Outpatient visit behavior in patients with epilepsy: Generalized Epilepsy is more frequently non-attendance than Focal Epilepsy.

BACKGROUND: Patients with epilepsy (PWE), especially those with Idiopathic Epilepsy (GE), are at a high risk of disadvantage caused by non-adherence. It has been suggested that medical visit behavior may be a surrogate indicator of medication adherence. We hypothesized that patients with IGE would adhere poorly to visits. METHODS: This was a retrospective study of PWE who visited the Department of Psychiatry and Neurology at Hokkaido University Hospital between January 2017 and December 2019. Demographic and clinical information on PWE were extracted from medical records and visit data from the medical information system. Non-attendance of outpatient appointments was defined as "not showing up for the day of an appointment without prior notice." Mixed-effects logistic regression analysis was conducted with non-attendance as the objective variable. RESULTS: Of the 9151 total appointments, 413 were non-attendances, with an overall non-attendance rate of 4.5%. IGE was a more frequent non-attendance than Focal Epilepsy (FE) (odds ratio (OR) 1.94; 95% confidence interval (CI) 1.17-3.21; p = 0.010). History of public assistance receipt was associated with higher non-attendance (OR 2.04; 95% CI 1.22-3.43; p = 0.007), while higher education (OR 0.64; 95% CI 0.43-0.93; p = 0.021) and farther distance to a hospital (OR 0.33; 95% CI 0.13-0.88; p = 0.022), and higher frequency of visits (OR 0.18; 95% CI 0.04-0.86; p = 0.031) were associated with fewer non-attendances. In a subgroup analysis of patients with GE, women were associated with fewer non-attendance (OR 0.31; 95% CI 0.14-0.72; p = 0.006). CONCLUSIONS: GE was more frequent in the non-attendance group than in the FE group. Among patients with GE, females were found to have non-attendance less frequently; however, there was no clear difference in the odds of non-attendance between Juvenile Myoclonic Epilepsy (JME) and IGE other than JME.

Anesthetic management of a pediatric patient with Freeman-Sheldon syndrome undergoing atrial septal defect closure: a case report.

BACKGROUND: Freeman-Sheldon syndrome (FSS) is a rare disorder characterized by specific deformities of the extremities and face. There have been no reports of open-heart surgery in pediatric patients with FSS. CASE PRESENTATION: We present the case of an 8-year-old girl with FSS who underwent atrial septal defect closure. Tracheal intubation was uncomplicated, although the patient had microstomia. Inhalational anesthetics and dopamine antagonists were avoided intraoperatively and perioperatively. We chose dexmedetomidine as an adjuvant for postoperative pain management contributing to adequate analgesia and early extubation without causing respiratory depression. CONCLUSIONS: Anesthetic management of FSS requires consideration for airway management and prevention of malignant hyperthermia and respiratory complications. We successfully managed the case avoiding the use of malignant hyperthermia-triggering drugs.

Use of remimazolam in living donor liver transplantation: a case report.

BACKGROUND: Remimazolam is an intravenous ultra-short-acting benzodiazepine with the benefit of hemodynamic stability, including blood pressure and pulse rate. We report a case in which remimazolam was used in living donor liver transplantation with stable hemodynamics. CASE PRESENTATION: A 19-year-old woman underwent living donor liver transplantation due to end-stage liver disease, which is associated with a hyperdynamic state and hemodynamic instability. The patient's sister had a history of malignant hyperthermia, so we chose total intravenous anesthesia with remimazolam. Intraoperative bleeding of seven liters occurred, but she had mild intraoperative blood pressure changes, and continuous catecholamine administration was not necessary. The patient had no memories or discomfort during the surgery. CONCLUSIONS: We maintained stable hemodynamics using remimazolam for anesthetic management of a patient undergoing a liver transplantation, which is characterized by a hyperdynamic state and circulatory instability.

[Neutrophil-to-Lymphocyte Ratio(NLR)as a Predictive Indicator of the Response to Nivolumab in Patients with Oral Squamous Cell Carcinoma].

BACKGROUND: The immune checkpoint inhibitor (ICI) nivolumab has revolutionized the treatment for recurrent or metastatic advanced oral cancer. Because the response rate remains low, the identification of predictive indicators of the response to nivolumab is among the most critical issues. The neutrophil-to-lymphocyte ratio(NLR)is a potential predictive marker of the response to nivolumab in patients with various cancer types. However, the utility of the NLR as a biomarker for predicting the response of oral cancer patients to ICIs is poorly understood. PATIENTS AND METHODS: In this retrospective cohort study, we evaluated the association between NLR and nivolumab treatment outcome in 13 patients diagnosed with recurrent or metastatic oral squamous cell carcinoma(OSCC)treated with nivolumab at the Toyama University Hospital between December 2017 and December 2019. RESULTS: Complete response(CR)and partial response(PR)rates of 38.5%(5/13)and 0% (0/13), respectively, were observed in responders; stable disease(SD)and progressive disease(PD)rates of 7.7%(1/13) and 53.8%(7/13), respectively, were observed in non-responders. After nivolumab treatment, the median NLR among responders decreased to 3.3(3.0-3.9)from 4.1(3.7-4.3)during pre-treatment assessment and increased from 5.6(3.2- 9.2)at pre-treatment to 9.4(5.3-17.9)among non-responders. Moreover, patients with higher NLRs(≥5)in the post- treatment group had a significantly worse overall survival than those with lower NLRs(<5). Specifically, patients with a higher post-treatment NLR(≥10)had significantly worse outcomes for post-nivolumab salvage chemotherapy. CONCLUSION: The NLR could be a useful marker for predicting the treatment response to nivolumab or post-nivolumab salvage chemotherapy in OSCC patients.

Resolution of multifocal micronodular pneumocyte hyperplasia with everolimus in a patient with tuberous sclerosis complex.

A woman with a diagnosis of tuberous sclerosis complex (TSC) presented with TSC2 gene mutation and various manifestations, including epilepsy, renal angiomyolipomas (AML), and pathologically confirmed multifocal micronodular pneumocyte hyperplasia (MMPH). With oral administration of everolimus, a mammalian target of rapamycin (mTOR) inhibitor, MMPH and AML were markedly reduced. Further, after starting treatment with everolimus, serum levels of surfactant protein (SP)-A and SP-D, which reflect type II pneumocyte hyperplasia, decreased to the normal range. At the time of writing of this manuscript, 6 years after starting everolimus, MMPH lesions did not relapse and SP-A/D remained the low levels. This is the first case of everolimus efficacy shown for histologically confirmed MMPH in genetically determined TSC patient, with time course of serum SP-A and SP-D.

Protumor role of estrogen receptor expression in oral squamous cell carcinoma cells.

OBJECTIVE: Accumulating evidence has demonstrated the protumor role of estrogen receptor (ER)-mediated signaling in multiple cancer types, which is distinct from this signaling in sex steroid-dependent organs. However, its role in oral squamous cell carcinoma (OSCC) remains unclear. STUDY DESIGN: We assessed the expression of ERα and ERß in human OSCC tissues by immunohistochemistry and evaluated the expression of both receptors in OSCC cell lines by immunoblotting and flow cytometry. To further assess the contribution of ER-mediated signals to oral cancer progression, proliferation, invasion, and chemosensitivity, cell lines were stimulated with the ER agonist ß-estradiol. RESULTS: Immunohistochemical analysis of OSCC tissues showed that ERß was present in the cytoplasm and nuclei of OSCC cells. In contrast, ERα was not detected in any of the cases analyzed. Additionally, the proliferation and invasiveness of OSCC cells were significantly elevated following stimulation with ß-estradiol. Chemotherapeutic agent-induced apoptosis of cancer cells was attenuated by pretreatment with ß-estradiol. CONCLUSIONS: ER-mediated signaling plays a crucial role in oral cancer progression by facilitating the proliferation, invasion, and chemoresistance of OSCC cells, indicating its potential for developing novel targeted therapies for this type of cancer.

EEG Contribution to the Diagnosis of Antibody-Negative Autoimmune Encephalitis: A Case Report.

Autoimmune encephalitis (AE) is a group of inflammatory brain diseases that are characterized by prominent neuropsychiatric symptoms. Early therapeutic intervention is important for AE. Therefore, without waiting for autoantibody test results, clinicians must consider the possibility of AE based solely on clinical symptoms and conventional test results. The case described herein is of antibody-negative encephalitis with abnormalities shown only by EEG, which contributed to the diagnosis and treatment. The patient, a 20-year-old woman, showed autonomic seizures in addition to movement disorders, psychiatric symptoms, and cognitive dysfunction, which worsened subacutely. Her seizures and movement disorders were not responsive to antiepileptic medications. Results obtained from MRI and cerebrospinal fluid (CSF) were normal; EEG findings showed repeated spikes in the right temporal area, with changes over time. Based on the clinical course and EEG, along with administered immunotherapy, which resolved seizures, movement disorders, and psychiatric symptoms, we suspected AE. For diagnosis of AE and for evaluating treatment responsiveness, EEG was useful. Results indicate that EEG can assist clinicians even with AE cases for which MRI and CSF findings are normal.

CD36 expression on oral squamous cell carcinoma cells correlates with enhanced proliferation and migratory activity.

OBJECTIVE: Recent studies have demonstrated the pro-tumour role of CD36 in multiple cancer types. However, its role has not been well elucidated in oral squamous cell carcinoma (OSCC). Here, we aimed to evaluate the role of CD36 in proliferation and migration of OSCC cells. METHODS: Human OSCC cell lines HSC-2, HSC-3, HSC-4 and Ca9-22 were assessed for proliferation by staining with the cell proliferation marker Ki-67. We also assessed migration activity, and the expression of cell adhesion molecules such as E-cadherin and ß-catenin and platelet-derived growth factor receptors (PDGFRs) of CD36-positive cells. RESULTS: CD36-positive cells showed increased expression of Ki-67 and migration activity compared with CD36-negative cells. Moreover, CD36-positive cells showed reduced expression of E-cadherin and ß-catenin, whereas the expression of PDGFRs increased compared with that in CD36-negative cells. CONCLUSIONS: Our results strongly suggest that CD36 has an important role in facilitating the proliferation and migration activity of OSCC cells, indicating its usefulness in the diagnosis of high-grade tumour and targeted therapy of oral cancer.

Alterations in composition of immune cells and impairment of anti-tumor immune response in aged oral cancer-bearing mice.

OBJECTIVES: Aging has been suggested to be associated with immune dysregulation. An understanding of alterations in the host immunity with advancing age is, therefore, important for designing immune therapy for elderly cancer patients. In this context, not much is known about age-associated alterations in the immune system in oral cancer. METHODS: To evaluate age-associated alterations in the immune system, which might affect anti-tumor immune responses in oral cancer, we performed a comparative analysis of the proportion of different immune cells, the proliferative capacity of T cell compartment, and the response against immune therapies targeting immune check point molecules between young and aged oral cancer-bearing mice. RESULTS: The proportion of immune regulatory cells, such as regulatory T cells and myeloid derived suppressor cells, was significantly increased in aged mice compared to that in young mice. Moreover, the expression of PD-1 and CTLA-4 on both CD4+ and CD8+ T cells was elevated in aged mice compared to that in young mice, and the proliferative abilities of CD4+ and CD8+ T cells derived from aged mice were significantly reduced following stimulation of T-cell receptors. Moreover, tumor growth was significantly enhanced in aged mice compared to that in young mice. However, immunotherapies targeting PD-1, CTLA-4, and PD-L1 resulted in faster tumor regression in aged mice than in young mice. CONCLUSIONS: Together, our results indicate that age-associated alterations in the immune system are directly associated with the impairment of anti-tumor immunity in aged mice bearing oral cancer, and might facilitate the progression of the tumor.

Decreased electrodermal activity in patients with epilepsy.

OBJECTIVE: Biofeedback therapy using electrodermal activity (EDA) is a new noninvasive therapy for intractable epilepsy. However, the characteristics of EDA in patients with epilepsy are little known; therefore, we assessed the EDA characteristics in patients with epilepsy. METHODS: A cross-sectional observational study was conducted in 22 patients with epilepsy and 24 healthy individuals. We collected information on demographic characteristics, EDA, and state anxiety from both groups, and epilepsy diagnosis, seizure number per month, disease duration, and number of antiepileptic drugs (AED) from the epilepsy group. A wristband device was used to measure resting EDA from both wrists for 10 min under controlled temperature and humidity. We compared the EDA levels between the epilepsy group and the control group and examined correlations between EDA and epilepsy-associated factors in the epilepsy group. RESULTS: A decreasing trend in EDA was observed during the first 1 min from the start of the measurement in 22 patients with epilepsy (with or without seizures) compared with healthy controls (P = 0.12). However, a significant decrease in EDA was found in 18 patients with epilepsy with seizures compared with healthy controls (-0.48 versus -0.26; P = 0.036). Furthermore, seizure frequency showed a significant inverse correlation with EDA in the epilepsy group (ρ = -0.50, P = 0.016). However, neither disease duration nor the number of drugs prescribed correlated with EDA in the epilepsy group . SIGNIFICANCE: Marginally decreased EDA was observed in patients with epilepsy, and significantly decreased EDA was found in patients with a higher seizure frequency. The present findings shed light on the appropriateness of EDA-biofeedback therapy in epilepsy.

Novel pathogenic VPS13A gene mutations in Japanese patients with chorea-acanthocytosis.

OBJECTIVE: To identify mutations in vacuolar protein sorting 13A (VPS13A) for Japanese patients with suspected chorea-acanthocytosis (ChAc). METHODS: We performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis of the VPS13A gene, and chorein Western blotting of erythrocyte ghosts. As the results of the analysis, 17 patients were molecularly diagnosed with ChAc. In addition, we investigated the distribution of VPS13A gene mutations and clinical symptoms in a total of 39 molecularly diagnosed Japanese patients with ChAc, including 22 previously reported cases. RESULTS: We identified 11 novel pathogenic mutations, including 1 novel CNV. Excluding 5 patients with the unknown symptoms, 97.1% of patients displayed various neuropsychiatric symptoms or forms of cognitive dysfunction during the course of disease. The patients carrying the 2 major mutations representing over half of the mutations, exon 60-61 deletion and exon 37 c.4411C>T (R1471X), were localized in western Japan. CONCLUSIONS: We identified 13 different mutations in VPS13A, including 11 novel mutations, and verified the clinical manifestations in 39 Japanese patients with ChAc.

Combination of 5-aminosalicylic acid and hyperthermia synergistically enhances apoptotic cell death in HSC-3 cells due to intracellular nitric oxide/peroxynitrite generation.

The repurposing of existing FDA-approved non-cancer drugs is a potential source of new treatment options for cancer patients. An anti-inflammatory drug, 5-aminosalicylic acid (5-ASA), has been clinically used to treat inflammatory bowel disease. Hyperthermia (HT) is widely applicable addendum therapy with the existing cancer treatment modalities. Here, we addressed how 5-ASA combined with HT induces lethal effects in human oral squamous cell carcinoma (OSCC) HSC-3 cells. We found that 5-ASA/HT combination significantly inhibited the viability of HSC-3 cells, while cytotoxic effects in primary human dermal fibroblast cells were minor. Apoptotic endpoints were significantly increased by the 5-ASA/HT combined treatment, as evidenced by presence of Annexin V-FITC/PI positive cells, loss of MMP, Bcl-2/Bax ratio alteration, and increased Fas, cleaved Bid, and caspase expression. Interestingly, the enhancement of apoptosis was reversed in the presence of ON/ONOO- scavengers. These findings indicate that the combination treatment enhances apoptosis via ON/ONOO- mediated ER stress-Ca2+-mitochondria signaling and caspase-dependent apoptotic pathways. Our findings provide novel evidence that the combination of 5-ASA and HT is a promising approach for the enhancement of apoptosis; it may serve as an effective strategy for treating human OSCC.

Seizure manifesting as a reaching/grasping movement in a patient with post-traumatic epilepsy.

Electrical stimulation (ES) of the pre-supplementary or cingulate motor area can cause reaching/grasping (R/G) movements with the hand contralateral to the side of the brain receiving the ES. We report this phenomenon occurring in a 23-year-old right-handed man during spontaneous epileptic seizure, which developed after traumatic brain injury.

Enhanced expression of PD-L1 in oral squamous cell carcinoma-derived CD11b(+)Gr-1(+) cells and its contribution to immunosuppressive activity.

Cancer is often associated with dysregulation of both the humoral and cellular immune response, which in some instances is believed to result from changes in immune cell populations. For example, immunosuppressive CD11b(+)Gr-1(+) myeloid-derived suppressor cells have been shown to proliferate in the tumor microenvironment and surrounding tissues, highlighting the relationship between tumor growth and impairment of the immune response. However, the role of myeloid-derived suppressor cells in cancer progression has not been fully characterized because these cells are heterogeneous with properties influenced by the type and location of the tumor. Here, we show that CD11b(+)Gr-1(+) cells are elevated in the peripheral blood, spleen, and tumor of mice with oral squamous cell carcinoma. The phenotype and function of these cells varied depending on the tissue of origin. In particular, CD11b(+)Gr-1(+) cells in tumors expressed PD-L1 more abundantly than those in other tissues. Accordingly, CD11b(+)Gr-1(+) cells from tumors, but not from the spleen, suppressed T cell proliferation in vitro. The results suggest that tumor-derived or immune factors result in the accumulation of phenotypically and functionally diverse populations of CD11b(+)Gr-1(+) cells in mice with oral squamous cell carcinoma. The data also indicate that PD-L1 expression in CD11b(+)Gr-1(+) cells contributes to immune suppression, implying that targeting both myeloid-derived suppressor cells and PD-L1 would be an effective immunotherapeutic strategy against oral cancer.

Very Long-Term Outcome of Non-Surgically Treated Patients with Temporal Lobe Epilepsy with Hippocampal Sclerosis: A Retrospective Study.

OBJECTIVE: Surgical intervention can result in complete seizure remission rates of up to 80% in patients with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS). However, certain patients cannot be treated surgically for various reasons. We analyzed the very long-term clinical outcomes of patients with TLE-HS who could not be treated surgically. METHODS: Subjects were selected from among patients with TLE-HS who were actively followed up for >10 years and treated with medication without surgical treatment. Patient medical records were used to retrospectively study seizure frequency, various clinical factors, and social adjustment. Patients who were seizure-free or had only aura were classified into Group 1; the others were classified into Group 2. Clinical factors including both patient and disease-specific factors were compared between the two groups. Current social adjustment, including the education, work, and economic status of each patient, was also investigated. RESULTS: Forty-one (41) subjects met the criteria for analysis, of which 12 (29%) were classified into Group 1. The average age of patients in Group 1 was higher than that of Group 2 (p = 0.0468). Group 2 included a significantly higher rate of patients who had more than one seizure per week at the onset (p = 0.0328), as well as a greater mean number of anti-epileptic drugs taken (p = 0.0024). Regarding social adjustment, Group 2 contained significantly fewer current jobholders than Group 1 (p = 0.0288). CONCLUSIONS: After very long-term follow-up periods, 29% of patients with TLE-HS had a good outcome through treatment with anticonvulsant medications. Older patients tended to have fewer seizures, and seizure frequency at the onset was the only factor that predicted outcome.

Video event data recording of a taxi driver used for diagnosis of epilepsy.

A video event data recorder (VEDR) in a motor vehicle records images before and after a traffic accident. This report describes a taxi driver whose seizures were recorded by VEDR, which was extremely useful for the diagnosis of epilepsy. The patient was a 63-year-old right-handed Japanese male taxi driver. He collided with a streetlight. Two years prior to this incident, he raced an engine for a long time while parked. The VEDR enabled confirmation that the accidents depended on an epileptic seizure and he was diagnosed with symptomatic localization-related epilepsy. The VEDR is useful not only for traffic accident evidence; it might also contribute to a driver's health care and road safety.

Magnetoencephalographic analysis of paroxysmal fast activity in patients with epileptic spasms.

PURPOSE: This study sought to demonstrate the origin and propagation of paroxysmal fast activity (PFA) in patients with epileptic spasms (ESs), using time-frequency analyses of magnetoencephalogram (MEG) PFA recordings. METHODS: A 204-channel helmet-shaped MEG, with a 600Hz sampling rate, was used to examine PFA in 3 children with ESs. We analyzed MEG recordings of PFA by short-time Fourier transform and the aberrant area or high-power spectrum was superimposed onto reconstructed three-dimensional magnetic resonance images as moving images. One ictal discharge was collected. One child and one adult with PFA due to Lennox-Gastaut syndrome were also examined for comparison. RESULTS: All four PFAs in Patient 1 and five PFAs in Patient 3 were generated from one hemisphere. In Patient 2, four of seven PFAs were generated from one hemisphere and the remaining three were generated from both hemispheres. In Patient 3, one ictal MEG showed ictal discharges that were generated from the same area as the PFA, although the electroencephalogram showed no discharge. In Patients with Lennox-Gastaut syndrome, all 10 PFAs were generated from bilateral hemispheres simultaneously. CONCLUSION: Short-time Fourier transform analyses of MEG PFA can show the origin and form of propagation of PFA. These results suggest that ESs are representative of focal seizures and the mechanism of PFA is different between ESs and Lennox-Gastaut syndrome.

Akinetopsia as epileptic seizure.

Akinetopsia is a rare syndrome in which a patient specifically loses the ability to perceive visual motion following bilateral cortical lesions outside the striate cortex. We describe a patient who showed akinetopsia recurrently as epileptic seizures. The patient was a 61-year-old man. At age 46, a cerebral arteriovenous malformation in the right parietal lobe was discovered. At age 58, he began to have a recurrent visual symptom by which smooth movements of objects suddenly appeared, resembling freeze frames in a motion picture. This symptom was paroxysmal and recurrent. Both EEG and magnetoencephalography showed repetitive right temporal spikes. We diagnosed his visual symptom as akinetopsia, which was aroused by hyperexcitability of the right temporal and parietal cortices, including area MT/V5. We administered carbamazepine 200 mg/day, which suppressed his akinetopsic symptom completely.

Pilomotor seizures in temporal lobe epilepsy: A case report with sequential changes in magnetic resonance imaging.

Piloerection is a rare ictal manifestation of temporal lobe epilepsy. The case is a 38-year-old man with acute onset of repetitive pilomotor seizures. Lacking other symptoms implicating epileptic seizures, a month passed before he was diagnosed with epilepsy. Ictal electroencephalography revealed rhythmic waves in the right temporal area. Reversible magnetic resonance imaging (MRI) abnormalities were visible in the right hippocampus, right uncus, and right amygdala. The appropriate antiepileptic drug therapy made him seizure-free, but following MRI, he showed right hippocampal atrophy one year after seizure cessation. This case is significant in that we can follow sequential MRI from onset, and it is meaningful for considering the mesial temporal area as involved with piloerection.