Dementia pugilistica: a severe tribute to a career.

A 59-year-old man, ex-professional boxer, met clinical criteria for probable Alzheimer's disease. The patient agreed to be included in a clinico-pathological study with donation to the brain bank, and he died at 71. The brain was grossly atrophic, with a prominent atrophy of the entorhinal cortex and hippocampus, and with pallor of the substantia nigra. Immunohistochemistry with anti-τ A4 revealed abundant and diffuse deposits in the neo-cortex, whereas amyloid angiopathy was absent. Coupled anti-τ AT8 immunohistochemistry and Congo red staining showed no neuritic plaques. τ-AT8-positive glial tangles and neurofibrillary tangles involved preferentially the superficial cortical layers, and were irregularly concentrated in the depth of cortical sulci and near vessels. Neurofibrillary degeneration was marked in amygdala, hippocampus, substantia nigra, and locus ceruleus. Enlarged and/or distorted axons were numerous in hippocampus and mid-brain. TDP 43-positive neuronal inclusions were numerous in amygdala and hippocampus. There was no synucleinopathy. These observations are in accordance with the previously reported data on chronic traumatic encephalopathy. The discussion is focused on professional boxing as it becomes evident that repetitive trauma on the brain provokes the deposition of abnormal proteins involved in neurodegeneration.

Peripheral neuropathy and parkinsonism: a large clinical and pathogenic spectrum.

Peripheral neuropathy (PN) has been reported in idiopathic and hereditary forms of parkinsonism, but the pathogenic mechanisms are unclear and likely heterogeneous. Levodopa-induced vitamin B12 deficiency has been discussed as a causal factor of PN in idiopathic Parkinson's disease, but peripheral nervous system involvement might also be a consequence of the underlying neurodegenerative process. Occurrence of PN with parkinsonism has been associated with a panel of mitochondrial cytopathies, more frequently related to a nuclear gene defect and mainly polymerase gamma (POLG1) gene. Parkin (PARK2) gene mutations are responsible for juvenile parkinsonism, and possible peripheral nervous system involvement has been reported. Rarely, an association of parkinsonism with PN may be encountered in other neurodegenerative diseases such as fragile X-associated tremor and ataxia syndrome related to premutation CGG repeat expansion in the fragile X mental retardation (FMR1) gene, Machado-Joseph disease related to an abnormal CAG repeat expansion in ataxin-3 (ATXN3) gene, Kufor-Rakeb syndrome caused by mutations in ATP13A2 gene, or in hereditary systemic disorders such as Gaucher disease due to mutations in the ß-glucocerebrosidase (GBA) gene and Chediak-Higashi syndrome due to LYST gene mutations. This article reviews conditions in which PN may coexist with parkinsonism.

Intra-axonal protein aggregation in the peripheral nervous system.

Intracellular protein aggregates are common pathological hallmarks of many neurodegenerative disorders, and a defect in axonal transport is also incriminated. Here, we studied intra-axonal abnormal protein aggregation and axonopathy by using immunohistochemistry and electron microscopy on peripheral nerve biopsies from 12 patients with chronic axonal peripheral neuropathy (PN) of unknown etiology. Among these patients, three had idiopathic Parkinson's disease (PD). Intra-axonal ubiquitin aggregates were more numerous in the patients with PD. Intra-axonal aggregates of tau AT8 were found in five patients without PD. Phosphorylated α-synuclein aggregation was absent in all cases, while intra-axonal colocalization of 14-3-3 ß and ubiquitin was observed in two PD cases. Electron microscopy revealed enlarged axons crowded with organelles in six cases, including the three patients with PD, thus attesting a slowing of the axoplasmic flux. The number of ubiquitin aggregates was correlated with features of reduced axonal flux, while no such correlation was found for tau and 14-3-3 ß. Age did not correlate with the number of tau, ubiquitin, and 14-3-3 aggregates. Thus, both ubiquitin and/or abnormal tau intra-axonal aggregates may be found in chronic axonal PN. Ubiquitin aggregates might reduce the axonal flux or result from a disease producing slowing of axonal transport.

Clinical Neuropathology practice guide 3-2014: combined nerve and muscle biopsy in the diagnostic workup of neuropathy - the Bordeaux experience.

Simultaneous combined superficial peroneal nerve and peroneous brevis muscle biopsy, via the same cutaneous incision, allows examination of several tissue specimens and significantly improves the diagnosis of systemic diseases with peripheral nerve involvement. Vasculitides are certainly the most frequently diagnosed on neuro-muscular biopsies, but this procedure is also well advised to asses a diagnosis of sarcoidosis or amyloidosis. More occasionally, combined nerve and muscle biopsy may reveal an unpredicted diagnosis of cholesterol embolism, intra-vascular lymphoma, or enables complementary diagnosis investigations on mitochondrial cytopathy or storage disease.

Severe Charcot-Marie-Tooth disease type 1E caused by a novel p.Phe84Leufs*24 PMP22 point mutation.

We report a severe phenotype of Charcot-Marie-Tooth (CMT) disease type 1E caused by a novel p.Phe84Leufs*24 PMP22 point mutation. Ultrastructural examination of a nerve biopsy showed non- or partly myelinated axons which were surrounded by "onion bulb" formations mainly composed of concentric basement membranes and characterized by the presence of prominent concentric or longitudinal collagen fibrils interspersed with basement membranes. PMP22 point mutations are rare and responsible for polyneuropathies often demyelinating with onion bulb formations composed of concentric and redundant basement membranes. Entrapment of prominent collagen fibrils within onion bulb formations is unusual, even in the large spectrum of CMT disease with long duration and severe damage.

An update on nerve biopsy.

Indications for nerve biopsy have decreased during the last 20 years. For the most part, this is a result of progress in the application of molecular biologic diagnostic testing for genetic peripheral neuropathies (PNs) and the increasing use of skin biopsy. The latter is primarily used to evaluate small-fiber PN, although it rarely discloses the specific etiology of a PN. Nerve biopsies are usually performed on either the sural or the superficial peroneal nerve, the latter in combination with removal of portions of the peroneus brevis muscle. The definite diagnosis of vasculitic lesions can be readily established on small paraffin-embedded nerve biopsy samples, although in some cases, the characteristic lesions are only apparent in muscle specimens. Other nerve specimens are routinely fixed in buffered glutaraldehyde and prepared for semithin sections and electron microscopy; frozen specimens are used for immunofluorescence studies. Electron microscopy is of great value in some cases of chronic inflammatory demyelinating polyneuropathies, monoclonal gammopathy, and storage diseases. Because more than 30 genes may be involved in genetic PNs, analysis of nerve lesions can direct the search for mutations in specific genes. Electron microscopy immunocytochemistry is mandatory in some cases of monoclonal dysglobulinemia. Thus, nerve biopsy is still of value in specific circumstances when it is performed by trained physicians and examined in a laboratory with expertise in nerve pathology.

The nigrostriatal pathway in Creutzfeldt-Jakob disease.

Parkinsonism, chorea, and dystonia are well-known clinical manifestations of Creutzfeldt-Jakob disease (CJD), but lesions of the nigrostriatal pathway have never been thoroughly studied. We performed a detailed neuropathologic study of the nigrostriatal pathway in 15 sporadic CJD and 2 variant CJD cases that included clinical correlations and assessment of neuron subtype loss, distribution of prion protein, alpha-synuclein, ubiquitin, and 14-3-3 aggregation. We found evidence of nigrostriatal pathway damage in these CJD cases. Dopaminergic neurons and striatal outflow neurons were markedly affected in sporadic CJD, whereas cholinergic interneurons were spared. In cases of CJD with chorea or myoclonus, there was less presynaptic dopaminergic loss than in cases of CJD with parkinsonism. The 2 variant CJD cases with parkinsonism or chorea showed severe cholinergic interneuron loss in the caudate and putamen, a pattern that differed from that found in sporadic CJD. alpha-Synuclein, ubiquitin, and 14-3-3 aggregation coexisted with prion protein aggregation, thereby generating mixed pathological features. These findings suggest a possible pathophysiological overlap of abnormal protein aggregation in CJD and Parkinson disease.

Presence of crystalline inclusions in the peripheral nerve of a patient with IgA lambda monoclonal gammopathy of undetermined significance.

Association of a peripheral neuropathy with an IgA monoclonal gammopathy of undetermined significance (MGUS) is not commonly observed and is sometimes considered as coincidental. We present a case in which the nerve biopsy revealed the presence of crystalline inclusions in the endoneurium, a very unusual finding. A 75-year-old man complained of paresthesiae in both feet and unsteady gait for 6 months. He had no weakness, but deep tendon reflexes were absent and vibratory sensation distally diminished in both legs. An IgA lambda MGUS was evidenced in his serum at 10.2 g/L with 7% plasma cells in his bone marrow and no lytic lesion at skeletal examination. A superficial peroneal nerve biopsy was performed and showed numerous crystalline inclusions in the endoneurium. These were located in the cytoplasm of macrophagic histiocytes or free in the vicinity of nerve fibers. There was also a marked loss of myelinated nerve fibers and several "onion bulb" formations surrounding either isolated remyelinating fibers or small clusters of remyelinating fibers. Such crystalline inclusions have mainly been observed in the cytoplasm of plasma cells in cases of multiple myeloma, and correspond to non-secreted IgA or IgG immunoglobulins with a kappa or rarely lambda light chain. Such inclusions have also been reported in the cytoplasm of the epithelial cells from corneal fragments, in patients with multiple myeloma or IgG MGUS, and in the tubular cells from the kidney of patients with multiple myeloma and a nephrotic syndrome. In the literature, there is only one very briefly mentioned case of neuropathy associated with a myeloma and with crystalline inclusions present in the epineurium. Thus, in dysglobulinemic neuropathy, nerve fibers can be damaged by three kinds of interstitial deposits, easily identified by immunohistochemistry and at ultrastructural examination: the well known amyloid fibrils, granulo-fibrillar deposits and also crystalline inclusions.

[Neurosciences in Bordeaux]. / Chronique historique Les Neurosciences à Bordeaux.

The Bordeaux Neuroscience Institute brings together all the disciplines that constitute the clinical and experimental neurosciences. Outside of the Paris region, the Institute represents the largest community of researchers working on the nervous system. The aim of this brief historical piece is to describe how neuroscientists in Bordeaux are the heirs to a long neuropsychiatric tradition established by pioneers of national and international renown. This tradition has been maintained, without interruption, through many generations. The careers and scientific work of these great neurologists and psychiatrists are briefly evoked, and particularly those of A. Pitres, E. Régis and E. Azam in the 19th century; and, in the 20th century, J. Abadie, H. Verger and R. Cruchet. The determining influence of P Delmas-Marsalet (1898-1977), Professor of Neuropsychiatry, on the development of modern neurosciences in Bordeaux is recalled through his work, his teachings, and his numerous students.

Neuro-muscular biopsy in Churg-Strauss syndrome: 24 cases.

Churg-Strauss syndrome (CSS) is a distinctive clinical entity in which systemic vasculitis, associated with eosinophilia, occurs almost exclusively in individuals with adult-onset asthma. The major complications of the condition result from damage to the lungs, heart, and peripheral nerves. Necrotizing vasculitis with eosinophils in the cellular infiltrate, vascular or perivascular infiltration by eosinophils in absence of vessel wall necrosis, extra-vascular eosinophil infiltrates, and vascular or extra-vascular granuloma are histopathological features supportive of CSS. As the peripheral nerve disease often dominates the clinical picture, the peripheral nerve biopsy may be decisive in establishing the diagnosis. In this retrospective study of neuro-muscular biopsies in 24 CSS cases, the authors give an extensive description of neuropathological lesions associated with this disorder. Fifteen patients (62.5%) exhibited eosinophils either in extra-vascular infiltrates or in vessel walls, and 6 of them (25%) had an associated necrotizing vasculitis. Granulomas were found in only 3 cases (12.5%). The clinical diagnosis of CSS was supported in 15 out of the 24 patients (62.5%), in the nerve in 2 cases (8.3%), in the muscle in 8 cases (33.3%), and in both nerve and muscle in 5 others (20.8%).

Axonal degeneration with unusual lesions of the myelin in an occupational neuropathy.

A 35-year-old man had prolonged occupational exposure to lead carboxylate, triethylbenzene, xylene, and dichloromethane, when he developed a subacute predominantly sensory neuropathy. Ultrastructural examination of a peripheral nerve biopsy showed axonal degeneration and unusual lesions of the myelin, with Schwann cell sequestration of vesicular and lamellar debris. Biochemical analysis of lead in a frozen peripheral nerve specimen revealed no significant difference between the propositus and a control. The authors were unable to find any similar peripheral nerve lesions in the literature dealing with neurotoxic chemicals. Any of the several organic solvents could have equally caused the neuropathy and may have been potentialized by the other chemicals.

[Neuromuscular biopsy and diagnosis of vasculitis]. / La biopsie neuro-musculaire dans le diagnostic des vascularites.

One characteristic histological lesion on biopsy specimens is mandatory to establish the diagnosis of vasculitis. Combined nerve and muscle biopsies, by the same cutaneous incision, improve significantly the percentage of positive results. Nerve fragments should be taken in every patient presenting sensory manifestations. Such vasculitic lesions are present in medium-sized arterioles and/or small vessels, and correspond mainly to 4 necrotizing vasculitis: panarteritis nodosa (PAN), microscopic polyangiitis (MPA), Churg and Strauss syndrome and Wegener granulomatosis. Microvasculitis should be added to these classical entities, because it corresponds to small vessel wall infiltration by inflammatory cells, as observed in PAN and MPA, but without any necrosis. Microvasculitis has to be differentiated from the inflammatory cell infiltrates surrounding small vessels. However, such perivascular inflammatory cell infiltrates enable the diagnosis of probable vasculitis when associated with clusters of neo-vessels, hemosiderin deposits, or a focal damage of nerve fibers. Grossly, one third of vasculitis diagnosis is confirmed on muscle fragments, a second third on nerve fragments, and the last third on both nerve and muscle fragments. Moreover, in the search for vasculitis, an unpredicted diagnosis of lymphoma or amyloidosis is occasionally established on the neuro-muscular biopsy.

Peripheral nerve lesions associated with a dominant missense mutation, E33D, of the lamin A/C gene.

Some mutations of the lamin A/C gene may be responsible for a combination of distinct phenotypes, such as muscular dystrophy and peripheral neuropathy. We describe muscle and peripheral nerve lesions in a patient with a dominant lamin A/C missense mutation, E33D. Myopathic and neurogenic patterns coexisted on muscle biopsy specimens, whereas the peripheral nerve presented a mixture of axonopathy and Schwann cell hypertrophy. A few abnormal nuclei were found in muscle fibers and Schwann cells. Our morphological findings in this case attest to the predominant axonal damage, but suggest possible involvement of Schwann cells in neuropathies related to laminopathies.

Peripheral nerve biopsy study in 19 cases with 17p11.2 deletion.

In most cases of hereditary neuropathy with liability to pressure palsy (HNPP) the diagnosis is now assessed by molecular detection of 17p11.2 deletion. However, the family history may be missing and the clinical presentation is not always informative. In such cases, a peripheral nerve biopsy showing the characteristic focal myelin sheath thickening ("tomaculae") may be helpful. We present a retrospective study of peripheral nerve biopsies performed in 19 patients suffering from either a mononeuropathy or a generalized sensory-motor polyneuropathy, and for whom the finding of tomaculae led to a search for 17p11.2 deletion, which was confirmed secondarily. Tomaculae and other coexisting neuropathological lesions such as uncompacted myelin, "onion bulb" formations, and axonal degeneration are described and discussed in the view of previously reported data. It appears that demyelinating lesions with tomaculae are strongly suggestive of HNPP but are not specific as they may be observed in other conditions. Moreover, these features may be overlooked if axonal degeneration is marked.

Pathologic prion protein spreading in the peripheral nervous system of a patient with sporadic Creutzfeldt-Jakob disease.

BACKGROUND: Involvement of the peripheral nervous system in the pathogenesis of prion diseases is becoming increasingly evident. However, pathologic protease-resistant prion protein deposition in the peripheral nerves of patients with Creutzfeldt-Jakob disease has never been demonstrated, to our knowledge. OBJECTIVE: To determine whether mutated prion protein accumulation could be shown in the peripheral nervous system of patients with sporadic Creutzfeldt-Jakob disease. DESIGN: Autopsy study. PATIENTS: Three patients with sporadic Creutzfeldt-Jakob disease. INTERVENTIONS: Study of the brain, spinal cord, and sciatic and superficial peroneal nerves by immunohistochemistry and Western blot analysis. MAIN OUTCOME MEASURE: Demonstration of protease-resistant prion protein accumulation. RESULTS: In all cases, protease-resistant prion protein accumulation was found in the brain and posterior horns of the spinal cord. In 1 case, protease-resistant prion protein deposits were also evidenced in the dorsal root ganglia and the superficial peroneal nerve. CONCLUSIONS: Protease-resistant prion protein may be found in the peripheral nervous system of some patients with sporadic Creutzfeldt-Jakob disease. However, a larger series is required to assess the incidence of peripheral nervous system involvement and to discuss the diagnostic usefulness of peripheral nerve biopsy in sporadic Creutzfeldt-Jakob disease.

Penetrating corneal transplant with inadvertent corneal button inversion.

PURPOSE: To report a penetrating corneal transplant in which there was inadvertent inversion of the corneal button. DESIGN: Interventional case report. METHODS: A 48-year-old man with lattice corneal dystrophy had a third penetrating keratoplasty in the right eye 3 years after the second procedure and 2 years following renal transplantation. RESULTS: Histologic examination of the corneal button from the second penetrating keratoplasty disclosed inadvertent corneal graft inversion. Survival epithelium from the donor in the anterior chamber may be explained by the ocular anterior chamber-associated immune deviation or by the patient's systemic cyclosporine A (CsA) treatment after renal transplantation. CONCLUSIONS: Histologically proven corneal button inversion is a rare cause of corneal graft failure.

[Amyloid neuropathies. Histopathological study of peripheral nerve biopsy in 18 cases]. / Les neuropathies amyloïdes. Etude histopathologique de nerf périphérique dans 18 cas.

OBJECTIVES: A retrospective study of nerve and muscle biopsies since 1983, with probable amyloidosis, has been performed. MATERIALS AND METHODS: Eighteen nerve and muscle biopsies, out of 29, were selected. RESULTS: Endoneurial amyloid deposits were visible on routine sections in 11 cases, revealed by ultrastructural study in 4 cases and by Congo red and/or thioflavine stains in 3 others. Amyloid deposits were marked by anti-transthyretin (TTR) serum in 13 patients, within endoneurium in 11 cases, and only around muscle fibers in 2 others. A mutation in the TTR gene, usually Val30Met, was evidenced in 8 cases and could not be assayed in the 5 others. An immunoglobulin light chain was revealed in amyloid deposits by direct immunofluorescence in the 5 other patients, of whom 4 had multiple myeloma and the fifth a lambda light chain Bence-Jones proteinuria. CONCLUSION: Nerve biopsy revealed amyloidosis in 10 patients: 5 of them had a mutation in TTR gene, without any family history.