The clinical practice guideline for the management of amyotrophic lateral sclerosis in Japan-update 2023.

Amyotrophic lateral sclerosis (ALS) is an adult-onset intractable motor neuron disease characterized by selective degeneration of cortical neurons in the frontotemporal lobe and motor neurons in the brainstem and spinal cord. Impairment of these neural networks causes progressive muscle atrophy and weakness that spreads throughout the body, resulting in life-threatening bulbar palsy and respiratory muscle paralysis. However, no therapeutic strategy has yet been established to halt ALS progression. Although evidence for clinical practice in ALS remains insufficient, novel research findings have steadily accumulated in recent years. To provide updated evidence-based or expert consensus recommendations for the diagnosis and management of ALS, the ALS Clinical Practice Guideline Development Committee, approved by the Japanese Society of Neurology, revised and published the Japanese clinical practice guidelines for the management of ALS in 2023. In this guideline, disease-modifying therapies that have accumulated evidence from randomized controlled trials were defined as "Clinical Questions," in which the level of evidence was determined by systematic reviews. In contrast, "Questions and Answers" were defined as issues of clinically important but insufficient evidence, according to reports of a small number of cases, observational studies, and expert opinions. Based on a literature search performed in February 2022, recommendations were reached by consensus, determined by an independent panel, reviewed by external reviewers, and submitted for public comments by Japanese Society of Neurology members before publication. In this article, we summarize the revised Japanese guidelines for ALS, highlighting the regional and cultural diversity of care processes and decision-making. The guidelines cover a broad range of essential topics such as etiology, diagnostic criteria, disease monitoring and treatments, management of symptoms, respiration, rehabilitation, nutrition, metabolism, patient instructions, and various types of care support. We believe that this summary will help improve the daily clinical practice for individuals living with ALS and their caregivers.

Correlation between Serum Zinc Levels and Levodopa in Parkinson's Disease.

Long-term intake of potential zinc-chelating drugs may cause zinc deficiency. We postulated that zinc deficiency in Parkinson's disease (PD) patients was related to the intake of drugs such as levodopa. We investigated the relationship between zinc levels and levodopa administration period, dosage, and symptoms of zinc deficiency in PD patients. We measured serum zinc levels and analyzed correlations between serum zinc levels, the levodopa oral administration period, dosage, dosing frequency, and zinc deficiency symptoms including taste disorders. Data analyses were performed using Spearman's rank correlation coefficient. The mean serum zinc level was 60.5 ± 11.6 µg/dL. The mean administration period for levodopa was 8.0 ± 5.5 years, mean administration frequency 3.4 ± 0.9 times/d, and mean administration dose 420.6 ± 237.1 mg/d. Negative correlations between zinc levels and levodopa dosage and dosing frequency were found. Multiple regression analysis showed a significant correlation with the frequency of levodopa (ß = -0.360, p = 0.007). No significant change in clinical symptoms was observed after zinc administration, but anxiety tended to improve. Our results indicated that frequent levodopa administration strongly influenced serum zinc levels which may have alleviating effects on psychiatric symptoms; therefore, preventing zinc deficiency can be important during PD treatment.

[A Brief Review on Recent Epidemiologic Literature and Risk Factors of Amyotrophic Lateral Sclerosis].

This brief review of recent epidemiologic literature and risk factors of sporadic ALS found that the incidence and prevalence of the condition is higher among Caucasians and lower in East Asians, with the Japanese in the middle. The review also found that worldwide, the prevalence increases with age and the condition is 1.3 to 1.6 times higher in males than in females. The number of patients with ALS was calculated based on official diagnostic certificates from fiscal 1997 to 2015 obtained from a registry managed by Japan's Ministry of Health, Labor and Welfare. The data matched with those reported in the guidelines of the Japanese Society of Neurology (2013), with an incidence of 1.1-2.5, and prevalence 7.0-8.5/100,000 people. Smoking has been considered an established risk factor for sporadic ALS. The following possible risk factors have been speculated but are to be confirmed: excessive physical activity, head trauma, farming, environmental pollutants, pesticides, exposure to certain metals/heavy metals, electromagnetic fields, alcohol, low BMI, and low-density lipoprotein. Bandres-Ciga et al. applied linkage disequilibrium score regression and Mendelian randomization to a large data set and concluded that elevated low-density lipoprotein cholesterol is a causal risk factor for ALS.

Proposition of zinc supplementation during levodopa-carbidopa intestinal gel treatment.

OBJECTIVES: Levodopa-carbidopa intestinal gel (LCIG) infusion is a useful therapy for the wearing-off phenomenon of advanced Parkinson's disease (PD) patients. Recently, we found three PD patients that may have had a zinc deficiency after the LCIG infusion, possibly due to the zinc-chelating action of levodopa. This study aims to evaluate changes in serum zinc levels in three patients that received LCIG treatment and to determine possible remedies for zinc deficiency during treatment. MATERIALS AND METHODS: We performed a prospective blood analysis of serum zinc levels before, when possible, and after LCIG treatment in our three PD patients. RESULTS: The serum zinc levels of the first patient before treatment and 4 months after beginning LCIG treatment were 69 and 58 µg/dl, respectively. For the second patient, serum zinc levels before treatment and two months after starting LCIG treatment were 87 and 46 µg/dl, respectively. The baseline serum zinc level for the third patient was not examined, but was 48 µg/dl 5 months after starting the LCIG infusion. CONCLUSIONS: Levodopa-carbidopa intestinal gel infusion might have caused a zinc deficiency through levodopa zinc chelation. Zinc deficiency with LCIG infusion has not yet been reported, though preventing zinc deficiency may be an important factor in future LCIG treatment strategies.

Clinical significance of cortical lesions in patients with multiple sclerosis: A neuropsychological and neuroimaging study.

Introduction: This study aims to investigate the association between the presence and frequency of cortical lesions (CLs), and the clinical and psychological features of multiple sclerosis (MS). Methods: A total of 19 patients with MS were examined using double inversion recovery (DIR) sequences with 3T magnetic resonance imaging (MRI) and classified into two groups: CL and non-CL. In-house software was used to quantitatively determine the atrophy of each brain region. Activities of daily living (ADL) were estimated using the Kurtzke Expanded Disability Status Scale (EDSS). Cognitive function was assessed using the following tests: Mini-Mental State Examination (MMSE), Trail Making Test (TMT), and Paced Auditory Serial Addition Task (PASAT). Z-scores were used to assess significant differences in the neuropsychological test outcomes between the groups. Results: Six of 19 patients had subcortical and deep WM lesions (non-CL group; diagnosed with relapsing-remitting MS). Thirteen of 19 patients had both subcortical and cortical lesions (CL group; 9-relapsing-remitting MS; 4-primary/secondary progressive MS). There were no significant differences in age, education, and disease duration, but EDSS scores were significantly higher in the CL group compared to the non-CL group. There were no significant differences in gray and white matter volume between the CL and the non-CL groups, but the white matter lesion volume was significantly higher in the CL group compared to the non-CL group. Neuropsychological tests showed significant performance worsening in the CL group as compared to the standard values for healthy individuals in their age group, especially in the TMT data. Conclusions: Progressive MS, which was associated with decreased physical functioning, ADL, and cognitive impairment, was found in patients in the CL group.

An Investigation of Perspectives of Respite Admission Among People Living With Amyotrophic Lateral Sclerosis and the Hospitals That Support Them.

BACKGROUND: Amyotrophic lateral sclerosis is a progressive disease with rapid degeneration. Respite care is an essential service for improving the well-being of both patients with this disease and their family caregivers, but accessibility of respite services is limited. This study investigates perspectives on respite admission among people living with amyotrophic lateral sclerosis and the hospitals supporting them. METHOD: We conducted semistructured interviews among 3 patients with amyotrophic lateral sclerosis and 12 family members, exploring demographic information and their awareness and experience of respite admission. We also interviewed 16 representatives from hospitals about awareness of and preparation for respite admission for patients with this disease, the role of regional networks for intractable diseases, and knowledge about communication support schemes. RESULTS: We found significant differences in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale between patients who had and had not received respite admission. Qualitative analysis of the data indicated that respite admission was a contributory factor in continuing and stabilizing home care. Limited provision of social services and hospital care quality were barriers to respite admission. CONCLUSION: Respite admission was essential to continued home care for patients with amyotrophic lateral sclerosis. Severe-stage patients were eligible for respite admission. Its accessibility, however, was limited, especially for patients living in rural areas. Supporting hospitals had limited capacity to respond to patients' needs. Individualized care and communication were internal barriers to respite admission.

Does infrared visualization improve selection of venipuncture sites for indwelling needle at the forearm in second-year nursing students?

OBJECTIVES: To evaluate the effectiveness of a vein visualization display system using near-infrared light ("Vein Display") for the safe and proper selection of venipuncture sites for indwelling needle placement in the forearm. METHODS: Ten second year nursing students were recruited to apply an indwelling needle line with and without Vein Display. Another ten participants were recruited from various faculty to serve as patients. The quality of the venipuncture procedure at various selected sites was evaluated according to a scale developed by the authors. Time, scores and patterns of puncture-site selection were compared with respect to three different methods: [1] attempt 1 (tourniquet only), [2] attempt 2 (Vein Display only) and [3] attempt 3 (both). To validate the effectiveness of Vein Display, 52 trials were conducted in total. RESULTS: We found that venipuncture site selection time was significantly improved with the Vein Display, particularly in the case of difficult to administer venipuncture sites. Overall, we found no significant difference with respect to venipuncture quality, as determined by our scale. CONCLUSION: These results suggest that equipment such as the Vein Display can contribute immensely to the improvement of practical skills, such as venipuncture, especially in the context of elderly patients.

Global aphasia without hemiparesis: the underlying mechanism examined by transcranial magnetic stimulation.

INTRODUCTION: Global aphasia without hemiparesis (GAWH) is a rare stroke syndrome. Using transcranial magnetic stimulation (TMS), we evaluated 2 possible pathogenic mechanisms for GAWH: sparing of the decussated pyramidal tract, or alternatively, compensation by the ipsilateral pyramidal tract. METHODS: Six patients were diagnosed to have GAWH by the Standard Language Test of Aphasia for Japanese. All patients underwent brain magnetic resonance (MR) imaging and angiography. According to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria, stroke subtype was determined as 3 patients with cardioembolic stroke, 2 with large-artery atherosclerosis, and 1 with another type. All patients underwent TMS, using a figure-of-8 coil, from 3 to 12 months after the onset, and motor evoked potentials were recorded on the abductor digiti minimi muscles. RESULTS: All patients had left-sided frontal or temporal lesions that were confirmed by MR diagnostic imaging. No motor evoked potential could be recorded by ipsilateral TMS. In 3 patients, brain stimulation on either side evoked the same amplitude on the contralateral abductor digiti minimi, whereas in the other 3 patients, the amplitude was suppressed on the right side. The infarction in the former patients was caused by cardioembolism and in the latter was not. In serial slices of brain MR imaging, the pyramidal tract was spared in the former and was involved to various degrees in the latter 3 patients. CONCLUSIONS: We recommend that GAWH was caused by the sparing of the decussated pyramidal tract. The pyramidal tract was intact in cases of GAWH caused by cardioembolism and subclinically impaired by other causes.

Health-related quality of life among community-dwelling patients with intractable neurological diseases and their caregivers in Japan.

AIMS: The aims of this study were: (i) to clarify the general quality of life (QOL) of patients with intractable neurological disease; (ii) to clarify the general QOL of the caregivers of these patients; and (iii) to explore the association of QOL in patient-caregiver pairs. METHODS: A cross-sectional survey was conducted between November 2003 and May 2004 among community-dwelling patients diagnosed with Parkinson's disease (PD), spinocerebellar degeneration (SCD), multiple system atrophy (MSA), and amyotrophic lateral sclerosis (ALS) and their caregivers using a mailed, self-administered questionnaire. To measure QOL, we used the Medical Outcome Study 36-Item Short Form (SF-36) for patients and the short form of the health-related QOL scale SF-36 (SF-8) for caregivers. RESULTS: A total of 418 questionnaires were analyzed. For the patients, all of the general QOL domains of the SF-36 were significantly lower than the national standard value for all of the diagnoses. Physical function, role physical, and role emotional domains were also low. For caregivers, all of the QOL summary scores of the SF-8 for all diagnoses were significantly lower than the national standard value. Although there were several significant correlations of QOL between patients and caregivers, overall the correlations were low. CONCLUSIONS: Support for patients with neurological diseases and their caregivers is needed in order to maintain physical and mental QOL.

Moral distress experienced by psychiatric nurses in Japan.

This study aimed to: (1) develop and evaluate the Moral Distress Scale for Psychiatric nurses (MDS-P); (2) use the MDS-P to examine the moral distress experienced by Japanese psychiatric nurses; and (3) explore the correlation between moral distress and burnout. A questionnaire on the intensity and frequency of moral distress items (the MDS-P: 15 items grouped into three factors), a burnout scale (Maslach Burnout Inventory - General Survey) and demographic questions were administered to 391 Japanese psychiatric nurses in 2007-2008. These nurses experienced relatively low levels of moral distress despite the fact that they were commonly confronted by morally distressing situations. All the circumstances in which the participants experienced moral distress were included in the 'low staffing' factor, which reflects the characteristics of Japanese psychiatric care. The frequency score of the low staffing factor was a significant predictor of burnout.

[Suggestion for neurologists to attend a palliative care seminar for doctors engaged in cancer treatment].

After the Cancer Control Act (Basic Act) was enforced in April of 2007, the Ministry of Health, Labour and Welfare and local governments nominated leading hospitals (1 chief center in every prefecture, and 1 core hospital in every secondary medical area) for comprehensive promotion of research, prevention and treatment of cancers. These hospitals are supposed to organize palliative care seminars at least once every year to conduct basic training on palliative care for all doctors engaged in cancer treatment, in order to implement palliative care from the early stage. The seminar contains lectures and role-plays regarding relief of pain and improving quality of life during recuperation for all cancer patients and their families. The author suggests that neurologists attend such seminars and introduce similar skills and knowledge to patients with neurological diseases, particularly intractable diseases, after the author had occasion to join such a seminar as an assistant facilitator. The training sessions for communication with patients and families, giving bad news, using opioids, and organizing support teams among local resources also seem useful for neurological fields, until similar teaching schemes are established by appropriate organizations, such as the Japanese Society of Neurology.

Care burden and depression in caregivers caring for patients with intractable neurological diseases at home in Japan.

OBJECTIVES: The aims of this study are to describe the care burden on caregivers of individuals with intractable neurological diseases and to clarify the prevalence of depression in caregivers and factors related to the presence of depression. METHODS: A cross-sectional survey was conducted among caregivers who provide home care to patients with neurological diseases such as Parkinson disease (PD), spinocerebellar degeneration (SCD), multiple system atrophy (MSA), and amyotrophic lateral sclerosis (ALS), using a mailed, self-administered questionnaire. We used the Burden Index of Caregivers to measure multi-dimensional care burden and the Center for Epidemiologic Studies Depression scale to determine the presence of depression among caregivers. RESULTS: A total of 418 questionnaires were analyzed. Although several domains of care burden for caregivers were significantly different among the four diseases, the intensity of caregiving and hours spent caregiving were the main definitive variables. In addition, we described different aspects of the care burden using the multi-dimensional care burden scale. The prevalence of depression in caregivers was high (PD, 46%; SCD, 42%; MSA, 63%; ALS, 61%). Hours required for close supervision of the patient (P=0.015), intensity of caregiving (P=0.024), and low household income (P=0.013) were independently-related variables for depression in caregivers. CONCLUSIONS: The care burden of caregivers was mainly explained by the intensity of caregiving and hours spent caregiving per day, not only according to the disease. The high prevalence of depression indicates the need for effective interventions, especially for caregivers of patients with MSA and ALS.

Neuro-Sweet disease: report of the first autopsy case.

BACKGROUND: Neuro-Sweet disease is a rare condition of central nervous involvement accompanied by cutaneous Sweet lesions. Neuropathological changes in neuro-Sweet disease are unknown. OBJECTIVE: To describe post-mortem findings of the first case of neuro-Sweet disease. RESULTS: A 44-year-old Japanese man developed recurrent episodes of cerebral and brainstem encephalitis with cutaneous Sweet lesions from the age of 34 years. His HLA typing was B54 and Cw1, and the symptoms and MRI abnormalities markedly subsided following corticosteroid therapy. Histologically, there were multiple lesions of perivascular cuffing of small venules by macrophages without vasculitis in the thalamus, temporal lobe, basal ganglia, pons, leptomeninges or ventricular ependym. CONCLUSIONS: THE CORE NEUROPATHOLOGICAL FINDINGS WERE: perivascular cuffing around particularly small veins; absence of granulomatous or necrotic angitis; mainly macrophage infiltration; and the thalamus being most affected. In the present case, the diagnosis of neuro-Sweet disease was made by skin biopsy 5 years after the onset of the central neuron system symptoms. We should pay more attention to skin lesions in steroid responsive recurrent encephalitis in patients who are HLA-B54 or Cw1 positive.

["Tram-track" sign and "donut configuration" in Tolosa-Hunt syndrome].

We report unique MRI abnormalities seen in a patient with Tolosa-Hunt syndrome (THS). A 60-year-old woman was admitted for left eye symptoms, including periorbital pain, numbness around the left eyebrow, blurred vision, delayed light reflex and impairment of abduction. Laboratory studies were unremarkable except for elevated erythrocyte sedimentation rates. T1-weighted MRI showed a mass lesion in the left orbital apex. Fat-suppressed T2-weighted MRI showed a hyperintense parallel linear lesion on the left optic nerve and a ring lesion around it, producing the "tram-track" sign on the axial view and the "donut configuration" on the coronal view. A diagnosis of THS was made, and corticosteroid therapy was started. Symptoms were improved rapidly, and MRI abnormalities disappeared. Reevaluation of MRI which had been taken at the previous episode of the right eye symptoms two years before also showed the "tram-track" sign and the "donut configuration" on the right. These signs are easy to be recognized and well reflect the stage of the disease. They are thus useful for diagnosing THS and evaluating the effect of the treatment. One should pay attention not only to the cavernous sinus and orbital apex, but also to the optic nerve for the MRI diagnosis of THS.

[Analysis of application form for Parkinson's disease provided by the specific diseases treatment research program of Ministry of Health, Labour and Welfare of Japan].

The Ministry of Health, Labour and Welfare (MHLW) of Japan has funded special research programs to investigate etiology and treatment of intractable neurodegenerative diseases. Individual health-care expenditures for registered patients with Parkinson's disease (PD) (Hoehn and Yahr Stage 3-5) have been evaluated by the government. The total number of patients registered with a diagnosis of degenerative parkinsonism including PD, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) was 75,026 in 2004. We analyzed the data from a survey of application forms completed by 23,058 PD patients, which had been entered into the MHLW's computer. The male to female ratio was 1: 1.47, and the mean ages of all patients at registration and at onset were 71.3 years and 62.7 years, respectively. Incidence of young-onset Parkinson's disease was 2.7% of all PD patients. The percentage of PD patients at Hoehn and Yahr Stage 3 was 48.8%, at Stage 4, 23.1%, and at Stage 5, 25.2%. About 60% of patients resided at home, whereas 20% were admitted into the hospital and 20% into a nursing home. The percentages of patients with diurnal fluctuations, dyskinesia and psychotic symptoms were 37.3%, 16.8% and 18.4%, respectively. Ages of patients at registration and at disease onset who presented with diurnal fluctuations and dyskinesia were typically younger and the duration of disease was longer than for those presented without them (p < 0.0001). Patients with psychotic symptoms were older and the duration of disease was longer than those without them (p < 0.0001). Ages of patients receiving ablative surgery were younger than those who received deep brain stimulation (DBS) (57.4 versus 63.1 years, p < 0.01). Approximately 70% of all the patients who underwent stereotactic surgeries were treated within 10 years from onset. The percentage of patients with feeding tube was 6.6%, and the age at registration was older (75.6 versus 71.0 years, p < 0.0001) and duration of disease was longer (11.0 versus 8.4 years, p < 0.0001) in patients with feeding tube than in patients with oral feeding. This is the first analysis of results from the survey of questionnaire for PD provided by MHLW.

Interexaminer variance of median nerve compound muscle action potential measurements in hand position with and without fixation in plaster.

OBJECTIVES: We examined how hand fixation affects interexaminer variance in measuring compound muscle action potential (CMAP) during nerve conduction studies of the median nerve. METHODS: Subjects comprised 6 experienced examiners [1 woman and 5 men; mean (SD) age, 38.3 +/- 8.5 years; range, 28-46 years]. The standardized median nerve motor conduction setting was used for electromyography. The mean of 5 serial stimulations was taken as 1 examination for each subject. Distal latency, conduction velocity, and peak-to-peak amplitude of CMAP were measured as parameters. Subjects were examined without hand fixation and with hands fixed in prepared plaster molds. RESULTS: Fixation yielded significantly decreased coefficient of variance for CMAP amplitude (5.0% +/- 3.4%) compared with measurement without fixation (8.4% +/- 3.7%; P = 0.028). No differences in distal latencies or conduction velocities were evident between fixation and nonfixation. CONCLUSIONS: This study provides quantitative evidence for empirical observations that hand fixation might decrease CMAP variability in median nerve studies.

Pressure ulcers in ALS patients on admission at a university hospital in Japan.

We aimed to review the incidence of pressure ulcers in patients with amyotrophic lateral sclerosis (ALS) on admission at a teaching hospital in Mie, Japan. 592 patients admitted to the neurological ward of Mie University Hospital from 1 April 2004 to 31 March 2006 were reviewed. A retrospective analysis was conducted based on medical and nursing records about pressure ulcers among patients with ALS, parkinsonism (Parkinson's disease, multisystem atrophy, corticobasal degeneration and progressive supranuclear palsy) and other neurological diseases. 16 patients (12 males and four females) aged 36 to 87 years, 71.2 +/- 14.2 years old (mean +/- SD), were identified as having one or more pressure ulcers on admission. No patients developed a new pressure ulcer after admission. The number of patients with pressure ulcers on admission was two in 41 ALS patients, five in 126 parkinsonism patients and nine in 425 patients with other neurological diseases. A proportional analysis by chi2 test for the groups did not show a lower incidence of pressure ulcers in ALS patients. In conclusion, no differences were found in the incidence of pressure ulcers on admission among three neurological groups at a teaching hospital in Mie, Japan.

Neuro-Sweet disease: report of the first autopsy case.

BACKGROUND: Neuro-Sweet disease is a rare condition of central nervous involvement accompanied by cutaneous Sweet lesions. Neuropathological changes in neuro-Sweet disease are unknown. OBJECTIVE: To describe post-mortem findings of the first case of neuro-Sweet disease. RESULTS: A 44-year-old Japanese man developed recurrent episodes of cerebral and brainstem encephalitis with cutaneous Sweet lesions from the age of 34 years. His HLA typing was B54 and Cw1, and the symptoms and MRI abnormalities markedly subsided following corticosteroid therapy. Histologically, there were multiple lesions of perivascular cuffing of small venules by macrophages without vasculitis in the thalamus, temporal lobe, basal ganglia, pons, leptomeninges or ventricular ependym. CONCLUSIONS: The core neuropathological findings were: perivascular cuffing around particularly small veins; absence of granulomatous or necrotic angitis; mainly macrophage infiltration; and the thalamus being most affected. In the present case, the diagnosis of neuro-Sweet disease was made by skin biopsy 5 years after the onset of the central neuron system symptoms. We should pay more attention to skin lesions in steroid responsive recurrent encephalitis in patients who are HLA-B54 or Cw1 positive.

[The present issues to advocate rights of patients with neurological diseases in Japan].

To advocate patient's right is an inevitable assignment of all neurologists who have clinical activities for patients with neurological diseases, though the assignment has very broad fields and is impossible to perform by one. The author summarized present issues of guardianship, the program to protect the social welfare rights in communities, and advance directives for patients with neurological diseases. The new guardianship for adults in Japan started in 2000 and has been increasingly used mainly for the demented. Proxy decision making for a medical care by the guardian is still unsettled. The author raised a possible question on identification of the person who wants medical certification for guardianship and his her intention to obtain such a document, in order to avoid unexpected troubles in the family or involved parties. Replies about the identification from an inspector at a family court, lawyers, judicial scriveners, social workers and Japan National Council of Social Welfare were shown on the table. In May 2007, the Ministry of Health. Labour and Welfare presented the guideline of process to decide the end-of-life-care. But advance directives for medical cares are still controversial in Japan. Multidisciplinary team to advocate patients' rights was stressed in this presentation.