Long-term clinical course of adult-onset refractory epilepsy in cardiofaciocutaneous syndrome with a pathogenic MAP2K1 variant: a case report.

Cardiofaciocutaneous syndrome (CFC) is a rare genetic disorder that presents with cardiac, craniofacial, and cutaneous symptoms, and is often accompanied by neurological abnormalities, including neurodevelopmental disorders and epilepsy. Regarding epilepsy in CFC, the onset of seizures commonly occurs in childhood. Since research data has mainly been collected from young patients with relatively short observation period, there is insufficient information regarding adult-onset epilepsy in CFC. Here, we report the long-term clinical course of epilepsy and other complications in a 45-year-old female with genetically confirmed CFC carrying a pathogenic de novo heterozygous variant of MAP2K1, c.389 A>G (p.Tyr130Cys). The patient presented psychomotor delay from infancy and had severe intellectual disability with autistic features. At the age of 30, she first developed combined generalized and focal epilepsy that was resistant to anti-seizure medication. Her refractory epilepsy was fairly controlled with a combination of three anti-seizure medications, especially lacosamide, which effectively suppressed both generalized and focal seizures. The present case provides detailed information regarding the clinical course and treatment of adult-onset epilepsy, which may be useful for optimal treatment and prognostic prediction of CFC.

Efgartigimod combined with steroids as a fast-acting therapy for myasthenic crisis: a case report.

BACKGROUND: Generalized myasthenia gravis (gMG) can be managed with acetylcholinesterase inhibitors (AChEis; e.g., pyridostigmine), corticosteroids, other immunosuppressive drugs (e.g., tacrolimus), and their combinations. Intravenous immunoglobulin (IVIg) or plasmapheresis (PLEX) may be administered if symptoms persist. PLEX and IVIg are also mainstays of treatment for myasthenic crisis. Recently, efgartigimod was approved in Japan for treating adults with gMG (irrespective of the antibody status) who do not have a sufficient response to corticosteroids and nonsteroidal immunosuppressive therapies. Efgartigimod is generally safe and well tolerated. However, since phase III trials of efgartigimod excluded those with myasthenic crisis, the efficacy of efgartigimod in treating myasthenic crisis is still unclear. Moreover, there are no reports that efgartigimod therapy can reduce the dose of corticosteroids needed to achieve a minimal manifestation status. CASE PRESENTATION: We report the case of a 70-yeat-old woman with gMG who developed a myasthenic crisis. After she was diagnosed with gMG, the patient had been treated with oral corticosteroids and tacrolimus for 1 year. However, she refused to continue taking the medication, and two weeks later, she developed ptosis, dysphagia and dyspnea. The patient was intubated and treated with efgartigimod in combination with steroid therapy, and she recovered without PLEX or IVIg. Afterward, when she experienced worsening of fatigue and increased levels of anti-acetylcholine receptor antibodies, efgartigimod therapy was effective. The patient achieved minimal manifestation status even after the reduction of corticosteroids and showed improvements in the Myasthenia Gravis Activities of Daily Living scales after 4 cycles of efgartigimod infusion. CONCLUSIONS: Our case suggests that efgartigimod can be an alternative drug for achieving minimal manifestation status in patients with myasthenic crisis. Considering its strong efficacy and safety, efgartigimod could be expanded to use as bridging therapy in the acute and chronic phases of gMG.

Elderly Woman With No Autoimmune Disease With Aseptic Meningitis Caused by Celecoxib.

Nonsteroidal anti-inflammatory drug (NSAID)-induced aseptic meningitis (NIAM) is frequently reported in patients with autoimmune disease. Ibuprofen-induced NIAM is the most common case report of NIAM. We report a patient without autoimmune disease who developed NIAM following oral celecoxib administration. A literature review and survey of cases registered in the Japanese Adverse Drug Event Report (JADER) database is also provided. A 73-year-old woman with no autoimmune disease developed a headache the day after taking celecoxib, and NIAM was suspected. The headache resolved quickly following celecoxib discontinuation. Although lumbar puncture was not available in this case, bacterial or viral meningitis was negative, and NIAM could not be ruled out. This case involved an older adult patient without an autoimmune disease, with celecoxib as the causative NSAID. A literature review found numerous cases of autoimmune diseases in younger patients. To date, only one case of celecoxib-induced NIAM has been reported. Analysis of NIAM cases in JADER revealed an onset time of approximately three days. JADER analysis indicated that NIAM tended to occur immediately after administration, although the onset with cyclooxygenase-2 selective agents might be slower.

Factors promoting research activities among Japanese pharmacists: a questionnaire survey.

Pharmacists are expected to demonstrate their expertise in clinical practice and conduct research activities to generate new evidence. However, the factors promoting research activities among pharmacists remain unclear. Therefore, we investigated the research activities of Japanese pharmacists through a questionnaire survey and examined the factors contributing to the promotion of research activities. A web-based questionnaire using Google Forms was disseminated across pharmacists working in community pharmacies, drugstores, hospitals, and clinics. The questionnaire included respondents' backgrounds, research activities, and research environments. Logistic regression analysis was used to examine the factors promoting pharmacists' research activities, with experience in research paper acceptance as the objective variable. In total, 401 responses were included in the analysis. Of the respondents, 54.1% were hospital pharmacists, and 77.1% were pharmacists with > 5 years of pharmacist experience. Furthermore, 50.4% of the pharmacists had presented at conferences, and 22.2% had experience in research paper acceptance. The influential factors were "master's degree or higher," "number of affiliated academic societies," "acquisition of specialists/certified pharmacists," and "daily availability of a consultant for writing research papers." This study revealed the factors contributing to the promotion of research activities among pharmacists. We believe that our findings will help promote research among pharmacists.

Impairment of bimanual in-phase movement during recovery from frontal lobe tumor surgery: a case report.

The mechanisms underlying bimanual coordination have not yet been fully elucidated. Here, we evaluated the clinical features of bimanual movement impairment in a patient following surgery for a frontal lobe tumor. The patient was an 80-year-old man who had undergone subtotal tumor resection for a tumor in the right superior frontal gyrus. Histological examination of the resected specimen led to the diagnosis of malignant lymphoma of the diffuse large B-cell type, and the patient subsequently received high-dose methotrexate-based chemotherapy. Postoperatively, the patient had difficulty with bimanual movement, and on the 5th postoperative day we found that the impairment could not be attributed to weakness. Temporal changes in the characteristics of manual movements were analyzed. Bimanual diadochokinesis (opening/closing of the hands, pronation/supination of the forearms, and sequential finger movements) was more disturbed than unilateral movements; in-phase movements were more severely impaired than anti-phase movements. Bimanual movement performance was better when cued using an auditory metronome. On the 15th postoperative day, movements improved. The present observations show that in addition to the disturbance of anti-phase bimanual movements, resection of the frontal lobe involving the supplementary motor area (SMA) and premotor cortex (PMC) can cause transient impairment of in-phase bimanual diadochokinesis, which can be more severe than the impairment of anti-phase movements. The effect of auditory cueing on bimanual skills may be useful in the diagnosis of anatomical localization of the superior frontal gyrus and functional localization of the SMA and PMC and in rehabilitation of patients with brain tumors, as in the case of degenerative movement disorders.

Role of Telomeres and Telomerase in Parkinson's Disease-A New Theranostics?

Parkinson's disease (PD) is a complex condition that is significantly influenced by oxidative stress and inflammation. It is also suggested that telomere shortening (TS) is regulated by oxidative stress which leads to various diseases including age-related neurodegenerative diseases like PD. Thus, it is anticipated that PD would result in TS of peripheral blood mononuclear cells (PBMCs). Telomeres protect the ends of eukaryotic chromosomes preserving them against fusion and destruction. The TS is a normal process because DNA polymerase is unable to replicate the linear ends of the DNA due to end replication complications and telomerase activity in various cell types counteracts this process. PD is usually observed in the aged population and progresses over time therefore, disparities among telomere length in PBMCs of PD patients are recorded and it is still a question whether it has any useful role. Here, the likelihood of telomere attrition in PD and its implications concerning microglia activation, ageing, oxidative stress, and the significance of telomerase activators are addressed. Also, the possibility of telomeres and telomerase as a diagnostic and therapeutic biomarker in PD is discussed.

Utility of scratch art therapy in adult epilepsy patients with difficulties in social adaptation.

OBJECTIVE: Adult patients with epilepsy are confronted with significant psychological and psychosocial burdens. However, the role of psychological intervention to improve quality of life has not been fully established yet. The basis of art therapy is symbolic representations of inner experiences but patients may have difficulty expressing themselves. Here, we investigated utilities of scratch art therapy in Japanese adult patients with epilepsy who feel difficulties in social adaptation. METHODS: Seven adult epilepsy patients (four males, age: 32.1 ± 9.9, mean ± SD) treated in epilepsy clinic of our hospital, who complained of psychosocial problems and underwent psychotherapy sessions combined with art therapy, were included. Six patients had focal epilepsy and two of them were sequelae of encephalitis. They were comorbid with depression, mood disorders, anxiety, memory disturbance, and insomnia. Psychotherapy sessions were scheduled at the same day of their clinic visit, every 4-12 weeks, 60 min per day, and art therapy was performed as a part (up to 30 min, in accord with the condition of the patient) of each session. Scratch art therapy was performed by using ready-made publications. Each patient selected favorite motives of figure out of several options suggested by the therapist. RESULTS: All patients quickly adapted themselves to scratch art therapy and verbally expressed their hidden emotions during drawing. One female patient with emotional lability appealed that she could stab herself by pointed end of the pen. Three patients added self-motivated lines to the designed draft. Two patients realized problems to be solved and moved to other suitable therapeutic procedures. SIGNIFICANCE: The current case series study demonstrated utilities of scratch art therapy in Japanese adult patients with epilepsy who feel difficulties in social adaptation. Scratch art therapy is easy to introduce in adult epilepsy patients who have trouble expressing themselves or have uncontrollable emotions.

[Chemical Stability after Mixing Continuous Infusion Drugs Used to Treat Cardiogenic Shock].

During the treatment of cardiogenic shock, various continuous infusion drugs are used simultaneously. However, administration from the same route may result in stability changes due to mixing of drugs. In addition, stability tests after mixing more than three types of drugs have hardly been conducted. In this study, noradrenaline, milrinone, dobutamine hydrochloride, and landiolol hydrochloride were used to evaluate the chemical stability of the mixture. Chemical stability was evaluated by measuring the change in each drug concentration over time and calculating the content. The concentration of each drug was measured using an optimized gradient elution method by HPLC. In a four-drug mixed sample, noradrenaline, milrinone, dobutamine hydrochloride, and landiolol hydrochloride had retention times of 2.1 min, 5.2 min, 9.3 min, and 11.9 min, respectively. The concentration immediately after mixing each drug was almost the same as the theoretical concentration at the time of mixing each drug. Furthermore, noradrenaline, milrinone, and dobutamine hydrochloride concentrations were maintained up to 99% in each drug mixture until 24 h after mixing all the samples. However, the content of landiolol hydrochloride was 90% or less 24 h after mixing, except for two types of mixed solutions with dobutamine hydrochloride. This result suggested that landiolol hydrochloride was being degraded owing to acidic conditions. The results of this study suggest that noradrenaline, milrinone, and dobutamine hydrochloride can be administered from one route, while it is recommended that landiolol hydrochloride be administered from another route.

Amplitude of Somatosensory Evoked Potentials (SEPs) Recorded in Short-Latency SEP Condition Is 80% of That in Giant SEP Condition.

PURPOSE: Giant somatosensory evoked potentials (SEPs) with enhanced long-loop reflex (C-reflex) are useful to detect cortical motor hyperexcitability in patients with myoclonic epilepsy. The recording conditions of giant SEPs are different from those of short-latency SEPs (SSEPs). We investigated the waveform characteristics obtained for each condition. METHODS: Forty-eight upper limbs of 24 adult normal subjects (12 men, age 35.5 ± 9.7 years [mean ± SD]) were investigated. Somatosensory evoked potentials of each subject were recorded in both conditions on the same day. The main differences in recording conditions were reference electrodes (SSEP: Fz vs. giant SEP: the earlobe electrode ipsilateral to the stimulated limb), stimulus rate (5 vs. 1 Hz), and bandpass filter (20 Hz-3 kHz vs. 1 Hz-1 kHz). Somatosensory evoked potentials were elicited by unilateral percutaneous electrical stimulation of the median nerve at the wrist with intensity of 110% of the movement threshold and recoded at C3'/C4'. RESULTS: The amplitudes of N20 onset-N20 and N20-P25 were significantly larger in giant SEP condition than in SSEP condition (p < 0.001). The mean + 3SD of N20-P25 amplitude was 10.0 µV in giant SEP condition and 7.8 µV in SSEP condition. The N20-P25 amplitude was significantly correlated between giant SEP condition and SSEP condition (R = 0.64, p < 0.001). C-reflex was not elicited. CONCLUSIONS: The amplitude of SEPs in SSEP condition is equivalent to 80% of that in giant SEP condition. The information is useful for detecting cortical hyperexcitability in various neurological disorders including myoclonic epilepsy.

Hyperperfusion in the cerebellum lobule VIIb in patients with epileptic seizures.

BACKGROUND: The cerebellum plays an important role in motor control, however, its involvement in epilepsy has not been fully understood. Arterial spin labelling perfusion magnetic resonance image (ASL) is a noninvasive method to evaluate cerebral and cerebellar blood flow. We investigated cerebellar perfusion in patients with epileptic seizures using ASL. METHODS: Adult patients with epileptic seizures who underwent ASL in three post labeling delay (PLD) conditions (1525, 1800, and 2500 msec) and conventional electroencephalography (EEG) on the same day were investigated. Clinical and EEG characteristics of them were retrospectively analyzed. RESULTS: Six patients (6 women, age; 36.2 ± 17.9 years (mean ± SD)) showed hyperperfusion in selective areas in the cerebellar paravermis of lobule VIIb. One patient with generalized epilepsy (tentative diagnosis of juvenile myoclonic epilepsy or epilepsy with myoclonic absences) showed unilateral hypoperfusion in PLD 1525 msec and hyperperfusion in PLD 1800 and 2500 msec at the area while EEG showed generalized spike-wave complexes. After successful treatment, these perfusion abnormalities disappeared. In two patients with focal epilepsy manifesting with asymmetrical motor symptoms, cerebellar hyperperfusion was found on the opposite side to the seizure focus estimated by seizure semiology. Besides hyperperfusion of the VIIb lobule, hypoperfusion at the same area was detected in shorter PLD condition in four patients and in longer PLD condition in one patient. CONCLUSION: The cerebellar paravermis of lobule VIIb can be a component of motor circuit and participate in epileptic network in humans. Cerebellar perfusion abnormalities can be associated with neurovascular coupling via capillary bed.

Cytotoxic lesions of the corpus callosum after COVID-19 vaccination.

A 23-year-old previously healthy man (Patient 1) and a 33-year-old woman with a past history of depression (Patient 2) developed neurological symptoms approximately 1 week after receipt of the first COVID-19 mRNA vaccination and deteriorated over the next week. Patient 1 reported nausea, headache, a high fever, and retrograde amnesia. Patient 2 reported visual disturbance, headache, dysarthria, a left forearm tremor, dysesthesia of the mouth and distal limbs, and visual agnosia. PCR test results for SARS-CoV-2 were negative. Complete blood cell count, biochemistry, and antibody test and cerebrospinal fluid test findings were unremarkable. Diffusion-weighted and fluid-attenuated inversion recovery MRI of the brain showed a high signal intensity lesion at the midline of the splenium of the corpus callosum compatible with cytotoxic lesions of the corpus callosum (CLOCCs). High-dose intravenous methylprednisolone improved their symptoms and imaging findings. CLOCCs should be considered in patients with neurological manifestation after COVID-19 vaccination.

Anisotine and amarogentin as promising inhibitory candidates against SARS-CoV-2 proteins: a computational investigation.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents an unprecedented challenge to global public health with researchers striving to find a possible therapeutic candidate that could limit the spread of the virus. In this context, the present study employed an in silico molecular interaction-based approach to estimate the inhibitory potential of the phytochemicals from ethnomedicinally relevant Indian plants including Justicia adhatoda, Ocimum sanctum and Swertia chirata, with reported antiviral activities against crucial SARS-CoV-2 proteins. SARS-CoV-2 proteins associated with host attachment and viral replication namely, spike protein, main protease enzyme Mpro and RNA-dependent RNA polymerase (RdRp) are promising druggable targets for COVID-19 therapeutic research. Extensive molecular docking of the phytocompounds at the binding pockets of the viral proteins revealed their promising inhibitory potential. Subsequent assessment of physicochemical features and potential toxicity of the compounds followed by robust molecular dynamics simulations and analysis of MM-PBSA energy scoring function revealed anisotine against SARS-CoV-2 spike and Mpro proteins and amarogentin against SARS-CoV-2 RdRp as potential inhibitors. It was interesting to note that these compounds displayed significantly higher binding energy scores against the respective SARS-CoV-2 proteins compared to the relevant drugs that are currently being targeted against them. Present research findings confer scopes to explore further the potential of these compounds in vitro and in vivo towards deployment as efficient SARS-CoV-2 inhibitors and development of novel effective therapeutics.Communicated by Ramaswamy H. Sarma.

Evaluation of the concordance between GluN1-GluN2 heteromer live-cell-based assay and GluN1 monomer biochip kit assay on anti-NMDAR autoantibody detection.

Anti-N-methyl-d-aspartate receptor (NMDAR) antibodies are most frequently detected in autoantibody-related autoimmune encephalitis. Anti-NMDAR encephalitis mainly affects young women with ovarian teratoma, including acute to subacute onset of psychosis, seizures, consciousness disturbance, dyskinetic involuntary movements, autonomic dysfunction, and others. Diagnosis is based on the detection of anti-NMDAR autoantibodies in cerebrospinal fluid (CSF). The autoantibody recognizes the conformational epitope of the NMDA receptor. NMDA receptors contain hetero-tetramers of GluN1 (NR1) and GluN2/3 (NR2/3), in which GluN1 is essential to form functional receptors on the synaptic membrane in the brain. Thus, the autoantibodies are detected using neurons or culture cells expressing conformational receptors on their cell membrane, the natural form in the brain. The antibodies detected using artificial GluN1 monosubunit expressing cells as the antigens have been widely used for anti-NMDAR-antibody test. In the present study two detection systems were compared, a live-cell-based assay using human embryonic kidney (HEK) 293 cells expressing both of GluN1 and GluN2B, and a commercially available GluN1-monotransfected HEK cell biochip system. As the result, both the methods were equivalent, and the clinical features of both groups were similar, suggesting both tests have equal clinical significance.

Inverse association between hypertension treatment and COVID-19 prevalence in Japan.

OBJECTIVES: Cell entry of SARS-CoV-2 depends on angiotensin-converting enzyme II. Angiotensin-converting enzyme II is homologous with, but acts antagonistically to, angiotensin-converting enzyme and has the critical function of protecting the lungs. Angiotensin-converting enzyme inhibitors are major antihypertensive agents. Thus, we aimed to analyze the impact of the prevalence of preexisting hypertension on the local spread of COVID-19. METHODS: Data on SARS-CoV-2 infection and the estimated number of patients who received medical treatment on the basis of disease classification using the International Statistical Classification of Diseases and Related Health Problems (10th Revision) in each prefecture were obtained from the official Japanese notifications database. We analyzed the association between the proportion of patients with each disease and SARS-CoV-2-infection prevalence. RESULTS: The ratio of patients treated for diseases of the circulatory system, especially hypertensive disorders, per population demonstrated the most significant negative correlation with SARS-CoV-2-infection prevalence (Spearman's rank correlation, P < 0.01). Age group analysis revealed a significant negative correlation in age groups 35-44, 45-54, 55-64, 75-84, and ≥85. CONCLUSIONS: Our findings suggest that hypertension treatment may play a protective role against the local spread of SARS-CoV-2 infection.