A novel SREBF1::NACC1 gene fusion in an unclassifiable intracranial tumour.

A 39-year-old man had an intracranial tumour without infiltration into the surrounding cerebral tissue. The tumour recurred seven times in 11 years but maintained a well-demarcated character. Histopathological examination of the 4th surgical specimens showed nests of tumour cells surrounding small blood vessels. The tumour cells harboured amphophilic cytoplasm and small round nuclei with fine chromatin, and perinuclear haloes and clear borders were frequently observed, which was unclassifiable histology. By the Deutsches Krebsforschungszentrum methylation classifier, the tumour was not classified into any of the methylation classes. mRNA sequencing identified a novel SREBF1::NACC1 gene fusion. This intracranial tumour could be a novel tumour entity with NACC1 rearrangement showing characteristic histological and diagnostic imaging findings.

Characterization of Moyamoya and Middle Cerebral Artery Diseases by Carotid Canal Diameter and RNF213 p.R4810K Genotype.

OBJECTIVES: It is sometimes difficult to differentiate middle cerebral artery disease from moyamoya disease because the two can present similarly yet have different treatment strategies. We investigated whether the presence of a narrow carotid canal and the RNF213 mutation can help differentiate between the two phenotypes. POPULATION AND METHODS: We analyzed 78 patients with moyamoya disease, 27 patients with middle cerebral artery disease, and 79 controls from 2 facilities. The carotid canal diameter was measured using computed tomography. The p.R4810K mutation was genotyped by TaqMan assay. A receiver operating characteristics analysis was performed to assess the significance of the carotid canal diameter for the accurate diagnosis of moyamoya disease. RESULTS: The carotid canal diameter was significantly narrower in patients with moyamoya disease than in controls. The optimal cutoff values were 5.0 mm for adult males and 4.5 mm for adult females and children (sensitivity: 0.82; specificity: 0.92). Among the patients with middle cerebral artery disease, 18.5% and 25.0% of the affected hemispheres had the p.R4810K mutation and narrow canal (i.e., below the cutoff), respectively, whereas only 3.1% of those had both. Contrastingly, 68.8% of the affected hemispheres in patients with moyamoya disease had both these characteristics. Among the patients with moyamoya disease, those with the p.R4810K mutation tended to have narrower carotid canals. CONCLUSIONS: Although the presence of a narrow carotid canal or the p.R4810K mutation alone could not be used to distinguish those with moyamoya disease from those with middle cerebral artery disease, the combination of these factors could better characterize the two phenotypes.

Moyamoya disease patient mutations in the RING domain of RNF213 reduce its ubiquitin ligase activity and enhance NFκB activation and apoptosis in an AAA+ domain-dependent manner.

Moyamoya disease (MMD) is a cerebrovascular disease characterized by progressive occlusion of the internal carotid arteries. Genetic studies originally identified RNF213 as an MMD susceptibility gene that encodes a large 591 kDa protein with a functional RING domain and dual AAA+ ATPase domains. As the functions of RNF213 and its relationship to MMD onset are unknown, we set out to characterize the ubiquitin ligase activity of RNF213, and the effects of MMD patient mutations on these activities and on other cellular processes. In vitro ubiquitination assays, using the RNF213 RING domain, identified Ubc13/Uev1A as a key ubiquitin conjugating enzyme that together generate K63-linked polyubiquitin chains. However, nearly all MMD patient mutations in the RING domain greatly reduced this activity. When full-length proteins were overexpressed in HEK293T cells, patient mutations that abolished the ubiquitin ligase activities conversely enhanced nuclear factor κB (NFκB) activation and induced apoptosis accompanied with Caspase-3 activation. These induced activities were dependent on the RNF213 AAA+ domain. Our results suggest that the NFκB- and apoptosis-inducing functions of RNF213 may be negatively regulated by its ubiquitin ligase activity and that disruption of this regulation could contribute towards MMD onset.

[Risk Factors for Early Progression of Carotid Stenosis after Cervical Radiation Therapy].

OBJECTIVE: Carotid stenosis may occur as a late complication following cervical radiation therapy(RT);however, it may also progress in the early post-RT period. This study aimed to characterize the clinical features associated with the early progression of post-RT carotid stenosis. METHODS: We retrospectively reviewed clinical records of 30 patients who had undergone unilateral or bilateral cervical RT between January 2010 and November 2014. We analyzed the pre- and post-RT stenosis of their carotid arteries using contrast-enhanced computed tomography images. The arteries were classified as progressive or non-progressive according to the presence or absence of stenosis progression within five years after RT. Using univariate and multivariate analyses, we evaluated the following potential clinical risk factors:age;gender;history of hypertension, hyperlipidemia, diabetes mellitus, coronary artery disease, or smoking habit;antiplatelet or statin use;radiation dose;and prior presence of carotid stenosis before RT. RESULTS: In total, we reviewed 57 irradiated carotid arteries and identified 9 with early post-RT progression. Carotid stenosis before RT was observed in 88.9% of arteries in the progressive group but only 2% of arteries in the non-progressive group and it predicted progression(univariate and multiple logistic regression analyses, p<0.0001). No other clinical characteristics had a significant association with the progression of carotid stenosis. CONCLUSION: Prior presence of carotid stenosis may be a risk factor for its early progression after RT. Pre-RT screening of cervical arteries may be useful, and strict management of carotid stenosis is critical in patients with cervical radiation therapy.

Presynaptic activity regulates Na(+) channel distribution at the axon initial segment.

Deprivation of afferent inputs in neural circuits leads to diverse plastic changes in both pre- and postsynaptic elements that restore neural activity. The axon initial segment (AIS) is the site at which neural signals arise, and should be the most efficient site to regulate neural activity. However, none of the plasticity currently known involves the AIS. We report here that deprivation of auditory input in an avian brainstem auditory neuron leads to an increase in AIS length, thus augmenting the excitability of the neuron. The length of the AIS, defined by the distribution of voltage-gated Na(+) channels and the AIS anchoring protein, increased by 1.7 times in seven days after auditory input deprivation. This was accompanied by an increase in the whole-cell Na(+) current, membrane excitability and spontaneous firing. Our work demonstrates homeostatic regulation of the AIS, which may contribute to the maintenance of the auditory pathway after hearing loss. Furthermore, plasticity at the spike initiation site suggests a powerful pathway for refining neuronal computation in the face of strong sensory deprivation.

Increased abundance of Ruminococcus gnavus in gut microbiota is associated with moyamoya disease and non-moyamoya intracranial large artery disease.

Moyamoya disease (MMD) is a rare cerebrovascular disease endemic in East Asia. The p.R4810K mutation in RNF213 gene confers a risk of MMD, but other factors remain largely unknown. We tested the association of gut microbiota with MMD. Fecal samples were collected from 27 patients with MMD, 7 patients with non-moyamoya intracranial large artery disease (ICAD) and 15 control individuals with other disorders, and 16S rRNA were sequenced. Although there was no difference in alpha diversity or beta diversity between patients with MMD and controls, the cladogram showed Streptococcaceae was enriched in patient samples. The relative abundance analysis demonstrated that 23 species were differentially abundant between patients with MMD and controls. Among them, increased abundance of Ruminococcus gnavus > 0.003 and decreased abundance of Roseburia inulinivorans < 0.002 were associated with higher risks of MMD (odds ratio 9.6, P = 0.0024; odds ratio 11.1, P = 0.0051). Also, Ruminococcus gnavus was more abundant and Roseburia inulinivorans was less abundant in patients with ICAD than controls (P = 0.046, P = 0.012). The relative abundance of Ruminococcus gnavus or Roseburia inulinivorans was not different between the p.R4810K mutant and wildtype. Our data demonstrated that gut microbiota was associated with both MMD and ICAD.

Plasticity of the bony carotid canal and its clinical use for assessing negative remodeling of the internal carotid artery.

BACKGROUND AND OBJECTIVE: It has long been believed that the bony carotid canal has no plasticity and that a small canal represents a hypoplastic internal carotid artery. We aimed to show whether the carotid canal can narrow according to morphological changes in the internal carotid artery. MATERIALS AND METHODS: The carotid canal diameter was longitudinally measured in seven individuals who underwent carotid artery ligation. As moyamoya disease is known to be associated with negative remodeling of the internal carotid artery, the carotid canal diameter was measured in 106 patients with moyamoya disease, and an association with the outer diameter of the internal carotid artery or a correlation with the disease stage was investigated. The carotid canal was measured by computed tomography (106 patients), and the outer diameter of the artery was measured by high-resolution magnetic resonance imaging (63 patients). The carotid canal area was calculated by the product of the maximum axial diameter and its perpendicular diameter. RESULTS: All seven patients who underwent carotid artery ligation showed narrowing of the carotid canal, and the carotid canal area decreased by 12.2%-28.9% during a mean follow-up period of 4.2 years. In patients with moyamoya disease, the carotid canal area showed a linear correlation with the outer area of the internal carotid artery (r = 0.657, p < 0.001), and a negative correlation with the disease stage (ρ = -0.283, p < 0.001). CONCLUSION: The bony carotid canal has plasticity, and its area reflects the outer area of the internal carotid artery, therefore, it can be used to assess the remodeling of the carotid artery. A narrow carotid canal may not necessarily indicate hypoplastic internal carotid artery.

Multiple Spinal Chronic Subdural Hematomas Associated with Thoracic Hematomyelia: A Case Report and Literature Review.

BACKGROUND: Chronic subdural hematoma (CSDH) is uncommon in the spine. Most spinal CSDHs occur as solitary lesions in the lumbosacral region. We report a rare case of multiple spinal CSDHs associated with hematomyelia. The diagnostic and therapeutic management of these complex spinal CSDHs is reviewed as well as the pertinent literature. CASE DESCRIPTION: A 79-year-old woman on warfarin therapy presented with lower back pain and progressive lower extremity weakness that had developed in the previous 2 weeks. She subsequently developed paraplegia and urinary incontinence. Thoracolumbar magnetic resonance imaging showed a CSDH from T12-L3 compressing the cauda equina. Single-shot whole-spine magnetic resonance imaging showed another CSDH and hematomyelia at T2-3. She underwent L2-3 hemilaminectomy, which revealed a liquefied subdural hematoma. Delayed T2 laminectomy exposed an organized subdural hematoma and xanthochromic hematomyelia. After each surgery, the patient showed significant motor recovery. Finally, the patient could walk, and the urinary catheter was removed. CONCLUSIONS: Spinal CSDH may occur in multiple regions and may be associated with hematomyelia. Whole-spine magnetic resonance imaging is useful to examine the entire spine for CSDH accurately and thoroughly. Comprehensive surgical exploration of all symptomatic hematomas may restore neurologic functions even with delayed surgery.

Investigation of Radiologic Landmarks Used to Decide the Appropriate Surgical Approach for Upper Thoracic Ventral Degenerative Disorders.

BACKGROUND: Ventral lesions of upper thoracic spinal cord due to degenerative diseases are rare and often have poor operative outcomes. Anterior decompression of the lesion is difficult because of the local anatomy. This retrospective study aimed to evaluate reproducible anatomic measurements for selecting the best surgical approach for anterior decompression of ventral lesions of upper thoracic spinal cord. METHODS: Cases of anterior decompression of ventral lesions of upper thoracic spinal cord due to degenerative diseases at our institution from 2004 to 2015 were assessed. Several lines were drawn on magnetic resonance imaging and computed tomography scans of midsagittal sections of the upper thoracic spine to evaluate the most optimal approach for treating upper thoracic lesions. A line from the suprasternal notch to the vertebral body (suprasternal notch to vertebral body [SV] line) was accepted as baseline. RESULTS: The caudal edge of the lesion was above the SV line in 10 cases, each of which was treated via an anterior approach without sternotomy. The caudal edge was below the SV line in 7 cases, 5 of which underwent surgery with the sternum-splitting or transthoracic approach. The other 2 lesions were approached via an obliquely deviated route without sternotomy. The SV line sometimes changed with patients' posture alterations. CONCLUSIONS: The SV line, a useful landmark for upper thoracic lesions, is not sufficiently reliable because it changes according to the patient's posture. By leaning in the direction of the surgical microscope, more caudal upper thoracic lesions can be reached than when using the SV line as a surgical landmark.

Occipital Sinus Dural Arteriovenous Fistula Presenting with Cerebellar Hemorrhage.

BACKGROUND: Occipital sinus (OS) dural arteriovenous fistula (DAVF) is extremely rare, and we are aware of no case accompanied by cerebral hemorrhage. We present a case of OS DAVF presenting with cerebellar hemorrhage, treated successfully by transvenous embolization. CASE DESCRIPTION: A 62-year-old female presented with headache and nausea of recent onset. Computed tomography revealed left cerebellar hemorrhage with perihematomal edema. Angiography showed OS DAVF fed by bilateral occipital and posterior meningeal arteries, with drainage into the left inferior hemispheric vein and right transverse sinus receiving the shunt flow from OS. The caudal side of the OS was occluded. The inferior hemispheric vein was dilated with 2 varices, and the junction between the OS and right transverse sinus was narrowed. Because the OS was not involved in normal cerebellar drainage, transvenous embolization of the OS was performed. The microcatheter was advanced to the OS from the transverse sinus during balloon occlusion at the confluence of sinuses. Coils were placed in the OS from the caudal to cranial side, and complete occlusion of the shunt was obtained. CONCLUSIONS: This is the first report of OS DAVF presenting with cerebellar hemorrhage. Transvenous embolization of the affected OS appears ideal when transvenous access is feasible, and the OS is not involved in normal venous drainage of the cerebellum.

Two cases of primary ocular adnexal lymphomas diagnosed after pre-biopsy corticosteroid treatment using polymerase chain reaction-based gene rearrangement analysis.

PURPOSE: To report the limited usefulness of polymerase chain reaction (PCR)-based immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangement analysis in diagnosing primary ocular adnexal lymphomas (OAL) treated with corticosteroids before biopsy. OBSERVATIONS: This was a case series of two patients: a 47-year-old woman and a 43-year-old man, who both presented with impaired visual acuity and ophthalmoplegia of the involved eyes. Both patients had previously received non-diagnostic biopsy and had been subsequently treated with corticosteroids. The visual acuity and ophthalmoplegia progressively worsened after a variable duration of remission. Ocular magnetic resonance imaging revealed gadolinium-enhancing intra- and extraconal lesions. Systemic evaluations did not reveal any other lesions outside of the orbit. Differential diagnoses were lymphoproliferative disorders, including undiagnosed primary OALs, and idiopathic ocular inflammation. Both patients were exposed to repeated biopsies. The biopsied tissue demonstrated marked lymphocytolysis due to corticosteroid usage; therefore, histology and immunophenotype were non-diagnostic. EuroClonality/BIOMED-2 PCR-based gene rearrangement analyses detected genetic clonalities of Ig and TCR and suggested diagnoses of primary OALs of B-cell and T-cell origins, respectively. An OAL of B-cell origin was treated with radiotherapy; an OAL of a rare T-cell origin was treated with high-dose methotrexate-based chemotherapy and adjuvant radiotherapy. Both patients remained progression free for more than 36 months. CONCLUSIONS AND IMPORTANCE: PCR-based gene rearrangement analysis can be of limited usefulness in suggesting a diagnosis of primary OAL in patients receiving pre-biopsy corticosteroid treatment. Identification of genetic clonality is of clinical importance to provide treatment options for undiagnosed OALs.

Morphological Patterns of the Anterior Median Fissure in the Cervical Spinal Cord Evaluated by Computed Tomography After Myelography.

OBJECTIVE: Computed tomography following myelography (CTM) revealed an unusual flow of contrast dye into the anterior median fissure (AMF) in a patient with cervical spondylotic myelopathy. Since then, several AMF configurations have been observed on CTM. Therefore, we evaluated morphological patterns of the AMF on CTM and investigated the significance and mechanisms of contrast dye flow into the AMF. METHODS: Morphological patterns of the AMF on CTM were examined in 79 patients. Group A (24 patients) underwent surgery because of symptomatic cervical myelopathy. Group B (43 patients) had no clinical symptoms but showed spinal cord compression on CTM. Group C (12 patients), who showed neither clinical symptoms nor cord changes, underwent CTM for lumbar lesion evaluation. AMF patterns were classified into 4 types according to their configurations on CTM (reversed T, Y, V, and O types). RESULTS: In group B, the reversed T type and Y type appeared significantly more often near the compressed portion (p<0.001). A similar tendency was seen in group A. The V and O types were most frequently observed in group C (p<0.001). CONCLUSION: On CTM, contrast dye tends to flow into the AMF of the cervical cord when the spinal cord is compressed. We speculate that there may be 3 possible mechanisms for this phenomenon: deformation of the epipial layer of the AMF due to cervical cord compression, AMF dilatation due to atrophy of the anterior funiculus or anterior horn, and temporary AMF dilatation when it becomes an alternative route for cerebrospinal fluid circulation.

Anticoagulant therapy for recurrent in-stent thrombosis following carotid artery stenting: A case report.

We report a case in which strict anticoagulant therapy management was useful for a recurrent in-stent thrombosis after carotid artery stenting (CAS). An 84-year-old man presented with cognitive decline that progressed rapidly over two months. Head magnetic resonance imaging showed an acute-stage infarct occurring frequently in the right cerebral hemisphere, and he underwent hospitalization and treatment. On neck magnetic resonance angiography (MRA), severe stenosis was found at the origin of the right internal carotid artery. Since he took aspirin, clopidogrel, and a statin after placement of an indwelling coronary stent, we treated him by adding argatroban and edaravone drip therapy to his existing medication. CAS was performed on day 15 of the hospitalization. A small in-stent thrombosis with plaque protrusion was observed on a carotid sonogram performed at the second day after CAS, and re-examination at the seventh day confirmed enlargement of the lesion and an increase in peak systolic velocity; thus, a second CAS procedure was performed on the same day. After the second CAS, oral cilostazol was added for triple antiplatelet therapy (TAPT), but as the in-stent thrombosis increased further, we started a continuous infusion of heparin with the goal of an activated partial thromboplastin time (APTT) of 50 to 65 seconds. After starting heparin, the lesion did not progress; after 14 days of continuous heparin infusion, the patient was switched to TAPT, and regression of the plaque was confirmed. This case demonstrated to us that controlled anticoagulation therapy can be an effective treatment for cases in which a thrombus recurs within a stent after CAS.

Current Status of Lumbar Interbody Fusion for Degenerative Spondylolisthesis.

Instrumented lumbar fusion can provide immediate stability and assist in satisfactory arthrodesis in patients who have pain or instability of the lumbar spine. Lumbar adjunctive fusion with decompression is often a good procedure for surgical management of degenerative spondylolisthesis (DS). Among various lumbar fusion techniques, lumbar interbody fusion (LIF) has an advantage in that it maintains favorable lumbar alignment and provides successful fusion with the added effect of indirect decompression. This technique has been widely used and represents an advancement in spinal instrumentation, although the rationale and optimal type of LIF for DS remains controversial. We evaluated the current status and role of LIF in DS treatment, mainly as a means to augment instrumentation. We addressed the basic concept of LIF, its indications, and various types including minimally invasive techniques. It also has acceptable biomechanical features, and offers reconstruction with ideal lumbar alignment. Postsurgical adverse events related to each LIF technique are also addressed.