Clinical characteristics of motor functional neurological disorder manifesting as limb weakness after vaccination against coronavirus disease 2019: A case series.

Background: The characteristics of functional limb weakness (FLW) as one of the manifestations of functional neurological disorder after vaccination against coronavirus disease 2019 (COVID-19) remain controversial. Methods: In this descriptive case series, we aimed to elucidate the characteristics of Japanese patients with FLW who claimed muscle weakness after COVID-19 vaccination among patients who visited our outpatient clinic between 1 June 2021 and 31 December 2022. Results: Nine patients were diagnosed with FLW (mean age: 30.8 years), including two men and seven women. Seven patients were vaccinated with the BioNTech/Pfizer vaccine and two with the mRNA-1273 Moderna vaccine. All patients demonstrated various positive signs for FLW. Magnetic resonance imaging or computed tomography indicated no abnormality that could explain their symptoms. At the time of the clinic visit, five patients were treated for psychiatric disorders, including depression, insomnia, attention-deficit hyperactivity disorder, and Asperger's syndrome. Muscle weakness spread to the limbs beyond the vaccinated arm in seven patients. Conclusions: We describe the basic characteristics of FLW in Japanese patients after COVID-19 vaccination. Further recognition of these characteristics could aid the diagnosis of FLW by physicians allowing them to support these patients effectively.

Characteristics of Malpractice Litigation Involving Pathological Autopsies Themselves in Japan: A Database Analysis.

Introduction: Following recently increased public awareness, the number of medical malpractice litigation cases in Japan has increased in all fields of health care. A pathological autopsy is important for medical practice but has not yet been subject to much litigation. Methods: This study presents a review of all civil lawsuits involving pathological autopsies identified in a Japanese database of lawsuits (Westlaw.com). The basic characteristics of cases, the main issues in each case, results, and reasons for the results given by the court were examined. Results: Over 500 cases were examined, among which four autopsy-related negligence lawsuits were retained for analysis. Judgments in these cases were delivered between February 2000 and February 2017. Two judgments were regarding the same case, which was discussed in two different civil procedures (monetary damages and request to return the specimens of patients to relatives). This included three factual cases, which were all civil. Each case was brought by close relatives, and all defendants were hospitals. The main issues were informed consent and the accuracy of autopsy results in two and one cases, respectively. The issues related to informed consent were the need for informed consent to take a specimen and the scope of informed consent. Conclusions: This study describes the basic characteristics of malpractice lawsuits related to autopsies. Lawsuits related to pathological autopsies seem to be relatively rare in Japan.

First evidence of tick-borne encephalitis (TBE) outside of Hokkaido Island in Japan.

Tick-borne encephalitis (TBE) is an infection of the central nervous system caused by the tick-borne encephalitis virus (TBEV). TBE is endemic in parts of Europe and Asia. TBEV is transmitted to humans primarily by Ixodes ticks. There have been 5 TBE cases identified in Japan, all on the northern island of Hokkaido. Rodents with TBEV antibodies and Ixodes ticks have been identified throughout Japan, indicating that TBEV infection might be undiagnosed in Japan. Residual serum and cerebrospinal fluid (CSF) collected in 2010-2021 from 520 patients ≥1 year-of-age previously hospitalized with encephalitis or meningitis of unknown etiology at 15 hospitals (including 13 hospitals outside of Hokkaido) were screened by ELISA for TBEV IgG and IgM antibodies; TBEV infection was confirmed by the gold standard neutralization test. Residual serum was available from 331 (63.6%) patients and CSF from 430 (82.6%) patients; both serum and CSF were available from 189 (36.3%). Two patients were TBE cases: a female aged 61 years hospitalized for 104 days in Oita (2000 km south of Hokkaido) and a male aged 24 years hospitalized for 11 days in Tokyo (1200 km south of Hokkaido). Retrospective testing also identified a previous TBEV infection in a female aged 45 years hospitalized for 12 days in Okayama (1700 km south of Hokkaido). TBEV infection should be considered as a potential cause of encephalitis or meningitis in Japan. TBE cases are likely undiagnosed in Japan, including outside of Hokkaido, due to limited clinical awareness and lack of availability of TBE diagnostic tests.

Functional Neurological Disorder Overlapping Paroxysmal Kinesigenic Dyskinesia Confirmed by Genetic Diagnosis.

Functional neurological disorder (FND) may mimic various kinds of neurologic diseases and may coexist with other neurologic disorders. In cases overlapped by FND, it might be challenging to distinguish symptoms induced by FND and those induced by other underlying neurological disorders, especially when patients show no positive signs indicative of FND. Here, we present the case of a patient who was genetically diagnosed with paroxysmal kinesigenic dyskinesia (PKD). However, most of the patient's symptoms were considered to indicate FND. To our knowledge, there are no reports of FND overlapping PKD. This case illustrates the possibility that FND can coexist with and mimic symptoms of other diseases. It is necessary to rule out coexisting FND symptoms that may modify clinical presentations that cannot simply be explained by a recognized neurological disease.

Neurological post-acute sequelae of SARS-CoV-2 infection.

The novel coronavirus disease 19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can have two phases: acute (generally 4 weeks after onset) and chronic (>4 weeks after onset). Both phases include a wide variety of signs and symptoms including neurological and psychiatric symptoms. The signs and symptoms that are considered sequelae of COVID-19 are termed post-COVID condition, long COVID-19, and post-acute sequelae of SARS-CoV-2 infection (PASC). PASC symptoms include fatigue, dyspnea, palpitation, dysosmia, subfever, hypertension, alopecia, sleep problems, loss of concentration, amnesia, numbness, pain, gastrointestinal symptoms, depression, and anxiety. Because the specific pathophysiology of PASC has not yet been clarified, there are no definite criteria of the condition, hence the World Health Organization's definition is quite broad. Consequently, it is difficult to correctly diagnose PASC. Approximately 50% of patients may show at least one PASC symptom up to 12 months after COVID-19 infection; however, the exact prevalence of PASC has not been determined. Despite extensive research in progress worldwide, there are currently no clear diagnostic methodologies or treatments for PASC. In this review, we discuss the currently available information on PASC and highlight the neurological sequelae of COVID-19 infection. Furthermore, we provide clinical suggestions for diagnosing and caring for patients with PASC based on our outpatient clinic experience.

Rapid and efficient syntheses of tryptophans using a continuous-flow quaternization-substitution reaction of gramines with a chiral nucleophilic glycine equivalent.

A continuous-flow quaternization reaction of gramines with MeI (<1 min) followed by a substitution reaction with a chiral nucleophilic glycine-derived Ni-complex (S)-2 (<1 min) has successfully been developed to afford the corresponding alkylated Ni-complexes 3 in good yields with excellent diastereoselectivity, based on the results of a one-pot quaternization-substitution reaction of gramines with (S)-2 in a batch process. The continuous-flow process allowed the safe and efficient scale-up synthesis of 3j (84% yield, 99% de, 540 g h-1) to give 7-azatryptophan derivative (S)-4j readily by an acid-catalyzed hydrolysis reaction followed by protection with an Fmoc group. The present method for the rapid and efficient syntheses of enantiopure unnatural tryptophan derivatives from various gramines and (S)-2 will be useful to further promote peptide and protein drug discovery and development research.

[Neurological Symptoms Associated With Vitamin Deficiency and Excess: Past and Present Findings].

Vitamin deficiencies and excesses are known to cause various types of brain or peripheral nerve injuries. Improved nutritional status and dietary patterns have led to reduced prevalence, and at least some of these conditions are rare in recent times. However, delayed diagnosis (For example, in patients with Wernicke's encephalopathy) may worsen patient prognosis even in current times. Recent studies have reported an association between cognitive function and some vitamins. In this article, we summarize past and present research focused on neurological symptoms that occur secondary to vitamin deficiencies and excesses.

Clinical features of patients who visited the outpatient clinic for long COVID in Japan.

Background: The clinical course, comorbidity, and management of symptoms after the acute phase of coronavirus disease 2019 (COVID-19) remain controversial. Methods: This was a descriptive case series study, examining the characteristics of patients with longstanding symptoms related to COVID-19 who visited our outpatient clinic between 1 June and 31 December 2021. We analyzed patients' background, chief complaints, clinical course after COVID-19 onset, and clinical examination results. Results: A total of 90 patients with a mean age of 39.8 years were confirmed as having long COVID. The median time between diagnosis of COVID-19 and visiting our clinic was 66.8 days, and 89 patients (98.9%) were unvaccinated. Depression was the most common comorbidity (nine patients, 10.0%). The most common chief complaint was disturbance of smell and/or taste (35, 38.9%), followed by memory disturbance (22, 24.4%) and fatigue (29, 31.1%). Head MRI was performed for 42 (46.7%) patients, and the most common finding was sinusitis (four patients). Olfactory testing was conducted in 25 patients (27.8%) using a T&T olfactometer, and 14 patients (56%) had mild olfactory impairment. Of the five odors in the T&T, recognition of ß-phenylethyl alcohol was most impaired. Conclusions: This study describes the basic characteristics of long COVID in Japan. It suggests that long COVID is complex because it results in a wide range of symptoms.

[Outpatient Clinic for Long COVID].

We summarize the current status of outpatient clinics for patients with long-term coronavirus disease 2019-associated post-acute sequelae severe acute respiratory syndrome coronavirus 2 infection (PASC) at the National Center of Neurology and Psychiatry Hospital. The pathogenesis of PASC is not well understood and its symptoms vary. Recently, the number of patients with PASC has been increasing, meaning that many physicians will need to treat such patients occasionally. Although diagnostic, testing, and treatment methods have not been established, clinicians must apply a long-term management approach to patients based on the clinical evaluation of each individual. Furthermore, there is an urgent need to establish a system for analyzing PASC on a long-term basis.

The efficacy of a novel zinc-containing desensitizer CAREDYNE Shield for cervical dentin hypersensitivity: a pilot randomized controlled trial.

BACKGROUND: Recently, a novel zinc-containing desensitizer, CAREDYNE Shield, was developed. This new type of desensitizer induces chemical occlusion of dentinal tubules for desensitization and releases zinc ion for root caries prevention. Despite these features, its clinical effectiveness in the improvement of cervical dentine hypersensitivity remains to be elucidated. Thus, we aimed to evaluate the effectiveness of CAREDYNE Shield in patients with CDH. METHODS: Forty CDH teeth which matched the eligibility criteria were randomly allocated to two groups in a 1:1 ratio: the CAREDYNE Shield group (intervention group) and the Nanoseal group (control group). The pain intensity in response to air stimuli, gingival condition, and oral hygiene status of CDH teeth were assessed before and at 4 weeks after treatment. The primary outcome was the reduction of pain intensity in response to air stimuli from baseline to 4 weeks after intervention. RESULTS: From November 2019 to April 2021, 24 participants with 40 teeth were enrolled in this study and 33 teeth in 20 participants were assessed at 4 weeks after treatment. A significant reduction of pain in response to air stimuli was observed in both groups; however, no significant difference was observed between the groups. CONCLUSIONS: This study showed that CAREDYNE Shield is effective for CDH and its effectiveness is similar to Nanoseal. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN-CTR), UMIN000038072. Registered on 21st September 2019, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000043331.

Neuropathological studies of serotonergic and noradrenergic systems in Lewy body disease patients with delusion or depression.

AIM: The association between psychiatric symptoms in Lewy body disease (LBD) and the noradrenergic and serotonergic systems is still controversial. This study investigated the quantitative relationships of depression and delusion with these systems. METHODS: We studied 24 postmortem tissues from individuals with a pathological diagnosis of LBD with sufficient clinical history. The numbers of neurons and Lewy bodies (LBs) in the locus coeruleus (LC) and dorsal raphe nucleus (DRN) were counted, and the density of neurons in the DRN was analyzed. In addition, the densities of tryptophan hydroxylase-positive neurites and norepinephrine transporter-positive neurites in the amygdala and dorsal prefrontal cortex were measured. Finally, we divided the cases into two groups: with or without depressive mood, and with or without delusion. Quantitative histological data were compared between the groups. RESULTS: The group with depressive mood had a significantly smaller number of neurons in the LC compared with the group without depressive mood. The group with delusion had a significantly larger number of LBs in the DRN compared with the group without delusion. The density of norepinephrine transporter-positive neurites in the dorsal prefrontal cortex was significantly correlated with the number of neurons in the LC. CONCLUSIONS: The accumulation of LBs in the DRN of individuals with LBD was associated with delusion, whereas a decrease in the number of neurons in the LC was associated with depressive mood. These neurodegenerative changes involved the serotonergic and noradrenergic systems and may be associated with the formation of delusion and depression, respectively, in LBD.

The efficacy of the novel zinc-containing desensitizer CAREDYNE Shield on dentin hypersensitivity: a study protocol for a pilot randomized controlled trial.

BACKGROUND: Dentin hypersensitivity (DH) is a condition characterized by short and sharp episodes of pain which will arise in response to tactile, chemical, thermal, evaporative or osmotic stimuli. The painful symptoms cause discomfort in patients and reduce their quality of life. Recently, the novel zinc-containing desensitizer CAREDYNE Shield has been developed as a new type of desensitizer that acts by inducing chemical occlusion of dentinal tubules, and releasing zinc ion for root caries prevention. However, the clinical effectiveness of CAREDYNE Shield on DH remains unclear. Therefore, the aim of this study is to evaluate the effectiveness of CAREDYNE Shield on DH by comparing with that of another desensitizer, Nanoseal, commonly used in Japan. METHODS/DESIGN: This study protocol is a two-arm, parallel, pilot randomized controlled trial. Forty DH patients will be randomly allocated to two groups. Participants in the intervention group will be treated with CAREDYNE Shield, while those in the control group will be treated with Nanoseal. The primary outcome is the reduction of pain intensity in response to air stimuli measured with a 5-point verbal response scale from baseline to 4 weeks after the intervention, and Fisher's exact test will be used for analyses. DISCUSSION: CAREDYNE Shield can be casually applied to subgingival areas and proximal surfaces because it reacts with only tooth substance. Furthermore, zinc has been reported to reduce the demineralization of enamel and dentin and inhibit biofilm formation, plaque growth and dentin-collagen degradation. Therefore, CAREDYNE Shield may be expected to be a useful novel desensitizer that acts not only as a desensitizer but also as a root caries inhibitor. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN-CTR), ID: UMIN000038072. Registered on 21 September 2019. TRIAL STATUS: This study (protocol version number: version 1.4.0; approved on 22 October 2019) is ongoing. The recruitment of participants began in December 2019 and will be continued until November 2020 (Hanke, Am Dent Assoc 27:1379-1393, 1940).

[Medical Malpractice in Neurological Diseases].

The results of medical lawsuits in Japan can affect actual clinical settings, and it might be useful to analyze medical lawsuits in order to understand medical issues. Some diseases such as subarachnoid hemorrhage, cerebral infarction treated with thrombolytic therapy and treatable encephalitis could cause problems, which in turn may lead to lawsuits, when the results of treatment for those situations are fatal. In addition, there are cases in which other neurological diseases are related to litigation. Therefore, I scrutinized such cases and suggested useful tips for establishing good relationships between doctors and patients and preventing troubles that could lead to medical lawsuits.

Nationwide epidemiological survey of superficial hemosiderosis in Japan.

BACKGROUND: The Japanese guideline for diagnosis and classification of superficial hemosiderosis (SHS) has recently been published, for which patient medical expenses are supported by the Ministry of Health. We sought to clarify the clinical features, method of diagnosis, and treatment for SHS in Japan. METHODS: We sent a questionnaire survey to 792 medical institutes of the Japanese Society of Neurology, to collect information about SHS, including patients during 2017. RESULTS: We received replies from 287 institutes (36.2%). Estimated total number of patients with SHS in 2017 was 129 at 55 institutes. All patients were diagnosed by neurologists. Among 123 patients with available data, 81 patients (63%) had "classical" type (c-SHS), 29 (24%) had "localized" type (l-SHS), and 13 patients (10%) had "atypical" type (a-SHS). Five patients with l-SHS were excluded because of lacking detailed information. There were available data for the cause of SHS in 77 patients (63%): 55 (69%) with c-SHS, 16 (55%) with l-SHS, and 6 (48%) with a-SHS. Pharmacological or surgical treatment was given at 31 institutes. Medical expense subsidies were filed for 41% of patients. CONCLUSIONS: Using the Japanese guideline for diagnosis of SHS, over 100 patients were confirmed as having SHS with characteristic clinical features. SHS is not a rare clinical condition in Japan.

Inflammatory myopathy associated with PD-1 inhibitors.

OBJECTIVE: To characterize the inflammatory myopathy associated with programmed cell death 1 inhibitors (PD-1 myopathy). METHODS: We studied 19 Japanese patients with PD-1 myopathy (13 men and 6 women, mean age 70 years), who were referred to Keio University. As control groups, we used 68 patients with anti-signal recognition particle antibodies, 51 patients with anti-aminoacyl transfer RNA synthetase antibodies and 460 healthy subjects. RESULTS: In regard to muscle-disease severity, 10 patients showed a mild form of disease and 9 patients showed a severe form. Non-small cell lung cancer was the most common underlying cancer. PD-1 inhibitor consisted of 11 nivolumab and 8 pembrolizumab. PD-1 myopathy occurred 29 days on average after the first administration of PD-1 inhibitor. The initial manifestation of muscle weakness was ptosis in 10 patients, 15 patients had ptosis, 13 diplopia, 8 facial muscle weakness, 10 bulbar symptoms, 13 limb weakness, 14 neck weakness, 4 cardiac involvement, 6 respiratory involvement and 16 myalgia. Ocular, facial, cardiac and respiratory involvement and myalgia were more frequently observed than controls. Serum creatine kinase was increased to 5247 IU/L on average. Autoantibodies related to inflammatory myopathy were negative, while anti-striational antibodies were found in 13 (68%) patients. HLA-C*12:02 alleles were more frequently detected than healthy controls. Muscle pathology was characterized by multifocal necrotic myofibers with endomysial inflammation and expression of MHC class I. Immunosuppressive therapy with corticosteroids was generally effective for muscle weakness. CONCLUSIONS: Based on our clinical, histological and immunological findings, PD-1 myopathy is a discrete subset of inflammatory myopathy.

Dolichoectasia of the right internal carotid artery diagnosed incidentally by MR angiography in a 17-year-old girl.

Dolichoectasia of the cerebral artery, a rare disorder of arterial elongation, dilatation, and tortuosity, usually involves the vertebrobasilar system in elderly patients with hypertension and is associated with the development of atherosclerosis in the aging process. We present a very rare case in a 17-year-old girl with multiple sclerosis of dolichoectasia of the supraclinoid segment of the internal carotid artery that was found incidentally on magnetic resonance angiography and seems to represent a congenital arterial malformation.

[Superficial Siderosis].

Superficial siderosis (SS) is a rare, neurodegenerative disease that results from toxic accumulation of hemosiderin on the surface of the brain and spinal cord. The Japanese guidelines for diagnosis and classification of SS have been classified into three categories, according to the distribution of iron deposition and the clinical symptoms, as follows: "classical" type, "localized" type and "atypical" type. In "classical" type SS, patients typically present with slowly progressive and irreversible cerebellar ataxia, sensorineural hearing loss, and/or myelopathy, due to involvement of the acoustic nerve, cerebellum, and spinal cord. T2-weighted imaging (WI) or T2* WI demonstrates characteristic linear low intensity signals along the surface of the brain and spinal cord. However, the natural history and clinical evolution of SS are poorly understood. Furthermore identification and resolution of the bleeding source do not elicit prompt clinical recovery or radiological reversal of SS in most cases. Pharmacological treatments for SS primarily include strategies that produce iron chelation. For example, deferiprone is the only treatment that crosses the blood-brain barrier and binds hemosiderin in the central nervous system.

Triptan-induced Reversible Cerebral Vasoconstriction Syndrome: Two Case Reports with a Literature Review.

We encountered two patients with sumatriptan-induced reversible cerebral vasoconstriction syndrome (RCVS). The present patients were taking sumatriptan for the first time because they had been tentatively diagnosed with a migraine. On reviewing the literature, we found nine other cases of triptan-induced RCVS, predominantly among women aged 30 to 40 years. RCVS has been precipitated by triptan at the first ever use, after daily use, and even with long-term use at a normal dose. Patients with acute onset of severe headache should be thoroughly evaluated, and triptan should be administered appropriately. If triptan-induced RCVS is suspected, vascular imaging should be repeated after several days.