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60 year-old man, without relevant medical history, noted a slight and progressive instability of gait for one month and right hand clumsiness. Brain MRI showed a cerebellar lesion, posterior to the middle cerebellar peduncle. This lesion was heterogeneous and hyperintense on FLAIR sequences, isointense on T1-weighted images, and showed gadolinium enhancement. Hematological and biological serum analyses were normal as were plasma and urine immunoelectrophoresis. CSF analysis including protein electrophoresis was unremarkable. CT scans of the abdomen, chest and pelvis were normal as were cervical echography and bone scintigraphy. A yellowish and firm lesion was surgically resected. The patient's recovery was good, with normal total body PET scan and bone marrow biopsy. Pathological study evidenced kappa light chain deposits and kappa-immunopositive mature plasma-cells in the vicinity. The deposits failed to show any birefringence in polarized light microscopy after Congo red staining, and electron microscopy revealed their granular ultrastructure. Light chains are well known for their amyloidogenic properties, but in a few cases, they are non amyloidogenic and may cause tissue deposits histologically similar to amyloid but Congo red-negative and non fibrillary at ultrastructural examination. Occurrence of light chain deposits in the brain is rare and the tumor-like MRI presentation is reminiscent of primary intracerebral amyloidoma presenting as a mass lesion. This is the first report of intracerebral kappa light chain deposits which presumably derived from local synthesis by mature plasma cells.

According to the current nomenclature and textbooks (Jellinger and Paulus, 1992; Burger and Scheithauer, 1994; Burger and Scheithauer, 1994; Rosenthal and Green, 1995), the different circumstances in which a lymphoma may affect the central nervous system (CNS) are listed below.

A female patient was 12 years old when she presented with hemiatrophy and muscle weakness on the right side of her body. Then a stepwise worsening occurred, and at 19 years of age sensory symptoms were also noticed, as well as a mild involvement of the left part of her body. The cerebrospinal fluid (CSF) protein level was elevated without cells. The main electrophysiological abnormality was a marked temporal dispersion of the compound muscle action potentials (CMAPs). Motor nerve conduction velocities were moderately reduced. A superficial peroneal nerve biopsy revealed well-demarcated areas of demyelination with prominent Schwann cell hyperplasia. Neither deletion nor duplication of the PMP22 gene nor mutation of the P0 or connexin 32 genes was found by molecular genetic investigations. Immunotherapy was administered, and over the next 6 years the symptomatology fluctuated. This unusual disorder seems to be a variant of chronic acquired demyelinating polyneuropathy and may be immunologically mediated.

The purpose of this study was to evaluate the relationship between immunoglobulin M (IgM) antibodies penetration into myelinated peripheral nerve fibers and the widening of the peripheral myelin sheaths in anti-myelin-associated glycoprotein (anti-MAG) demyelinating IgM monoclonal polyneuropathy. Demyelinating polyneuropathy with monoclonal IgM is often associated with anti-MAG autoantibodies, which are thought to initiate the disease with IgM deposits usually present on the myelin sheaths. We analyzed nerve biopsies from 12 patients with an anti-MAG demyelinating neuropathy by confocal and electron microscopy. The total number of nerve fibers and the proportion of IgM-associated fibers were quantified after immunohistochemical staining. The affinities of IgM were examined by analyzing the binding pattern of serum IgM on normal peripheral nerve sections. Ultrastructural examinations of the biopsies showed a good correlation between in situ widened myelin sheaths and the IgM penetration level into myelinated fibers. The terminal complement complex appears not be involved in the penetration of IgM into the myelinated fibers. Our findings suggest a causative role of the IgM anti-MAG antibodies in the ultrastructural modifications of the myelin sheaths. The basement membrane and myelin components appear to be the major targets of the IgM monoclonal antibodies. However, the pathogenic mechanism whereby IgM antibodies reach their targets and induce nerve damage are still unclear.

Summary p53 protein expression was evaluated by immunohistochemistry in a homogeneous series of 100 supratentorial grade II astrocytomas with long-term follow-up. The staining was positive in 72 cases. The proportion of p53 positive tumors was slightly higher in younger patients. The tumor regrowths which derived from p53 positive tumors were themselves p53 positive, and this p53 immunopositivity was often stronger than in the initial tumors. All of the 10 gernistocytic astrocytomas included in our series were p53 positive, and age more than histological type appeared decisive in prognosis. p53 protein expression did not quite reach statistical significance as an independent predictive variable in multivariate analysis, whereas survival was related with age, mass effect, surgery and tumor location. Only a tendency to a longer survival was observed on the curves in younger patients with mildly positive tumors.

High frequency stimulation (HFS) of the subthalamic nucleus (STN) is recognized as a therapeutic choice for advanced forms of Parkinson disease (PD) with motor fluctuations.1 However, the location of the best target remains a matter of debate. Although the STN is considered as the gold standard, good therapeutic results have been obtained using electrode contacts located outside the STN, within adjacent structures such as the zona incerta (ZI).2–4 In this study, we report the first pathologically proven case of direct bilateral ZI stimulation which dramatically improved the cardinal symptoms of PD in a patient implanted for severe PD 6 years previously and who suddenly died. ### Clinical data. A 52-year-old man was proposed deep brain stimulation (DBS) because he had severe PD for 13 years that had reached the stage of motor fluctuations with incapacitating levodopa-induced dyskinesia. He was operated under local anesthesia. Peroperative single-unit activity recordings could not be completed in this patient for technical reasons. However, the surgical procedure was the same as that used for patients reported in a previous article.5 The position of the active contacts was determined in relation to the mid-commisural point and revealed that the right electrode was located more anteriorly and less deep compared to the left one. In this article, we focus on the …

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In a 64-year-old woman presenting with rapidly progressive dementia, brain magnetic resonance imaging revealed a diffuse leukoencephalopathy without gadolinium enhancement, and the 14.3.3 protein was found to be positive in the cerebrospinal fluid. An electroencephalogram showed diffused slow waves and epileptic seizures without periodic paroxysmal activity. The patient died 3 months after onset of symptoms, and an autopsy restricted to the brain was performed. Gross examination was not informative, and only microscopic examination permitted identification of scattered lymphomatous cells on all sections from the brain hemispheres, brain stems and cerebellum. Immunopositivity of these tumor cells for CD20 attested their B phenotype. This observation illustrates "lymphomatosis cerebri," a recently described entity, which has to be considered in the differential diagnosis of rapidly progressive dementia in adults.

Glioblastomas with a proneural expression signature are characterized by frequent IDH1 mutations (i.e. genetic hallmarks of secondary glioblastomas) and PDGFRA amplification. Most glioblastomas with IDH1 mutations (11/12, 92%) show a proneural signature, the majority with wild-type PDGFRA, while approximately 30% of glioblastomas with a proneural signature had IDH1 mutations. IDH1/2 mutations are frequent and early genetic events in diffuse astrocytomas WHO grade II, precursor to secondary glioblastomas, but little is known about the role and timing of PDGFRA amplification in these tumors. In the present study, we assessed PDGFRA gain in 342 low-grade diffuse gliomas (166 low-grade diffuse astrocytomas, as well as 61 oligoastrocytomas and 115 oligodendrogliomas) by quantitative PCR. PDGFRA gain was detected in 27/166 (16.3%) diffuse astrocytomas, significantly more frequent than in oligoastrocytomas (6.6%; P=0.04) or in oligodendrogliomas (3/115; 2.6%; P We correlated PDGFRA gain with other genetic alterations in low-grade diffuse gliomas previously reported from our laboratory. PDGFRA gain was significantly more frequent in diffuse astrocytomas, oligodendrogliomas and low-grade diffuse gliomas without IDH1/2 mutations than those with IDH1/2 mutations (36.8% vs 13.6%; P=0.018, 16.7% vs 1.0%; P=0.028, 24.3% vs 8.3%; P=0.006, respectively). PDGFRA gain was most frequent (28.6%) in gliomas lacking any of common genetic alterations (IDH1/2 mutations, TP53 mutations and 1p/19q loss). PDGFRA gain was found in low-grade diffuse gliomas with TP53 mutation ± IDH1/2 mutations (16.3%) and those with IDH1/2 mutation only (10.5%), but rare in tumors with 1p/19q loss ± IDH1/2 mutations (1.4%). In diffuse astrocytomas, PDGFRA gain positively correlated with MET gain (P=0.016) and inversely correlated with 1p/19q loss (P=0.005) and IDH1/2 mutations (P=0.018). The vast majority of diffuse astrocytomas showed IDH1/2 mutations and/or PDGFRA gain (154/166; 93%). Mean survival of diffuse astrocytoma patients with PDGFRA gain was 8.8 ± 1.6 years, similar to that with IDH1/2 mutations (7.8 ± 0.5 years) or TP53 mutations (7.6 ± 0.6 years), but significantly longer than those with MET gain (4.4 ± 0.7 years). The mean survival of diffuse astrocytoma patients with co-gain of MET and PDGFRA was 7.7 ± 2.0 years, which was similar to those with PDGFRA gain only. Dual-color FISH in 6 diffuse astrocytomas with PDGFRA / MET co-gain identified by quantitative PCR revealed PDGFRA and MET were typically amplified in different tumor cell populations within the tumor, but tumor cells with co-amplification were also focally observed, suggesting intra-tumoral heterogeneity even in diffuse astrocytomas. Citation Format: Kazuya Motomura, Michel Mittelbronn, Werner Paulus, Benjamin Brokinkel, Kathy Keyvani, Ulrich Sure, Karsten Wrede, Yoichi Nakazato, Yuko Tanaka, Naosuke Nonoguchi, Daniela Pierscianek, Young-Ho Kim, Luigi Mariani, Anne Vital, Arie Perry, Hiroko Ohgaki. Intra-tumoral heterogeneity of PDGFRA / MET gain in WHO grade II diffuse astrocytomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2406. doi:10.1158/1538-7445.AM2013-2406

✓ An unusual case of primary parenchymal Langerhans' cell histiocytosis of the central nervous system is reported. The definitive diagnosis was obtained by ultrastructural detection of Birbeck granules and by immunohistochemical evidence of CD1a expression. Despite complete surgical resection, there was an early recurrence with multiple central nervous system metastases leading to a fatal outcome.

We studied 33 patients presenting with a peripheral neuropathy associated with non-malignant anti-myelin-associated glycoprotein (MAG) IgM monoclonal gammopathy (MG) in an attempt to delineate their clinical, immunological, electrophysiological and pathological characteristics; we also reviewed our experience concerning long-term follow-up and therapy. Peripheral neuropathy associated with non-malignant anti-MAG IgM MG was observed mostly in males (sex ratio 7.2), and mean age at onset was 67 years (range 46–81). A predominantly sensory pattern was noted in more than 80% of cases, although some patients were affected by a predominantly motor peripheral neuropathy. Although disease progression was slow in most cases, 45% of patients suffered severe disability, and in 2 cases, the patient's death appeared to stem directly from the neuropathy. The electrophysiological findings were indicative of a demyelinating process in 90% of cases, and electron microscopic examination of nerve biopsy specimens demonstrated widening of the myelin lamellae in more than 95% of cases. Most of our patients showed a disappointing response to steroids and chemotherapy or plasma exchanges. Intravenous immune globulin, evaluated in 17 patients, had a transient, mostly subjective effect in 35% and led to a clear-cut improvement in 24% of cases. We did not observe any correlation between the severity of the clinical picture and the anti-sulphoglucuronyl paragloboside antibody titre; in individual cases, clinical improvement occurred without lowering of IgM levels. Although the severity and the rate of progression may greatly vary from patient to patient, the combination of clinical, electrophysiological and pathological features delineates a characteristic pattern in peripheral neuropathy associated with non-malignant anti-MAG IgM MG.

Article abstract—A 74-year-old woman with a sensory neuropathy and IgM M-protein monoclonal gammopathy of undetermined significance developed a fatal B-cell cerebral lymphoma. CSF protein immunofixation revealed intrathecal secretion of a paraprotein of the same heavy- and light-chain isotypes as the serum monoclonal component (IgM-$LD). Reactivation of Epstein-Barr virus was present in the lymphoma cells. Different factors may be involved in the preferential malignant development of the monoclonal B-cell clone within the CNS.

Gliosarcoma is a rare glioblastoma variant characterized by a biphasic tissue pattern with alternating areas displaying glial (GFAP-positive) or mesenchymal (reticulin-positive) differentiation. Previous analyses showed identical genetic alterations in both glial and mesenchymal tumor areas, suggesting that gliosarcomas are genetically monoclonal, and mesenchymal differentiation was considered to reflect the elevated genomic instability of glioblastomas. In the present study, we compared genome-wide chromosomal imbalances using array CGH (105K) in glial and mesenchymal tumor areas of 13 gliosarcomas. Patterns of gain and loss were similar, except for gain at 13q13.3-q14.1 (log2 ratio ≤ 3), containing the STOML3, FREM2, and LHFP genes, which was restricted to the mesenchymal tumor area of a gliosarcoma. Further analyses of 64 cases of gliosarcoma using quantitative PCR showed amplification of the STOML3, FREM2 and LHFP genes in 14 (21%), 10 (15%), and 7 (11%) of mesenchymal tumor areas but not in glial tumor areas. Immunohistochemistry confirmed that STOML3 and FREM2 overexpression was more extensive in mesenchymal than in glial tumor areas. These results suggest that mesenchymal components in a small fraction of gliosarcomas may be derived from glial cells with additional genetic alterations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3401. doi:1538-7445.AM2012-3401

We report two patients who presented severe polyneuropathy in the postpartum period. Electrophysiological studies evidenced an axonal process which was associated with proximal demyelination in the second patient. In both cases, a peripheral nerve biopsy showed severe axonal Wallerian-like degeneration and no feature of demyelination. The first patient had a dramatic loss of myelinated fibres, and severe disability persisted for several months. These two patients are different from cases of acute or chronic inflammatory demyelinating polyradiculoneuropathy previously reported in relation with pregnancy.

Sir, we read with great interest the article by Schwarzacher et al. (2011) describing the neuroanatomical characteristics of the human pre-Botzinger complex and its involvement in multiple system atrophy and spinocerebellar ataxia 3 (SCA3). In this study, the authors provide a thorough analysis of the pre-Botzinger complex and demonstrate that somatostatin and neurokinin 1 receptor expressing neurons are severely reduced in a neurodegenerative disorder presenting with severe central respiratory dysfunction (multiple system atrophy), but spared in patients with no history of such respiratory deficits (SCA3). This study provides strong neuropathological evidence that degeneration of the pre-Botzinger complex occurs in multiple system atrophy and extends previous findings showing a drastic reduction of putative brainstem chemosensory neurons in this disease (Benarroch, 2007). Altogether, these findings strongly support the hypothesis that degeneration of these brainstem respiratory neurons underlies respiratory dysfunction in multiple system atrophy. In addition to the characterization of the pre-Botzinger complex, Schwarzacher et al. (2011) also provide a detailed analysis of the nucleus ambiguus in multiple system atrophy and SCA3. In both diseases, the ventral part of the nucleus ambiguus (containing pre-ganglionic cardiovagal neurons) display severe neuronal …

This article reports a new MERRF family. The mother, regarded as suffering from Ramsay-Hunt Syndrome, and her three daughters, had the same clinical pattern: myoclonic epilepsy and ataxia. Two daughters were studied on morphological, biochemical and molecular genetic levels. Muscle biopsies showed ragged-red fibres and mitochondrial vasculopathy. Arterioles were strongly SDH-reactive and COX-negative. By electron microscopy, abnormal mitochondria were observed in skeletal muscle fibres, in smooth muscle fibres of intramuscular vessels and in sweat gland epithelium. The study of the respiratory chain showed complex IV and I + IV deficiency, respectively. Mitochondrial tRNA (lys) mutation at position 8344 was pointed out as previously reported in the MERRF syndrome.

We report a 30 year old patient with acute lymphoblastic leukemia (ALL) whose leukemic relapse presented as an isolated symmetrical peripheral neuropathy with facial diplegia. Initially, this was consistent with a Guillain-Barre syndrome but the peripheral nerve biopsy revealed leukaemic infiltration. This was followed by a systemic relapse. Reports of peripheral nerve infiltration are scarce and to the best of our knowledge this is the first documented case of peripheral polyneuropathy as a presenting manifestation of ALL relapse.

BACKGROUND Cases of adult T-cell leukemia/lymphoma (ATLL) resulting from human T-cell leukemia virus type I (HTLV-I) have been observed mainly in the southern part of Japan. Recently, the authors performed a second examination of cutaneous, muscle, and nerve biopsy specimens from a French white woman who died of ATLL in 1979. METHODS A 67-year-old white woman had a lymphoma diagnosed on a lymph node biopsy. She then had acute pains and a thickened skin on both legs. Blood examination showed a leukocyte count of 16,000/ml with 75% leukemia T-cells. Biopsies were performed on the antero-external surface of the right leg. She died after 2 years of illness. RESULTS Lymphomatous infiltrates of T-cell origin were seen in the dermis, between muscle fibers, and in a peripheral nerve. The recent ultrastructural examination of a few vacuoles located in the cytoplasm of certain lymphomatous cells showed rounded structures mixed with larger virus-like formations having a central nucleoid and spike material around the envelope. Polymerase chain reaction experiments performed on deparaffinized sections demonstrated the presence of a tax sequence homologous to that of HTLV-I. Other structural genes were not detected. CONCLUSIONS These results contrast with other ultrastructural studies in which HTLV-I was detected only after cultivation of leukemia cells from patients with ATLL. This case probably resulted from an HTLV-I variant.

Massive occurrence of polyglucosan bodies (PBs) was found within the surgically removed temporal lobe of a 34 year old woman with complex partial seizures. This peculiar feature is very unusual in neuropathological examinations of epileptogenic foci. This patient could not be included in any of the classic diseases in which PBs are found. She exhibited a localised form of glycogen storage disease.

In a patient with Waldenstrom's macroglobulinaemia and peripheral neuropathy, direct immunofluorescence of a peripheral nerve revealed the presence of abundant IgM and kappa light chain deposits in the endoneurium. Electron microscopic examination showed the microtubular structure of these endoneurial deposits, which strongly suggested the presence of cryoglobulin; this was then found in the serum.

Schilder’s disease or myelinoclastic diffuse sclerosis is a rare acute or subacute demyelinating disorder which primarily affects children and young adults.1 2 We report the clinical and neuroradiological follow up of two boys affected by a demyelinating disease with a prolonged relapsing-remitting course, response to corticosteroids, and relatively good long term prognosis. Brain MRI of patient 1 at the age of 14.5 years. The T 2 weighted image (TR 2000/TE 50) shows a high intensive signal in the parieto-occipital white matter, involving the right centrum semiovale, with mass effect. The first patient presented at the age of 12 with a 2 month history of repeated episodes of headache and blurred vision followed by weakness in the left leg, lasting a few hours. Head CT and bilateral carotid angiography were normal. Two weeks later the left hemiparesis and headache recurred. T2 weighted images on brain MRI disclosed a hyperintense signal in the right parieto-occipital white matter of the centrum semiovale, without a mass effect. Flash visual evoked stimuli elicited a decreased potential on the left side. Motor and sensory nerve conduction were normal. Corticosteroid treatment (prednisone (1mg/kg/day)) reversed the clinical symptoms. At the age of 14, …

Introduction Les mutations du gene VCP sont responsables d’une dystrophie des ceintures autosomique dominante pouvant s’associer a une maladie de Paget et a une demence fronto-temporale. Observations Dossier 06-346. Un homme âge de 40 ans presentait depuis deux ans d’un deficit moteur des ceintures d’aggravation rapidement progressive responsable d’une limitation du perimetre de marche et d’une limitation de l’antepulsion-abduction des epaules a 80. Il n’existait pas de deficit moteur distal, axial ou facial, de deformation osseuse ni de trouble cognitif. Chez mere et sa grand-mere, actuellement decedees, un deficit moteur des membres inferieurs avait ete observe a partir de l’âge de 35 ans avec perte de la marche vers l’âge de 45 ans, associe a une maladie de Paget chez sa mere. Le bilan biologique etait normal en dehors d’une elevation minime des creatines kinases a 1.2 fois la normale. Les phosphatases alcalines etaient normales. Les radiographies du squelette entier montraient seulement une hyperostose de la voute du crâne, sans dedifferenciation des tables internes et externes, peu en faveur d’une maladie de Paget. La scintigraphie osseuse etait normale. La biopsie musculaire retrouvait une atteinte myogene moderee avec la presence de fibres musculaires discretement vacuolisees. Le sequencage direct de l’exon 5 du gene VCP permit d’identifier la mutation faux-sens p. R155C deja decrite dans la litterature. Discussion Le gene VCP situe sur le chromosome 9p13-p12 code pour la valosin-containing protein. La manifestation la plus frequente des mutations de VCP est une dystrophie des ceintures autosomique dominante. Dans la moitie des cas, celle-ci s’accompagne d’une maladie de Paget. Plus rarement, les manifestations osseuses peuvent etre differentes d’une maladie de Paget. Enfin 30 p. 100 des patients presentent une demence fronto-temporale d’apparition plus tardive. Conclusion La presence de signes osseux, meme differents de ceux evoquant une maladie de Paget, chez un patient presentant une dystrophie des ceintures doit faire evoquer l’hypothese d’une mutation du gene VCP.

A case of amyloid neuropathy associated with a multiple myeloma IgG light chain is reported. Under light microscopy the peripheral nerve exhibited several amyloid deposits. Electron microscopy revealed numerous amyloid deposits; at their periphery, macropha-gic histiocytes were observed, containing a few tufts of parallel fibrils in their cytoplasm. A few plasma cells were scattered in the endoneurium and did not exhibit such a relationship. These findings resemble those recently observed in stem-cell cultures of IgG lambda chain human myeloma.

Angiotropic lymphoma can present as a vascular disease in the central nervous system. The patient described in this report had a sudden pain in the region of the right superficial peroneal nerve and a nerve biopsy showed tumoral cells in the lumen of most small blood vessels. This pathology, first described in the skin as malignant angioendotheliomatosis, can be compared with the occurrence of multiple emboli in the vasa nervorum. In recent cases, tumoral markers have evidenced a lymphomatous origin, generally of the B type.

We report a case of congenital neuropathy taking a rapidly fatal clinical course. Ultrastructural features of the peripheral nerve were unusual with sparsity of myelinated fibres, lack of “onion bulb” formation and presence of axonal damage. This case is compared with previously reported cases of early infantile neuropathy.