterior olfactory nucleus, dentate gyrus, substantia nigra, inferior olivary nucleus, and dentate nucleus of the cerebellum. In addition, intranuclear inclusions were prevalent in neurones in layers II, V, and VI of the cerebral cortex. They were particularly prevalent in the mesial basal temporal neocortex. The relationship of these structures to the intranuclear rods and sheets of the classical microscopists is uncertain. The demonstration that they are composed, at least in part, of tubulin, a major cytoskeletal protein, provides important clues regarding the mechanisms underlying their formation and provides a springboard for developing hypotheses regarding their functional significance. Furthermore, the ability to demonstrate these inclusions immunohistochemically provides an avenue for further studies directed at elucidating the potential involvement of these inclusions in various pathological settings.

Abnormal (dystrophic) neurites are widespread in the brains of patients with Alzheimer's disease (AD). Subsets of these neurites cluster in intimate association with amyloid deposits, constituting classic senile plaques. Two major markers expressed by many plaque-associated neurites are the microtubule associated protein tau and chromogranin A, a soluble protein of large dense core synaptic vesicles. The authors show a new type of lesion, tangle-associated neuritic clusters (TANCs), in which abnormal neurites form dense aggregates, each centered by an extracellular (ghost) neurofibrillary tangle, rather than an amyloid deposit. Neurites in TANCs are similar to plaque neurites in shape and expression of tau and chromogranin A, and different from a second, nonaggregating subset of dystrophic neurites in AD, neuropil threads. TANCs are abundant in the hippocampus of all patients with AD; a few are found in some aged nondemented people, and in the nucleus basalis of Meynert and occasionally the neocortex of AD patients. Ultrastructurally, the core of a TANC is made up of extracellular bundles of straight filaments. This core is not recognized by antibodies to native or synthetic beta A4 peptide, the major protein of plaque amyloid, thus showing that not all neuritic clusters in AD are associated with this peptide.

We report three patients with malignant rhabdoid tumor (MRT) of the brain, two children and an adult. There were three purposes to this report: to describe the clinical course in an adult with MRT; to describe the interesting histopathological metamorphosis of one of the tumors; and to report the outcome of the treatment regimens we used in order to help guide future treatment. Since these tumors are quite rare it is important to continue to try new regimens in the search for effective therapy rather than to repeat ineffective ones. Report of three patients. The clinical course in all three patients was typical of these aggressive neoplasms in that chemotherapy and radiotherapy were ineffective in modifying the rapid deterioration leading to death. MRT can occur in adults. Autopsy in one patient showed that the tumor seemed to undergo an evolution in appearance when compared with the original pathology specimen from craniotomy. Administration of systemic therapy should be prompt and include intrathecal chemotherapy.

Perikaryal collections of intermediate filaments have been described in the anterior horn motoneurons of patients with amyotrophic lateral sclerosis (ALS), but these inclusions have generally been considered rare and mainly associated with the familial form of ALS. Using the monoclonal antibody NF2F11, which recognizes phosphorylated neurofilament epitopes, we showed that focal collections of neurofilaments in anterior horn motoneurons were a characteristic finding in sporadic as well as in familial ALS; they were present in seven of nine ALS patients, but in none of nine control spinal cords. These neurofilamentous collections are not cross-reactive with antibodies directed against paired helical filaments and the microtubule associated protein tau. In addition, diffuse staining for phosphorylated neurofilament epitopes in chromatolytic anterior horn perikarya was significantly more frequent in ALS patients than in controls.

A relationship between epilepsy and damage to mesial temporal structures has long been recognized. Recent advances have clarified somewhat the issue of whether the pathological changes seen in mesial temporal sclerosis represent the cause or the effect of seizures. This paper reviews mesial temporal sclerosis from an historical perspective and summarizes recent developments in the fields of excitotoxicity, selective vulnerability, and synaptic reorganization as they pertain to the pathogenesis of mesial temporal sclerosis.

A 41-year old resident of a nursing home presented with bloody diarrhea, and subsequently developed hemolytic-uremic syndrome. E. coli serotype O157:H7 was isolated from the stool culture. At autopsy she was found to have bilateral symmetrical striatal necrosis involving mainly the putamen and lateral globus pallidus. The main microscopic findings consisted of coagulative necrosis, endothelial damage and microthrombosis. Scattered microscopic lesions of similar appearances were noted in the parietal cortex, external capsule and fornix. This case is of particular interest because of the rarity of bilateral striatal necrosis in hemolytic-uremic syndrome and the recent experimental data which implicate E. coli endotoxin in the pathogenesis of cerebral lesions in this syndrome.

Chordoma is a rare tumor arising in the sacrum, clivus, or vertebrae. It is often not completely resectable and shows a high incidence of recurrence and progression with shortened patient survival and impaired quality of life. Chemotherapeutic options are limited to investigational therapies at present. Therefore, adjuvant therapy for control of tumor recurrence and progression is of great interest, especially in skull base lesions where complete tumor resection is often not possible because of the proximity of cranial nerves. To understand the extent of genetic instability and associated chromosomal and gene losses or gains in skull base chordoma, we undertook whole-genome single-nucleotide polymorphism microarray analysis of flash frozen surgical chordoma specimens, 21 from the clivus and 1 from C1 to C2 vertebrae. We confirm the presence of a deletion at 9p involving CDKN2A, CDKN2B, and MTAP but at a much lower rate (22%) than previously reported for sacral chordoma. At a similar frequency (21%), we found aneuploidy of chromosome 3. Tissue microarray immunohistochemistry demonstrated absent or reduced fragile histidine triad (FHIT) protein expression in 98% of sacral chordomas and 67%of skull base chordomas. Our data suggest that chromosome 3 aneuploidy and epigenetic regulation of FHIT contribute to loss of the FHIT tumor suppressor in chordoma. The finding that FHIT is lost in a majority of chordomas provides new insight into chordoma pathogenesis and points to a potential new therapeutic target for this challenging neoplasm.

Increased interest in types of dementia has developed as more cases are identified in aging populations. Here we compare the rates of cognitive decline over time in three groups with dementia from the University of Western Ontario Dementia Study: Alzheimer's disease (AD), dementia with Lewy bodies and a group with both AD and Lewy bodies. All diagnoses were verified by autopsy using standard diagnostic methods. Cognitive impairment was measured with the Extended Scale for Dementia (ESD). Members of each group with dementia were age and sex matched with individuals without dementia as controls. The 15 cases of AD, 7 cases with Lewy bodies and 8 cases with both conditions were all free of significant vascular disease. Linear regression was used to determine the rate of changes in ESD scores over time in months. All three control groups showed no change in cognitive status over time. As expected, all groups with dementia showed progressive cognitive impairment. Analysis of the slop...

Sarcoidosis is a multisystem disorder commonly affecting the lungs, but also the liver, with cirrhosis and portal hypertension occurring in fewer than 1% of cases. Although hepatopulmonary syndrome (HPS) is seen in 15% to 20% of patients with cirrhosis of varying causes, it has rarely been associated with sarcoidosis. Also, although a brain abscess is not uncommon in patients with discrete pulmonary arteriovenous malformations, it is rarely seen in patients with the much smaller intrapulmonary vascular dilations that characterize HPS. A patient with an unusual series of uncommon sarcoidosis complications, including cirrhosis with HPS, brain abscess and finally Nocardia meningitis, is reported. The possibility of HPS should be considered in sarcoidosis patients with liver involvement, if gas-exchange abnormalities are out of proportion to the degree of lung involvement. These patients may also be susceptible to a cerebral abscess by paradoxical embolization, and to opportunistic infe...

We describe the clinical phenotype of nine kindred with presenile Alzheimer's disease (AD) caused by different presenilin 1 (PS1) point mutations, and compare them with reported families with mutations in the same codons. Mutations were in exon 4 (Phe105Val), exon 5 (Pro117Arg, Glu120Gly), exon 6 (His163Arg), exon 7 (Leu226Phe), exon 8 (Val261Leu, Val272Ala, Leu282Arg), and exon 12 (Ile439Ser). Three of these amino acid changes (Phe105Val, Glu120Gly, and Ile439Ser) had not been previously reported. Distinct clinical features, including age of onset, symptoms and signs associated with the cortical-type dementia and aggressiveness of the disease, characterized the different mutations and were quite homogeneous across family members. Age of onset fell within a consistent range: some mutations caused the disease in the thirties (P117R, L226F, V272A), other in the forties (E120G, H163R, V261L, L282R), and other in the fifties (F105V, I439S). Associated features also segregated with s...

Pituitary tumor-transforming gene (PTTG1) has been implicated in several oncogenic processes. The aim of this study was to determine PTTG expression in brain tumors. We investigated 88 benign and malignant brain tumors. PTTG immunoexpression was evaluated using a scale of 0 to 3. PTTG immunoexpression was nuclear and cytoplasmic in most tumors, except for medulloblastomas and hemangiopericytomas. Expression was highest in medulloblastomas. Higher grade gliomas including glioblastoma multiforme (GBM) IV and astrocytoma III had the highest level of PTTG expression, whereas low-grade gliomas had the lowest levels of PTTG expression. Hemangiopericytomas had the lowest levels of PTTG immunoreactivity, with meningiomas and schwannomas exhibiting similarly low PTTG levels. Nuclear PTTG immunoreactivity was higher than cytoplasmic in higher-grade tumors. Our results indicate that PTTG immunoexpression is higher in aggressive brain tumors including medulloblastomas, GBM IV, and astrocytoma I...

The authors report a case of lateral posterior choroidal artery pseudoaneurysm that caused a spontaneous thalamic hemorrhage. The case supports obtaining computed tomographic angiography (CTA) even in seemingly routine cases of hypertensive hemorrhage and demonstrates a possibly unreported type of aneurysm causing thalamic hemorrhage. A 60-year-old man with a history of hypertension presented with a spontaneous right thalamic hemorrhage, and CTA showed a focus of contrast inside the hematoma. One month later, the patient was well but a CTA showed that the hematoma had resolved but that there was enlargement of the contrast-enhancing lesion in the thalamus. Catheter angiography showed an aneurysm of the lateral posterior choroidal artery. This was excised via an occipital interhemispheric supratentorial subcallosal approach. The patient recovered fully and returned to work 3 months later. The case shows the need to carefully review CTA after ICH, even in cases of seemingly typical hy...

Numerous clinical and epidemiological reports indicate that patients with history of vascular illness such as stroke are more likely to develop dementia as the clinical manifestation of Alzheimer's disease. However, there are little data regarding the pathologic mechanisms that link vascular risk factors to the factors associated with dementia onset. We provide evidence that suggests intriguing detrimental interactions between stroke and β-amyloid (Aβ) toxicity in the hippocampus. Stroke was induced by unilateral striatal injection of endothelin-1, the potent vasoconstrictor. Aβ toxicity was modeled by bilateral intracerebroventricular injections of the toxic fragment Aβ. Gross morphologic changes in comorbid Aβ and stroke rats were enlargement of the lateral ventricles with concomitant shrinkage of the hippocampus. The hippocampus displayed a series of synergistic biochemical alterations, including microgliosis, deposition of Aβ precursor protein fragments, and cellular degener...

Meningiomas are the most common primary cranial tumor arising in the central nervous system and its coverings, constituting 35.5% of primary brain tumors. Schwannomas account for 8.3% of primary neoplasms of the central nervous system. Occasionally these tumors can show overlapping morphology, most conspicuously in the fibrous variant of meningioma. In such cases, immunohistochemistry can help to establish a definitive diagnosis. Currently S100 is the most commonly used immunohistochemical stain to show neural crest differentiation in tumors. This may lead to potential misclassification of meningeal tumors, as up to 70% of fibrous meningiomas can show S100 expression. Our study sought to determine if Sox10 would prove a more specific alternative to S100 in cases of meningioma when the differential diagnosis includes schwannoma. We compared the mRNA expression of S100B and Sox10 using the publicly available GSE16581 meningioma dataset. We then studied Sox10 and S100 protein expressio...

Chordoid meningioma (CM) is a rare subtype of meningioma, classified as grade II, which exhibits a high rate of recurrence following subtotal resection. We retrospectively examined nine cases of chordoid meningioma over a case series of 1743 meningiomas (0.52%) operated upon at our institution from 1995 to 2013. All the reported clinicopathological findings were analyzed. Two hundred and twenty-one CM cases have been published to date worldwide and few single-center large case series have been issued. Seventy-five percent of the cases that underwent subtotal resection at our institution had recurrence within 1 year. Total resection of the tumor should be the major objective of surgery to reduce the possibility of tumor recurrence. The percentage of chordoid features within the tumor specimen could assist in predicting the pathogenesis of the lesion. The correlation of the index of proliferation to recurrence rate is still controversial. Much debate exists with regard to the role of ...

Ovarian teratomas are frequently described in patients with N-methyl-d-aspartate receptor (NMDAR) encephalitis, yet NMDAR encephalitis is rarely described in patients with ovarian teratomas. Understanding why a minority of patients with teratomas are seen with autoimmune encephalitis may improve the management of NMDAR encephalitis and other teratoma-associated autoimmune diseases. To characterize the unique organization of neuroglial elements within ovarian teratomas resected from patients with NMDAR encephalitis. Case-control study comparing the pathological features of ovarian teratomas resected from consecutively accrued cases with NMDAR encephalitis between January 1, 2009, and December 15, 2013, and ovarian teratomas resected from controls between June 1, 2012, and June 30, 2013. Pathology tissue database at a tertiary academic care center. Five cases with teratoma-associated NMDAR encephalitis and serum or cerebrospinal fluid autoantibodies against central nervous system (CNS) NMDAR and 38 controls (39 ovarian teratomas) without neurological symptoms or signs. Formalin-fixed, paraffin-embedded ovarian teratomas were examined for the presence of CNS tissue and inflammatory infiltrates using direct microscopy, enhanced with standard histopathological and immunological stains. Frequency of detection of atypical (dysplastic) CNS neuronal elements in ovarian teratomas resected from cases vs controls, as well as characterization of the relationship between atypical neurons and immune infiltrates. Central nervous system neuronal elements were detected in 4 of 5 teratomas resected from cases with NMDAR encephalitis and in 20 of 39 controls (P = .36). Atypical neurons were seen within teratomas resected from 4 of 5 cases but not in 39 controls, reliably distinguishing teratomas associated with NMDAR encephalitis (P < .001). If found within the CNS, these histological abnormalities would have received the diagnosis of gangliogliomas (n = 3) and ganglioneuroblastoma (n = 1). Reactive changes were present in teratomas from controls, including ferruginated neurons and Rosenthal fibers. Abnormal neuroglial elements were closely related to immune infiltrates in teratomas resected from 4 of 4 cases. Inflammatory infiltrates were not associated with neuroglial tissue in 20 controls, further differentiating these populations (P < .001). Abnormal neurons within teratomas distinguish cases with NMDAR encephalitis from controls and may promote the development of autoimmunity.

The objectives of this study were to examine the clinical and pathologic features of two subgroups of patients with dementia with Lewy bodies (DLB) differing in Alzheimer disease (AD)-type pathology load and to identify clinical variables useful in the differential diagnosis from AD. The records of 64 consecutive demented patients were reviewed. Pathologic diagnoses were independently established [35 AD cases, 11 cases of pure dementia with Lewy bodies (pDLB), and 18 cases of combined AD plus Lewy bodies (AD+LB)], and several neurodegenerative lesions were quantified. Clinical and pathologic data were compared between groups with univariate and multivariate analyses. Compared with the other groups, pDLB cases had more frequent acute-subacute onset of dementia [45% vs. AD (3%) and AD+LB (16%)], early parkinsonism [45% vs. AD (0%) and AD+LB (0%)], early [27% vs. AD (0%) and AD+LB (0%)] and late [73% vs. AD (11%) and AD+LB (16%)] hallucinations, fluctuating course [46% vs. AD (9%) and AD+LB (22%)], delusions [45% vs. AD (11%) and AD+LB (6%)], spontaneous parkinsonism [63% vs. AD (8%) and AD+LB (16%)], less frequent ideomotor apraxia and loss of insight, earlier urinary incontinence [3.2 +/- 1.4 years after onset vs. AD (6.3 years) and AD+LB (5.8 years)], shorter duration of dementia [7.7 +/- 2.4 years vs. AD (9.6 years) and AD+LB (11 years)], milder atrophy in computed tomography scans, greater brain weight, more transcortical spongiosis, wider cortex and subcortex, and less amyloid angiopathy. All pDLB cases but no AD cases had abnormal CA2 neurites. The clinical features of AD+LB patients were similar to those of AD patients other than more frequent acute-subacute onset and fluctuating evolution. Discriminant analyses selected four clinical variables differentiating pDLB from the other two groups as a whole: acute-subacute onset, early parkinsonism, early hallucinations, and early onset of urinary incontinence. Two or more of these features identified pDLB with a sensitivity of 81.8% and a specificity of 95.9%. Differentiation between the three groups (pDLB, AD+LB, and AD) or between both groups with LB (DLB) from AD could be only attained in 70% of cases. We conclude that early symptomatology is the main clue for the diagnosis of pDLB. We identified by discriminant analysis a set of clinical diagnostic criteria similar to those proposed by the Consortium on Dementia With Lewy Bodies. Accuracy was excellent for the diagnosis of pDLB but only mediocre for separating AD+LB as well as the entire DLB group from AD.

The finding of a colloid cyst on neuroimaging is often incidental. These lesions are usually located at the foramen of Monro, are hyperdense on CT scans, and generally demonstrate signal intensity of water on MR images, although this depends on their content. When symptomatic, they frequently present with headaches and nausea due to an obstructive hydrocephalus. The authors describe a case of a giant colloid cyst in a patient presenting with complete left-sided vision loss and progressive memory loss, two very atypical findings in colloid cyst presentation. Imaging findings were also atypical, and this case proved to be a diagnostic dilemma because of its clinical and radiological presentation. Histopathological investigation was of utmost importance in the final diagnosis of a colloid cyst. To the authors' knowledge this colloid cyst is larger than any other described in the literature.

Primary progressive aphasia (PPA) is a progressive loss of specific language functions with relative sparing of other cognitive domains at least for the first few years of the illness. Based on the constellation of symptoms, PPA has been recently classified into a nonfluent, semantic, or logopenic variant. Nonfluent variant PPA is characterized by dysfluent and effortful speech, often combined with agrammatism. Also, some patients have initially predominant apraxia of speech. The neuroimaging findings in nfvPPA are in most cases progressive atrophy within the left inferior, opercular, and insular regions. Pathology is a tauopathy (FTLD-T), most often Pick's disease or CBD. Semantic variant PPA, on the other hand is characterized by fluent, but circumlocutory speech, then severe anomia and word-finding difficulties, all being associated with a progressive loss of lexical-semantic knowledge. As the disease progresses, the semantic impairment typically becomes multimodal. The clinical picture of svPPA is often associated with atrophy of the anterior regions of the temporal lobes, usually more prominent on the left side. The majority of these patients have TDP-43 pathology. The third, most recently described form of PPA is the logopenic variant characterized by decreased spontaneous speech output with frequent word-finding pauses, phonologic parahpasias, and repetition deficits. It resembles aphasia in Alzheimer's disease. Imaging abnormalities in lvPPA have been predominantly found in the left temporo-parietal junction area, and the pathological changes have been often those of AD.

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