Prenatally Diagnosed Aggressive Intracranial Immature Teratoma-Clinicopathological Correlation.

OBJECTIVE: To describe clinicopathological correlation of congenital intracranial immature teratoma. METHODS: A retrospective case analysis from a tertiary medical center. RESULTS: We report a case of an intracranial immature teratoma detected prenatally at 35 weeks of gestation. The tumor showed rapid growth, causing acute hydrocephalus requiring subsequent ventriculoperitoneal shunting. Resective surgery was performed within 2 weeks after birth. The infant died at day of life 29. Histological examination revealed an immature teratoma, with high MIB1/Ki-67 proliferation index. CONCLUSION/IMPLICATIONS: Intracranial immature teratoma with high MIB1/Ki-67 proliferation index may serve as an independent poor prognostic factor.

TNF-like weak inducer of apoptosis promotes blood brain barrier disruption and increases neuronal cell death in MRL/lpr mice.

Neuropsychiatric disease is one of the most common manifestations of human systemic lupus erythematosus, but the mechanisms remain poorly understood. In human brain microvascular endothelial cells in vitro, TNF-like weak inducer of apoptosis (TWEAK) decreases tight junction ZO-1 expression and increases the permeability of monolayer cell cultures. Furthermore, knockout (KO) of the TWEAK receptor, Fn14, in the MRL/lpr lupus mouse strain markedly attenuates neuropsychiatric disease, as demonstrated by significant reductions in depressive-like behavior and improved cognitive function. The purpose of the present study was to determine the mechanisms by which TWEAK signaling is instrumental in the pathogenesis of neuropsychiatric lupus (NPSLE). Evaluating brain sections of MRL/lpr Fn14WT and Fn14KO mice, we found that Fn14KO mice displayed significantly decreased cellular infiltrates in the choroid plexus. To evaluate the integrity of the blood brain barrier (BBB) in MRL/lpr mice, Western blot for fibronectin, qPCR for iNOS, and immunohistochemical staining for VCAM-1/ICAM-1 were performed. We found preserved BBB permeability in MRL/lpr Fn14KO mice, attributable to reduced brain expression of VCAM-1/ICAM-1 and iNOS. Additionally, administration of Fc-TWEAK intravenously directly increased the leakage of a tracer (dextran-FITC) into brain tissue. Furthermore, MRL/lpr Fn14KO mice displayed reduced antibody (IgG) and complement (C3, C6, and C4a) deposition in the brain. Finally, we found that MRL/lpr Fn14KO mice manifested reduced neuron degeneration and hippocampal gliosis. Our studies indicate that TWEAK/Fn14 interactions play an important role in the pathogenesis of NPSLE by increasing the accumulation of inflammatory cells in the choroid plexus, disrupting BBB integrity, and increasing neuronal damage, suggesting a novel target for therapy in this disease.

Dynamic perfusion MRI characteristics of dural metastases and meningiomas: a pilot study characterizing the first-pass wash-in phase beyond relative cerebral blood volume.

OBJECTIVE: Dural metastases and meningiomas are extraaxial lesions that may be difficult to distinguish using conventional imaging methods. This distinction, however, is clinically important. Perfusion MRI may play a role in preoperative assessment. The aim of this study was to evaluate the utility of perfusion parameters in differentiating between these two entities. In particular, we evaluated two new metrics that reflect the first-pass wash-in characteristics of perfusion. MATERIALS AND METHODS: Patients with intracranial extraaxial masses who underwent perfusion MRI were included. Region-of-interest analysis was performed and several perfusion metrics were calculated including relative cerebral blood volume (rCBV), mean transit time and time to peak (TTP) enhancement from initial bolus enhancement (T0), calculated as TTP-T(0). Two new metrics characterizing first pass wash-in enhancement were also measured: relative wash-in time and wash-in slope. Lesions were divided into two groups: meningioma and metastasis. Comparisons between the two groups were made using Wilcoxon rank sum and Fisher exact tests. RESULTS: Twenty lesions were studied (12 meningioma and 8 metastases). Compared with meningiomas, relative wash-in time was statistically lower in metastases (p < 0.05). No other statistically significant differences were observed. Specifically, there was no difference between the two study groups in rCBV. CONCLUSION: First-pass wash-in characteristics of dural lesions may be useful for evaluating and characterizing lesions. In particular, a metric describing the wash-in phase of perfusion-that is, relative wash-in time-was found to be lower in metastases compared with meningiomas. Contrary to a prior report, we found rCBV to be limited in the evaluation of extraaxial lesions.

Extradural Dumbbell-Shaped Tuberculoma Masquerading as Nerve Sheath Tumor: Case Report and Review of Literature.

BACKGROUND: Spinal tuberculosis has been listed as a rare cause of neuroforaminal widening with only 2 previous reports in the literature. Here, we report the third case of an extradural tuberculoma extending through and expanding the neural foramen closely masquerading as a nerve sheath tumor including, to the best of our knowledge, the first description of magnetic resonance imaging, operative, and histopathology findings. CASE DESCRIPTION: A 65-year-old Nigerian man presented with signs and symptoms of worsening thoracic myeloradiculopathy for the past month. Imaging found an extradural dumbbell-shaped lesion involving the spinal canal, neural foramen, and paraspinal area with a combination of solid and cystic components causing bony remodeling of the pedicle and vertebral body, as well as enlargement of the neural foramen. Surgery was performed to resect the mass, and pathology postoperatively demonstrated caseating granulomas, rare thin elongated organisms on Ziehl-Neelsen staining, and involvement of nerve fascicles. CONCLUSIONS: This case illustrates that a tuberculoma can have many of the features of a benign neoplasm, such as encapsulation, appearance of a slow rate of growth, and development of necrosis or even cystic degeneration. With the specific findings of entrapped nerve fascicles, we postulate that the lesion represents a nerve sheath tuberculoma rather than spinal tuberculosis of the pedicle or posterior elements. Furthermore, only a lesion of the nerve sheath would have the characteristic dumbbell appearance as it extends through the foramen.

Tertiary lymphoid structures in the choroid plexus in neuropsychiatric lupus.

The central nervous system manifestations of systemic lupus erythematosus (SLE) remain poorly understood. Given the well-defined role of autoantibodies in other lupus manifestations, extensive work has gone into the identification of neuropathic autoantibodies. However, attempts to translate these findings to patients with SLE have yielded mixed results. We used the MRL/MpJ-Faslpr/lpr mouse, a well-established, spontaneous model of SLE, to establish the immune effectors responsible for brain disease. Transcriptomic analysis of the MRL/MpJ-Faslpr/lpr choroid plexus revealed an expression signature driving tertiary lymphoid structure formation, including chemokines related to stromal reorganization and lymphocyte compartmentalization. Additionally, transcriptional profiles indicated various stages of lymphocyte activation and germinal center formation. The extensive choroid plexus infiltrate present in MRL/MpJ-Faslpr/lpr mice with overt neurobehavioral deficits included locally proliferating B and T cells, intercellular interactions between lymphocytes and antigen-presenting cells, as well as evidence for in situ somatic hypermutation and class switch recombination. Furthermore, the choroid plexus was a site for trafficking lymphocytes into the brain. Finally, histological evaluation in human lupus patients with neuropsychiatric manifestations revealed increased leukocyte migration through the choroid plexus. These studies identify a potential new pathway underlying neuropsychiatric lupus and support tertiary lymphoid structure formation in the choroid plexus as a novel mechanism of brain-immune interfacing.

Hydroxychloroquine-induced toxic myopathy causing respiratory failure.

Chloroquine and hydroxychloroquine (HCQ) are commonly prescribed antimalarial agents used for a variety of systemic diseases. HCQ neuromyotoxicity is a rare complication characterized by proximal muscle weakness, normal creatinine kinase levels, and characteristic ultrastructural changes on muscle biopsy of curvilinear body formation. In this report, we describe a patient with rheumatoid arthritis and respiratory failure associated with proximal myopathy secondary to HCQ. Characteristic changes on muscle biopsy were present. Patients treated with HCQ in whom proximal myopathy, neuropathy, or cardiomyopathy develop should be evaluated for possible HCQ toxicity. Clinicians should be aware of this unusual complication of antimalarials, as discontinuation of the agent may result in clinical improvement.

Hemorrhagic intracranial follicular dendritic cell sarcoma: A case report.

BACKGROUND: Follicular dendritic cell (FDC) sarcoma is an extremely rare neoplasm, which has only been reported once in the literature with an intracranial occurrence. Neither hemorrhagic presentation of an intracranial instance of FDC sarcoma nor its rapid recurrence has yet been published in the literature. CASE DESCRIPTION: We report the case of a 61-year-old female who presented with confusion and headaches secondary to a right frontal hemorrhagic lesion, and her subsequent presentations for recurrence of the lesion and finding of a new intracranial lesion. Immunohistopathologic analysis confirmed the diagnosis based on immunoreactivity for clusterin and CD 35. CONCLUSION: As demonstrated in this case report, the presentation and progression of primary intracranial follicular dendritic cell sarcoma can often be misleading, and consideration for this rare entity should be made in cases of hemorrhagic dural-based lesions without a primary source of malignancy.

Glioblastoma multiforme presenting with an open ring pattern of enhancement on MR imaging.

BACKGROUND: Intracerebral ring enhancing lesions can be the presentation of a variety of pathologies, including neoplasia, inflammation, and autoimmune demyelination. Use of a precise diagnostic algorithm is imperative in correctly treating these lesions and minimizing potential adverse treatment effects. CASE DESCRIPTION: A 55-year-old patient presented to the hospital with complaints of a post-concussive syndrome and a non-focal neurologic exam. Imaging revealed a lesion with an open ring enhancement pattern, minimal surrounding vasogenic edema, and minimal mass effect. Given the minimal mass effect, small size of the lesion, and nonfocal neurological exam, we elected to pursue a comprehensive noninvasive neurologic workup because our differential ranged from inflammatory/infectious to neoplasm. Over the next 8 weeks, the patient's condition worsened, and repeat imaging showed marked enlargement of the lesion with a now closed ring pattern of enhancement with satellite lesions and a magnetic resonance (MR) spectroscopy and perfusion signature suggestive of neoplasm. The patient was taken to surgery for biopsy and debulking of the lesion. Surgical neuropathology examination revealed glioblastoma multiforme. CONCLUSION: The unique open ring enhancement pattern of this lesion on initial imaging is highly specific for a demyelinating process, however, high-grade glial neoplasms can also present with complex and irregular ring enhancement including an open ring sign. Therefore, other imaging modalities should be used, and close follow-up is warranted when the open ring sign is encountered.

Identification of G-protein coupled receptor kinase 2 in paired helical filaments and neurofibrillary tangles.

G-protein coupled receptor kinases (GRKs) constitute a serine/threonine kinase family playing a major role in agonist-induced phosphorylation and desensitization of G-protein coupled receptors. Recently, GRK2 and GRK5 have been demonstrated to phosphorylate alpha-synuclein (Ser129) and other synuclein isoforms. We studied colocalization of GRK2, GRK5, alpha-synuclein, and tau in neurodegenerative disorders characterized by fibrillary tau inclusions and/or alpha-synuclein-enriched Lewy bodies. We found that Lewy bodies were negative for both GRK2 and GRK5 in Lewy body disease (LBD) and LBD mixed with Alzheimer disease (AD + LBD). Instead, GRK2 but not GRK5 colocalized with 40% to 50% of neurofibrillary tangles in AD + LBD and AD brains. In disorders with less prominent alpha-synucleinopathy, neuronal and glial fibrillary tau deposits known to contain distinct subsets of tau isoforms were also positive for GRK2. These deposits included tufted astrocytes and coiled bodies in progressive supranuclear palsy, astrocytic plaques in corticobasal degeneration, and Pick bodies in Pick disease. In addition, paired helical filaments isolated from AD and AD + LBD brains were found to immunogold-label for GRK2, suggesting that GRK2 could be a potential tau kinase associated with fibrillary tau. Our studies indicate that GRK2 is a novel component of neuronal and glial fibrillary tau deposits with no preference in tau isoform binding. GRK2 may play a role in hyperphosphorylation of tau in tauopathies.

Cockayne syndrome in adults: review with clinical and pathologic study of a new case.

Cockayne syndrome and xeroderma pigmentosum-Cockayne syndrome complex are rare autosomal recessive disorders with poorly understood biology. They are characterized by profound postnatal brain and somatic growth failure and by degeneration of multiple tissues resulting in cachexia, dementia, and premature aging. They result in premature death, usually in childhood, exceptionally in adults. This study compares the clinical course and pathology of a man with Cockayne syndrome group A who died at age 31(1/2) years with 15 adequately documented other adults with Cockayne syndrome and 5 with xeroderma pigmentosum-Cockayne syndrome complex. Slowing of head and somatic growth was apparent before age 2 years, mental retardation and slowly progressive spasticity at 4 years, ataxia and hearing loss at 9 years, visual impairment at 14 years, typical Cockayne facies at 17 years, and cachexia and dementia in his twenties, with a retained outgoing personality. He experienced several transient right and left hemipareses and two episodes of status epilepticus following falls. Neuropathology disclosed profound microencephaly, bilateral old subdural hematomas, white-matter atrophy, tigroid leukodystrophy with string vessels, oligodendrocyte proliferation, bizarre reactive astrocytes, multifocal dystrophic calcification that was most marked in the basal ganglia, advanced atherosclerosis, mixed demyelinating and axonal neuropathy, and neurogenic muscular atrophy. Cellular degeneration of the organ of Corti, spiral and vestibular ganglia, and all chambers of the eye was severe. Rarely, and for unexplained reasons, in some patients with Cockayne syndrome the course is slower than usual, resulting in survival into adulthood. The profound dwarfing, failure of brain growth, cachexia, selectivity of tissue degeneration, and poor correlation between genotypes and phenotypes are not understood. Deficient repair of DNA can increase vulnerability to oxidative stress and play a role in the premature aging, but why patients with mutations in xeroderma pigmentosum genes present with the Cockayne syndrome phenotype is still not known.

Etanercept-induced myositis: do we have to stop it? A surprising outcome.

We discuss a case of a 47-year-old man who presented with progressive proximal muscle weakness of the upper and lower extremities and unstable gait. He had been on etanercept for 6 months for severe psoriasis and psoriatic arthritis with good control of his disease. Serum creatine kinase (CK) level was found to be 5666 U/L and muscle biopsy showed a marked inflammatory myopathic process likely secondary to etanercept. He was started on high-dose steroids and advised to discontinue etanercept. Despite our recommendation, he never stopped using etanercept due to fear of a psoriasis flare. Three months later, he had significant improvement of clinical symptoms, normalised serum CK levels and discontinued prednisone.

Dermatomyositis and HIV.

HIV has been linked to several autoimmune disorders since its emergence in the 1980s. By affecting different cells and pathways in the immune system, HIV induces the development of certain autoimmune diseases while prohibiting the emergence of others. Dermatomyositis has been rarely described in patients with HIV. We present a case of dermatomyositis in a patient with HIV and explore the pathogenesis of autoimmune disorders in HIV focusing on dermatomyositis.

Ollier disease with anaplastic astrocytoma: A review of the literature and a unique case.

BACKGROUND: Ollier disease is a rare, nonfamilial disorder that primary affects the long bones and cartilage of joints with multiple enchondromas. It is associated with a higher risk of central nervous system (CNS) malignancies; although the incidence is unknown. CASE DESCRIPTION: Here, we present the case of a 55-year-old woman who developed an anaplastic astrocytoma with a known diagnosis of Ollier disease with a survival time of over 3 years. CONCLUSION: This report draws attention to the rarity of this disease and the paucity of information regarding CNS involvement in Ollier disease, as well as reviews the current literature.

Accreditation council for graduate medical education (ACGME) competencies in neuropathology training.

The Accreditation Council for Graduate Medical Education (ACGME) has defined 6 core competencies for all physicians: patient care; medical knowledge; practice-based learning and improvement; interpersonal and communication skills; professionalism; and systems-based practice. However, the specific wording of the descriptions often assumes that the physician is a clinician rather than a pathologist. Therefore, the American Association of Neuropathologists, Inc. asked its Professional Affairs Committee to examine the core competencies and determine how they relate to training in neuropathology. The Committee's report is presented here in 6 sections, corresponding to the 6 competencies. In each section, the ACGME definition of that particular competency is either quoted directly or, more often, modified slightly to clarify how the competency applies to neuropathology. Each of the defined competencies is then followed by possible assessment tools, selected from those recommended in the ACGME's "toolbox." Specific suggestions are given for designing tools that apply to neuropathology. Many of the suggested activities and documentation methods can be combined into efficient, carefully formulated training/evaluation exercises. Different tools may be more applicable in some training programs.

ILAE type 3 hippocampal sclerosis in patients with anti-GAD-related epilepsy.

OBJECTIVE: To describe the neuropathologic findings and clinical course of 2 patients who underwent temporal lobectomy for medically refractive epilepsy and were later found to have high anti-glutamic acid decarboxylase (GAD) concentrations. METHODS: Small case series. RESULTS: Neuropathologic examination of both patients revealed International League Against Epilepsy (ILAE) type 3 hippocampal sclerosis. Following surgery, both developed signs and symptoms of stiff person syndrome and later cerebellar ataxia. Laboratory studies demonstrated high concentrations of anti-GAD antibodies in both patients. CONCLUSIONS: These cases suggest that ILAE type 3 hippocampal sclerosis may be immunologically related to and may exist as part of a broader anti-GAD-related neurologic syndrome in some instances.

Morphological and biochemical correlations of abnormal tau filaments in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is characterized by specific filamentous tau inclusions present in 3 types of cells including oligodendrocytes (coiled bodies), astrocytes (tufted astrocytes), and neurons (neurofibrillary tangles; NFTs). To correlate the morphological features and biochemical composition of tau in the inclusions, we examined tau filament-enriched fractions isolated from selected brain regions. Frontal and cerebellar white matter manifested a predominance of coiled bodies. The isolated fractions contained straight, 14-nm-wide filaments of relatively smooth appearance. Caudate nucleus and motor cortex with numerous tufted astrocytes contained mostly straight, but irregular, 22-nm-wide filaments with jagged contours. Perirhinal cortex and hippocampus, rich in NFTs, contained 22-nm-wide filaments that were twisted at 80-nm intervals. Among the regions, those with tufted astrocytes showed the most heterogeneity in the ultrastructure of filaments. In all regions, isolated filaments were immunolabeled with PHF-1, Tau 46, and AT8. Fractions from all regions showed 2 PHF-1 immunoreactive bands of 64 and 68 kDa, while an additional band of 60 kDa was detected in NFT-enriched regions. All fractions, in varying extents, showed Tau-1-immunoreactive bands between 45-64 kDa. The results indicate that the 3 types of PSP tau inclusions vary in the ultrastructure although with some overlapping features. Neuronal and glial inclusions also vary in the biochemical profile of tau protein. These differences may depend on the metabolism of tau in the diseased oligodendrocytes, astrocytes, and neurons.

Two cases of spinal meningeal melanocytoma.

Meningeal melanocytoma is a rare pigmented tumor originating from the melanocytes that generally occurs in the posterior fossa and the spinal cord. Although it is known as a relatively benign tumor, some recurrences have been reported. We report two cases of spinal meningeal melanocytoma with immunohistochemical and ultrastructural studies. In addition, we include a summary of published cases since the first case of Limas and Tio in 1972.

Optimizing the skeletal muscle biopsy.

Knowledge of disorders of skeletal muscle remains of importance for the practicing pathologist. While genetic testing has proved useful in the diagnosis of many patients, especially those with the more common forms of muscular dystrophy, less common genetic myopathies, congenital myopathies, and toxic myopathies, often related to commonly used therapeutic agents such as statins, still require pathological analysis for diagnostic purposes. A contemporary pathologist may expect to be consulted about unusual familial neuromuscular disorders, autoimmune disorders, and drug-induced myopathies, often in the context of patients with multiple medical conditions that complicate the clinical and pathological analysis. A working knowledge of skeletal muscle biopsy and its clinical utility as well as its limitations is therefore important for all pathologists. Each pathologist must decide if they wish to process the biopsy in their own laboratory, or if the specimen should be sent to a reference laboratory for analysis.