The effect of paramagnetic contrast in choline peak in patients with glioblastoma multiforme might not be significant.

BACKGROUND AND PURPOSE: (1)H-MR spectroscopy is a useful tool in brain tumor evaluation. A critical point in obtaining representative spectra is the correct voxel positioning, which can be more accurate after Gd administration. Some experimental data suggested that Gd could cause Cho signal loss. Our aim was to evaluate the effect of Gd in the Cho peak area and width in patients with GBM. MATERIALS AND METHODS: We performed multivoxel (1)H-MR spectroscopy before and after Gd administration in 18 patients with GBM. Quantification of Cho peak area and width in each voxel was completed, and the Cho mean and maximum values before and after Gd injection were calculated in the tumor and contralateral hemisphere. Choline peak area and width values obtained before and after contrast were compared, considering as separate entities enhancing and nonenhancing tumoral voxels and the contralateral hemisphere. RESULTS: No statistically significant differences were found for the Cho peak area mean values in the tumoral voxels or contralaterally (P > .05). A tendency for an increase in the Cho peak width mean value was found in the tumoral enhancing voxels (P = .055). A statistically significant decrease was found for the mean value of the maximum Cho peak area in enhancing tumoral voxels (P = .020). No significant differences were found in the nonenhancing tumoral voxels or contralaterally (P > .05). CONCLUSIONS: The injection of Gd before performing (1)H-MR spectroscopy might not significantly affect the Cho peak area in patients with GBM. The paramagnetic contrast seems to cause a different effect, depending on Gd enhancement.

Extraneural metastases in medulloblastoma / Mestástases extraneurais em moduloblastoma

Medulloblastoma is the most common childhood malignant tumor of central nervous system, but it may also occur in adults. It presents high invasive growth with spreading of tumor cells into the leptomeningeal space along the neuroaxis early in the course of the disease. Extraneural metastases are rare but frequently lethal, occurring only in 1 to 5 percent of patients, and are related, in the most of cases, to the presence of ventriculoperitoneal shunt. Here we characterize the clinical profile of five cases of medulloblastoma with systemic spreading of tumor cells, also comparing them to cases already described in the literature.

O meduloblastoma é o tumor maligno mais frequente do sistema nervoso central na infância, mas também pode ocorrer em adultos. Ele apresenta crescimento altamente invasivo com disseminação de células tumorais ao longo do neuroeixo precocemente no curso da doença. Metástases extraneurais são raras mas frequentemente letais, ocorrendo apenas em 1 a 5 por cento dos pacientes, e estão relacionadas, na maioria dos casos, a presença de derivação ventriculperitoneal. Neste artigo ,apresentamos o perfil de cinco casos de meduloblastoma com disseminção sistêmica das células tumorais, comparando-os com os casos já descritos na literatura.

Association of EGFR c.2073A>T polymorphism with decreased risk of diffusely infiltrating astrocytoma in a Brazilian case-control study.

Epidermal growth factor receptor (EGFR) gene overexpression has been implicated in the development of many types of tumors, including glioblastomas, the most frequent diffusely infiltrating astrocytomas. However, little is known about the influence of the polymorphisms of EGFR on EGFR production and/or activity, possibly modulating the susceptibility to astrocytomas. This study aimed to examine the association of two EGFR promoter polymorphisms (c.-191C>A and c.-216G>T) and the c.2073A>T polymorphism located in exon 16 with susceptibility to astrocytomas, EGFR gene expression and survival in a case-control study of 193 astrocytoma patients and 200 cancer-free controls. We found that the variant TT genotype of the EGFR c.2073A>T polymorphism was associated with a significantly decreased risk of astrocytoma when compared with the AA genotype [sex- and age-adjusted odds ratio 0.51, 95% confidence interval 0.26-0.98]. No association of the two promoter EGFR polymorphisms (or combinations of these polymorphisms) and risk of astrocytomas, EGFR expression or survival was found. Our findings suggest that modulation of the EGFR c.2073A>T polymorphism could play a role in future therapeutic approaches to astrocytoma.

Optimizing therapy of seizures in patients with HIV and cysticercosis.

Worldwide, about 40 million people are living with HIV and 50 million people have neurocysticercosis (NCC). About 5% of patients with HIV and the majority of patients with NCC develop recurrent seizures. Mechanisms of seizure production in HIV include mass lesions, meningitis, encephalitis, and ischemia. Seizures in NCC may occur at all stages of cyst development, from the vesicular and colloidal to the calcified stages. Seizures in HIV present special problems with regard to choice of antiepileptic drug (AED) and the potential for drug-drug interactions with antiretroviral (ARV) treatments. Newer AEDs with simpler pharmacokinetic profiles may be the preferred agents, particularly when protease inhibitors form part of ARV regimens. Seizures in NCC are easily controlled with the older AEDs. Although there has been some debate about the value of antiparasitic drugs in NCC, accumulating data suggest that the use of these agents in active disease decreases the risk for development of chronic epilepsy.

Association of TP53 mutation, p53 overexpression, and p53 codon 72 polymorphism with susceptibility to apoptosis in adult patients with diffuse astrocytomas.

Clarification of TP53 alterations is important to understand the mechanisms underlying the development of diffuse astrocytomas. It has been suggested that the alleles of TP53 at codon 72 differ in their ability to induce apoptosis in human cancers. The aim of this study was to analyze the possible association of TP53 mutation, p53 overexpression, and p53 codon 72 polymorphism with susceptibility to apoptosis in adult Brazilian patients with diffuse astrocytomas. We analyzed 56 surgical specimens of diffuse astrocytomas for alterations of TP53, using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) direct sequencing. p53 and cleaved caspase 3 protein expression were assessed by immunohistochemistry. We found TP53 mutations in 19.6% (11 out of 56) of tumors tested, with the lowest mutation rate found in the cases of glioblastomas (8.8%) (p = 0.03). Only 16.1% of tumors tested showed cleaved caspase 3-positive staining, demonstrating that apoptosis is very inhibited in these tumors. All tumors having TP53 mutation and p53 accumulation had no expression of cleaved caspase 3. Additionally, no association was observed in tumors having proline and arginine alleles and expression of cleaved caspase 3. We concluded that clarification of the TP53 alterations allows a better understanding of the mechanisms involved in the progression of diffuse astrocytomas, and the allele status at codon 72 was not associated with apoptosis in these tumors.

Proton MR spectroscopy and imaging of a galactosemic patient before and after dietary treatment.

We describe how proton MR spectroscopy ((1)H-MR spectroscopy) was useful in elucidating the diagnosis of galactosemia in an undiagnosed 6-month-old infant. In vivo (1)H-MR spectroscopy of the brain showed a doublet at 3.7 parts per million, which was identified as galactitol (Gal-ol) by in vitro (1)H-MR spectroscopy of the urine. Galactosemia was subsequently confirmed by laboratory tests and treatment was initiated. A follow-up brain MR imaging and (1)H-MR spectroscopy study revealed resolution of white matter lesions and disappearance of Gal-ol peaks.

Leukoencephalopathy, cerebral calcifications, and cysts: new observations.

We describe three cases of the rare syndrome of leukoencephalopathy, brain calcifications, and cysts. Conventional MRI, proton spectroscopy, and diffusion-weighted imaging yielded additional information on the disease. Imaging findings favor increased water content rather than a demyelinating process in the pathophysiology of this disease. Clinical features of Coats disease and consanguinity were also encountered.

Molecular analysis of collagen XVIII reveals novel mutations, presence of a third isoform, and possible genetic heterogeneity in Knobloch syndrome.

Knobloch syndrome (KS) is a rare disease characterized by severe ocular alterations, including vitreoretinal degeneration associated with retinal detachment and occipital scalp defect. The responsible gene, COL18A1, has been mapped to 21q22.3, and, on the basis of the analysis of one family, we have demonstrated that a mutation affecting only one of the three COL18A1 isoforms causes this phenotype. We report here the results of the screening of both the entire coding region and the exon-intron boundaries of the COL18A1 gene (which includes 43 exons), in eight unrelated patients with KS. Besides 20 polymorphic changes, we identified 6 different pathogenic changes in both alleles of five unrelated patients with KS (three compound heterozygotes and two homozygotes). All are truncating mutations leading to deficiency of one or all collagen XVIII isoforms and endostatin. We have verified that, in exon 41, the deletion c3514-3515delCT, found in three unrelated alleles, is embedded in different haplotypes, suggesting that this mutation has occurred more than once. In addition, our results provide evidence of nonallelic genetic heterogeneity in KS. We also show that the longest human isoform (NC11-728) is expressed in several tissues (including the human eye) and that lack of either the short variant or all of the collagen XVIII isoforms causes similar phenotypes but that those patients who lack all forms present more-severe ocular alterations. Despite the small sample size, we found low endostatin plasma levels in those patients with mutations leading to deficiency of all isoforms; in addition, it seems that absence of all collagen XVIII isoforms causes predisposition to epilepsy.

Inter-laboratory comparison of DNA preservation in archival paraffin-embedded human brain tissue from participating centres on four continents.

DNA extracted from formalin-fixed and paraffin-embedded brain tissue is known to contain as yet ill-characterized inhibitors of the PCR process. As part of a project that aims to clarify the role of mitochondrial DNA sequence variation in human neurodegenerative diseases using DNA from various ethnic backgrounds, we have investigated factors that influence the preservation of archival DNA and its suitability for PCR. In this study, neuropathological tissue samples were analysed that had been routinely processed in 18 international centres on four continents. Following DNA extraction, PCR amplification of mitochondrial and nuclear DNA sequences was performed with and without additional purification of the template DNA. In addition, the DNA used for PCR was analysed by HPLC. Phosphate-buffered formalin proved to be a superior fixative compared with unbuffered aldehyde: DNA extraction resulted in greater yields, the molecular weight of the isolated DNA was higher and PCR was more successful. PCR inhibitors were identified as (1) high concentrations of small (<300 bp) DNA fragments that competitively compete with template DNA and (2) contaminants of the DNA template solution including denatured protein that cannot be completely removed by phenolic extraction. HPLC analysis did not reveal significant qualitative differences between DNA isolated from fresh-frozen tissue samples and DNA recovered from formalin-fixed, paraffin-embedded brain tissue. The fact that DNA could be amplified from the majority of tissue specimens in this study suggests that rare diseases and diseases where ethnic background plays an important role can be sampled for genetic polymorphism analysis on a global scale using archival neuropathological collections.

Rasmussen encephalitis associated with segmental vitiligo of the scalp: clinicopathologic report.

A 3-year-old boy with segmental vitiligo, poliosis, and alopecia over the right side of the scalp developed epilepsia partialis continua involving the left side of the body and progressive atrophy of the right cerebral hemisphere. There was a right ear dysacusia and a perilimbal vitiligo associated with an area of iris depigmentation in the right eye. Pleocytosis and hypergammaglobulin were detected in cerebrospinal fluid. Because medical treatment that included phenobarbital, phenytoin, carbamazepine, oxcarbazepine, benzodiazepines, corticosteroids, gamma-globulin, and a ketogenic diet was ineffective, he underwent a right hemispherectomy. Neuropathologic examination showed a widespread scattered inflammatory process with numerous microglial nodules and perivascular lymphocytic cuffing associated with degenerative changes with severe neuronal loss, loosening of the neuropil, and microcystic changes with tissue collapse. The coexistence of vitiligo and possibly Vogt-Koyanagi-Harada syndrome in this child reinforces the autoimmune theory as the pathogenesis of Rasmussen syndrome.

Prion disease resembling frontotemporal dementia and parkinsonism linked to chromosome 17.

OBJECTIVE: To compare the clinical features of a familial prion disease with those of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). BACKGROUND: Prion diseases are not usually considered in the differential diagnosis of FTDP-17, since familial Creutzfeldt-Jakob disease (CJD), the most common inherited prion disease, often manifests as a rapidly progressive dementia. Conversely, FTDP-17 usually has an insidious onset in the fifth decade, with abnormal behavior and parkinsonian features. METHOD: We present the clinical features of 12 patients from a family with CJD associated with a point mutation at codon 183 of the prion protein gene. RESULTS: The mean age at onset was 44.0 +/- 3.7; the duration of the symptoms until death ranged from two to nine years. Behavioral disturbances were the predominant presenting symptoms. Nine patients were first seen by psychiatrists. Eight patients manifested parkinsonian signs. CONCLUSION: These clinical features bear a considerable resemblance to those described in FTDP-17.

Friedreich's ataxia: clinical and molecular study of 25 Brazilian cases.

INTRODUCTION: Friedreich's ataxia is a neurodegenerative disorder whose clinical diagnostic criteria for typical cases basically include: a) early age of onset (< 20 or 25 years), b) autosomal recessive inheritance, c) progressive ataxia of limbs and gait, and d) absence of lower limb tendon reflexes. METHODS: We studied the frequency and the size of expanded GAA and their influence on neurologic findings, age at onset, and disease progression in 25 Brazilian patients with clinical diagnosis of Friedreich's ataxia - 19 typical and 6 atypical - using a long-range PCR test. RESULTS: Abnormalities in cerebellar signs, in electrocardiography, and pes cavus occurred more frequently in typical cases; however, plantar response and speech were more frequently normal in this group when the both typical and atypical cases were compared. Homozygous GAA expansion repeats were detected in 17 cases (68%) - all typical cases. In 8 patients (32%) (6 atypical and 2 typical), no expansion was observed, ruling out the diagnosis of Friedreich's ataxia. In cases with GAA expansions, foot deformity, cardiac abnormalities, and some neurologic findings occurred more frequently; however, abnormalities in cranial nerves and in tomographic findings were detected less frequently than in patients without GAA expansions. DISCUSSION: Molecular analysis was imperative for the diagnosis of Friedreich's ataxia, not only for typical cases but also for atypical ones. There was no genotype-phenotype correlation. Diagnosis based only on clinical findings is limited; however, it aids in better screening for suspected cases that should be tested. Evaluation for vitamin E deficiency is recommended, especially in cases without GAA expansion.

Clinical characteristics and surgical outcome of patients with temporal lobe tumors and epilepsy.

This is a retrospective study of 21 surgically treated patients with temporal lobe tumors and epilepsy. Evaluation included clinical data, EEG findings, structural scans, pathological diagnosis and post-surgical follow-up. There were 9 cases of ganglioglioma, 5 pilocytic astrocytoma, 3 ganglioneuroma, 2 dysembryoplastic neuroepithelial tumor, 1 pleomorphic xantoastrocytoma, and 1 meningioangiomatosis. Mean follow-up time was 22 months and outcome was evaluated according to Engel's classification; 76.2% were classified in class I and 23.8% in II and III. All patients classes II and III had been submitted to mesial and neocortical resections. There were no differences related to clinical characteristics, pathological diagnosis or duration of follow-up in patients seizure-free or not. All patients had abnormal MRI and ten of these had normal CT; the MRI characteristics were compared to pathological diagnosis and specific histological characteristics of the tumors were not discernible by MRI. We concluded that MRI was essential for the diagnosis and precise location of TL tumors. Ganglioglioma was the most frequent tumor and lesionectomy associated to mesial resection doesn't guarantee a better prognosis.

Pleomorphic xanthoastrocytoma of the cerebellum.

We report a clinicopathologic case of a pure cerebellar pleomorphic xanthoastrocytoma occurring in a 68-year-old male patient. The occurrence of pleomorphic xanthoastrocytoma outside the cerebral hemispheres is exceedingly rare. In the cerebellum only five cases have been reported so far, four of which are composite pleomorphic xanthoastrocytoma-gangliogliomas. This observation reinforces the argument that pleomorphic xanthoastrocytomas should be included in the differential diagnosis of cerebellar neoplasms.

Subacute sclerosing panencephalitis. Clinical aspects and prognosis. The Brazilian registry.

Subacute sclerosing panencephalitis (SSPE) is an inflammatory neurodegenerative disease related to the persistence of measles virus. Although its frequency is declining because of measles eradication, we still have some cases being diagnosed. With the aim to describe epidemiological aspects of SSPE in Brazil, we sent a protocol to Child Neurologists around the country, 48 patients were registered, 27 (56%) were from the southeast region, 34 (71%) were male and 35 (73%) white, 27 (56%) had measles, 9 (19%) had measles and were also immunized, 7 (14%) received only immunization, 1 patient had a probable neonatal form. Mean time between first symptoms and diagnosis was 12 months (22 started with myoclonus or tonic-clonic seizures, 7 (14%) with behavioral disturbances); 36 patients (75%) had EEG with pseudoperiodic complexes. Follow up performed in 28 (58%) patients showed: 12 died, 2 had complete remission and the others had variable neurological disability. Our data shows endemic regions in the country, a high incidence of post-immunization SSPE and a delay between first symptom and diagnosis.

Psychotic symptoms in dementia associated with motor neuron disease: a pathophysiological hypothesis.

Three patients with neuropathologically confirmed frontotemporal dementia, motor neuron disease type, manifested hallucinations. In this dementia, the superficial layers of the frontal and temporal cortices are predominantly affected. Hallucinations may emerge as release phenomena secondary to selective laminar cortical involvement.

[Diagnosis of metabolic diseases of the nervous system in children through ultrastructural analysis of non cerebral tissue]. / Diagnóstico de doenças metabólicas do sistema nervoso da infância por exame ultra-estrutural de tecido não cerebral.

Although biochemical and molecular genetic analysis are the most precise methods for the diagnosis of metabolic diseases, morphological studies remain a very important diagnostic method mainly in countries like Brazil, where clinical laboratories are unable to perform most of the exams required for the diagnosis of these diseases. Moreover, pathologic evaluation is the single diagnostic method for some disorders whose metabolic defect is unknown such as neuronal ceroid-lipofuscinosis, infantile neuroaxonal dystrophy or Lafora disease. We present our experience with ultrastructural analysis in 582 exams of ocular conjunctiva (n = 320), skin (n = 92) or peripheral nerve (n = 170) performed between 1975 and 1996, in 486 children. In 112 cases there were definite ultrastructural changes. In 59 cases, the sole ultrastructural exam allowed the diagnosis. In 29, the changes were less specific, and the final diagnosis was performed by a combination of clinical and pathological analysis. In the remaining 24 cases, a generic diagnosis of mucopolysaccharidosis was done in 8 cases, oligosaccharidosis in 4 cases and GM2 gangliosidosis in 12 cases. Whenever a biochemical test was performed in overseas laboratories, the initial diagnosis was confirmed. These results stress the importance of ultrastructural analysis in non-cerebral tissues for the diagnosis of many metabolic disorders mainly when biochemical tests cannot be performed.

[Dysembryoplastic neuroepithelial tumor. An epidemiological study from a single institution]. / Tumor neuroepitelial disembrioplástico. Estudo epidemiológico de uma única instituição.

The true incidence of dysembryoplastic neuroepithelial tumor (DNT) is unknown. Variable estimations have been advanced according to the type of recruitment of patients. In series of patients with tumors who were operated on for pharmacoresistant epilepsy, the rates varied widely, from 5% to 87%. Among 600 pediatric tumors in a series, 9 DNT (1.5%) were found. Since DNT was identified only in 1988, we reviewed our cases (1975-1991) of gangliogliomas (n = 25), oligoastrocytomas (n = 9), temporal oligodendrogliomas (n = 11), temporal astrocytomas grade II (OMS 1993) (n = 44) irrespective to age, as well as all astrocytomas grade II (n = 61) and oligodendrogliomas (n = 10) in patients up to 20 years of age. Seven DNT were encountered. Four cases had been formerly diagnosed as gangliogliomas and 3 as astrocytomas grade II. From 1992 on, 4 more DNT were diagnosed, making up a total of 11 cases. Eight patients were under age 17 (6 y to 17 y, mean 10.3 y) and 3 were 27, 42 and 51 year-old. Eight tumors were temporal, 1 frontal and 2 occipital. All patients have had pharmacoresistant epilepsy. Among all neuroepithelial tumors diagnosed in our Division in the last 22 years, DNT comprises 1.2% in patients under age 20 (n = 660), 0.24% in patients over 20 years (n = 1254), and 0.63% all ages considered (n = 1914).

Familial spongiform encephalopathy associated with a novel prion protein gene mutation.

Human prion diseases include Creutzfeldt-Jakob disease, Gerstmann-Stráussler-Scheinker disease, fatal familial insomnia, and kuru. Each of these diseases has a specific clinical presentation while spongiform encephalopathy, neuronal loss, and gliosis are their neuropathological hallmarks. We studied a Brazilian family with an autosomal dominant form of dementia. Nine members of the family were affected by a dementia with frontotemporal clinical features, with a mean age at onset of 44.8 +/- 3.8 years and a mean duration of symptoms of 4.2 +/- 2.4 years. Neuropathological examination of 3 patients showed severe spongiform change and neuronal loss in the deep cortical layers and in the putamen, but minimal gliosis in the most severely affected areas. The putamen and cerebellum, but not other areas of the affected brain, displayed prion protein immunoreactivity. A novel prion protein gene mutation causing a nonconservative substitution at codon 183 was identified in 2 neuropathologically confirmed affected individuals (mother and son). The mutation was transmitted in a mendelian fashion to 12 members of the family. Therefore, we identified a novel prion disease variant characterized by an early onset and long duration of the symptoms, severe spongiform change with minimal gliosis, associated with a prion protein gene mutation at codon 183.

Double pathology in Rasmussen's encephalitis: etiologic considerations.

In a 7-year-old girl with epilepsia partialis continua (EPC) involving the left face, arm, and leg for 1 year, serial neuroimaging studies showed progressive, brain atrophy. Because medical treatment was ineffective, she underwent a large fronto-temporal surgical resection. Neuropathological examination showed loss of lamination and dysplastic neurons, gliosis, microglial nodules, and perivascular cuffing. Such "double pathology" (dysgenesia and a chronic inflammatory process) may have implications for the pathophysiology of Rasmussen's syndrome.