Parkin (PRKN), identified in 1998 as the primary gene responsible for familial Parkinson disease (PD), is also the most common cause of young–onset PD. PRKN, which encodes a ubiquitin–protein ligase, plays a crucial role in mitophagy and mitochondrial quality control, alongside PTEN–induced putative kinase 1 (PINK1). The discovery of PRKN's role in PD has highlighted the importance of the proteolytic system in neurodegenerative diseases. Our research has further identified CHCHD2 and prosaposin (PSAP), both involved in the Parkin mechanism. With over 25 genes and loci linked to PD, it's clear that PD is a diverse group of diseases. Diagnosis is currently based on clinical symptoms and imaging, but early detection is crucial for effective treatment. Our group is also researching potential biomarkers for PD.

Since 1982, The Japanese Society of Neurological Therapeutics has promoted (1) publication of treatment guidelines for rare diseases, (2) industry–government–academia collaboration, (3) globalization, and (4) support of clinical trials. In the future its role will be expanded focusing on clinical trial support and drug recovery/development. In 2021, the committee for promotion of drug discovery has been launched. The committee will activate (1) research and development, advices on the trial protocol and participating institutes, (2) support for collection of participants (patients), matching of industry and academia, (3) development of trial–ready registry, and (4) patient and public involvement. So far, the committee has supported 5 clinical trials by pharmaceutical industries. The Japanese Society of Neurological Therapeutics should play an important role in the promotion of drug recovery and clinical trials.

In introducing disease modifying therapy (DMT) for Alzheimer disease, Japanese Society for Neurological Therapeutics (JSNT) has investigated online survey for JSNT menbers concerning on recognition and present status of DMT. Ninty eight % of the response was obtained from neurologist and the response rare was 48.9% (298/609). Majority of instituitututions planed to introduce DMT (63%), and select amyloid PET (77%) as as a diagnostic method. This survey may provide a useful tool for facilitating introduction of DMT for Alzheimer disease in Japan.

Recently, the treatment strategy for central nerve system inflammatory demyelinating disease has been remarkably progressing. In multiple sclerosis (MS), eight disease modifying drugs (DMD) became available and made it possible to suppress not only relapses but also disease progression. Now it is a consensus that early DMD initiation will lead to better long–term outcome. In neuromyelitis optica spectrum disorders (NMOSD), aquaporin 4 (AQP4) protein, which is expressed on the foot process of astrocyte, is the key target of the disease–specific autoantibody, especially in those with AQP4 antibody–positive NMOSD. Recently, multiple biological products got covered by health insurance, which contributed to achieve prevention of clinical relapses. Each product has distinct mode of action and possible adverse events. So those biological products should be safely utilized with accurate understanding of possible adverse events and enough explanation to patients. Finally, a novel disease entity of which characteristics is the positivity of autoantibody against myelin oligodendrocyte glycoprotein (MOG) protein. MOG antibody–associated disease (MOGAD) demonstrates acute disseminated encephalomyelitis, optic neuritis, or multiple other phenotypes. Novel and the first international diagnostic criteria for MOGAD has been published. So far it is not recommended to measure MOG antibody for all the patients with MS even though it is important to differentiate MOGAD from MS.

Alzheimer disease (AD), the most common age–related neurodegenerative disorder, is characterized by pathological hallmarks in the brain, including plaques composed of amyloid β (Aβ) protein, neurofibrillary tangles of tau protein, and neuronal death. Aβ monomers are generated from amyloid precursor protein by the cleavage of β– and γ–secretase and aggregate to form oligomers, protofibrils, and mature fibrils. Although insoluble fibrils of Aβ protein, which accumulates as amyloid in the brain, were previously considered toxic, recent attention has been focused on oligomers and protofibrils, more highly toxic aggregates of Aβ protein. Remarkable disease–modifying therapies (DMT) for AD targeting Aβ protein were recently developed. Anti–Aβ antibodies such as aducanumab, lecanemab, and donanemab slowed the clinical progression of AD, and the US Food and Drug Administration approved the former two for its treatment. Aducanumab showed stronger binding to fibrils than to protofibrils, whereas lecanemab demonstrated selectivity towards protofibrils over fibrils. These antibodies bound monomers with low affinity. ALZ–801 is an oral small–molecule agent for which a phase 3 trial is ongoing in homozygous apolipoprotein E 4/4 patients with early AD. Although most clinical trials to date failed to show significant improvements, many new agents are still in clinical trials to find effective DMT for AD.

Disease–modifying agents for dementia have been clinically implemented in Japan. In order to select appropriate patients for treatment with disease–modifying drugs, it is necessary to estimate brain pathology more accurately than ever before. As is clear from many previous studies, the conventional clinical diagnosis of Alzheimer disease, which is based primarily on the evaluation of clinical symptoms, has a troubling misdiagnosis rate of more than 30%. In order to overcome this barrier of misdiagnosis, it is essential to evaluate brain pathology using a variety of biomarkers, and a good understanding of the significance and usefulness of various biomarkers as well as their limitations and pitfalls is required for clinicians involved in dementia treatment. In this article, this paper focus on imaging biomarkers in the evaluation of dementia pathophysiology, and summarize the current minimum requirements to be understood mainly in the diagnosis of brain pathophysiology. In addition, the potential problems that may arise in the future when amyloid PET imaging becomes widely used in clinical practice will be outlined.

Although disease modifying drugs for Alzheimer disease (AD) have been developed, it is unfeasible to implement disease–modifying therapy in all patients with AD, considering the large number of AD patients and the socio–economic burden of treatment. The WHO guidelines on risk reduction of cognitive decline and dementia (2019) provide 12–item evidence–based recommendations on lifestyle behaviors and interventions. We focus on nutrition and physical activity among them and discuss using own experiences.

Basic studies on AD models have reported that rosmarinic acid (RA) can inhibit the aggregation including oligomerization of amyloid β–protein (Aβ). We conducted clinical trials using lemon balm (Melissa officinalis) extract containing RA, and showed RA is tolerable and safe, in addition it may prevent cognitive decline in older adults without hypertension.

Regarding physical activity, we showed that decreased walking speed was significantly associated with hippocampal atrophy, global brain atrophy and white matter hypo intensities in community dwelling older adults. We also developed an exercise program for prevention of cognitive decline and improve physical function in the older adults.

According to the change of concept of Alzheimer disease, the informed concent in dementia clincal setting is also about to change significantly. This article describes about the problem of informed concent of dementia daily clinical setting, including future announcements, including the draft of revised Criteria for Diagnosis and Staging of Alzheimer's Disease : Alzheimer's Association Workgroup, which has been anounced in AAIC 2023.

In recent years, the disease concept of autoimmune cerebellar ataxia has expanded with the identification of anti–neural antibodies. Autoimmune cerebellar ataxia (ACA) is a group of diseases for which pathophysiological elucidation and therapeutic strategies are expected to be established in the future. Although proposed diagnostic criteria for ACA were published from Europe in 2022, the number of patients with ACA and its pathophysiology is still unknown in Japan. That is why early diagnosis and classification of ACA is difficult, which often leads to difficulties in treatment. It is important to establish diagnostic criteria of ACA in Japan.

Chorea is a disorder characterized by relatively fast and irregular movements that mainly affect the limbs and facial muscles. The causes of chorea are varied and can be classified as genetic or acquired. In the present review, we summarize autoimmune chorea, which is an acquired form. The clinical features of autoimmune chorea involve a generally acute or subacute onset and are frequently complicated with other neurological symptoms. Brain MRI rarely shows abnormal intensities in the basal ganglia, and CSF examination usually demonstrates increased cell counts and/or protein concentrations. Hypermetabolism in the basal ganglia has been reported in fluorodeoxyglucose positron emission tomography, indicating that this imaging method may be useful in patients with suspected autoimmune chorea. Moreover, specific anti–neuronal antibodies are sometimes detected in patients and are an important diagnostic marker of autoimmune chorea. Autoimmune chorea is treatable and requires a combination of symptomatic treatment, immunotherapy, anticoagulant therapy, and antitumor therapy, depending on the causative disease.

ILAE classification of the epilepsies (2017) has adopted “immune” as one of the etiologies of epilepsy. Autoimmune epilepsy is regarded as a forme fruste of autoimmune encephalitis, where epileptic seizure is the sole or main feature of the disease. I will review the clinical characteristics of autoimmune epilepsy, practical diagnostic algorithm and score (without antibody testing), treatment and underlying autoimmune pathophysiology in this review. The earlier diagnosis and treatment impact the prognosis of this entity.

The prevalence of migraine is higher in women than in men, especially in women after adolescence. Female hormones, especially estrogen, are greatly involved in the onset of migraine, and migraine attacks increase after a woman's menarche. In women, menstrual migraine that occurs during menstruation is generally known to be more severe and last longer than migraine attacks that occur outside of menstruation. It's also known that migraine attacks are reduced during pregnancy. There are many reports that there is a marked improvement, especially in the late pregnancy (8^th to 10^th month of pregnancy). It's said that this is because the concentration of estrogen in the blood is maintained at a high level from the second trimester (5^th to 7^th month of pregnancy) onwards, making it easier for the attacks to subside. However, it has been reported that about half of migraineurs experience a reccurence within one month after giving birth. This is thought to be due to the rapid drop in blood estrogen levels immediately after childbirth and the burden of childcare (lack of sleep, mental stress, etc.). Treatment is carried out in accordance with general migraine treatment. As an acute treatment, triptans are used to treat menstrual migraine, but as the duration of the attack is longer and more severe than normal migraine attacks, naratriptan, which is a long–acting type of triptan, is often selected. This can be treated by taking acetaminophen or NSAIDs at the same time. Regarding preventive therapy, options include the use of existing preventive drugs and CGRP–related antibody preparations that have appeared in recent years, but there are reports that they are somewhat less effective against menstrual migraines. Additionally, drugs should basically be avoided during pregnancy, but the first–choice acute phase treatment drug is acetaminophen, and when it comes to triptans, sumatriptan is often used. Although there are many reports, there is no clear evidence of safety, and triptans are used when the benefits outweigh the risks in severe migraine attacks. Propranolol, a beta–blocker, is used as a prophylactic drug. As described above, treatment especially for women, who have a large number of patients, requires detailed treatment tailored to each individual patient.

Epilepsy is one of the most frequent neurological disorders, affecting approximately 1 in 100 people. Epilepsy is a disorder involving a variety of syndromes and has many different causes and conditions. There are slight gender differences in the onset of epilepsy, with epilepsy as a whole reported to be slightly more common in males. However, among the epilepsy syndromes, such as childhood absence epilepsy, juvenile absence epilepsy and juvenile myoclonic epilepsy, are reported to occur more frequently in women. The causes of these sex differences are less clear, although some hypotheses have been put forward, including differences in sex hormone secretion, neurosteroids, cranial neurodevelopment, GABAergic neurotransmission and vulnerability to hypoxia at birth. Sex hormones influence seizures, with progesterone and testosterone having antiepileptic effects and estrogen making seizures more likely. On the other hand, epileptic discharges may affect the hypothalamic–pituitary–gonadal system, causing dysfunction of the hormonal system. In relation to this, seizures may increase during ovulation and menstruation.

In the pharmacological treatment of women with epilepsy, the choice of drug is based on considerations such as teratogenicity, neurodevelopment of the child after birth. The incidence of major malformations in infants born to women taking antiepileptic drugs is two to three times higher than in those not taking the drugs, although it has also been shown that the effect is less severe with single drugs and lower doses. Japanese Epilepsy Practice Guidelines 2018 state that drugs other than VPA should be considered in women of childbearing age and, if unavoidable, should be administered at 600 mg/day or less. Folic acid supplementation with 0.4–0.6 mg/day is recommended during pregnancy, as folic acid reduces the teratogenic effects of antiepileptic drugs and the neurodevelopmental effects of the child.

With regard to sexual function, patients with epilepsy have a higher frequency of sexual dysfunction than the general population. Polycystic ovary syndrome should be carefully monitored, as the complication rate in female epileptic patients is 10–18%, compared with 6.6% in the general female population.

The incidence of Parkinson disease (PD) is twice as high in men as in women in the West. The cause of the gender difference has been suggested to be the protective effect of estrogen on neurodegeneration, but this has not been clarified. In Japan, the incidence of PD is higher in women. Gender differences in clinical symptoms of PD have also been reported. Women have a later age of onset of motor symptoms, but are more prone to postural instability, are at higher risk for falls and progression to frailty, and are at higher risk for levodopa–associated motor complications. There are also gender differences in the pharmacokinetics of L–dopa preparations, the gold standard for PD treatment. In general, the bioavailability of levodopa is higher in women, and the area under the curve (AUC) of L–dopa is known to be 17∼27% higher in women than in men. This is speculated to be a contributing factor to dyskinesia induction. Furthermore, it has been noted that female patients with PD have disparities in treatment choice and care, including inadequate opportunities to choose device–aided therapies such as deep brain stimulation, and fewer opportunities to receive nursing care. Although information on gender differences is limited, we would like to provide appropriate treatment for each patient.

Multiple sclerosis (MS) occurs in young adults in their 20s to 40s, with a male to female ratio of 1:2. Neuromyelitis optica spectrum disorders (NMOSD) are more common in people in their late 30s to 50s, but are seen from the childhood to the elderly. About 90% of aquaporin 4 (AQP4) antibody–positive patients are female. Women are more likely to develop autoimmune disease and have a higher risk of relapse due to inflammatory demyelination in MS. However, recent advances in disease–modifying drugs have reduced relapses and the rate of conversion to secondary progressive MS is decreasing. Therefore, treatment strategies based on life stages are important to ensure lifelong quality of life despite neurological disease.

In adolescence, vaccination should be completed in anticipation of the future introduction of disease–modifying drugs, attention should be paid to menstrual irregularities associated with steroid treatment, and osteoporosis prevention should be addressed. Appropriate treatment according to disease activity should also be considered in younger patients, as frequent relapses and disability during this period can be a major disadvantage in later life, including employment and marriage.

Pregnancy and childbirth do not have any negative impact on MS, but data show that people with MS are significantly more likely to live alone or be childless. It is therefore important that healthcare providers and patients actively discuss family planning. Appropriate treatment should be given prior to pregnancy, as a stable MS condition prior to conception is important in preventing relapses in the postpartum period. It should be noted that NMOSD, unlike MS, has a negative impact on the course of pregnancy and relapses after delivery. Therefore, the patient's medical and parental support system should be identified before delivery.

On the other hand, men with MS are more likely to develop axonal degeneration and grey matter lesions, and male gender is known to be a poor prognostic factor in MS. The onset of the disease in young adults, leaving physical and cognitive impairments, leads to employment and economic disadvantages. Treatment and social support for male patients is therefore also important.

Biodesign is a process that realizes innovation through the development of medical technology (devices and systems), initiated at Stanford University in the late 1990s. It enables the practice of human–centered design in the complex landscape of medical and healthcare, where stakeholders are intricately involved, serving as a trusted approach to value–based innovation in the field. Currently, Biodesign has expanded to approximately 10 countries across Asia, Oceania, Europe, South America, and Africa, establishing hubs with individuals who have completed the Stanford Biodesign faculty course.

Particularly in Silicon Valley, a hub for driving innovation, Biodesign demonstrates a strong impact by fostering the construction of innovative projects and developing individuals capable of leading them at the pre–incubation stage, prior to entering incubation facilities. Understanding the distinct characteristics of the processes involved in the development of medical devices and pharmaceuticals, it is crucial to advance individual projects.

Medical device development often follows the identification of wishes and wants perceived by experts, such as specialized physicians, resulting in the proposal of new products and the progression of research and development. Projects initiated in such a manner frequently face challenges related to what is commonly referred to as the “exit strategy” in Japan, leading to project stagnation. Biodesign addresses this by examining business perspectives in the early stages of development, generating technology solutions starting from the needs in healthcare settings, and thus creating projects with a high probability of reaching patients.

Whether in the context of medical device development projects or aiming at patient treatment, Biodesign is considered valuable for designing new solutions with drugs―essentially new technologies―and strategically thinking about the design of the patient's treatment experience.

Pharmaceutical companies have high expectations for the use of Real World Data (RWD) in drug development. There have been the issues of long–term duration taken, large amount of costs required and low success rate for a drug to be approved. One of the solutions is to utilize an accumulated RWD in daily clinical practice. The use of RWD has being promoted around the world, and the new coronavirus infection pandemic has accelerated its efforts. In May 2022, the European Union released the European Health Data Space (EHDS) Initiative and Bill, and clearly indicated a policy that links medical data of EU citizens and that will be used not only for their own health management but also for medical, administrative, and R&D. In Japan, the government declared the Healthcare DX Reiwa Vision 2030 in 2022 and began putting a lot of efforts into promoting the Healthcare DX. Japanese RWD has been decentralized for data management and to make full use of RWD is necessary to establish the medical information infrastructure for RWD and legal arrangement to enable it with reference to EHDS. Japan's RWD has more attractive characteristics than those of other countries. I believe that once evidence generation system which enables the full use of Japanese people's RWD would be established, it will lead not only to the future medicinal advancement and sustainability of medical care in Japan but also provide excellent insight to the world.

Rare diseases have been slow to progress in elucidating their pathogenesis and developing new drugs. Establishing a platform to facilitate drug discovery research and implementing a patient registry for rare diseases are crucial endeavors in this field. Moreover, the platform should serve to uncover pathological conditions through clinical epidemiological analysis and genomic and omics studies, while also fostering corporate collaboration to drive drug development forward.

The Rare Disease Data Registry of Japan (RADDAR–J) serves as an invaluable information hub, covering approximately half of the 338 designated intractable diseases. Its website offers comprehensive catalog information on rare disease research group registries and repositories, facilitating collaboration between these groups and corporate entities.

In recent times, there has been a notable rise in the utilization of patient registries in various aspects of pharmaceutical and product development, including post–marketing surveillance, disease control groups, and patient recruitment. This paper outlines the activities of the Rare Disease Platform and introduces trends in the utilization of real–world data in the field of rare diseases.

The Neurotherapeutic Society, aiming to improve treatments for neurological diseases, established a Drug Discovery Promotion Committee which conducted a survey from October 17 to November 5, 2022, to gauge member opinions on society functions and support. The web–based survey, which received 113 responses, gathered insights on previous R&D experiences, support received from various organizations, and desired roles and support from the society. Most respondents were involved in research and clinical practice. Key feedback indicated a preference for support from Academic Research Organizations (AROs) and a need for help in development planning, obtaining research funding, and educational programs for researchers. Additional suggestions included improving patient recruitment, promoting societal contributions through drug development, and enhancing interactions with pharmaceutical entities and regulatory bodies. The committee will use these findings to inform future support initiatives for the society.

Recent Advance in Antiplatelet Therapy : The problem of clopidogrel–refractory cases derived from CYP2C19 gene polymorphisms has been highlighted. The frequency is particularly high in high–risk cases on Fukuoka Stroke Risk score for Japanese. Prasugrel was developed in Japan to address this problem, and the PRASTRO trial added it to the treatment options for atherothrombotic and lacunar infarctions. Dual Pathway Inhibition utilizing Factor XIa inhibitors : Factor XI is in the spotlight as a target that can inhibit thrombosis while preserving the hemostatic mechanism. The application of dual pathway inhibition, i.e. antiplatelet plus anticoagulation, in the treatment of non–cardiogenic stroke is being investigated, and phase III trials with milvexian and asundexian are underway. New Generation Thrombolytic Drug : Currently, a series of investigator–initiated clinical trials are being conducted to apply tenecteplase, which is used overseas as a treatment for myocardial infarction, to the treatment of cerebral infarction. In many countries, clinical application has begun with off–label use, and tenecteplase is gaining recommendations as a treatment for cerebral infarction in foreign guidelines. In Japan, T–FLAVOR trial is underway to prove efficacy and safety of tenecteplase in Japanese population.

The p.R4810K variant in the RNF213 gene was identified as the founder variant in East Asian moyamoya disease. The association of this variant with non–moyamoya intracranial arterial stenosis was also demonstrated, and the disease concept of RNF213–related vasculopathy was proposed, suggesting a continuous spectrum with moyamoya disease. In addition, moyamoya disease is occasionally accompanied by polyvascular disease involving not only intracranial vessels but also neck vessels, coronary arteries (especially vasospastic angina), pulmonary arteries, aorta, abdominal visceral arteries and peripheral arteries, which have been found to be associated with RNF213 variants, mainly the p.R4810K. The severity of vascular disease caused by the RNF213 variant is not uniform, and some environmental and genetic factors are thought to jointly define the phenotype. The RNF213 gene is the largest risk for cardiovascular diseases in East Asia, and successful targeting on the RNF213 gene is essential for the control of cardiovascular diseases including stroke in East Asian countries.

Axonal regeneration plays a pivotal role in tissue repair and is compelling for functional recovery after stroke. On the other hand, several inhibitory molecules for axonal outgrowth exist in the central nervous system (CNS). In the peri–infarct area of the middle cerebral artery occlusion (MCAO) rat model, we identified that the axons and dendrites were regenerated in the chronic phase of stroke (2 months). In vitro, we showed that PTEN/Akt/GSK–3β signaling is involved in axonal outgrowth after stroke. Several studies documented that exosomes, intrinsic cell–derived membrane vesicles in the size range of 40–100 nm, enhanced tissue repair and functional recovery after stroke. Exosome treatment tends to have less tumorigenicity, does not occlude the microvascular system in CNS, and has low immunogenicity, as compared to conventional cell therapy. Recently, we found that anti–inflammatory regulation of post–stroke glial scars via MAPK/NF–κB/ TNF–α/Il–1β signaling, and treatment with miR–146a–5p facilitated stroke recovery in rat MCAO model. Thus, exosomes can be a therapeutic candidate of treatment for stroke recovery.

The development of medical research, such as molecular biology and genomic medicine, has advanced the elucidation of diseases and pathologies at the molecular level, and many drug target candidate molecules have been discovered. In the 1990s, biologics, in the 2010s, nucleic acid drugs, regenerative medicine products (gene therapy, cell therapy), and other new modalities emerged, and the development of molecular targeted drugs became mainstream. Such drug discovery innovation has been the driving force for the growth of the pharmaceutical industry. The evaluation of the added value of pharmaceuticals is based on the treatment outcomes such as efficacy, safety, and convenience. The evaluation based on the degree of improvement in the quality and quantity of life (survival period) of the patient, and the evaluation from the perspective of supporters and caregivers other than the patient are also important. The indicator of the economic value of pharmaceuticals in medical economics is the drug price, and it is important that the clinical value of pharmaceuticals is appropriately evaluated as the drug price.

The drug price calculation system for appropriately evaluating the innovation of new drugs has been revised many times, and it has supported the recovery of the cost involved in the development of innovative pharmaceuticals and the investment in the next innovative drug discovery at a high drug price as soon as possible, by rewarding the corporate efforts to create innovative pharmaceuticals. On the other hand, systems such as market expansion recalculation have been introduced to control the total amount of drug costs to make the medical insurance system sustainable, and they have had a greater impact on the drug prices of individual pharmaceuticals than ever before. For pharmaceutical companies, the appropriate drug price of new pharmaceuticals is an important business driver as a drug discovery incentive. In this paper, I discuss the drug price system from the perspective of how the breakthrough of pharmaceuticals is reflected in the drug price in the neurological field.

Amyotrophic lateral sclerosis (ALS) has been synonymous with incurable neurological diseases. To date, there is no treatment that patients can fully benefit from, but therapies are being developed that are expected to control the progression of the disease. The two treatments listed as Clinical Questions (CQs) in the ALS Clinical Guidelines 2023 are riluzole and edaravone, both of which are conditionally recommended. Along with attention to common side effects, information about the limited efficacy of the drug should be provided before its use.

Significant progress has been made since the development of the ALS Clinical Practice Guideline 2023. In June 2022, it was announced that the Phase III methylcobalamin trial in early ALS patients showed efficacy. In September 2022, AMX0035 (sodium phenylbutyrate/taurursodiol) was approved by the US FDA for the treatment of ALS. In December 2022, edaravone oral suspension was approved, eliminating the burden of hospital visits associated with intravenous infusions and the difficulties of securing a peripheral vein, thus improving the limitations of its use. In April 2023, the US FDA approved tofersen, an antisense oligonucleotide (ASO) for ALS patients who are SOD1 mutation positive. Although the tofersen Phase 3 trial did not show a significant difference in the primary endpoint, the significant suppression of the plasma neurofilament light chain (NfL) biomarker was the basis for approval. A method has been used to detect pathological phenotypes in motor neurons derived from iPS cells of ALS patients and to search for drugs that can ameliorate these phenotypes. Ropinirole and bosutinib, discovered by this method, have been tested in clinical trials.

Much progress has been made in the development of treatments for ALS in just the last two years, and more is expected in the future.

Amyotrophic lateral sclerosis (ALS) is an adult–onset motor neuron syndrome characterized by selective involvement of motor and cortical neurons in the frontotemporal lobe, brainstem, and spinal cord, eventually leading to multisystem neurodegeneration. Currently, it is not possible to alleviate progressive skeletal muscle wasting and weakness. In addition to the motor symptoms of ALS, non–motor symptoms such as pain, fatigue, cognitive impairment, anxiety, depression, pseudobulbar affect, sleep disturbances, and weight loss can occur. Although not all symptoms appear in all patients with ALS, it is necessary to know the characteristics of non–motor symptoms and practice multidisciplinary medical care to mitigate them as much as possible. Common symptomatic approaches include (1) prevention whenever possible, (2) listening actively to symptoms and assessing their nature and severity, (3) identifying the cause and contributing factors by physical examination, (4) communicating with the patient and caregivers in an easy–to–understand manner, and (5) considering from non–pharmacological therapy to medication. Morphine is effective against the intractable pain and heaviness as well as dyspnea associated with ALS, and can be considered even in the early stage of the disease. Based on the Japanese clinical practice guideline for ALS revised in 2023, I will review here an update on symptomatic management for patients with ALS. There is a great need to elucidate the pathophysiological basis and accumulate evidence for symptomatic treatment through intervention studies that focus on non–motor symptoms.

In Japan, the ALS guidelines are revised approximately every 10 years, with new guidelines published in 2002, 2013, and now 2023. Although the cause of ALS remains unclear and the treatment method has not yet been established, the “landscape” of ALS care has changed considerably in the past 20 years.

The publication of two Clinical Questions (CQs) for the first time was a milestone, but does not encapsulate the entirety of ALS care. With the extremely limited number of items for which the total body of evidence from systematic reviews could be evaluated, many were combined into Questions and Answers (Q&A) to collate clinical knowledge. The author participated in this process as a non–physician member of the committee and learned a great deal. The discussions in the working groups and panel meetings were, to put it colloquially, an all–Japan multidisciplinary team.

In this article, I would like to introduce the current state of ALS care, tracing the transition of the chapters in the past three guidelines, and share the changes in the “view” of ALS care over the past 20 years.

Communicating the diagnosis of ALS to patients and their families and introducing tracheostomy ventilation (TIV) is mentally burdensome not only for the patients but also for the medical staff. The diagnosis of ALS is generally confirmed by the fulfillment of various diagnostic criteria, but the sensitivity and specificity vary depending on the diagnostic criteria used. The decision to introduce TIV should not be made hastily, and it is important to take time to support the decision–making process by multidisciplinary staff. It is also necessary to simulate the care and financial burden after the introduction of TIV.

Percutaneous endoscopic gastrostomy under local anesthesia is a necessary surgical procedure for ALS patients. It is recommended for weight stabilization, but there are reports of a shorter prognosis if the procedure is performed in patients with reduced lung capacity. When the patient's lung capacity is less than about 50%, gastrostomy should be performed safely with noninvasive artificial ventilation. If surgery requiring general anesthesia is necessary, more careful judgment is required because of the risk of not being able to extubate the patient due to decreased respiratory function. It has been reported that nearly 90% of patients with spondylolisthesis, which is a differential disease of ALS, do not improve after surgery and survival is not prolonged. Therefore, even if surgery is indicated, conservative treatment should be chosen as much as possible.