How and why I fell into neuropathology

I'm going to explain how and why I fell into the Department of Neuropathology at the Pitié-Salpêtrière Hospital of Paris. I'd also like to sketch the history of French neuropathology in the years 1960-2010, as seen by a naive young student, and then by a practicing neuropathologist (often still very naive). As a matter of fact, although the history of neurosciences [1-2] and the Pitié-Salpêtrière Hospital in Paris [3-4] have been the subject of numerous publications, the history of neuropathology in this hospital has been rarely documented [5-6]. I spent more than forty years strolling along the alleys of La Salpêtrière, among its old pavilions, the Saint Louis chapel, the “Pavillon des folles,” the courtyard of Manon Lescaut and the guard room. I worked full-time between the Escourolle laboratory, the “Amphithéâtre des morts” and the University. It has been a real pleasure to be part of this world. I would also like to offer young doctors in training and future neuropathologists some advice that might help them in the choice and development of their future careers

Charcot identifies and illustrates amyotrophic lateral sclerosis

Jean-Martin Charcot described what he called amyotrophic lateral sclerosis in his 12th and 13th lessons published in 1873 by Bourneville. He distinguished the symptoms that were related to the lesion of the anterior horn of the spinal cord and those that were due to the degeneration (that he named “sclerosis”) of its lateral column. He thought that “inflammation” progressed from the lateral column to the anterior horn (but the term inflammation is not to be taken in the current meaning): the lesion of the anterior horn was thus “deuteropathic”. An album containing drawings made by Charcot is kept in La Salpêtrière Neuropathology Department. Four drawings are pasted on one of its pages, showing the degeneration of the pyramidal tract. They constitute the original of the engravings illustrating Charcot’s 12th lesson. The illustration of the fascicular atrophy of the adductor pollicis presented in the album does not appear in the lessons, even though this alteration is widely discussed and linked to the lesion of the anterior horn, which was supposed to ensure the “nutrition” of the muscle. The technique used by Charcot and his interpretation of the microscopic pictures, as exposed in his lessons, are discussed

Association between a Primitive Brain Tumor and Cerebral Aspergillosis

Cerebral aspergillosis is a rare pathology of poor prognosis in spite of the use of adapted antifungal treatments. This infection of the central nervous system is generally the complication of an invasive aspergillosis with hematogenic scattering from pulmonary focal spots. It can arise in immunocompetent patients treated with prolonged corticotherapy or chemoradiotherapy for cancer. A case of lethal cerebral aspergillosis in a patient with an infiltrative glioma treated with corticotherapy and radiotherapy is reported. Clinicopathological aspects and therapeutic approach are described

Creutzfeldt-Jakob disease : update

Although rare, human diseases induced by non-conventional transmissible agents (NCTA or prions) are under constant scrutiny and associated with sometimes irrational fears. This article reviews briefly the clinical, biological, neuro-imaging, genetic and neuropathology data on the different variants of Creutzfeldt-Jakob disease. The recent leads on their pathogenesis, the resulting public health challenges, the running of French surveillance networks, and the recent diagnostic and therapeutic hopes are summarised.La rareté des maladies humaines à Agents Transmissibles Non Conventionnels (ATNC ou prions) ne doit pas faire sous-estimer l'intérêt constant et les craintes, parfois irrationnelles, qu'elles entraînent. Les données concernant la clinique, la biologie, l'imagerie, la génétique et la neuropathologie des différentes variantes de la maladie de Creutzfeldt-Jakob, sont brièvement mises en perspective. Les pistes récentes concernant leur mécanisme, les nouveaux défis pour la santé publique qu'apportent ces affections, les principales mesures mises en oeuvre pour les prévenir, les modalités de fonctionnement des réseaux de surveillance français et les espoirs diagnostiques et thérapeutiques récents sont résumés

Beyond PrPres Type 1/Type 2 Dichotomy in Creutzfeldt-Jakob Disease

Sporadic Creutzfeldt-Jakob disease (sCJD) cases are currently subclassified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the proteinase K (PK) digested abnormal prion protein (PrPres) identified on Western blotting (type 1 or type 2). These biochemically distinct PrPres types have been considered to represent potential distinct prion strains. However, since cases of CJD show co-occurrence of type 1 and type 2 PrPres in the brain, the basis of this classification system and its relationship to agent strain are under discussion. Different brain areas from 41 sCJD and 12 iatrogenic CJD (iCJD) cases were investigated, using Western blotting for PrPres and two other biochemical assays reflecting the behaviour of the disease-associated form of the prion protein (PrPSc) under variable PK digestion conditions. In 30% of cases, both type 1 and type 2 PrPres were identified. Despite this, the other two biochemical assays found that PrPSc from an individual patient demonstrated uniform biochemical properties. Moreover, in sCJD, four distinct biochemical PrPSc subgroups were identified that correlated with the current sCJD clinico-pathological classification. In iCJD, four similar biochemical clusters were observed, but these did not correlate to any particular PRNP 129 polymorphism or western blot PrPres pattern. The identification of four different PrPSc biochemical subgroups in sCJD and iCJD, irrespective of the PRNP polymorphism at codon 129 and the PrPres isoform provides an alternative biochemical definition of PrPSc diversity and new insight in the perception of Human TSE agents variability

Consensus classification of human prion disease histotypes allows reliable identification of molecular subtypes: an inter-rater study among surveillance centres in Europe and USA

The current classification of human sporadic prion diseases recognizes six major phenotypic subtypes with distinctive clinicopathological features, which largely correlate at the molecular level with the genotype at the polymorphic codon 129 (methionine, M, or valine, V) in the prion protein gene and with the size of the protease-resistant core of the abnormal prion protein, PrP(Sc) (i.e. type 1 migrating at 21 kDa and type 2 at 19 kDa). We previously demonstrated that PrP(Sc) typing by Western blotting is a reliable means of strain typing and disease classification. Limitations of this approach, however, particularly in the interlaboratory setting, are the association of PrP(Sc) types 1 or 2 with more than one clinicopathological phenotype, which precludes definitive case classification if not supported by further analysis, and the difficulty of fully recognizing cases with mixed phenotypic features. In this study, we tested the inter-rater reliability of disease classification based only on histopathological criteria. Slides from 21 cases covering the whole phenotypic spectrum of human sporadic prion diseases, and also including two cases of variant Creutzfeldt-Jakob disease (CJD), were distributed blindly to 13 assessors for classification according to given instructions. The results showed good-to-excellent agreement between assessors in the classification of cases. In particular, there was full agreement (100 %) for the two most common sporadic CJD subtypes and variant CJD, and very high concordance in general for all pure phenotypes and the most common subtype with mixed phenotypic features. The present data fully support the basis for the current classification of sporadic human prion diseases and indicate that, besides molecular PrP(Sc) typing, histopathological analysis permits reliable disease classification with high interlaboratory accuracy

Regulating Factors of PrPres Glycosylation in Creutzfeldt-Jakob Disease - Implications for the Dissemination and the Diagnosis of Human Prion Strains

OBJECTIVE: The glycoprofile of pathological prion protein (PrP(res)) is widely used as a diagnosis marker in Creutzfeldt-Jakob disease (CJD) and is thought to vary in a strain-specific manner. However, that the same glycoprofile of PrP(res) always accumulates in the whole brain of one individual has been questioned. We aimed to determine whether and how PrP(res) glycosylation is regulated in the brain of patients with sporadic and variant Creutzfeldt-Jakob disease. METHODS: PrP(res) glycoprofiles in four brain regions from 134 patients with sporadic or variant CJD were analyzed as a function of the genotype at codon 129 of PRNP and the Western blot type of PrP(res). RESULTS: The regional distribution of PrP(res) glycoforms within one individual was heterogeneous in sporadic but not in variant CJD. PrP(res) glycoforms ratio significantly correlated with the genotype at codon 129 of the prion protein gene and the Western blot type of PrP(res) in a region-specific manner. In some cases of sCJD, the glycoprofile of thalamic PrP(res) was undistinguishable from that observed in variant CJD. INTERPRETATION: Regulations leading to variations of PrP(res) pattern between brain regions in sCJD patients, involving host genotype and Western blot type of PrP(res) may contribute to the specific brain targeting of prion strains and have direct implications for the diagnosis of the different forms of CJD

Nodes of Ranvier and Paranodes in Chronic Acquired Neuropathies

Chronic acquired neuropathies of unknown origin are classified as chronic inflammatory demyelinating polyneuropathies (CIDP) and chronic idiopathic axonal polyneuropathies (CIAP). The diagnosis can be very difficult, although it has important therapeutic implications since CIDP can be improved by immunomodulating treatment. The aim of this study was to examine the possible abnormalities of nodal and paranodal regions in these two types of neuropathies. Longitudinal sections of superficial peroneal nerves were obtained from biopsy material from 12 patients with CIDP and 10 patients with CIAP and studied by immunofluorescence and in some cases electron microscopy. Electron microscopy revealed multiple alterations in the nodal and paranodal regions which predominated in Schwann cells in CIDP and in axons in CIAP. In CIDP paranodin/Caspr immunofluorescence was more widespread than in control nerves, extending along the axon in internodes where it appeared intense. Nodal channels Nav and KCNQ2 were less altered but were also detected in the internodes. In CIAP paranodes, paranodin labeling was irregular and/or decreased. To test the consequences of acquired primary Schwann cells alteration on axonal proteins, we used a mouse model based on induced deletion of the transcription factor Krox-20 gene. In the demyelinated sciatic nerves of these mice we observed alterations similar to those found in CIDP by immunofluorescence, and immunoblotting demonstrated increased levels of paranodin. Finally we examined whether the alterations in paranodin immunoreactivity could have a diagnosis value. In a sample of 16 biopsies, the study of paranodin immunofluorescence by blind evaluators led to correct diagnosis in 70±4% of the cases. This study characterizes for the first time the abnormalities of nodes of Ranvier in CIAP and CIDP, and the altered expression and distribution of nodal and paranodal proteins. Marked differences were observed between CIDP and CIAP and the alterations in paranodin immunofluorescence may be an interesting tool for their differential diagnosis