Identification and characterization of GABA(A) receptor autoantibodies in autoimmune encephalitis.

Autoimmune forms of encephalitis have been associated with autoantibodies against synaptic cell surface antigens such as NMDA- and AMPA-type glutamate receptors, GABA(B) receptor, and LGI1. However, it remains unclear how many synaptic autoantigens are yet to be defined. Using immunoproteomics, we identified autoantibodies against the GABA(A) receptor in human sera from two patients diagnosed with encephalitis who presented with cognitive impairment and multifocal brain MRI abnormalities. Both patients had antibodies directed against the extracellular epitope of the ß3 subunit of the GABA(A) receptor. The ß3-subunit-containing GABA(A) receptor was a major target of the patients' serum antibodies in rat hippocampal neurons because the serum reactivity to the neuronal surface was greatly decreased by 80% when the ß3 subunit was knocked down. Our developed multiplex ELISA testing showed that both patients had similar levels of GABA(A) receptor antibodies, one patient also had a low level of LGI1 antibodies, and the other also had CASPR2 antibodies. Application of the patients' serum at the time of symptom presentation of encephalitis to rat hippocampal neuron cultures specifically decreased both synaptic and surface GABA(A) receptors. Furthermore, treatment of neurons with the patients' serum selectively reduced miniature IPSC amplitude and frequency without affecting miniature EPSCs. These results strongly suggest that the patients' GABA(A) receptor antibodies play a central role in the patients' symptoms. Therefore, this study establishes anti-GABA(A) receptor encephalitis and expands the pathogenic roles of GABA(A) receptor autoantibodies.

Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors.

More than 30 mutations in LGI1, a secreted neuronal protein, have been reported with autosomal dominant lateral temporal lobe epilepsy (ADLTE). Although LGI1 haploinsufficiency is thought to cause ADLTE, the underlying molecular mechanism that results in abnormal brain excitability remains mysterious. Here, we focused on a mode of action of LGI1 autoantibodies associated with limbic encephalitis (LE), which is one of acquired epileptic disorders characterized by subacute onset of amnesia and seizures. We comprehensively screened human sera from patients with immune-mediated neurological disorders for LGI1 autoantibodies, which also uncovered novel autoantibodies against six cell surface antigens including DCC, DPP10, and ADAM23. Our developed ELISA arrays revealed a specific role for LGI1 antibodies in LE and concomitant involvement of multiple antibodies, including LGI1 antibodies in neuromyotonia, a peripheral nerve disorder. LGI1 antibodies associated with LE specifically inhibited the ligand-receptor interaction between LGI1 and ADAM22/23 by targeting the EPTP repeat domain of LGI1 and reversibly reduced synaptic AMPA receptor clusters in rat hippocampal neurons. Furthermore, we found that disruption of LGI1-ADAM22 interaction by soluble extracellular domain of ADAM22 was sufficient to reduce synaptic AMPA receptors in rat hippocampal neurons and that levels of AMPA receptor were greatly reduced in the hippocampal dentate gyrus in the epileptic LGI1 knock-out mouse. Therefore, either genetic or acquired loss of the LGI1-ADAM22 interaction reduces the AMPA receptor function, causing epileptic disorders. These results suggest that by finely regulating the synaptic AMPA receptors, the LGI1-ADAM22 interaction maintains physiological brain excitability throughout life.

IgG4-related small-sized occlusive vasculitis in Mikulicz's disease.

Mikulicz's disease is one of the IgG4-related diseases (IgG4-RDs) that involves the cardiovascular system; however, small-sized vasculitis is rare in IgG4-related diseases. A 64-year-old man presented with distal occlusive disease and developed left cerebrovascular infarction with occlusion of the middle cerebral artery and diseased temporal artery branches. He underwent superficial temporal artery-middle cerebral artery anastomosis surgery. Histology of the temporal artery biopsy showed smooth muscle cell proliferation with many IgG4-positive plasma cells. He then developed salivary gland inflammation, and Mikulicz's disease was diagnosed. Small-sized occlusive vasculitis was observed in this IgG4-RD. Low-dose corticosteroid therapy is effective in preventing progressive occlusive disease.

Concurrent combination of irradiation and immune checkpoint inhibitor for recurrent pleomorphic carcinoma of the lung.

We report the case of a 49-year-old patient who developed brain, sternal, and spine metastases almost simultaneously after the radical resection of a yp-T4N0M0 pulmonary pleomorphic carcinoma of the right upper lobe following induction chemotherapy. The left occipital brain metastasis was surgically removed and followed by radiation therapy. The sternal and vertebral metastases were treated with radiation therapy. Concurrently, the immune checkpoint inhibitor nivolumab was administered. After 12 cycles of nivolumab, the two bone metastases were well-controlled. However, the brain metastasis recurred and was surgically removed again. We were able to investigate the tumor-infiltrating lymphocytes in brain metastases resected before and after radio-immunotherapy. The results revealed the increased number of CD8- and CD68-positive cells after the combined therapy compared with before the therapy. In addition, the high-level expression of program death-ligand 1 was maintained in the brain metastasis.

Promotion of astrocytoma cell invasion by micro RNA-22 targeting of tissue inhibitor of matrix metalloproteinase-2.

OBJECTIVE Diffuse astrocytomas (DAs) have a high recurrence rate due to diffuse infiltration into the brain and spinal cord. Micro RNAs (miRNAs) are small noncoding RNAs that regulate gene expression by binding to complementary sequences of target messenger RNA (mRNA). It has been reported that miRNA-22 (miR-22) is involved in the invasion of some cancer cell lines. The aim of this study was to identify the biological effects of miR-22 in regard to the invasion of human DAs. METHODS The authors evaluated whether the level of miR-22 is elevated in human spinal DAs by using miRNA chips. Next, the role of miR-22 in 1321N1 human astrocytoma cells was investigated. Finally, to elucidate whether miR-22 promotes invasion by astrocytoma cells in vivo, the authors transplanted miR-22 overexpressed astrocytoma cells into mouse thoracic spinal cord. RESULTS The miR-22 significantly upregulated the invasion capacity of 1321N1 cells. Computational in silico analysis predicted that tissue inhibitor of matrix metalloproteinase-2 (TIMP2) is a target gene of miR-22. This was confirmed by quantitative reverse transcription polymerase chain reaction and Western blotting, which showed that miR-22 inhibited TIMP2 mRNA and protein expression, respectively. Luciferase reporter assays demonstrated that miR-22 directly bound the 3'-untranslated regions of TIMP2. The authors further showed that miR-22 promoted invasiveness in 1321N1 astrocytoma cells when transplanted into mouse spinal cord. CONCLUSIONS These data suggest that miR-22 acts to regulate invasion of 1321N1 astrocytoma cells by targeting TIMP2 expression. Additional studies with more cases and cell lines are required to elucidate the findings of this study for a novel treatment target for spinal DAs.

Significance of the Pars Interarticularis in the Cortical Bone Trajectory Screw Technique: An In Vivo Insertional Torque Study.

STUDY DESIGN: Retrospective study. PURPOSE: Cortical bone trajectory (CBT), a more medial-to-lateral and shorter path than the traditional one for spinal fusion, is thought to be effective for severely degenerated vertebrae because screws are primarily stabilized at the posterior elements. We evaluated the efficacy of this approach through in vivo insertional torque measurement. OVERVIEW OF LITERATURE: There has been only one prior in vivo study on CBT insertional torque. METHODS: Between January 2013 and April 2014, a total of 22 patients underwent posterior lumbar fusion using the CBT technique. The maximum insertional torque, which covers the radial strength needed for insertion, was measured for 113 screws, 8 of which were inserted for L5 spondylolysis. The insertional torque for cases with (n=8) and without (n=31) spondylolysis of L5 were compared using one-way analysis of variance (ANOVA). To evaluate vertebral degeneration, we classified 53 vertebrae without spondylolysis by lumbar radiography using semiquantitative methods; the insertional torque for the 105 screws used was compared on the basis of this classification. Additionally, differences in insertional torque among cases grouped by age, sex, and lumbar level were evaluated for these 105 screws using ANOVA and the Tukey test. RESULTS: The mean insertional torque was significantly lower for patients with spondylolysis than for those without spondylolysis (4.25 vs. 8.24 in-lb). There were no statistical differences in insertional torque according to vertebral grading or level. The only significant difference in insertional torque between age and sex groups was in men <75 years and women ≥75 years (10 vs. 5.5 in-lb). CONCLUSIONS: Although CBT should be used with great caution in patient with lysis who are ≥75 years, it is well suited for dealing with severely degenerated vertebrae because the pars interarticularis plays a very important role in the implementation of this technique.

[Craniotomy for organized subdural hematoma].

We reported 3 cases of organized chronic subdural hematoma (CSDH), which required radical treatment by craniotomy. All patients were in the 70s (male, two; female, one). Two cases had previously received craniotomy and neck clipping for intracranial aneurysm. All of them received trephine evacuation of hematoma more than two times, although the hematoma was not removed due to organization. Because of this, we performed craniotomy and removal of the hematoma with its thick outer membrane. In order to obliterate the subdural space completely, we stripped the dura mater from the skull and attached it to the inner membrane with fibrine glue. After a period of more than two years of followed-up, no recurrences had been discovered.

Clear Zone Formation around Screws in the Early Postoperative Stages after Posterior Lumbar Fusion Using the Cortical Bone Trajectory Technique.

STUDY DESIGN: Retrospective study. PURPOSE: To evaluate the initial fixation using the cortical bone trajectory (CBT) technique for posterior lumbar fusion through assessment of the clear zones around the screws and the risk factors involved. OVERVIEW OF LITERATURE: Postoperative radiolucent zones (clear zones) are an indicator of poor conventional pedicle screw fixation. METHODS: Between January 2013 and April 2014, 19 patients (8 men and 11 women) underwent posterior lumbar interbody fusion or posterior lumbar fusion using the CBT technique. A total of 109 screws were used for evaluation with measurement of the maximum insertional torque of last two screw rotations. Clear zone-positivity on plain radiographs was investigated 6 months after surgery. The relation between intraoperative insertional torque and clear zone-positivity was investigated by one-way analysis of variance. In addition, the correlation between clear zone-positivity and gender, age (<75 years old or >75 years old), or operative stabilization level (<2 or >3 vertebral levels) was evaluated using the chi-square test. RESULTS: Clear zones were observed around six screws (5.50%) in five patients (26.3%). The mean insertional torque (4.00±2.09 inlbs) of clear zone-positive screws was lower than that of clear zone-negative screws (8.12±0.50 in-lbs), but the difference was not significant. There was a significant correlation between clear zone-positivity and operative level of stabilization. CONCLUSIONS: The low incidence of clear zone-positive screws indicates good initial fixation using the CBT technique. Multilevel fusions may be risk factors for clear zone generation.

Intranasal delivery of bone marrow stromal cells to spinal cord lesions.

OBJECT: The intranasal delivery of bone marrow stromal cells (BMSCs) or mesenchymal stem cells to the injured brains of rodents has been previously reported. In this study, the authors investigated whether BMSCs migrate to spinal cord lesions through an intranasal route and whether the administration affected functional recovery. METHODS: Forty Sprague-Dawley rats that were subjected to spinal cord injuries at the T7-8 level were divided into 5 groups (injured + intranasal BMSC-treated group, injured + intrathecal BMSC-treated group, injured-only group, injured + intranasal vehicle-treated group, and injured + intrathecal vehicle-treated group). The Basso-Beattie-Bresnahan (BBB) scale was used to assess hind limb motor functional recovery for 2 or 4 weeks. Intralesionally migrated BMSCs were examined histologically and counted at 2 and 4 weeks. To evaluate the neuroprotective and trophic effects of BMSCs, the relative volume of the lesion cavity was measured at 4 weeks. In addition, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) levels in the CSF were evaluated at 2 weeks. RESULTS: Intranasally administered BMSCs were confirmed within spinal cord sections at both 2 and 4 weeks. The highest number, which was detected in the intrathecal BMSC-treated group at 2 weeks, was significantly higher than that in all the other groups. The BBB score of the intranasal BMSC-treated group showed statistically significant improvements by 1 week compared with the control group. However, in the final BBB scores, there was a statistically significant difference only between the intrathecal BMSC-treated group and the control group. The cavity ratios in the BMSC-treated groups were smaller than those of the control groups, but the authors did not find any significant differences in the NGF and BDNF levels in the CSF among the treatment and control groups. CONCLUSIONS: BMSCs reached the injured spinal cord through the intranasal route and contributed to the recovery of hind limb motor function and lesion cavity reduction. However, the effects were not as significant as those seen in the intrathecal BMSC-treated group.

Isthmus-guided Cortical Bone Trajectory Reduces Postoperative Increases in Serum Creatinine Phosphokinase Concentrations.

OBJECTIVE: This study aimed to determine whether an isthmus-guided cortical bone trajectory (CBT) technique provides better clinical outcomes than the original cortical bone trajectory CBT technique for screw fixation. METHODS: A consecutive series of 21 patients with lumbar spondylolisthesis who had undergone CBT screw fixation using the original technique from June 2012 to February 2013 and 33 who had undergone the isthmus-guided technique from March 2013 to August 2014 was retrospectively reviewed. The number of screws inserted, interbody fusion and screw misplacements, amount of blood loss, and creatinine phosphokinase (CPK) ratios (postoperative day 1 CPK/preoperative CPK) were reviewed to evaluate clinical outcomes and compared between the original and isthmus-guided CBT techniques. RESULTS: Postoperative serum CPK concentrations were significantly lower with the isthmus-guided than the original CBT technique (P < 0.05). There were no significant differences in age, blood loss, or number of screws, vertebral interbody fusions and patients with history of previous decompression surgery at the same level. There was a trend to higher incidence of screw misplacement with the original than the isthmus-guided CBT technique; this difference was not significant (P = 0.53). There were no major intraoperative complications. In all the CBT procedures performed in our institution, almost half (47%) the screw misplacements have occurred at the level of L5 , and most on the right side. CONCLUSIONS: Right-handed operators should take care inserting screws on the right side. From the viewpoint of screw misplacement, isthmus-guided CBT provides superior or equivalent safety to the original CBT technique.

Differences between Cervical Schwannomas of the Anterior and Posterior Nerve Roots in Relation to the Incidence of Postoperative Radicular Dysfunction.

STUDY DESIGN: A retrospective study. PURPOSE: To assess the case files of patients who underwent surgery for cervical dumbbell schwannoma for determining the differences between schwannomas of the anterior and posterior nerve roots with respect to the incidence of postoperative radicular dysfunction. OVERVIEW OF LITERATURE: The spinal roots giving origin to schwannoma are frequently nonfunctional, but there is a risk of postoperative neurological deficit once these roots are resected during surgery. METHODS: Fifteen patients with cervical dumbbell schwannomas were treated surgically. Ten men and 5 women, who were 35-79 years old (mean age, 61.5 years), presented with neck pain (n=6), radiculopathy (n=10), and myelopathy (n=11). RESULTS: Fourteen patients underwent gross total resection and exhibited no recurrence. Follow-ups were performed for a period of 6-66 months (mean, 28 months). Preoperative symptoms resolved in 11 patients (73.3%) but they persisted partially in 4 patients (26.7%). Six patients had tumors of anterior nerve root origin, and 9 patients had tumors of posterior nerve root origin. Two patients who underwent total resection of anterior nerve root tumors (33.3%) displayed minor postoperative motor weakness. One patient who underwent total resection of a posterior nerve root tumor (11.1%) showed postoperative numbness. CONCLUSIONS: Appropriate tumor removal improved the neurological symptoms. In this study, the incidence of radicular dysfunction was higher in patients who underwent resection of anterior nerve root tumors than in patients who underwent resection of posterior nerve root tumors.

Isolation of human adult olfactory sphere cells as a cell source of neural progenitors.

Olfactory stem cells are generated from olfactory mucosa. Various culture conditions generate olfactory stem cells that differ according to species and developmental stage and have different progenitor or stem cell characteristics. Olfactory spheres (OSs) are clusters of progenitor or stem cells generated from olfactory mucosa in suspension culture. In this study, adult human OSs were generated and their characteristics analyzed. Human OSs were adequately produced from olfactory mucosa with area over 40 mm(2). Immunocytochemistry (ICC) and fluorescence-activated cell sorting showed that human OSs were AN2 and A2B5-positive. Immunofluorescence analysis of cell type-specific ICC indicated that the number of Tuj1-positive OS cells was significantly elevated. Tuj1-positive cells displayed typical neuronal soma and dendritic morphology. Human OS cells were also immunopositive for MAP2. By contrast, few RIP-, O4-, and GFAP-positive cells were present. These RIP, O4, and GFAP-positive cells did not resemble bona fide oligodendrocytes and astrocytes morphologically. In culture to induce differentiation of oligodendrocytes, human OS cells also expressed neuronal markers, but neither oligodendrocyte or astrocyte markers. These findings suggest that human OS cells autonomously differentiate into neurons in our culture condition and have potential to be used as a cell source of neural progenitors for their own regenerative grafts, avoiding the need for immunosuppression and ethical controversies.

Chemical corrector treatment ameliorates increased seizure susceptibility in a mouse model of familial epilepsy.

Epilepsy is one of the most common and intractable brain disorders. Mutations in the human gene LGI1, encoding a neuronal secreted protein, cause autosomal dominant lateral temporal lobe epilepsy (ADLTE). However, the pathogenic mechanisms of LGI1 mutations remain unclear. We classified 22 reported LGI1 missense mutations as either secretion defective or secretion competent, and we generated and analyzed two mouse models of ADLTE encoding mutant proteins representative of the two groups. The secretion-defective LGI1(E383A) protein was recognized by the ER quality-control machinery and prematurely degraded, whereas the secretable LGI1(S473L) protein abnormally dimerized and was selectively defective in binding to one of its receptors, ADAM22. Both mutations caused a loss of function, compromising intracellular trafficking or ligand activity of LGI1 and converging on reduced synaptic LGI1-ADAM22 interaction. A chemical corrector, 4-phenylbutyrate (4PBA), restored LGI1(E383A) folding and binding to ADAM22 and ameliorated the increased seizure susceptibility of the LGI1(E383A) model mice. This study establishes LGI1-related epilepsy as a conformational disease and suggests new therapeutic options for human epilepsy.

Adjacent lumbar disc herniation after lumbar short spinal fusion.

A 70-year-old outpatient presented with a chief complaint of sudden left leg motor weakness and sensory disturbance. He had undergone L4/5 posterior interbody fusion with L3-5 posterior fusions for spondylolisthesis 3 years prior, and the screws were removed 1 year later. He has been followed up for 3 years, and there had been no adjacent segment problems before this presentation. Lumbar magnetic resonance imaging (MRI) showed a large L2/3 disc hernia descending to the L3/4 level. Compared to the initial MRI, this hernia occurred in an "intact" disc among multilevel severely degenerated discs. Right leg paresis and bladder dysfunction appeared a few days after admission. Microscopic lumbar disc herniotomy was performed. The right leg motor weakness improved just after the operation, but the moderate left leg motor weakness and difficulty in urination persisted.

Isthmus-guided cortical bone trajectory for pedicle screw insertion.

Herein is described cortical bone trajectory (CBT), a new path for pedicle screw insertion for lumbar vertebral fusion. Because the points of insertion are under the end of the inferior articular process, and because the screws are inserted toward the lateral side, there is less soft tissue development than with the conventional technique; the CBT technique therefore enables less invasive surgery than the conventional technique. However, it has some drawbacks. For example, in the original CBT approach, the points of insertion are in the vicinity of the end of the inferior articular process. Because this joint has been destroyed in many patients who have indications for intervertebral fusion surgery, it is sometimes difficult to use it as a reference point for screw insertion location. With severe lateral slippage, the screw insertion site can become significantly dislocated sideways, with possible resultant damaging to the spinal canal and/or nerve root. The CBT technique here involved inserting the screws while keeping clear of the intervertebral foramen with the assistance of side view X-ray fluoroscopy and using the end of the inferior articular process and the isthmus as points of reference for screw location.

Syringomyelia associated with spinal arachnoiditis treated by partial arachnoid dissection and syrinx-far distal subarachnoid shunt.

The authors describe a new modified surgical approach to minimize the postoperative recurrence of a syrinx after surgery to treat syringomyelia associated with spinal adhesive arachnoiditis in two cases. Both patients presented with progressive gait disturbance without any remarkable history, and spinal magnetic resonance imaging revealed a syrinx and broad irregular disappearance of the subarachnoid space and/or deformity of the cord. We successfully performed a partial arachnoid dissection and syrinx-far distal subarachnoid shunt for both cases.

Analysis of factors affecting the long-term functional outcome of patients with skull base meningioma.

We analyzed the factors that affect the long-term clinical outcome of a series of patients with skull base meningiomas. Clinical records of 73 patients with cranial base meningiomas were reviewed retrospectively, of whom 13 patients experienced a recurrence at various times following the initial surgery. The mean follow-up time was 90.4 ± 21.2 months (range=60-124 months). Based on the location of the recurrence, patients with recurrence were divided into peripheral (n=6) and central (n=7) skull base groups. Of several variables analyzed using a multivariate logistic regression model, "high MIB-1 (Ki-67 proliferation antigen) labeling index" was an independent variable predicting poor long-term functional outcomes. Recurrence of the tumor at the central skull base was also a strong predictor of poor long-term outcomes. An increased proliferative potential, as indicated by a high MIB-1 labeling index, may induce repeated recurrences, eventually leading to worse functional outcomes, particularly for patients with central skull base meningiomas.

Temporal lobe encephalocele in the lateral recess of the sphenoid sinus presenting with intraventricular tension pneumocephalus.

A basal encephalocele often shows an insidious clinical course. Only two cases of temporal lobe encephalocele accompanied with tension pneumocephalus have previously been reported. In this paper, we describe a case of lateral sphenoid sinus encephalocele presenting with intraventricular tension pneumocephalus. A 54-year-old man was referred to our institution presenting with intraventricular tension pneumocephalus. He had undergone ventriculoperitoneal shunt placement for postmeningitis hydrocephalus 3 months before this admission. Precise imaging examinations detected evidence suggestive of a lateral sphenoidal sinus recess encephalocele. Endoscopic transnasal approach was performed for surgical repair of the encephalocele. The encephalocele was removed with subsequent repair of the bony defect. Histological examination showed that the encephalocele includes a part of the ventricular system. This indicates that air might enter directly into the ventricular system after rupture of the temporal lobe encephalocele. A lateral sphenoid sinus encephalocele would potentially cause intraventricular tension pneumocephalus, although pneumocephalus is an extremely unusual complication of this type of basal encephaloceles.

Surgical treatment and outcome of skull base meningiomas with extracranial extensions.

OBJECTIVE: Recurrent cranial base meningiomas occasionally extend into craniofacial structures, and are one of the most difficult tumors to surgically manage. We reviewed our experience of surgical treatment in a series of patients with meningiomas showing extensive extracranial extensions. METHODS: We surgically treated a total of 10 patients with recurrent cranial base meningiomas with large extension to multiple craniofacial structures. All patients underwent orbitozygomatic or zygomatic frontotemporal craniotomy for surgical resection of the tumor. An endoscopic endonasal technique was also employed, if necessary, as an adjunct to the transcranial approach. RESULTS: Eight patients were treated solely with a frontotemporal approach associated with an extended resection of the floor of the middle fossa. In 2 patients, an endoscopic endonasal approach was additionally required for resection of tumors located in the nasal cavity and ethmoid sinus. A gross total resection was achieved without serious surgical complications in 9 out of the 10 patients. In all patients, the tumors were found to invade the surrounding tissue such as the bone and skeletal muscle to varying degrees. CONCLUSION: Our data indicate that recurrent craniofacial meningiomas can usually be managed by using a lateral cranial base approach. Whereas it would be expected that a radical resection may prevent further recurrence with an acceptable quality of life, a long-term follow-up would be required for confirming the benefit of this treatment strategy.