Volume 27, No. 5/2008(Sept/Oct)
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 Clinical Neuropathology
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Muscle
Challenges for the genetic screening in dysferlin deficiency – report of an instructive case and review of the literature
A. Gal, E. Siska, Z. Nagy, G. Karpati and M.J. Molnar,
Abstract
A. Gal1, E. Siska2, Z. Nagy2, G. Karpati3 and M.J. Molnar1,3
1Department of Neurology, Semmelweis University, 2National Institute of Psychiatry and Neurology, Budapest, Hungary and 3Montreal Neurological Institute, McGill University, Montreal, Canada
The homozygous or compound heterozygous mutation of the alleles of DYSF gene causes dysferlinopathy resulting in limb girdle muscular dystrophy Type 2B (LGMD 2B) or Miyoshi myopathy. However, patients with only 1 (heterozygous) mutation on 1 allele are increasingly recognized. Based on the Leiden database (www.dmd.nl) among 257 different mutations resulting in dysferlin-deficient muscular dystrophy, pathogenic mutations were detected only on 1 allele in 45 cases, while the exons of the other allele did not show any pathological alterations. The relatively high number of these so-called heterozygous cases raises the question if present routine molecular techniques are sufficient alone for confirming the diagnosis of dysferlin deficiency. In fact, the heterogenous genetic background of the disease makes it impossible to make the correct diagnosis without Western blot of the muscle dysferlin. This paper presents the clinical, myopathological and molecular genetic results of a 30-year-old male with dysferlinopathy as an instructive case. The cDNA sequencing of the dysferlin gene revealed a single C5302T heterozygous mutation resulting in Arg1768Trp exchange. The paper highlights the importance of the protein analysis in the diagnosis of dysferlin deficiency, discusses the difficulties of the complete genomic analysis of the dysferlin gene alterations and the possible etiopathogenetic role of the noncoding DNA sequence of the dysferlin gene in dysferlin deficiencies.Correspondence to:
M.J. Molnar, MD, PhD; Department of Neurology, Semmelweis University, 1083 Balassa J. Str. 6, Budapest, Hungary
Email: molnarmj@gmail.com
Storage disease
Krabbe’s disease in two West Highland White terriers
M.T. Capucchio, M. Prunotto, D. Lotti, A. Valazza, M. Galloni, B. Dore, P. Pregel, S. Amedeo, D. Catalano, E. Cornaglia and D. Schiffer
Abstract
M.T. Capucchio1, M. Prunotto2, D. Lotti4, A. Valazza1, M. Galloni2, B. Dore3, P. Pregel1, S. Amedeo1, D. Catalano1, E. Cornaglia1 and D. Schiffer4
1Animal Pathology Department, Veterinary Medicine Faculty, University of Turin, 2Veterinary Morphophysiology Department, Veterinary Medicine Faculty, University of Turin, 3Human and Animal Biology Department, University of Turin, 4Veterinary Practitioner and 5CNBO Fondazione Policlinico di Monza/University of Turin, Vercelli, Italy
Two 3-month-old male West Highland White terriers were referred for progressive neurological disease. Histological examination of the central nervous system of the animals euthanized at the owner’ request, revealed diffuse, bilateral and symmetrical white matter lesion consisting of varying degrees of demyelination and axonal degeneration. Accumulation of round to ovoid large mononuclear cells was especially observed along the blood vessels in the white matter. These cells were characterized by central or eccentric nuclei and highly eosinophilic, granular and PAS-positive cytoplasm. Stored material was stained with toluidine blue both at pH 4 and pH 11 and exhibited a strong PAC and no PALK activities. Staining for lectins revealed a positivity using Ricinus communis agglutinin-I, Ricinus communis agglutin-II, Triticum vulgaris and Concavalin A. Histochemical evaluation of intracellular material was performed on the kidney and on the liver, too. Ultrastructural investigations allowed to observe the cytoplasmic contents of globoid cells that is an admixture of degraded myelin membranes and different kinds of tubular aggregates. To verify if the two dogs bore the mutation at position 473, a method involving PCR amplification of genomic DNA followed by restriction-digestion was used. The diagnosis of Krabbe’s disease was performed based on the clinical evaluation, morphological, histochemical and ultrastructural features.Correspondence to:
M.T. Capucchio; Animal Pathology, Department
Veterinary Medicine Faculty, University of Turin, via Leonardo Da Vinci 44, 10095 Grugliasco, Italy
Email: mariateresa.capucchio@unito.it
Storage disease
Neuropathology of chronic GM2 gangliosidosis due to hexosaminidase A deficiency
M. Kornfeld
Abstract
M. Kornfeld
Pathology Department, School of Medicine, University of New Mexico, Albuquerque, NM, USA
Autopsy studies of late-onset GM2 gangliosidosis are sparse and only one adult case is on record. The case of partial Hex A deficiency presented here started in childhood as spinal muscular atrophy which progressed slowly over 4 decades. Cognitive function remained intact throughout the entire course, but during the last few years of life allodynia supervened. The patient died at 44 years of age. In good correlation with clinical observations the autopsy findings showed the most severe accumulation of lipid and consequent regressive change in the anterior horns of the spinal cord. Extensive but less severe storage was found in other spinal cord neurons, brain stem and selected basal ganglia. Cerebral cortex was virtually spared by storage but was the site of excessive formation of lipofuscin which was also present in many other neurons in the CNS. Marked storage and ganglionic loss was also found in the dorsal root ganglia, and the fasciculus gracilis was severely depleted of myelinated fibers. Electron microscopy showed accumulated gangliosides almost exclusively in the form of single and coalescing zebra bodies. In conclusion, the pathology in this case of chronic GM2 gangliosidosis, though in part conforming with previous observations, differed in several aspects. First, the cerebral cortex was – with only a few exceptions – free of ganglioside storage. Also spared was the cerebellum. In addition, homogeneous accumulation of zebra bodies contrasted with heterogeneity of neuronal inclusions found in other chronic cases. Finally, the involvement of sensory neurons was prominent and potentially related to allodynia. Molecular study of HEXA gene in this patient showed an TATC1278/? genotype.Correspondence to:
M. Kornfeld, MD; Pathology Department, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA
Email: MKornfeld@salud.unm.edu
Neurodegeneration
Anti-DARPP32 antibody-immunopositive inclusions in the brain of patients with multiple system atrophy
Y. Honjo, Y. Shirakashi, Y. Kawamoto and I. Akiguchi
Abstract
Y. Honjo, Y. Shirakashi, Y. Kawamoto and I. Akiguchi
Department of Neurology, Faculty of Medicine, Kyoto University, Kyoto, Japan
MSA is a neurodegenerative disease and GCIs are specific pathological hallmarks in the brain of MSA patients. Recently, Cdk5 immunopositive GCIs were reported, but the function of Cdk5 in the adult human brain is not clear. Cdk5 has several substrates such as neurofilament and t proteins. Among these substrates, t and MAP 1B are immunopositive in GCIs. DARPP32 has been identified as a target for dopamine and PKA in the striatum. DARPP32 has multiple phosphorylation sites, and Cdk5 can phosphorylate DARPP32 at Thr75. The phosphorylation of Thr75 converts DARPP32 into an inhibitor of PKA. DARPP32 is also one of the major substrates of Cdk5, and DARPP32 is widely expressed in both neurons and glial cells. In this study, we determined the immunohistochemical localization of DARPP32 in the brains of a normal control group and patients with MSA. An anti-DARPP32 antibody revealed immunopositive oligodendrocytes and astrocytes widely distributed in the brains of the normal control group and the brain of patients with MSA. Neurons in the caudate, globus pallidus, substantia nigra, hypothalamus, neocortex layers II and III, and cerebellar Purkinje cells were all immunopositive for DARPP32 in the normal control brains, and the immunostaining patterns were very similar to those observed in patients with MSA. We found that DARPP32 was immunopositive in GCIs, and the localization of DARPP32 and Cdk5 was very similar in GCIs. We suggest that Cdk5 and its substrate DARPP32 may be involved in the formation of GCIs through the phosphorylation of DARPP32 in the oligodendrocytes of brains with MSA.Correspondence to:
Y. Honjo, MD; Department of Neurology, Faculty of Medicine, Kyoto University Kyoto, 606-8507 Japan
Email: honjyo@kuhp.kyoto-u.ac.jp
Tumor
Aggressive papillary glioneuronal tumor: case report and literature review
H.B. Newton, J. Dalton, A. Ray-Chaudhury, R. Gahbauer and J. McGregor
Abstract
H.B. Newton1, J. Dalton1,2, A. Ray-Chaudhury3, R. Gahbauer4 and J. McGregor5
1Dardinger Neuro-Oncology Center, 2Ohio State University Medical Center, Departments of Neurology, 3Pathology, 4Radiation Medicine, 5Neurosurgery, Ohio State University Medical Center and James Cancer Hospital, Columbus, OH, USA
Papillary glioneuronal tumors (PGNT) are a rare, recently described form of mixed neoplasm composed of glial and neuronal components. PGNT usually occur in children and young adults, and typically demonstrate low-grade pathology, with a low proliferative index of 1 – 3%. Here we describe a newly diagnosed case of PGNT with a more aggressive phenotype that required irradiation and chemotherapy. The patient was a 19-year-old female who developed progressive headaches and visual seizures. An MRI revealed a heterogeneously enhancing solid mass in the left temporo-occipital region, with significant surrounding edema and mass effect. The mass was resected under stealth guidance without complication. Postoperative MRI scans showed patchy enhancement and residual T2 and FLAIR abnormality. Pathology revealed a highly cellular neoplasm with papillary-like structures, containing cells with glial and neuronal differentiation. Regions of mitoses and focal necrosis were noted, along with a Ki-67 labeling index of 26%. The diagnosis was aggressive PGNT, and treatment consisted of conformal irradiation and concomitant temozolomide over 6 weeks. Postirradiation follow-up MRI scans demonstrated a reduction of residual enhancement and FLAIR abnormality. The patient continues standard-dose adjuvant temozolomide on a monthly basis, with further improvement on subsequent MRI scans and a stable neurologic exam. This patient demonstrates that PGNT may, in rare cases, display an aggressive clinicopathologic phenotype that requires a therapeutic approach more consistent with a high-grade glioma.Correspondence to:
H.B. Newton, MD; 465 Means Hall, 1654 Upham Drive, Columbus, OH 43210, USA
Email: newton.12@osu.edu
Tumor
Pineal parenchymal tumors – utility of immunohistochemical markers in prognostication
A. Arivazhagan, B. Anandh, V. Santosh and B.A. Chandramouli
Abstract
A. Arivazhagan1, B. Anandh1, V. Santosh2 and B.A. Chandramouli1
1Department of Neurosurgery and 2Department of Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Background and objective: The pineal parenchymal tumors are rare, comprising 15 – 30% of all tumors of pineal region. Their histological classification alone has been found to be inadequate for prognostication. Hence, we correlated their immunohistochemical profile with the prognosis. Methods: A retrospective analysis of 33 pineal parenchymal tumors treated from 1990 – 2004 was performed. The histological features of the tumors were reviewed and immunohistochemical staining for neurofilament protein (NF), MIB-1, synaptophysin and GFAP were performed. Results were correlated with the patients’ survival. Results: The study comprised 6 pineocytomas (PC), 17 pineoblastomas (PB) and 10 pineal parenchymal tumors with intermediate differentiation (PPT-ID) which included 3 mixed PC/PB. The histological diagnosis was obtained from microsurgical biopsy/decompression, stereotactic or endoscopic biopsy. Adjuvant therapy was advised based on histology. All pineocytomas stained positive for NF. Most pineoblastomas (13/16) failed to show any immunoreactivity with NF. The mean MIB-1 labeling index in pineocytomas, PPT of ID and pineoblastomas were 1.58, 16.1 and 23.52 respectively (p < 0.001). All the tumors stained positive for synaptophysin, although the intensity of the staining varied. NF-positive tumors had a higher chance of disease-free state, irrespective of histological subgroup (p = 0.0036). The median disease-free survival in pineoblastomas with negative NF staining was 5 months, which was less than that of pineoblastomas with positive NF staining (32 months). Conclusions: Neurofilament immunoreactivity indicates better prognosis in pineal parenchymal tumors. The MIB-1 labeling index can be utilized as an additional tool to differentiate pineal parenchymal tumors into various subgroups.Correspondence to:
Dr. B. Anandh; Associate Professor, Department of Neurosurgery, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, 560029, India
Email: anandhbala@gmail.com
Tumor
Expression of c-Myc, neurofibromatosis Type 2, somatostatin receptor 2 and erb-B2 in human meningiomas: relation to grades or histotypes
A. Durand, J. Champier, A. Jouvet, F. Labrousse, J. Honnorat, J. Guyotat and M. Fèvre-Montange
Abstract
A. Durand1, J. Champier1, A. Jouvet1,2, F. Labrousse3, J. Honnorat1,2, J. Guyotat2 and M. Fèvre-Montange1
1Université de Lyon, Lyon 1, INSERM U842, UMR-S842, 2Centre de Pathologie, Service de Neurochirurgie et de Neurologie, Groupement Hospitalier Est, Lyon and 3Service d’Anatomopathologie, CHRU Dupuytren, Limoges, France
Meningiomas, which originate from arachnoid cells, represent one of the largest subgroups of intracranial tumors. They are generally benign, but can progress to malignancy. The aim of our study was to determine the expression of 4 genes, c-Myc, neurofibromatosis Type 2 (NF2), somatostatin receptor isoform 2 (sst2) and erb-B2, that have been associated with tumorogenesis or, possibly, with aggressive behavior or recurrence of meningiomas. We measured levels of mRNAs coding for these genes by qRT-PCR in 51 cases and levels of c-Myc protooncogene and sst2 protein by immunohistochemistry in 26 cases of meningiomas of various grades and histotypes. C-Myc mRNA and protein levels were not grade-related, but validated subdivision of the 36 benign meningiomas into two groups, Groups IA and IB, based on histological and clinical features (Ki-67-proliferative index, absence or presence of mitoses, rate of recurrence and incidence of perilesional edema). In addition to histopathological grading, c-Myc expression may be useful in predicting tumor recurrence in patients with low-grade meningiomas. NF2 mRNA levels and sst2 mRNA and receptor levels were not grade-related, but were histotype-related, with significantly higher levels in the meningothelial subtype than in the fibroblastic subtype. Erb-B2 mRNA levels were not grade- or histotype-related. Furthermore, the high expression of sst2 in meningothelial meningioma suggests the possibility of a different tumorigenesis process in this meningioma subtype and may open perspectives for the diagnosis and therapy of this subtype using somatostatin as an antiproliferative agent.Correspondence to:
M. Fèvre-Montange; INSERM U842, Faculté de Médecine RTH Laennec, 69372 Lyon Cedex 08, France
Email: montange@lyon.inserm.fr
Tumor
Concomitant radiochemotherapy in a patient with multiple sclerosis and glioblastoma
S. Oberndorfer, P.C. Ruzin and W. Grisold
Abstract
S. Oberndorfer, P.C. Ruzin and W. Grisold
Department of Neurology, LBI-Neurooncology, Kaiser Franz Josef Hospital, Vienna, Austria
The coincidence of multiple sclerosis (MS) and glioblastoma has been reported in several anecdotal reports. Little is known concerning the effects of radio- and/or chemotherapy on demyelinating brain lesions in MS patients. Moreover, there are no data concerning the effect of concomitant radiochemotherapy according to the STUPP protocol on the course of MS in patients with coexisting glioblastoma. A 43-year-old male patient was diagnosed for relapsing-remitting MS in 1997. He received interferon and glatiramer acetate for immunomodulatory treatment and was stable until 2006 (EDSS < 1.5), when neurological deterioration occurred. He developed a left-sided hemiparesis, and an MRI showed right temporal contrast-enhancing mass lesion. A subsequent tumor resection was performed and histology revealed a glioblastoma. At the beginning of radiochemotherapy, treatment for multiple sclerosis (glatiramer acetate) was stopped. The tumor responded well to treatment and was clinically as well as radiologically stable until 9 months after diagnosis of glioblastoma. The typical radiological MS lesions remained unchanged. The patient died 12 months after diagnosis of glioblastoma due to tumor progression. This report demonstrates that concomitant radiochemotherapy according to the STUPP protocol, was safe in our patient with respect to the radiological as well as the clinical course of multiple sclerosis.Correspondence to:
S. Oberndorfer, MD; LBI Neurooncology, Department of Neurology, KFJ-Hospital, Kundratstraße 3, 1100 Vienna, Austria
Email: stefan.oberndorfer@wienkav.at
Tumor
Spinal cord compression through extraosseous extension of a vertebral low-grade hemangioendothelioma with histiocytoid differentiation
M. Mittelbronn, J. Schittenhelm, R. Ritz, U. Hahn, A. Bornemann and F. Roser
Abstract
M. Mittelbronn1, J. Schittenhelm1, R. Ritz2, U. Hahn3, A. Bornemann1 and F. Roser2
1Institute of Brain Research, 2Department of Neurosurgery and 3Department of Neuroradiology, University of Tübingen, Germany
Herein, we report the case of a 47-year-old man clinically presenting a slow progressive loss of lower extremity functions within 8 weeks followed by an acute neurogenic bladder dysfunction. The patient exhibited high-grade paralysis of both legs with reduced sensation from dermatome Th11 downwards as well as marked spasticity of the lower extremity. Neuroradiological examinations revealed a protruding spinal tumor with extraosseous-intraspinal extension. The resected tumor mass exhibited a highly vascularized tumor with architectural complexity and high cellularity finally leading to the diagnosis of a hemangioendothelioma. Interesting was the fact that the tumor vasculature exhibited many CD68-positive cells protruding into the lumen and, therefore, being part of a partially histiocytoid differentiation which is all the more uncommon in hemangioendothelioma. The time frame of 3 hours between embolization and tumor resection is too short to explain a monocytic intravascular reaction. Usually, hemangioendotheliomas arise from the soft tissue, lungs or liver, but intraspinal manifestations are only rarely observed. Furthermore, the clinical course with a progressive development of a paraparesis due to a hemangioendothelioma is very uncommon.Correspondence to:
M. Mittelbronn, MD; Institute of Brain Research, University of Tübingen, Hoppe-Seyler-Straße 3, 72076 Tübingen, Germany
Email: hirnforschung@uni-tuebingen.de
Malformation
Spontaneous middle-ear encephalocele: report of two cases and brief review
H. Alkhalidi, L.N. de Tilly, R. Fenton and D.G. Munoz
Abstract
H. Alkhalidi1, L.N. de Tilly2, R. Fenton3 and D.G. Munoz1
1Department of Laboratory Medicine and Pathobiology, 2Department of Radiology, 3Department of Otolaryngology, St. Michael’s Hospital and Li Ka Shing Knowledge Institute, University of Toronto, Ontario, Canada
We report two cases of middle-ear spontaneous (idiopathic) encephalocele in patients aged 69 and 82 years. To our knowledge the latter represents the oldest individual reported to have such a lesion. Microscopic examination shows a disorganized neuropil with reactive inflammatory changes and in one case, several cysts lined by simple cylindrical ciliated epithelium. Encephalocele must be included in the differential diagnoses of otorrhea and masses in the middle ear.Correspondence to:
D. Munoz, MD; Department of Laboratory Medicine, Division of Pathology, St. Michael’s Hospital and Li Ka Shing Knowledge Institute, Cardinal Carter Wing, 2nd floor, 30 Bond Street, Toronto, Ontario, M5B 1W8, Canada
Email: munozd@smh.toronto.on.ca
Biomaterials
Histological analysis of DuraGen in a human subject: case report
L. Khorasani, R.P. Kapur, C. Lee and A.M. Avellino
Abstract
L. Khorasani1, R.P. Kapur2, C. Lee1 and A.M. Avellino1
1Division of Pediatric Neurosurgery and 2Department of Pathology, Children’s Hospital and Regional Medical Center, Seattle, WA, USA
Object: DuraGen (Integra Neurosciences, Plainsboro, NJ, USA) is an avascular collagen matrix used for dural closure. Although, numerous animal models have been studied, histological transformation of DuraGen in humans has not been reported. Material and method: We analyzed a sample of scarred DuraGen used in a craniectomy patient at time of delayed cranioplasty. Conclusion: Histological analysis revealed evidence for both fibroblast infiltration and neovascularization of the DuraGen.Correspondence to:
A.M. Avellino, MD, FACS; Children’s Hospital and Regional Medical Center, Division of Pediatric Neurosurgery, 4800 Sand Point Way NE, Mailstop W-7729, Seattle, WA 98105, USA
Email: anthony.avellino@seattlechildrens.org
Letter to the Editor
Comment to Shukla et al.
K.A. Jellinger
Euro-CNS News
Society News of the European Confederation of Neuropathological Societies
Euro-CNS
