Phase I/II Study of a Vascular Endothelial Growth Factor Receptor Vaccine in Patients With NF2-Related Schwannomatosis.

PURPOSE: The humanized antivascular endothelial growth factor (VEGF) antibody bevacizumab (Bev) is efficacious for the treatment of NF2-related schwannomatosis (NF2), previously known as neurofibromatosis type 2. This study evaluated the safety and efficacy of a VEGF receptor (VEGFR) vaccine containing VEGFR1 and VEGFR2 peptides in patients with NF2 with progressive schwannomas (jRCTs031180184). MATERIALS AND METHODS: VEGFR1 and VEGFR2 peptides were injected subcutaneously into infra-axillary and inguinal regions, once a week for 4 weeks and then once a month for 4 months. The primary end point was safety. Secondary end points included tolerability, hearing response, imaging response, and immunologic response. RESULTS: Sixteen patients with NF2 with progressive schwannomas completed treatment and were assessed. No severe vaccine-related adverse events occurred. Among the 13 patients with assessable hearing, word recognition score improved in five patients at 6 months and two at 12 months. Progression of average hearing level of pure tone was 0.168 dB/mo during the year of treatment period, whereas long-term progression was 0.364 dB/mo. Among all 16 patients, a partial response was observed in more than one schwannoma in four (including one in which Bev had not been effective), minor response in 5, and stable disease in 4. Both VEGFR1-specific and VEGFR2-specific cytotoxic T lymphocytes (CTLs) were induced in 11 patients. Two years after vaccination, a radiologic response was achieved in nine of 20 assessable schwannomas. CONCLUSION: This study demonstrated the safety and preliminary efficacy of VEGFR peptide vaccination in patients with NF2. Memory-induced CTLs after VEGFR vaccination may persistently suppress tumor progression.

Middle Meningeal Artery Embolization for Refractory Chronic Subdural Hematoma Associated with Acute Myeloid Leukemia: A Case Report.

Objective: We describe a patient with leukemia-related chronic subdural hematoma (CSDH) who was successfully treated using the combination of surgical evacuation and middle meningeal artery (MMA) embolization. Case Presentation: A 73-year-old man without apparent head trauma history was admitted to our hospital because of acute myeloid leukemia (AML). Head CT on admission revealed mild CSDH on both sides. Medical treatment options, including chemotherapy, were started. Since a decrease in platelet count and disseminated intravascular coagulation were observed on day 4, recombinant thrombomodulin was administered. As the patient exhibited signs of altered consciousness due to the enlargement of the right CSDH on day 10, we performed surgical drainage. Despite subsequent platelet transfusion and administration of goreisan, the right CSDH recurred within a short period. On day 17, we performed the second surgery and MMA embolization in one stage. The postoperative clinical course was favorable without recurrence of the hematoma. The patient eventually died on day 123 from a deterioration of his general condition. Conclusion: Although MMA embolization has recently been recognized as an effective treatment option for recurrent CSDH, there are no published reports addressing the efficacy of MMA embolization for refractory CSDH associated with hematological malignancies. Findings from the management of this case suggest that MMA embolization can be the effective treatment option for CSDH in patients with severe hemorrhagic diathesis due to AML.

Neuroprotective Effects of Genome-Edited Human iPS Cell-Derived Neural Stem/Progenitor Cells on Traumatic Brain Injury.

Despite developing neurosurgical procedures, few treatment options have achieved functional recovery from traumatic brain injury (TBI). Neural stem/progenitor cells (NS/PCs) may produce a long-term effect on neurological recovery. Although induced pluripotent stem cells (iPSCs) can overcome ethical and practical issues of human embryonic or fetal-derived tissues in clinical applications, the tumorigenicity of iPSC-derived populations remains an obstacle to their safe use in regenerative medicine. We herein established a novel treatment strategy for TBI using iPSCs expressing the enzyme-prodrug gene yeast cytosine deaminase-uracil phosphoribosyl transferase (yCD-UPRT). NS/PCs derived from human iPSCs displayed stable and high transgene expression of yCD-UPRT following CRISPR/Cas9-mediated genome editing. In vivo bioluminescent imaging and histopathological analysis demonstrated that NS/PCs concentrated around the damaged cortex of the TBI mouse model. During the subacute phase, performances in both beam walking test and accelerating rotarod test were significantly improved in the treatment group transplanted with genome-edited iPSC-derived NS/PCs compared with the control group. The injury area visualized by extravasation of Evans blue was smaller in the treatment group compared with the control group, suggesting the prevention of secondary brain injury. During the chronic phase, cerebral atrophy and ventricle enlargement were significantly less evident in the treatment group. Furthermore, after 5-fluorocytosine (5-FC) administration, 5-fluorouracil converted from 5-FC selectively eliminated undifferentiated NS/PCs while preserving the adjacent neuronal structures. NS/PCs expressing yCD-UPRT can be applied for safe regenerative medicine without the concern for tumorigenesis.

Intraoperative Neuromonitoring of Hypoglossal Nerves Using Transcranial and Direct Electrical Stimulation During Extracranial Internal Carotid Artery Surgery.

BACKGROUND: We explored whether the electromyogram (EMG) and the motor evoked potential (MEP) are useful for monitoring the function of the hypoglossal nerve during surgery targeting the cervical segment of the internal carotid artery. METHODS: The present study included 6 patients with internal carotid arterial stenosis (1 patient underwent bilateral surgeries) and 1 patient with a cervical carotid artery aneurysm. In 5 of the 8 procedures, the EMGs were recorded. We examined whether changes in the MEP and/or EMG were capable of predicting postoperative hypoglossal nerve deficits. RESULTS: None of the 6 patients who underwent a total of 7 carotid endarterectomy (CEA) procedures experienced postoperative hypoglossal nerve morbidity. In 2 of the 7 procedures, the MEP disappeared or decreased significantly during CEA. In all 4 cases in which the hypoglossal nerve was directly stimulated during CEA, stable and reproducible EMGs were obtained throughout the manipulation of the internal carotid artery. Hypoglossal nerve morbidity was observed in the one case that underwent aneurysm removal and end-to-end anastomosis of the internal carotid artery. In this case, while the MEP decreased significantly during the operation, the EMG showed true-positive results and false-negative results, depending on the stimulation site. CONCLUSIONS: The monitoring of hypoglossal nerve function using EMG appears to be accurate if an appropriate stimulation site is selected. Hypoglossal nerve monitoring using MEP can produce false-positive results. Combined monitoring using both MEP and EMG is recommended in cases where exposure of the hypoglossal nerve is expected to be technically difficult.

Targeted embolisation for coexisting conus medullaris arteriovenous malformation and cauda equina arteriovenous fistulas with a varix on a shared drainer†.

BACKGROUND: The coexistence of vascular malformations in the conus medullaris and cauda equina has been rarely reported, and the complex angioarchitecture in multiple arteriovenous lesions remains poorly understood. CASE DESCRIPTION: A 17-year-old woman presented with a sudden-onset, stepwise worsening of weakness and pain in the bilateral legs. Angiography revealed conus medullaris arteriovenous malformation and cauda equina arteriovenous fistulas. One of the drainers was shared between the coexisting lesions and harboured a varix. Targeted embolisation of a fistulous point in the conus lesion was performed with precaution to prevent occluding the common drainage route, which led to symptom improvement with angiographical diminishment of the varix. CONCLUSIONS: Recognising that communications between drainers can be observed in multiple spinal arteriovenous lesions is important in facilitating a safe embolisation. Cautious assessment of angiogram with fusion images of cone-beam computed tomography and volumetric T2 magnetic resonance imaging can help in establishing the diagnosis and treatment strategy.

[Vagus Nerve Stimulation Therapy for Drug-Resistant Epilepsy].

Epilepsy is a neurological disorder with abnormal brain activity. It causes convulsions or periods of unusual behavior, sensations, and sometimes loss of awareness. Drug-resistant epilepsy (DRE) affects an estimated 15%-20% of patients with epilepsy. Vagus nerve stimulation (VNS) is a type of neuromodulation. VNS therapy is an adjunctive neurostimulation treatment for DRE patients who are unsuitable for respective surgery or have experienced unsuccessful surgery. VNS involves the use of a device to stimulate the vagus nerve with electrical impulses. VNS is not a cure for epilepsy, and most epilepsy patients can still experience seizures or use epilepsy medication after the procedure. However, 60%-70% of patients can have over 50% reduction in seizures 5 years after the VNS procedure. Seizure intensity may also reduce. VNS is safe with tolerable side effects in most cases. The mechanism of VNS action against epilepsy is still not accurately verified. Some people believe that VNS therapy improves their mood, memory, or alertness and may also help reduce depression. VNS therapy is also expected to work in other indications, including psychiatric, gastrointestinal, endocrinological, and immunological disorders.

Combined transarterial and transvenous embolization of multi-hole pial arteriovenous fistula with large varix.

BACKGROUND: Pial arteriovenous fistula (AVF) is a vascular fistulous disease in which the cerebral pial artery and vein are directly connected without the intervening nidus within a sub-pial space. Multi-hole pial AVFs, wherein multiple feeders flow into one drainer, are usually formed with complex angioarchitecture and are difficult to treat. METHODS: A rare case of an adult patient with hereditary hemorrhagic telangiectasia and multi-hole pial AVF was described. A 23-year-old woman was referred to our hospital. She was previously diagnosed with left cerebellar pial AVF with multiple feeders (bilateral superior cerebellar artery and common trunk of the left anterior inferior cerebellar artery and posterior inferior cerebellar) and large varix that had been untreated for 9 years. The enlargement of the large varix with the new second varix formation was revealed by angiography. Although asymptomatic, considered to be a risk for future hemorrhage was the continuous high hemodynamic stress. RESULTS: Endovascular embolization was performed by securing safe transarterial n-butyl-2-cyanoacrylate injection by transarterial and transvenous coil placement to the shunt points and feeders, resulting in total occlusion of the fistula without any complications. Extensive transvenous coil placement inside the varix allowed safe embolization of the entire fistula with multiple high-flow feeders. Moreover, bidirectional (transarterial and transvenous) retrograde coil embolization enabled firm obliteration of the shunt points. CONCLUSIONS: Performing combined transarterial and transvenous embolization in a well-balanced manner was considered to treat multi-hole pial AVF to provide a safe and effective embolization.

A case of central nervous system lesion pathologically characterized by angiocentric, T-cell-rich lymphoid cell infiltrates: a case report and literature review.

Lymphomatoid granulomatosis (LYG) is a rare lymphoproliferative disease with angiocentric and angiodestructive infiltrates, and by definition, Epstein-Barr virus (EBV)-associated B-cell malignancy. It most frequently involves the lung, and in some cases, the lesions are confined to the central nervous system (isolated CNS-LYG). However, it remains a controversial disease in terms of pathophysiology, especially in those confined to the CNS. We report the case of a 37-year-old man with CNS lesion pathologically characterized by angiocentric, T-cell-rich lymphoid cell infiltrates that resembled CNS-LYG. The lesion was clinically aggressive with subacute onset and irregular ring-like enhancement on MRI. The resected specimen showed no cytological atypia, EBV-infected cells, or monoclonality for IgH and TCR gene rearrangements. Considering the possibility of latent malignancy, the patient was successfully treated with corticosteroid and chemoradiotherapy with high-dose methotrexate. The present case and the literature suggest that EBV-negative CNS lesions with angiocentric lymphoid infiltrates are probably heterogeneous in their pathogenesis, including those that could fit into the so-called CNS-LYG and those with T-cell predominance. The accumulation of similar cases is warranted for the classification and appropriate treatment of these lesions.

Cystic Dumbbell-Shaped C1 Schwannoma with Intracranial Extension and Hydrocephalus.

BACKGROUND: Schwannomas at the craniocervical junction commonly originate from the lower cranial nerves or C1 and C2 nerves. To date, very few cases of C1 schwannomas have been described in the literature, and the majority involve either the intra- or the extradural compartment, but not both. To our knowledge, this report documents the first case of a dumbbell-shaped C1 schwannoma that encompassed both intra- and extradural compartments and was accompanied by hydrocephalus. CASE DESCRIPTION: The patient was admitted to our hospital, where magnetic resonance imaging revealed a tumor at the craniocervical junction, extending from the C1 level of the right first cervical vertebra into the cerebellopontine angle with 2 giant cysts. We removed the tumor by performing a midline posterior craniectomy and cervical laminectomy. Intraoperatively, the tumor was found to originate from the right C1 posterior root. The pathological diagnosis was of a schwannoma. The patient was subsequently discharged without any neurologic deficits. CONCLUSIONS: To our knowledge, we present the first case of a dumbbell-shaped C1 schwannoma with intracranial extensions and accompanying hydrocephalus. The tumor had spread inside and outside the dura, but was safely removed. Our findings in this case emphasize that to achieve safe resection, detailed case-specific preoperative consideration is essential.

Sinking skin flap syndrome visualized by upright computed tomography.

Sinking skin flap syndrome is a craniectomy complication characterized by new neurological dysfunction that typically worsens in the upright position and improves after cranioplasty. We present a 33-year-old man who experienced hemiparesis in the upright position after craniectomy. Upright computed tomography (CT) before cranioplasty showed a remarkable shift of the brain compared to supine CT. After cranioplasty, both symptoms and brain shift on CT resolved. Upright CT enables detection and objective evaluation of paradoxical herniation and midline shift that is not obvious on supine imaging modalities. Clinicians need to be aware of positional brain shift in postcraniectomy patients.

Cerebrospinal fluid leakage due to nasoseptal flap partial necrosis: A pitfall for skull base reconstruction of endoscopic endonasal surgery.

BACKGROUND: Vascularized nasoseptal flaps allow for the reconstruction of large dural defects and have remarkably reduced the incidence of postoperative complications during endoscopic endonasal skull base surgery. Nevertheless, some complications related to nasoseptal flap have been reported. Flap necrosis is a rare, but serious issue is associated with meningitis and cerebrospinal fluid (CSF) leak. CASE DESCRIPTION: We performed endoscopic endonasal removal of the tuberculum sella meningioma in a 39-year-old woman with a history of Turner syndrome using abdominal fat, fascia, and a vascularized nasoseptal flap for dural and skull base defect reconstruction. After surgery, she developed CSF leak, and reoperation revealed partial necrosis of the septal flap that caused leakage. At this time, with a concern that removal of the necrotic part may lead to the insufficient size of the flap, we filled the gap tightly with fat pieces. However, the CSF leak recurred, and thus, we performed debridement of the necrotic region and reformed the multilayered reconstruction, following which she no longer experienced CSF leakage. CONCLUSION: Our case suggested that partial rather than total flap necrosis could occur, possibly due to variances of vascular anatomy, leading to focal ischemia. Debridement of the necrotic region may be an important solution for recurrent cerebrospinal leakage secondary to partial necrosis of a nasoseptal flap.