Expression of semaphorin 3A, semaphorin 7A and their receptors in multiple sclerosis lesions.

BACKGROUND: Studies in multiple sclerosis (MS) and in experimental models point to a critical role of semaphorin (sema)3A and sema7A in MS pathogenesis. OBJECTIVE: The objective of this paper is to characterise the expression of sema3A, sema7A, and their receptors in MS lesions. METHODS: We included 44 demyelinating lesions from MS patients, 12 lesions with acute cerebral infarct, 11 lesions with progressive multifocal leucoencephalopathy and 10 non-neurological control patients. MS lesions were classified according to inflammatory activity and all samples were immunostained for sema3A, sema7A, neuropilin 1 (Np-1), α1-integrin, and ß1-integrin. RESULTS: In MS-damaged white matter sema3A and Np-1 were both detected in microglia/macrophages, whereas reactive astrocytes expressed only sema3A. Otherwise, sema7A, α1-integrin and ß1-integrin were observed in reactive astrocytes, and microglia/macrophages only expressed ß1-integrin. The expression of sema3A, sema7A and their receptors is more relevant in MS than in other demyelinating diseases. Sema3A and sema7A expression correlated with the inflammatory activity of the MS lesions, suggesting their involvement in the immunological process that takes place in MS. CONCLUSIONS: The expression pattern of sema3A, sema7A and their receptors in MS lesions suggests that both molecules contribute to create a negative environment for tissue regeneration, influencing the ability to regenerate the damaged tissue.

[Clinico-pathological and molecular aspects of diagnostic and prognostic value in gliomas]. / Aspectos clinicopatologicos y moleculares de valor diagnostico y pronostico en gliomas.

INTRODUCTION: Diffuse infiltrative gliomas, the most common primary brain tumours, account for almost 80% of malignant brain tumours. 60-70% of gliomas are astrocytic and over 80% of these tumours is considered high grade malignancy (grade III and IV) according to current World Health Organization classification. Infiltrating gliomas include diffuse astrocytomas, oligodendrogliomas and oligoastrocytomas. AIM: To review the clinical and histological features of cerebral gliomas, and molecular alterations that add relevant information for novel approaches in diagnosis, prognosis and treatment. DEVELOPMENT: The current gold standard diagnosis of these tumours relies on histopathological classification, which provides a grading of malignancy as a predictor of biological behaviour. However emerging molecular abnormalities have been discovered in the last years and these molecular changes are playing an increasingly prominent role as predictive biomarkers or in the development of diagnostic and prognostic. Now the neuropathologist is in crossroads between pathology and molecular biology and he plays a significant role in implementation of treatments and/or clinical trials. CONCLUSIONS: The study of proteomics and molecular biomarkers should complement the histopathological analysis and sometimes allows to determine direct or indirect predictive factors as well as the study of affected pathways which may become selective therapeutic targets.

Brain contusions induce a strong local overexpression of MMP-9. Results of a pilot study.

BACKGROUND: Brain contusions are inflammatory evolutive lesions that induce intracranial pressure increase and edema, contributing to neurological outcome. Matrix metalloproteinases (MMPs) 2 and 9 can degrade the majority of the extracellular matrix components, and are implicated in blood-brain barrier disruption and edema formation. The aim of this study was to investigate MMP-2 and MMP-9 profiles in human brain contusions using zymography. METHODS: A prospective study was conducted in 20 traumatic brain injury patients where contusion brain tissue was resected. Brain tissues from lobectomies were used as controls. Brain homogenates were analysed by gelatin zymography and in situ zimography was performed to confirm results, on one control and one brain contusion tissue sample. FINDINGS: MMP-2 and MMP-9 levels were higher in brain contusions when compared to controls. MMP-9 was high during the first 24 hours and at 48 to 96 hours, whereas MMP-2 was slightly high at 24 to 96 hours. In situ zymography confirmed gelatin zymography results. A relation between outcome and MMP-9 levels was found; MMP-9 levels were higher in patients with worst outcome. CONCLUSIONS: Our results indicate strong time-dependent gelatinase expression primarily from MMP-9, suggesting that the inflammatory response induced by focal lesions should be considered as a new therapeutic target.

Angeítis aislada del sistema nervioso central / Isolated cerebral angiitis

Introducción. La angeítis granulomatosa aislada del sistema nervioso central se define histológicamente por la presencia de una inflamación granulomatosa que se distribuye desde los vasos meníngeos y se extiende hacia el parénquima a lo largo de venas y de arterias de calibre variable. Las alteraciones clínicas más frecuentes en estos pacientes son la cefalea y cuadros de encefalopatía. Caso clínico. Presentamos el caso clínico de una paciente que inicia crisis convulsivas de inicio parcial con generalización secundaria, diagnosticado mediante biopsia cerebral, con buena respuesta clínica al tratamiento inmunosupresor (corticoides y ciclofosfamida). Realizamos una actualización bibliográfica sobre esta patología. Conclusiones. La sintomatología tan heterogénea que presentan los pacientes con esta patología provoca en numerosas ocasiones confusión y retraso en el diagnóstico. La confirmación histológica mediante la realización de una biopsia cerebral y meníngea es el parámetro determinante para el diagnóstico de la angeítis granulomatosa del sistema nervioso central (AU)

Introduction: Isolated cerebral angiitis of the central nervous system is defined histologically by presence of granulomatous inflammation in the meningeal vessels, and parenchyma throughout veins and arteries of variable size. The most common clinical manifestations are headache and encephalopathy. Case Report: We present the clinical case of a patient with epileptic seizures of focal onset, secondary generalized, diagnosed by cerebral biopsy. Clinical response to immunosuppressive treatment (corticosteroid and cyclophosphamyde) was excellent. We make a bibliographic review and update. Conclusion: The heterogeneous clinical symptomatology of this disease leads to confusion and delay in diagnosis. Histological confirmation by cerebral and meningeal biopsy is the best parameter for diagnosis of isolated cerebral angiitis of the central nervous system (AU)

[Isolated cerebral angiitis]. / Angeítis aislada del sistema nervioso central.

INTRODUCTION: Isolated cerebral angiitis of the central nervous system is defined histologically by presence of granulomatous inflammation in the meningeal vessels, and parenchyma throughout veins and arteries of variable size. The most common clinical manifestations are headache and encephalopathy. CASE REPORT: We present the clinical case of a patient with epileptic seizures of focal onset, secondary generalized, diagnosed by cerebral biopsy. Clinical response to immunosuppressive treatment (corticosteroid and cyclophosphamyde) was excellent. We make a bibliographic review and update. CONCLUSION: The heterogeneous clinical symptomatology of this disease leads to confusion and delay in diagnosis. Histological confirmation by cerebral and meningeal biopsy is the best parameter for diagnosis of isolated cerebral angiitis of the central nervous system.

[Central nervous system tumours in childhood: their clinical pathological aspects]. / Tumores del sistema nervioso central en la infancia: aspectos clinicopatologicos.

AIMS: Paediatric tumours affecting the central nervous system (CNS) constitute the second most frequent group of tumours at this age. Taking the WHO 2000 classification as our starting point, our intention was to describe the more important clinical and pathological features in the differential diagnosis of the different tumourous entities with the highest incidence in childhood. We highlight, above all, the characteristics that justify the need for a smooth flow of information between neurologists, neurosurgeons, neuroradiologists, neuropathologists and oncologists. We do not deal with familial tumourous syndromes, genetic aspects or clinical information derived from analyses of molecular alterations. DEVELOPMENT: Among CNS tumours, enough age related differences exist to be able to consider those appearing during childhood in their own right. Their topographic specificity is very characteristic and while 50% of them are infratentorial, 90% of those that occur in adults are supratentorial. Embryonic tumours are very frequent in childhood, but rare in adults, and the opposite happens with meningiomas. They are also different as regards their histological features, clinical characteristics, the early tendency to spread throughout the nervous system in the course of the disease and their biological behaviour. These data make us think that, in the pathogenesis of brain tumours in children, the molecular and epigenetic factors involved are different from those at play in the case of adults. CONCLUSIONS: A correct diagnosis requires a multidisciplinary approach and an understanding of the histological criteria and nomenclature by the health professionals involved in treating these patients.

Tumores del sistema nervioso central en la infancia: aspectos clinicopatológicos / Central nervous system tumours in childhood: their clinical-pathological aspects

Objetivo. Los tumores pediátricos del sistema nervioso central (SNC) constituyen el segundo grupo de tumores más frecuente en esta edad. Basándonos en la clasificación WHO 2000, nos proponemos describir los rasgos clínicos y patológicos de importancia en el diagnóstico diferencial de las distintas entidades tumorales de mayor incidencia en la infancia. Señalamos, sobre todo, aquellas características que justifican la necesidad de un intercambio de información fluido entre neurólogos, neurocirujanos, neurorradiólogos, neuropatólogos y oncólogos. No abordamos los síndromes tumorales familiares, los aspectos genéticos o aquella información clínica derivada de los análisis de las alteraciones moleculares. Desarrollo. Entre los tumores del SNC existen suficientes diferencias relacionadas con la edad como para poder considerar aparte los propios de la infancia. Es muy característica su especificidad topográfica: mientras que el 50 por ciento de los mismos son infratentoriales, el 90 por ciento de los que se dan en adultos son supratentoriales. Los tumores embrionarios son muy frecuentes en la infancia, pero raros en adultos, y todo lo contrario ocurre con los meningiomas. Difieren, también, en sus rasgos histológicos, clínica, tendencia precoz a la diseminación a través del sistema nervioso en el curso de la enfermedad y comportamiento biológico. Estos datos hacen pensar que, en la patogénesis de los tumores cerebrales en los niños, resultan afectados factores moleculares y epigenéticos diferentes de los adultos. Conclusiones. Se hace necesario el abordaje multidisciplinaro del hecho diagnóstico y la comprensión de los criterios histológicos y la nomenclatura por parte de los profesionales implicados en el tratamiento de estos pacientes (AU)

Aims. Paediatric tumours affecting the central nervous system (CNS) constitute the second most frequent group of tumours at this age. Taking the WHO 2000 classification as our starting point, our intention was to describe the more important clinical and pathological features in the differential diagnosis of the different tumourous entities with the highest incidence in childhood. We highlight, above all, the characteristics that justify the need for a smooth flow of information between neurologists, neurosurgeons, neuroradiologists, neuropathologists and oncologists. We do not deal with familial tumourous syndromes, genetic aspects or clinical information derived from analyses of molecular alterations. Development. Among CNS tumours, enough age-related differences exist to be able to consider those appearing during childhood in their own right. Their topographic specificity is very characteristic and while 50% of them are infratentorial, 90% of those that occur in adults are supratentorial. Embryonic tumours are very frequent in childhood, but rare in adults, and the opposite happens with meningiomas. They are also different as regards their histological features, clinical characteristics, the early tendency to spread throughout the nervous system in the course of the disease and their biological behaviour. These data make us think that, in the pathogenesis of brain tumours in children, the molecular and epigenetic factors involved are different from those at play in the case of adults. Conclusions. A correct diagnosis requires a multidisciplinary approach and an understanding of the histological criteria and nomenclature by the health professionals involved in treating these patients (AU)

Metallothionein expression in the central nervous system of multiple sclerosis patients.

Multiple sclerosis (MS) is a major chronic demyelinating and inflammatory disease of the central nervous system (CNS) in which oxidative stress likely plays a pathogenic role in the development of myelin and neuronal damage. Metallothioneins (MTs) are antioxidant proteins induced in the CNS by tissue injury, stress and some neurodegenerative diseases, which have been postulated to play a neuroprotective role. In fact, MT-I+II-deficient mice are more susceptible to developing experimental autoimmune encephalomyelitis (EAE), and treatment of Lewis rats with Zn-MT-II reduces EAE severity. We show here that, as in EAE, MT-I+II proteins were expressed in brain lesions of MS patients. Cells expressing MT-I+II were mainly astrocytes and activated monocytes/macrophages. Interestingly, the levels of MT-I+II were slightly increased in the inactive MS lesions in comparison with the active lesions, suggesting that MTs may be important in disease remission.

Adult-onset subacute sclerosing panencephalitis: clinico-pathological findings in 2 new cases.

Subacute sclerosing panencephalitis (SSPE), an uncommon disease usually affecting children and adolescents, is caused by persistent measles infection that progresses to chronic infection with fatal outcome. The debut of this disease in adults is rare, with a small number of cases in the medical literature. This article presents the clinical, radiologic and post-mortem neuropathologic findings in 2 new cases of women with SSPE (1 of them during pregnancy), which showed very atypical clinical characteristics, presentation and evolution. The influence of pregnancy on the course of the disease was unfavorable, in keeping with earlier reports. Our patients showed a very prolonged biphasal clinical course, with a period of disease-free remission that lasted several years. Histological study disclosed features of inflammatory disease associated with others of a neurodegenerative nature, such as the formation of neurofibrillary tangles, which would relate SSPE with other tauopathies.

Neonatal tumors of the CNS: a report of 9 cases and a review.

Neonatal central nervous system (CNS) tumors are an uncommon and histologically heterogeneous group of neoplasms with different clinical and biological features from those arising in childhood. We report 9 cases in which a diagnosis of CNS tumor was confirmed by biopsy or autopsy during the years 1982-1997 in the Vall d'Hebrón Children's Hospital, Barcelona. Two cases were fetal tumors detected by fetal sonography, 3 patients were symptomatic in the first days after birth and 4 patients presented initial clinical signs in the first weeks or months of life. Eight lesions were supratentorial and 1 was located in the spinal cord. According to histologic types, there were 2 glioneuronal tumors, 1 anaplastic astrocytoma, 1 choroid plexus carcinoma, 1 immature teratoma, 1 craniopharyngioma, 1 hemangioblastoma, 1 astroblastoma and 1 hemangioendothelioma. Extensive review of the literature indicates that our cases of hemangioblastoma, astroblastoma and hemangioendothelioma are exceptional and one more of the very rare and isolated previously published cases.

Paquimeningitis hipertrófica.Revisión histórica a propósito de dos casos y relación patogénicacon el síndrome Tolosa-Hunt y el pseudotumor orbitario / Hypertrophic pachymeningitis. A review of the histories of two cases and the pathological relationship with the Tolosa-Hunt syndrome and the orbital pseudotumor

Introducción. La paquimeningitis hipertrófica es una entidad infrecuente que origina un engrosamiento de la duramadre y cuya patogenia permanece sin aclarar. Presentamos dos nuevos casos de etiología indeterminada. Casos clínicos. Caso 1. Varón de 53 años que presenta desde febrero de 1981 cefalea occipital, acúfenos e hipoacusia derecha. Ingresa en octubre del mismo año por aumento de su cefalea, dolor periorbitario, disgeusia y parálisis facial periférica ipsilateral. En diciembre presenta convulsiones tonicoclónicas generalizadas y parálisis del VII y XI par derechos y del IX, X y XII izquierdos. En febrero de 1982 inicia neuralgia trigeminal derecha. Reingresa en noviembre de 1983 por cefalea continua con vómitos y trastorno de conducta. La tomografía computarizada mostró imágenes de alta atenuación en duramadre posterior, desestimándose por neurocirugía la biopsia. En marzo de 1985 fallece. El estudio necrópsico mostró una paquimeningitis hipertrófica. Caso 2. Paciente de 62 años que consulta en noviembre de 1995 por hipoacusia derecha de seis meses de evolución, a la que se añaden progresivamente parálisis ipsilaterales de los pares craneales II, IV, VI, VII y VIII, sin otras alteraciones en la exploración física. La analítica y los estudios serológicos fueron normales. La resonancia magnética craneal mostró una lesión infiltrativa extraparenquimatosa en fosa craneal media. Se decidió biopsia tras no mejorar clínicamente con tratamiento corticosteroideo. La anatomía patológica demostró una paquimeningitis hipertrófica. Se inició tratamiento con ciclofosfamida en forma de pulsos mensuales, permaneciendo estable hasta la fecha. Conclusión. Con estos dos nuevos casos queremos establecer una relación patogénica con el síndrome Tolosa-Hunt y el pseudotumor orbitario, así como reflejar el papel del tratamiento inmunosupresor en el control evolutivo de la paquimeningitis hipertrófica (AU)

[Disseminated acute encephalomyelitis with fatal evolution: clinicopathological study]. / Encefalomielitis aguda diseminada de evolución fatal: estudio clinicopatológico.

INTRODUCTION: Disseminated acute encephalomyelitis is a monophasic demyelinating disease which progresses rapidly and is often fatal. It is an autoimmune condition, mediated by T lymphocytes, in which the immune response is directed against the myelin antigens. CLINICAL CASE: We describe the clinical, radiological and neuropathological findings in the case of a 31 year old woman who, ten days after complaining of a clinical condition of upper respiratory tract inflammation, presented with unilateral focal neurological signs, subsequent rapid deterioration of consciousness and death. On autopsy the neuropathological characteristics of disseminated acute encephalomyelitis were seen. CONCLUSIONS: The relative rarity of this condition at the present time makes clinical diagnosis difficult. The differential diagnosis with other conditions may be difficult also. Thus, this disease often leads to a neuropathological diagnosis.

[The CNS amyloid]. / Amiloide en el sistema nervioso central.

INTRODUCTION: In this article we wish to review the most relevant pathogenic aspects and histological characteristics of the deposition of amyloid in the central nervous system (CNS). DEVELOPMENT: The beta A4, a product of protein APP, codified on chromosome 21, is related to sporadic cerebral amyloid angiopathy not associated with dementia, Alzheimer's disease, senile dementia of Alzheimer type or Down's syndrome, whilst a specific mutation on the 693 codon of the gene which codifies beta-APP is related to hereditary haemorrhage with Dutch-type amyloid angiopathy. The gene which codifies cystatin C, a member of the family of cystatin genes grouped on chromosome 20p11.2, undergoes specific mutation giving rise to a mutant protein which, at the position 68, substitutes leucine for glutamine. The mutant cystatin C has a greater tendency to aggregation when the temperature is increased. This pathogenic molecular mechanism underlies cases of amyloidosis due to hereditary type cystatin C, considered to be a systemic amylosidosis. The formation and deposition of amyloid may also occur in other neurodegenerative diseases of animals and humans in relation to the accumulation of abnormal isoforms of the prion protein, especially in Gerstman-Straussler-Scheinke's disease and the Japanese type of prion cerebral amyloid angiopathy. The fact that these aberrant isoforms mostly undergo conformational changes involving a shift from alpha-helix to beta-sheet structure is basic to the amyloidogenesis of prion disease. CONCLUSIONS: Amyloid is a family of proteins which is physically, chemically and structurally related, with common histochemical characteristics. In the CNS it is deposited in the vessel walls and parenchyma with topographic patterns and morphological differences according to the different disorders in which the amyloid is involved. Only neuropathological studies will enable us to discover its true incidence in senility with or without clinical features of dementia, and with or without haemorrhagic changes.

Encefalomielitis aguda diseminada de evolución fatal: estudio clinicopatológico / Disseminated acute encephalomyelitis with fatal evolution: clinicopathological study

Introducción y caso clínico. La encefalomielitis aguda diseminada es una enfermedad desmielinizante, monofásica, rápidamente progresiva y frecuentemente fatal, de carácter autoinmune mediada por linfocitos T, en la que la respuesta inmunológica se dirige contra los antígenos de la mielina. Describimos los hallazgos clínicos, radiológicos y neuropatológicos en el caso de una mujer de 31 años que tras un cuadro inflamatorio de vías altas presentó, 10 días después, signos neurológicos focales unilaterales y posteriormente afectación rápidamente progresiva del nivel de conciencia que le llevó al éxitus. El estudio autópsico demostró características neuropatológicas de encefalomielitis aguda diseminada. Conclusiones. La relativa poca frecuencia de esta enfermedad en la actualidad y el hecho de que el antecedente infeccioso puede pasar desapercibido, dificultan el diagnóstico clínico. Junto a esto cabe tener en cuenta que el diagnóstico diferencial con otras entidades puede ser difícil. Todo ello hace que esta enfermedad represente con frecuencia un diagnóstico neuropatológico (AU)

Amiloide en el sistema nervioso central / Amyloid in the central nervous system

Introducción. Este artículo se propone revisar los aspectos patogénicos más relevantes y las características histológicas del depósito de amiloide en el sistema nervioso central (SNC).Desarrollo. El BetaA4, producto de la proteína APP codificada en el cromosoma 21, está relacionado con la angiopatía amiloide cerebral esporádica no asociada a demencia, enfermedad de Alzheimer, demencia senil tipo Alzheimer o el síndrome de Down, mientras una mutación puntual en el codon 693 del gen que codifica la Beta-APP lo está con la hemorragia hereditaria con angiopatía amiloide tipo holandés. El gen que codifica la cistatina C, miembro de la familia de genes de cistatina agrupados en el cromosoma 20p11.2, sufre una mutación puntual que da lugar a una proteína mutante, la cual, en la posición 68, sustituye la leucina por la glutamina. La cistatina C mutante tiene mayor tendencia a agregarse en relación con los aumentos de temperatura. Este mecanismo molecular y patogénico es el que subyace en el caso de las amiloidosis por cistatina C de tipo hereditario, considerada como una amiloidosis sistémica. La formación y depósito de amiloide puede ocurrir también en aquellas enfermedades neurodegenerativas animales y humanas relacionadas con el acúmulo de isoformas anormales de la proteína priónica, especialmente en las enfermedades de Gerstman-Sträussler-Scheinker y la angiopatía amiloide cerebral priónica tipo japonés. El hecho de que estas isoformas aberrantes adquieran mayoritariamente un cambio conformacional con plegamientos Beta es fundamental en la amiloidogénesis de las enfermedades priónicas. Conclusiones. El amiloide es una familia de proteínas relacionadas fisicoquímica y estructuralmente, con características histoquímicas comunes. Su depósito en el SNC ocurre en las paredes de los vasos y en parénquima, con patrones topográficos y diferencias morfológicas, según las diferentes enfermedades en las que el amiloide está implicado. Sólo estudios neuropatológicos nos permitirán conocer la verdadera incidencia del mismo en la senilidad con o sin clínica de demencia y con o sin cuadro hemorrágico (AU)

[Hypertrophic pachymeningitis. A review of the histories of two cases and pathological relationship with the Tolosa-Hunt syndrome and the orbital pseudotumor]. / Paquimeningitis hipertrófica. Revisión histórica a propósito de dos casos y relación patogénica con el síndrome Tolosa-Hunt y el pseudotumor orbitario.

INTRODUCTION: Hypertrophic pachymeningitis is an infrequent condition which starts with a thickening of the dura mater and whose pathogenesis is unknown. We present two new cases of unknown aetiology. CLINICAL CASE: Case 1. A 53 year old man complained of occipital headache, tinnitus and deafness since February 1981. In October 1981 he was admitted to hospital with a worse headache, perio-orbital pain, dysgeusia and ipsilateral peripheral facial palsy. In December he had generalized tonic-clonic seizures and paralysis of the VII and XI right cranial nerves and IX, X and XII left cranial nerves. In February 1982 he developed right trigeminal neuralgia. He was readmitted in November 1983 with continuous headache, vomiting and a behavior disorder. On CT there was marked attenuation of the posterior dura mater, which the neurosurgical department considered unsuitable for biopsy. He died in March 1985. On necropsy there was hypertrophic pachymeningitis. Case 2. A 62 year old patient consulted in November 1995 complaining of right hypoacusia for the past six months, progressively accompanied by ipsilateral paralysis of the II, IV, VI, VII and VIII cranial nerves but with no other alterations on physical examination. Analytical and serological investigations were normal. Cranial MR showed an extraparenchymatous infiltrating lesion in the middle cranial fossa. Biopsy was decided on when no clinical improvement was seen with corticosteroid treatment. The pathologist reported hypertrophic pachymeningitis. Treatment was started with cyclophosphamide in monthly doses and the condition has remained stable to date. CONCLUSION: With these two cases we wish to establish a pathogenic relation between the Tolosa-Hunt syndrome and orbital pseudotumor and show the role played by immunosuppressive treatment in the control of hypertrophic pachymeningitis.