Real-world safety of nusinersen in Japan: results from an interim analysis of a post-marketing surveillance and safety database.

PURPOSE: Nusinersen is the first disease-modifying therapy to treat spinal muscular atrophy (SMA). This report describes the safety and effectiveness of nusinersen in Japanese clinical use using two data sources: an ongoing Japanese post-marketing surveillance (PMS) and the safety database of the marketing authorisation holder, Biogen . MATERIALS AND METHODS: The PMS is evaluating the safety and effectiveness of nusinersen in all patients treated with nusinersen in Japan between August 2017 and August 2025; this interim analysis included data up to May 30, 2019. Biogen safety database data up to June 30, 2019 were also included to capture adverse events (AEs) from after the interim analysis cutoff date. Collected data included medical history, dosage and administration, and AEs. Safety assessment included AEs and serious AEs (SAEs). Effectiveness analyses included motor function assessments and clinical global impressions of improvement. RESULTS: Of 271 patients in the PMS population, 94 had SMA type I (34.7%), and 177 had SMA types II-IV (65.3%). AEs occurred in 67 patients (24.7%) and SAEs in 23 patients (8.5%). The Biogen safety database contained reports of 345 AEs; the most common were pneumonia, headache, and pyrexia, consistent with symptoms of SMA and lumbar puncture. In the analysis set, 26.2% of patients receiving nusinersen showed motor function improvements and 99.6-100.0% showed overall improvement. CONCLUSION: In this interim analysis of the PMS and Biogen safety database, nusinersen had a favourable benefit-risk profile in Japanese patients with SMA.

Generation of neuropeptidergic hypothalamic neurons from human pluripotent stem cells.

Hypothalamic neurons orchestrate many essential physiological and behavioral processes via secreted neuropeptides, and are relevant to human diseases such as obesity, narcolepsy and infertility. We report the differentiation of human pluripotent stem cells into many of the major types of neuropeptidergic hypothalamic neurons, including those producing pro-opiolemelanocortin, agouti-related peptide, hypocretin/orexin, melanin-concentrating hormone, oxytocin, arginine vasopressin, corticotropin-releasing hormone (CRH) or thyrotropin-releasing hormone. Hypothalamic neurons can be generated using a 'self-patterning' strategy that yields a broad array of cell types, or via a more reproducible directed differentiation approach. Stem cell-derived human hypothalamic neurons share characteristic morphological properties and gene expression patterns with their counterparts in vivo, and are able to integrate into the mouse brain. These neurons could form the basis of cellular models, chemical screens or cellular therapies to study and treat common human diseases.

The use of 5-aminolevulinic acid to assist gross total resection of pediatric astroblastoma.

PURPOSE: Astroblastoma is an uncommon pediatric neuroepithelial tumor. The prognosis and appropriate treatment of astroblastoma were not well understood. Previous reports suggested the best treatment for astroblastoma is surgical total resection. The authors report a case of pediatric astroblastoma that underwent gross total resection with the use of fluorescent guidance by 5-aminolevulinic acid (5-ALA). CASE REPORT: A 13-year-old girl presented with the tumor that was well-circumscribed cystic and solid mass with marked gadolinium enhancement in the right occipital lobe. At surgery, fluorescence of the tumor was clearly distinctive from the normal cerebral tissue. All fluorescent tissue including residual cyst wall was removed. Postoperative MRI showed gross total resection of the tumor. No serious side effect or complications occurred. The histopathologic diagnosis was suggestive of astroblastoma. The patients had no evidence of recurrence of tumor without adjuvant radiotherapy during the last 1 year of follow-up time. CONCLUSION: 5-ALA is useful to achieve gross total resection including cystic lesion of pediatric astroblastoma. A larger prospective study is warranted to establish the use of 5-ALA in pediatric brain tumor.

Self-formation of functional adenohypophysis in three-dimensional culture.

The adenohypophysis (anterior pituitary) is a major centre for systemic hormones. At present, no efficient stem-cell culture for its generation is available, partly because of insufficient knowledge about how the pituitary primordium (Rathke's pouch) is induced in the embryonic head ectoderm. Here we report efficient self-formation of three-dimensional adenohypophysis tissues in an aggregate culture of mouse embryonic stem (ES) cells. ES cells were stimulated to differentiate into non-neural head ectoderm and hypothalamic neuroectoderm in adjacent layers within the aggregate, and treated with hedgehog signalling. Self-organization of Rathke's-pouch-like three-dimensional structures occurred at the interface of these two epithelia, as seen in vivo, and various endocrine cells including corticotrophs and somatotrophs were subsequently produced. The corticotrophs efficiently secreted adrenocorticotropic hormone in response to corticotrophin releasing hormone and, when grafted in vivo, these cells rescued the systemic glucocorticoid level in hypopituitary mice. Thus, functional anterior pituitary tissue self-forms in ES cell culture, recapitulating local tissue interactions.

Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis.

BACKGROUND: Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner. METHODS: We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (<1·5 cm(2) tumour remaining), or sub-total resection (≥1·5 cm(2) tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs ≥3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival. FINDINGS: We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07-1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87-1·72, p=0·24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1·05, 0·71-1·53, p=0·8158 for progression-free survival and HR 1·14, 0·75-1·72, p=0·55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1·03, 0·67-1·58, p=0·89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1·97, 1·22-3·17, p=0·0056), especially for those with metastatic disease (HR 2·22, 1·00-4·93, p=0·050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1·67, 0·93-2·99, p=0·084). INTERPRETATION: The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection. FUNDING: Canadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research.

Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis.

BACKGROUND: Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. METHODS: We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. FINDINGS: Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. INTERPRETATION: An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours. FUNDING: C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.

A role for matrix remodelling proteins in invasive and malignant meningiomas.

AIMS: Meningiomas are one of the most common brain tumours in adults. Invasive and malignant meningiomas present a significant therapeutic challenge due to high recurrence rates and invasion into surrounding bone, brain, neural and soft tissues. Understanding the molecular mechanism of invasion could help in designing novel therapeutic approaches in order to prevent the need for repeat surgery, decrease morbidity and improve patient survival. The aim of this study was to identify the key factors and underlying mechanisms which govern invasive properties of meningiomas. METHODS: Formalin-fixed paraffin-embedded (FFPE) as well as frozen tumour tissues from bone-invasive, non-invasive and malignant meningiomas were used for RNA microarray, quantitative real-time PCR or Western blot analyses. Malignant meningioma cell lines (F5) were subject to MMP16 downregulation or overexpression and used for in vitro and in vivo functional assays. Subdural xenograft meningioma tumours were generated to study the invasion of tumour cells into brain parenchyma using cell lines with altered MMP16 expression. RESULTS: We establish that the expression level of MMP16 was significantly elevated in both bone-invasive and brain invasive meningiomas. Gain- and loss-of-function experiments indicated a role for MMP16 in meningioma cell movement, invasion and tumour cell growth. Furthermore, MMP16 was shown to positively regulate MMP2, suggesting this mechanism may modulate meningioma invasion in invasive meningiomas. CONCLUSIONS: Overall, the results support a role for MMP16 in promoting invasive properties of the meningioma tumours. Further studies to explore the potential value for clinical use of matrix metalloproteinases inhibitors are warranted.

Germinoma in the bilateral basal ganglia presented with cognitive deterioration.

PURPOSE: Here, we report a case of pediatric germinoma located in the bilateral basal ganglia, which presented with severe cognitive deteriorations. CASE REPORT: A 15-year-old boy presented with decreased school performance and mild cognitive disturbances. Magnetic resonance images (MRI) of the brain revealed T2 hyperintensity in the bilateral basal ganglia. The patient was initially observed by a local hospital and had screening for metabolic diseases or inflammatory diseases. Lesions with similar characteristics were also found in the pituitary stalk and infundibulum, and these lesions were enhanced with gadolinium (Gad). MR spectroscopy suggested that these should be neoplastic lesions other than metabolic or inflammatory diseases. Biopsy was performed with ventriculoscope, which proved all lesions of infundibulum, pineal, and basal ganglia were pathologically germinoma. The lesions responded well to the chemotherapy and radiation, and his cognitive function improved significantly. CONCLUSION: A case of germinoma in the bilateral basal ganglia which significantly affect cognitive functions is reported. Differential diagnoses of cognitive symptoms are various, but germinoma could be considered as a possible pathology for it. Early MRI and tumor marker exams are recommended, unless organic brain diseases are completely denied. MR spectroscopy and biopsy with ventriculoscope are useful for diagnosis.

[Molecular subgrouping and characterization analysis of medulloblastomas in a cohort of Japanese patients].

Medulloblastoma is the most common solid malignancy and cause of oncologic death among children. Recent advances in genomic analysis obtained through international large-scale collaborations, Medulloblastoma Advanced Genomics International Consortium(MAGIC), have revealed that medulloblastomas can be classified into at least four distinct subgroups depending on their molecular expression profiles. These studies showed that the prognosis, age distributions, and molecular mechanisms of these subgroups of medulloblastomas completely differ from each other. Here we report the first analysis of molecular subgroups of medulloblastoma in Japanese patients(Shizuoka cohort). Molecular subgroups were predicted for 18 medulloblastomas;and age distributions, radiographic features, and histological characteristics were analyzed. It was predicted that 11% of the medulloblastomas were of the WNT type, 50% of the SHH type, 6% of the group 3 type, and 33% of the group 4 type. The percentage of group 3 type medulloblastomas was smaller than in the MAGIC study, while the percentage of the SHH type was larger. However, age distribution, recurrence-free survival, and overall survival for each group were quite similar to the MAGIC study. In addition, in an imaging study, 78% of patients with medulloblastomas of the SHH type presented tumors in the cerebellar hemispheres. The classical pathohistological hallmarks that may predict medulloblastoma prognosis were mainly seen in tumors of the SHH type. Molecular subgrouping of medulloblastomas could be important in the future, not only for prediction of prognosis, but also for decision making regarding the use of future new treatments such as molecular targeting therapy. The establishment of a public molecular analysis system of medulloblastomas in Japan is greatly desired, and it is currently under development;this database will help establish the molecular diagnosis of medulloblastomas in Japan.

Bone Flap Preservation in Subcutaneous Abdominal Pocket for Decompressive Craniectomy.

We report our experiences of two pediatric cases in which a bone flap was preserved in the subcutaneous abdominal pocket for decompressive craniectomy. In one case, the bone flap was divided and preserved for cranioplasty without complications; in the other case, the bone flap was left intact as one piece. In pediatric patients, the storage space for a bone flap is sometimes difficult to achieve, and the technique described herein is useful in such situations. Notably, because the bone resorption rate with cryopreservation is higher in pediatric patients, in vivo preservation may be more useful in this population.

Minimization of exogenous signals in ES cell culture induces rostral hypothalamic differentiation.

Embryonic stem (ES) cells differentiate into neuroectodermal progenitors when cultured as floating aggregates in serum-free conditions. Here, we show that strict removal of exogenous patterning factors during early differentiation steps induces efficient generation of rostral hypothalamic-like progenitors (Rax(+)/Six3(+)/Vax1(+)) in mouse ES cell-derived neuroectodermal cells. The use of growth factor-free chemically defined medium is critical and even the presence of exogenous insulin, which is commonly used in cell culture, strongly inhibits the differentiation via the Akt-dependent pathway. The ES cell-derived Rax(+) progenitors generate Otp(+)/Brn2(+) neuronal precursors (characteristic of rostral-dorsal hypothalamic neurons) and subsequently magnocellular vasopressinergic neurons that efficiently release the hormone upon stimulation. Differentiation markers of rostral-ventral hypothalamic precursors and neurons are induced from ES cell-derived Rax(+) progenitors by treatment with Shh. Thus, in the absence of exogenous growth factors in medium, the ES cell-derived neuroectodermal cells spontaneously differentiate into rostral (particularly rostral-dorsal) hypothalamic-like progenitors, which generate characteristic hypothalamic neuroendocrine neurons in a stepwise fashion, as observed in vivo. These findings indicate that, instead of the addition of inductive signals, minimization of exogenous patterning signaling plays a key role in rostral hypothalamic specification of neural progenitors derived from pluripotent cells.

GLI3 Is Associated With Neuronal Differentiation in SHH-Activated and WNT-Activated Medulloblastoma.

Glioma-associated oncogene homolog 3 (GLI3), whose main function is to inhibit GLI1, has been associated with neuronal differentiation in medulloblastoma. However, it is not clear what molecular subtype(s) show increased GLI3 expression. GLI3 levels were assessed by immunohistochemistry in 2 independent cohorts, including a total of 88 cases, and found to be high in both WNT- and SHH-activated medulloblastoma. Analysis of bulk mRNA expression data and single cell RNA sequencing studies confirmed that GLI1 and GLI3 are highly expressed in SHH-activated medulloblastoma, whereas GLI3 but not GLI1 is highly expressed in WNT-activated medulloblastoma. Immunohistochemical analysis has shown that GLI3 is expressed inside the neuronal differentiated nodules of SHH-activated medulloblastoma, whereas GLI1/2 are expressed in desmoplastic areas. In contrast, GLI3 is diffusely expressed in WNT-activated medulloblastoma, whereas GLI1 is suppressed. Our data suggest that GLI3 may be a master regulator of neuronal differentiation and morphology in these subgroups.

A ROCK inhibitor permits survival of dissociated human embryonic stem cells.

Poor survival of human embryonic stem (hES) cells after cell dissociation is an obstacle to research, hindering manipulations such as subcloning. Here we show that application of a selective Rho-associated kinase (ROCK) inhibitor, Y-27632, to hES cells markedly diminishes dissociation-induced apoptosis, increases cloning efficiency (from approximately 1% to approximately 27%) and facilitates subcloning after gene transfer. Furthermore, dissociated hES cells treated with Y-27632 are protected from apoptosis even in serum-free suspension (SFEB) culture and form floating aggregates. We demonstrate that the protective ability of Y-27632 enables SFEB-cultured hES cells to survive and differentiate into Bf1(+) cortical and basal telencephalic progenitors, as do SFEB-cultured mouse ES cells.

Significance of molecular classification of ependymomas: C11orf95-RELA fusion-negative supratentorial ependymomas are a heterogeneous group of tumors.

Extensive molecular analyses of ependymal tumors have revealed that supratentorial and posterior fossa ependymomas have distinct molecular profiles and are likely to be different diseases. The presence of C11orf95-RELA fusion genes in a subset of supratentorial ependymomas (ST-EPN) indicated the existence of molecular subgroups. However, the pathogenesis of RELA fusion-negative ependymomas remains elusive. To investigate the molecular pathogenesis of these tumors and validate the molecular classification of ependymal tumors, we conducted thorough molecular analyses of 113 locally diagnosed ependymal tumors from 107 patients in the Japan Pediatric Molecular Neuro-Oncology Group. All tumors were histopathologically reviewed and 12 tumors were re-classified as non-ependymomas. A combination of RT-PCR, FISH, and RNA sequencing identified RELA fusion in 19 of 29 histologically verified ST-EPN cases, whereas another case was diagnosed as ependymoma RELA fusion-positive via the methylation classifier (68.9%). Among the 9 RELA fusion-negative ST-EPN cases, either the YAP1 fusion, BCOR tandem duplication, EP300-BCORL1 fusion, or FOXO1-STK24 fusion was detected in single cases. Methylation classification did not identify a consistent molecular class within this group. Genome-wide methylation profiling successfully sub-classified posterior fossa ependymoma (PF-EPN) into PF-EPN-A (PFA) and PF-EPN-B (PFB). A multivariate analysis using Cox regression confirmed that PFA was the sole molecular marker which was independently associated with patient survival. A clinically applicable pyrosequencing assay was developed to determine the PFB subgroup with 100% specificity using the methylation status of 3 genes, CRIP1, DRD4 and LBX2. Our results emphasized the significance of molecular classification in the diagnosis of ependymomas. RELA fusion-negative ST-EPN appear to be a heterogeneous group of tumors that do not fall into any of the existing molecular subgroups and are unlikely to form a single category.

Thoracic meningocele in lumbo-costo-vertebral syndrome in a child: possible enlargement with repeated motion by anchoring to the diaphragm.

Lumbo-costo-vertebral syndrome (LCVS) is a rare disorder in children that is characterized by hemivertebrae, congenital absence of ribs, meningocele, and hypoplasia of the truncal and abdominal wall presenting as a congenital lumbar hernia. An otherwise healthy 12-month-old girl was referred to the authors' hospital with soft swelling on her left middle back; scoliosis had been present since birth. Imaging revealed a thoracic meningocele, ectopia of the spleen suggesting lumbar hernia, multiple anomalies of the thoracic vertebral columns, and defects of the ribs; thus, LCVS was diagnosed. Surgical observation revealed that the meningocele was firmly anchored to part of the diaphragm, which created stretching tension in the meningocele continuously with exhalation. Once detached, the meningocele shrank spontaneously and never developed again after cauterization. In this case, continuous or pulsatile pressure in the presence of a vertebral defect was thus considered to be an important factor for formation of the thoracic meningocele.

Surgical clipping of a recurrent small saccular aneurysm after repeated coil embolization.

A 59-year-old healthy woman presented with sudden onset of severe headache. Computed tomography and digital subtraction angiography (DSA) demonstrated subarachnoid hemorrhage (grade I according to the Hunt and Hess classification) due to a ruptured small right posterior cerebral artery (PCA) aneurysm. The ruptured PCA aneurysm was completely embolized with three Guglielmi detachable coils (GDCs). However, follow-up DSA 3 months after the initial coiling confirmed refilling of the aneurysm. The aneurysm was successfully re-embolized with two GDCs. Follow-up DSA 10 months later revealed regrowth of the aneurysm. Surgical clipping was performed without compromising the parent vessels. Long-term angiographic follow up is necessary even in patients with small saccular aneurysms which are apparently completely embolized by endovascular coil treatment.

[Noninvasive carotid plaque characterization by black blood MRI].

Management of atherosclerotic carotid arteries requires both plaque characterization and determination of the degree of stenosis, especially when carotid stenting (CAS) is being considered for severe carotid stenosis. Recent studies have demonstrated that high-resolution MRI can identify plaque components, such as the lipid-rich necrotic core, intraplaque hemorrhage, fibrous tissue, and the calcification present in human carotid atherosclerosis. The purpose of this study was to assess the feasibility of black blood MRI (BB-MRI) for accurately identifying the plaque components in vivo. Twenty-six consecutive patients scheduled for carotid endarterectomy (CEA) underwent a BB-MRI examination within 2 weeks before the surgical procedure using a 1.5-T Philips scanner with a protocol that generated 2 contrast weightings (T1 and T2). The MR images were acquired using cardiac gating to minimize motion artifact and fat suppression to reduce MR signals from subcutaneous fatty tissue. The plaque evaluations obtained by BB-MRI were compared with the intra-operative video recordings, the excised specimens, and the histological sections. With BB-MRI, the combination of the signal intensities in the T1- and T2-weighted images for each component (lipid deposits, intra-plaque hemorrhage, fibrous plaque, and calcification) showed findings that corresponded with the excised specimens. Complex morphological features could also be assessed by BB-MRI. BB-MRI is a useful method for noninvasively imaging and characterizing atherosclerotic carotid arteries. This MRI technique can provide valuable information that can be used to decide whether to perform a CEA or a CAS in patients with severe carotid stenosis. Furthermore, BB-MRI appears to be a useful tool for the investigation of the pathogenesis and natural history of carotid atherosclerosis.

[Bilateral vertebral artery dissection and its chronological changes detected by MR angiography: a case report].

A case of intracranial bilateral vertebral artery (VA) dissection presenting with ischemic symptoms which following unilateral dissection is presented. A 42-year-old male with an occipital headache was pointed out right vertebral artery stenosis with magnetic resonance (MR) angiography 8 day before admission. He admitted to our hospital complaining of severe vertigo and tinnitus. MR images and cerebral angiograms revealed bilateral VA dissection with infarcts in light lower surface of cerebellum perfused by posterior inferior cerebellar artery and right hypothalamus. Conservative therapy was adopted and serial MR angiography was performed. His symptoms were improved gradually and MR angiograms obtained 2 months later revealed improvement of bilateral VA stenosis. It is generally accepted that VA dissection presenting ischemic symptoms has good outcome by conservative therapy only. However, its pathological process of progression is still unknown. Based on the serial MR findings, we discuss the mechanisms of bilateral VA dissection. In this case, we consider that unilateral VA dissection extended to contralateral vertebral artery through the vertebrobasilar junction. Frequent MR angiography in acute phase could be of great use for monitoring the progression of dissection.