Cognitive impairment due to widespread enlarged perivascular spaces.

Perivascular spaces, also known as Virchow-Robin spaces, are usually considered as a normal, asymptomatic finding. However, this finding can occasionally demonstrate an atypical appearance and can be symptomatic. We report herein a rare case of cognitive impairment associated with extremely enlarged perivascular spaces. A 68-year-old Japanese woman visited our hospital with a 1-year history of progressive memory impairment. In addition to temporal disorientation and short-term memory impairment, neuropsychological testing showed frontal lobe-related symptoms such as slowed thinking processes, reduced verbal fluency, attention deficit, and reduced working memory. Magnetic resonance imaging of the brain showed widespread enlarged perivascular spaces almost symmetrically in the subcortical white matter of bilateral hemispheres, prominently in bilateral insulas, and frontal opercula. On 99mTc-ethyl cysteinate dimer single photon emission computed tomography, hypoperfusion was apparent in bilateral insulas and frontal opercula where enlarged periventricular spaces were prominent, whereas cerebral perfusion was preserved in areas where enlargement of perivascular spaces was mild or absent. Because symptoms were consistent with the distribution of the enlarged perivascular spaces and hypoperfusion in the brain, cognitive impairment due to enlarged perivascular spaces was diagnosed. Clinicians should note enlarged perivascular spaces as a potential cause of neurological deficits including cognitive impairment.

Atezolizumab-associated Dermatomyositis in Advanced Small-cell Lung Carcinoma.

Dermatomyositis is a rare immune-related adverse event caused by immune checkpoint inhibitors. We herein report a 75-year-old Japanese man with small-cell lung carcinoma who developed dermatomyositis after the administration of atezolizumab. He developed rashes on day 13 and myalgia and motor weakness on day 30 of the first administration of atezolizumab. Anti-transcriptional intermediary factor 1-gamma antibody was positive, and serum interleukin-6 levels were prominently elevated in the acute phase. Symptoms were improved by corticosteroid therapy. This is the first report of dermatomyositis associated with atezolizumab. Clinicians should be aware of the possibility of dermatomyositis after the administration of immune checkpoint inhibitors.

Atezolizumab-associated encephalitis in metastatic lung adenocarcinoma: a case report.

BACKGROUND: In recent years, immune checkpoint inhibitors have been widely used as a crucial therapy in malignant tumors. Immune checkpoint inhibitors can cause various autoimmune side effects called immune-related adverse events because they generate an exaggerated inflammatory response. Encephalitis associated with atezolizumab has rarely been reported as an immune-related adverse event. A case of encephalitis caused by treatment with atezolizumab is presented. CASE PRESENTATION: A 56-year-old Japanese man with lung cancer previously treated with surgery and chemotherapy was admitted with high fever, consciousness disorder, and motor aphasia. His first atezolizumab treatment was 17 days earlier. Admission brain magnetic resonance imaging with gadolinium enhancement showed no abnormalities. Cerebrospinal fluid showed cell count 20/l, protein 166 mg/dl, glucose 73 mg/dl, and interleukin 6 82.9 pg/ml (normal< 8.7 pg/ml). Atezolizumab-induced encephalitis was diagnosed. His symptoms improved the day after steroid pulse therapy was started. Following steroid pulse therapy, oral prednisolone 30 mg was started and tapered. The cerebrospinal fluid findings normalized on day 14. He was discharged on day 16 without neurological sequelae. CONCLUSION: In this case of encephalitis associated with atezolizumab, prompt steroid pulse therapy led to a successful response, and the outcome was good. The cerebrospinal fluid level of interleukin 6 reflected the severity of the encephalitis well. Clinicians should be aware of the possibility of encephalitis after initiation of immune checkpoint inhibitors.

Clinical and radiological diversity in genetically confirmed primary familial brain calcification.

Primary familial brain calcification (PFBC) is a rare neuropsychiatric disorder with characteristic symmetrical brain calcifications. Patients with PFBC may have a variety of symptoms, although they also may be clinically asymptomatic. Parkinsonism is one of the most common movement disorders; however, the underlying mechanism remains unclear. This condition is typically transmitted in an autosomal dominant fashion. To date, mutations in SLC20A2, PDGFRB, PDGFB, and XPR1 have been reported to cause PFBC. The aim of the study was to identify the genetic cause of brain calcification in probands from three PFBC families and in 8 sporadic patients and to perform clinical and radiological assessments focusing on parkinsonism in mutation carriers. Three familial PFBC probands and their relatives and eight sporadic patients affected with brain calcifications were enrolled in this study. Whole-exome sequencing identified three novel mutations: c.269G > T, p.(Gly90Val) and c.516+1G > A in SLC20A2 in familial cases, and c.602-1G > T in PDGFB in a sporadic patient. The c.516+1G > A mutation resulted in exon 4 skipping in SLC20A2 (p.Val144Glyfs*85). Dopamine transporter single photon emission computed tomography using 123I-ioflupane and 123I-metaiodobenzylguanidine cardiac scintigraphy revealed pre-synaptic dopaminergic deficit and cardiac sympathetic nerve dysfunction in two SLC20A2-related PFBC patients with parkinsonism.

Whole-exome sequencing and digital PCR identified a novel compound heterozygous mutation in the NPHP1 gene in a case of Joubert syndrome and related disorders.

BACKGROUND: Joubert syndrome and related disorders (JSRD) is a clinically and genetically heterogeneous condition with autosomal recessive or X-linked inheritance, which share a distinctive neuroradiological hallmark, the so-called molar tooth sign. JSRD is classified into six clinical subtypes based on associated variable multiorgan involvement. To date, 21 causative genes have been identified in JSRD, which makes genetic diagnosis difficult. CASE PRESENTATION: We report here a case of a 28-year-old Japanese woman diagnosed with JS with oculorenal defects with a novel compound heterozygous mutation (p.Ser219*/deletion) in the NPHP1 gene. Whole-exome sequencing (WES) of the patient identified the novel nonsense mutation in an apparently homozygous state. However, it was absent in her mother and heterozygous in her father. A read depth-based copy number variation (CNV) detection algorithm using WES data of the family predicted a large heterozygous deletion mutation in the patient and her mother, which was validated by digital polymerase chain reaction, indicating that the patient was compound heterozygous for the paternal nonsense mutation and the maternal deletion mutation spanning the site of the single nucleotide change. CONCLUSION: It should be noted that analytical pipelines that focus purely on sequence information cannot distinguish homozygosity from hemizygosity because of its inability to detect large deletions. The ability to detect CNVs in addition to single nucleotide variants and small insertion/deletions makes WES an attractive diagnostic tool for genetically heterogeneous disorders.

Inflammatory Pseudotumor of the Brain Parenchyma with IgG4 Hypergammaglobulinemia.

A 58-year-old woman with a 1-month history of right hand clumsiness and speaking difficulty was admitted to our hospital. A neurological examination revealed sensory aphasia and right hemiparesis. Her laboratory tests showed elevated serum levels of IgG and IgG4, pancytopenia, and liver dysfunction. The results of the imaging studies of her abdomen were compatible with sclerosing cholangitis. Brain MRI showed extensive signal abnormalities in the left hemisphere on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images, extending from left internal capsule to the cerebral peduncle with an irregularly enhancing lesion in the left parietal lobe. A brain biopsy revealed lymphocyte and plasma cell infiltration and reactive gliosis. Most of the plasma cells were IgG positive; however, IgG4-positive plasma cells were sparsely observed. After the initiation of betamethasone treatment, her symptoms and the brain MRI abnormalities showed significant improvement. The brain biopsy results did not meet the current criteria of IgG4-related disease. This is the first reported case of a tumefactive lesion of the brain parenchyma with serum IgG4 elevation, which was responsive to steroid treatment. The accumulation of a greater number of reports on the pathological investigation of cases of possible IgG4-related disease may help to elucidate the exact role of IgG4 in IgG4-related disorders.

Lymphomatosis cerebri with intramedullary spinal cord involvement.

Lymphomatosis cerebri (LC) is a rare form of primary central nervous system lymphoma (PCNSL). Little is known about cases of LC with spinal cord involvement. Among the 11 PCNSL patients treated in our hospital during a four-year period, we identified two cases of LC with spinal cord lesions. One showed a spinal cord lesion followed by leukoencephalopathy. The other showed a spinal cord lesion after LC. In both cases, the histopathology was diffuse large B-cell lymphoma. It is possible that LC may affect the entire central nerve system, and tumor infiltration to the brain and spinal cord in LC may occur more frequently than has been previously considered.

[A case of inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) showing clinical features of motor neuron disease].

Inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) is caused by mutations in the valosin-containing protein (VCP) gene. Varied clinical features caused by VCP mutations have been reported: these clinical phenotypes include distal myopathy, frontotemporal dementia and amyotrophic lateral sclerosis. We report a 49-year-old woman with 3-year history of progressive proximal limb muscle weakness. Family history was notable for her father with motor neuron disease and an elder brother with a myopathy involving tibialis anterior and quadriceps. Neurological examinations showed proximal muscle atrophy, especially severe atrophy of paravertebral muscles, right-dominant scapular winging, bilateral pyramidal signs and hyperreflexia. Serum CK level was normal and EMG showed chronic neurogenic changes. Muscle imaging (CT) showed adipose tissue replacement of paravertebral muscles and right serratus anterior, and marked atrophy of bilateral trapezius and vastus intermedius muscles. Her lumbar spine X-ray showed an osteosclerotic change in the vertebral body, where an increased uptake of Tc99m was also observed in bone scintigraphy. Although brain MRI was normal, neuropsychological examination showed a mild attention deficit with cognitive impairment. A muscle biopsy specimen revealed scattered fibers with rimmed vacuoles. These findings prompted us to analyze a mutation in the VCP gene. Genomic sequencing of all exons of the gene showed a heterozygous missense mutation in exon 5 (c.1315G>C; p.Ala439Pro).

Marked improvement in opsoclonus and cerebellar ataxia after the surgical removal of a squamous cell carcinoma of the thymus: a case report.

A 69-year-old man with rapidly evolving vertigo and ataxia was admitted to our hospital. He was presented with a dysarthric speech and chaotic eye movements, identified as opsoclonus. Neurological examination revealed limb and truncal ataxias and an inability to stand unless fully assisted. A chest CT scan revealed a mass at the anterior mediastinum, which suggested paraneoplastic neurological syndrome (PNS). However, an extensive search for anti-neuronal antibodies linked to cerebellar ataxia failed to find any autoantibodies, including cell surface autoantibodies. Subsequently, a total surgical removal of the thymic tumor was performed, leading to marked improvements in his signs and symptoms. The pathological findings by conventional and immunohistochemical examinations confirmed a squamous cell carcinoma of the thymus. Three months after onset his signs and symptoms improved and he was able to walk without support. In contrast to thymomas, PNS is extremely rare in patients with thymic carcinoma. Previous reports have shown that neurological symptoms, similar to opsoclonus or cerebellar ataxia, deteriorated in cases of thymic carcinoma that could not be controlled. The present report indicates that early diagnosis and total removal of the rare neoplasm may increase the possibility of neurological recovery.

[Case of acute limbic encephalitis associated with SLE accompanied with anti-glutamate receptor antibodies].

A 23-year-old woman was admitted to our hospital because of consciousness disturbance and convulsion, preceded by high fever, headache and erythema multiforme. Her brain magnetic resonance images showed hyperintense lesions in the left medial temporal lobe and the left pulvinar nucleus of the thalamus on fluid attenuated inversion recovery images. Analysis of cerebrospinal fluid showed mild pleocytosis, but DNA of herpes simplex or herpes type 6 viruses was negative on PCR. Laboratory investigations showed the presence of anti-nuclear antibodies, anti-RNP antibodies and lupus anticoagulant. The clinical diagnosis was made as acute limbic encephalitis associated with SLE, and subsequent administration of prednisolone improved her conditions. In her serum and cerebrospinal fluid, anti-glutamate receptor (ε2, δ2, ζ1) antibodies were detected, and the titers of the antibodies decreased as the symptoms improved. Although the mechanism underlying limbic encephalitis associated with SLE remains unclear, at least in some cases, the anti-glutamate antibodies may play an important role in the pathogenesis of limbic encephalitis with SLE.

An elderly Japanese patient with adult-onset type II citrullinemia with a novel D493G mutation in the SLC25A13 gene.

Mutations in the SLC25A13 gene lead to neonatal intrahepatic cholestasis caused by citrin deficiency and/or adult-onset type II citrullinemia (CTLN2). A 62-year-old man presented with recurrent episodes of neuropsychiatric manifestations. On admission, he had disorientation and flapping tremor. Laboratory data showed hyperferritinemia in addition to postprandial hyperammonemia and citrullinemia. A liver biopsy specimen revealed moderate hemosiderin deposits and hepatocytes with macrovesicular fat droplets. Genetic analysis of the SLC25A13 gene identified the previously reported p.S225X mutation and a novel p.D493G mutation. Hyperferritinemia might also be a characteristic finding of CTLN2-related fatty changes of the liver.

A Japanese adult case of megalencephalic leukoencephalopathy with subcortical cysts with a good long-term prognosis.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a recently recognized neurological disease, and mutations in the MLC1 gene have been identified as the cause of the disorder. A 54-year-old Japanese woman with macrocephaly presented with progressive mental decline, gait disturbance due to spasticity and ataxia, and choreoathetotic movement in the left upper extremity. Brain magnetic resonance imaging (MRI) revealed characteristic subcortical cysts in addition to diffuse white matter involvement. Genetic analysis of the MLC1 gene identified an S93L mutation in a homozygous state. This case is particularly valuable because of the lack of knowledge on the long-term prognosis of MLC.

[A case of neurofibromatosis type 2 (NF2) presenting with late-onset axonal polyneuropathy].

The patient was a 69-year-old man who had a two-year history of slowly-progressive gait disturbance, paresthesia of the distal legs and bilateral hearing impairment. Nerve conduction study showed symmetric motor-dominant axonal polyneuropathy of the legs. Gadolinium-enhanced brain and spinal cord MRI revealed bilateral vestibular schwannomas, and multiple small schwannomas in the cauda equina, the surface of spinal cord and lumbar muscles. Genetic examination disclosed a point mutation in the exon 2 (T161C: L54P) of the neurofibromatosis 2 (NF2) gene, and the diagnosis of NF2 was made. It has been reported that axonal polyneuropathy is frequently observed in patients with NF2. Therefore, it is possible that axonal polyneuropathy of the present patient may be due to the abnormality of the NF2 gene, but not to the direct compression of the tumors, because the localization of his schwannomas in the cauda equina and the spinal cord could not explain his symmetric polyneuropathy. Although this patient showed no characteristic clinical manifestations such as cutaneous lesions, gadolinium-enhanced brain and spinal cord MRI was useful for the detection of asymptomatic schwannomas. NF2 should be considered as a differential diagnosis in patients with axonal polyneuropathy, even if it is late-onset.

Restoration of RUNX3 enhances transforming growth factor-beta-dependent p21 expression in a biliary tract cancer cell line.

RUNX3 is a candidate tumor suppressor gene localized in 1p36, a region commonly inactivated by deletion and methylation in various human tumors. To elucidate the role of RUNX3 in transforming growth factor (TGF)-beta signaling in biliary tract cancer, we transfected Mz-ChA-2 cells, which do not express RUNX3 but have intact TGF-beta type II receptor and SMAD4 genes, with the RUNX3 expression plasmid pcDNA3.1/RUNX3 or with the vector pcDNA3.1 as a control. Four Mz-ChA-2/RUNX3 clones and one control clone were obtained. Although TGF-beta1 only slightly inhibited growth of the control cells, growth inhibition and TGF-beta-dependent G(1) arrest were significantly enhanced in the RUNX3-transfected clones. None of the clones, however, exhibited apoptosis. The slightly increased TGF-beta1-induced p21 expression in the control clone was strongly enhanced in the RUNX3-transfected clones, and was accompanied by augmented decreases in the expression of cyclins D1 and E. When RUNX3 small interfering RNA was added, TGF-beta-dependent induction of p21 was reduced in the RUNX3-transfected clones. Xenografts of the clones in nude mice demonstrated that tumorigenicity was significantly decreased in the RUNX3-transfected clones in inverse proportion to the expression levels of RUNX3. Based on these results, RUNX3 is involved in TGF-beta-induced expression of p21 and the resulting induction of TGF-beta-dependent G(1) arrest.

[A case of non-herpetic acute limbic encephalitis associated with a type-2 adenovirus infection].

This is a report of a 31-year-old woman with non-herpetic acute limbic encephalitis following a type-2 adenovirus infection. The patient was admitted to a hospital with high fever, severe liver dysfunction, and thrombocytopenia. Six days after admission, she became afebrile, and her liver dysfunction was normalized by conservative therapy. However, the patient started to experience generalized seizures that developed into status epileptics. The patient was then transferred to a referred hospital. Brain MR images revealed faint high-signal intensity in the bilateral limbic systems on FLAIR images. A CSF examination indicated mild pleocytosis. These findings suggested acute limbic encephalitis, which may have been mediated by an autoimmune reaction following some viral infection. Thus, steroid pulse therapy was started on the day of admission. The patient's condition, including the seizures and disturbances involving consciousness, improved gradually. The patient was discharged from the hospital in one month while still experiencing mild memory disturbances. Three months after onset of the illness, a T1-weighted MR image showed a linear high-signal intensity in the hippocampi, which indicated focal necrosis. Six months after onset, the patient's memory disturbance had been improved (her MMSE score was 28/30 points). We investigated the titers of many viruses that are known to cause liver dysfunction and found that a titer of the type-2 adenovirus was significantly elevated within three weeks. Although the anti-voltage-gated potassium channel (VGKC) antibody was not detected in the patient's serum, it seems that the autoimmune reaction after the type-2 adenovirus infection may have caused the acute limbic encephalitis.

All-trans retinoic acid modulates radiation-induced proliferation of lung fibroblasts via IL-6/IL-6R system.

Although high-dose thoracic radiotherapy is an effective strategy for some malignancies including lung cancers and malignant lymphomas, it often causes complications of radiation fibrosis. To study the mechanism initiating tissue fibrosis, we investigated irradiation-induced cytokine production from human lung fibroblastic cells and found that IL-6 production was stimulated by irradiation. IL-6 is an autocrine growth factor for human myeloma cells, and retinoic acid is reported to inhibit their growth. Thus we evaluated the effect of all-trans retinoic acid (ATRA) on cell proliferation of lung fibroblasts along with the cytokine/receptor system. Irradiation-dependent stimulation of IL-6 production was correlated with increased NF-kappaB activity, and ATRA reduced this effect. Irradiation also increased the levels of mRNA for IL-6R and gp130, which were blocked by coexisting ATRA. Furthermore, IL-6 stimulated cell proliferation in dose-dependent manner but was overcome by pharmacological concentration of ATRA. These effects of ATRA were inhibited by rottlerin, which suggests ATRA abolished irradiation-induced stimulation through a PKCdelta-dependent pathway. Finally, we demonstrated that IL-6 transcripts in the lung were upregulated at 2 mo after irradiation, and the effect was inhibited by the intraperitoneal administration of ATRA. ATRA is expected to have an advantage for radiotherapy in its antitumor effects, as reported previously, and to prevent radiotherapy-induced pulmonary injury.

[Abducens nerve palsy as the first manifestation of cavernous sinus sarcoidosis].

We report a 33-year-old man who presented with an acute onset of diplopia and orbitalgia. Neurological examination revealed right abducent nerve palsy. Brain MRI showed a gadolinium-enhancing mass lesion in the right cavernous sinus. Chest CT showed a small lymph node swelling in the subcarinal compartment. Serum angiotensin converting enzyme and lysozyme levels were within normal range. Biopsied lymph node in the left supraclavicular fossa showed non-caseating epitheloid granulomas, consistent with sarcoidosis. After oral administration of predonisolone, his right abducent nerve palsy ameliorated in a few days and completely disappeared by 6 weeks after treatment. Abducent nerve palsy can be the first clinical manifestation of cavernous sinus sarcoidosis.

Improvement of collateral vessels in the vicinity of gastric cardia after endoscopic variceal ligation therapy for esophageal varices.

BACKGROUND & AIMS: Endoscopic variceal ligation (EVL) therapy has been performed widely to treat or prevent variceal bleeding. We sought to examine the influence of EVL for esophageal varices on collateral vessels in the vicinity of gastric cardia. METHODS: In 42 patients with esophagogastric varices, conventional endoscopy and endoscopic ultrasonography with a 20-MHz probe (CUP-EUS) were performed before and at every 3 months after EVL for esophageal varices. By using conventional endoscopy, cardial variceal sizes were divided into 3 grades: F0, F1, and F2. The sizes of submucosal, perforating, and paracardial vessels at the cardia also were classified into 3 grades according to CUP-EUS findings. RESULTS: Conventional endoscopy showed cardial varices in 33 (79%) patients before and 23 (55%) patients at 3 months after the treatment (P < 0.05). CUP EUS showed that 29 (69%) patients had severe grade cardial submucosal vessels before EVL, but only 13 (31%) patients did after the treatment (P < 0.01). Nineteen (45%) patients had severe grade cardial perforating vessels before EVL, but only 4 (10%) patients did after the treatment (P < 0.001). Furthermore, patients with severe grade residual submucosal or perforating vessels at the cardia had shorter recurrence-free times of esophageal varices (P < 0.01, 0.05, respectively). CONCLUSIONS: Collateral vessels in the vicinity of gastric cardia were improved significantly after EVL, indicating that esophageal varices can be treated by EVL even though they connect with cardial varices. Furthermore, eradication of such collateral vessels by EVL may lead to longer recurrence-free status of esophageal varices.

Frequent loss of RUNX3 gene expression in human bile duct and pancreatic cancer cell lines.

RUNX3, a Runt domain transcription factor involved in TGF-beta signaling, is a candidate tumor-suppressor gene localized in 1p36, a region commonly deleted in a wide variety of human tumors, including those of the stomach, bile duct, and pancreas. Recently, frequent inactivation of RUNX3 has been demonstrated in human gastric carcinomas. In this study, to examine the involvement of RUNX3 abnormalities in tumorigenesis of bile duct as well as pancreatic cancers, we investigated not only the expression but also methylation status of RUNX3 in 10 human bile duct and 12 pancreatic cancer cell lines. Seven (70%) of the bile duct and nine (75%) of the pancreatic cancer cell lines exhibited no expression of RUNX3 by both Northern blot analysis and the reverse transcriptase polymerase chain reaction. All of the 16 cell lines that did not express RUNX3 also showed methylation of the promoter CpG island of the gene, whereas the six cell lines that showed RUNX3 expression were not methylated or only partially methylated in the RUNX3 promoter region. Moreover, treatment with the methylation inhibitor 5'-aza-2'-deoxycitidine activated RUNX3 mRNA expression in all of 16 cancer cell lines that originally lacked RUNX3 expression. Finally, hemizygous deletion of RUNX3, as detected by fluorescence in situ hybridization, was found in 15 of the 16 cancer cell lines that lacked RUNX3 expression. These data suggest that the inactivation of RUNX3 plays an important role in bile duct and pancreatic carcinogenesis, and that methylation is a common mechanism by which the gene is inactivated.

Cyclooxygenase-2 expression and angiogenesis in gastric hyperplastic polyp--association with polyp size.

BACKGROUND: Cyclooxygenase (COX)-2 is the rate-limiting enzyme in prostaglandin synthesis, and plays an important role in tumor enlargement. COX-2 is expressed in human gastric and colorectal tumors, and the expression increases in a tumor size-dependent manner. In the present study, we attempted to examine the COX-2 expression pattern in gastric hyperplastic polyp, a non-tumorous lesion. PATIENTS AND METHODS: Fifty-eight gastric hyperplastic polyps, obtained by endoscopic polypectomy, were immunostained with anti-COX-2 and antivascular endothelial growth factor (VEGF) antibodies. Microvessel density (MVD) was determined by von Willebrand factor immunostaining. RESULTS: In larger gastric hyperplastic polyps, COX-2 was expressed mainly on the luminal side of the polyp stroma, while it was absent in smaller polyps. A significant correlation between COX-2 immunoreactivity and polyp size was observed (p < 0.01). High VEGF expression and MVD were observed mainly in the same stromal region of the polyps where COX-2 was expressed. Both VEGF expression and MVD were also correlated with polyp size significantly (ps < 0.01). CONCLUSIONS: COX-2 expression increased in a size-dependent manner in non-tumorous hyperplastic polyps, suggesting that COX-2 expression is not necessarily linked to epithelial cell transformation. Moreover, COX-2 may participate in polyp enlargement through angiogenesis by promoting VEGF production.