This article outlines the approach to patients and caregivers regarding diagnosis, prognosis, medical treatment, decision making, and response to emergencies.

In the past, there was a tendency not to explain ALS until it was clearly confirmed, but now it is recommended that ALS patients' future life plans be taken into consideration, and if ALS patients are deemed to have a high probability of ALS, medical personnel should explain how they perceive the disease, even before the diagnosis is confirmed. Regarding medical procedures that are in line with progression, such as gastrostomy, introduction of NIV, and psychological care, it is important that the patient and family fully understand the need for such procedures. The introduction of tracheostomy invasive ventilation (TIV) can make all the difference in the patient's prognosis. We should take the time to simulate the communication methods, nursing care, and financial aspects of TIV before decision making. It is also important to ease their mental burden by informing them that they are free to change their mind. In decision–making, including TIV, it is recommended that the patient, family, and caregivers share information with multidisciplinary professionals, and that collaborative decision making, which emphasizes the process of decision making, be encouraged. In addition, it is necessary to confirm the decision–making process in the event of a sudden emergency. Advance directives and medical information letters should be prepared in advance, considering the possibility of sudden emergency and unexpected situations.

Amyotrophic lateral sclerosis (ALS) is an adult–onset, relentlessly progressive motor neuron disease characterized by dominantly involving cortical neurons in frontotemporal lobe and motor neurons in brainstem and spinal cord, but ultimately leading to multisystem neurodegeneration. As motor symptoms progress, muscle wasting with weakness in the limbs and trunk, bulbar palsy, and respiratory muscle paralysis appear. In addition, non–motor symptoms such as cognitive decline, mood disorders, pseudobulbar affect, sleep disturbances, fatigue, pain, and weight loss due to hypermetabolism may occur. However, each symptom may not occur in all cases. Disease–associated hypometabolism and multisystem involvement, particularly in the advanced stages after the introduction of tracheostomy invasive ventilation (TIV), may lead to other non–motor symptoms including autonomic disturbance, glucose intolerance, and macroglossia. Although lack of sufficient evidence in therapeutic intervention and underlying pathomechanism essentially limit concrete recommendations, I will review here an update on clinical management of non–motor symptoms in patients with ALS.

Weight loss is frequently observed in early–stage amyotrophic lateral sclerosis (ALS) and is considered an independent predictor of survival. Weight loss observed in ALS is associated with multifactorial etiology, including muscle wasting and dysphagia. Recent studies have implicated disease–specific hypermetabolism as one of causes of weight loss in ALS. Involvement of the hypothalamus in ALS has been the other topic in metabolic dysfunction in ALS. TDP–43 protein aggregates detected in the hypothalamic subnuclei may be associated with weight loss or abnormalities of eating behavior in patients with ALS. Nutritional intervention to maintain body weight could become one of disease–modifying therapies, and recent studies have reported that slowing of weight reduction rate after diagnosis was associated with better survival and that a high–calorie fat diet improved survival in patients with rapidly progressive disease. Nutritional education regarding a high–calorie diet, weight control, and early gastric tube placement is required at the time of diagnosis. Formulas to estimate the recommended daily energy intake for patients with early–stage ALS were reported from USA, Europe and Japan. Multidisciplinary team approach and rehabilitation is necessary to support patients with swallowing disturbance. Surgical intervention to prevent aspiration is often needed for patients who frequently develop aspiration pneumonia.

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of upper and lower motor neurons that also affects the diaphragm and other respiratory muscles. Respiratory dysfunction, including hypoventilation and respiratory failure and respiratory infection are common causes of death and respiratory function significantly affects both survival and quality of life in patients with ALS. Progress in devices such as ventilators and mechanical insufflation–exsufflation and respiratory physiotherapy are recognized to prolong survival without tracheostomy and to maintain or improve quality of life and maintaining or improving quality of life. Due to ethical concerns, intervention studies for non–invasive ventilation cannot be conducted, making observational studies the only viable option. Additionally, the wide variety of ventilator models and settings makes it challenging to evaluate appropriate settings, though several settings have been suggested in observational studies. Respiratory management of ALS is now expected to be a disease–modifying therapy.

A “recovery from functional disabilities” is the major highlight of rehabilitation medicine. However, in diseases such as amyotrophic lateral sclerosis (ALS), which is characterized by a progressive muscular weakness including that of the respiratory muscles, and where a curative treatment is not available, the rehabilitation goal is to maintain the remaining abilities, or allow the maximum performance of activities using aids and other devices to achieve an optimal mental state during treatment, ultimately improving the quality of life of the patient and their family.

Thus, in the course of ALS, various disabilities such as physical, speech and swallowing, nutritional, communication, respiratory, and psychological impairments (anxiety and depression, among others) can become significant issues. In rehabilitation medicine, training and support such as physical, occupational, and speech therapies are provided to address these issues. Moreover, efforts are exerted to improve the treatment environment through financial, human, and material social resources as well as through environmental improvements such as housing renovations.

Currently, the guideline revision for the treatment of ALS is in the final stages, and the revised version includes a chapter on rehabilitation. However, the lack of large–scale randomized controlled trials on effective ALS rehabilitation indicates that there is a dearth of evidence or recommendations demonstrating the effectiveness of rehabilitation in disease treatment.

In this report, we summarize the current rehabilitation strategies for ALS based on papers and references used in guideline creation. Furthermore, effective rehabilitation techniques and future considerations for ALS treatment are also reported.

MOGAD (myelin oligodendrocyte glycoprotein antibody–associated disease) has been recognized as a new disease entity which predominantly involves optic nerves, spinal cord, and brain including brainstem and cerebral cortex. The clinical and radiological features of MOGAD has been elucidated comparing with the ones of aquaporin–4 antibody–associated disease (AQPAD) and multiple sclerosis. In this review, I summarize the clinical and radiological features of MOGAD.

Myelin oligodendrocyte glycoprotein (MOG) is one of the myelin sheath component which exclusively expressed in the central nervous system. Recently, cell–based assays have provided the identification of conformation–sensitive MOG antibodies, establishing the disease concept of MOG antibody–associated disease (MOGAD).

Based on previous case reports, demyelinating lesions in MOGAD have been considered to have MS Pattern II features. However, we and others recently conducted a detailed histopathological analysis of MOGAD and revealed that the lesions were characterized by ADEM–like perivenous demyelination and the fusion pattern localized in both the white and gray matters, but not by MS–like radially expanding confluent demyelination. We also found that one–third of the demyelinating plaques in MOGAD showed that decrease of MOG staining was greater than those of other myelin proteins, suggesting a MOG–targeted pathology in the disease. Unlike the AQP4 antibody–positive NMOSD, no destructive changes in astrocytes or AQP4–loss were observed. Perivascular cuffings were mainly consisted of macrophages and T cells with CD4–dominancy, which is also different from CD8+ T cell–dominant inflammation in MS. Meanwhile the pathogenetic contribution of complements in MOGAD is still under debate, as the reported results have been inconsistent.

MOGAD is considered an independent disease concept in inflammatory demyelinating diseases in terms of histopathological features. However, the clinical phenotype of MOGAD and its response to treatment is variable between cases. Further research is need to clarify the exact mechanism of demyelination and how the pathophysiology affects the clinical phenotype and disability in MOGAD.

Myelin oligodendrocyte glycoprotein (MOG) antibody associated disease (MOGAD) is an inflammatory demyelinating disease of the central nervous system. The disease entity encompasses a group of disorders in which autoantibodies (MOG antibodies) are directed against MOG, one of the myelin sheath proteins of the central nervous system, and which present with a variety of symptoms, including optic neuritis, myelitis, acute disseminated encephalomyelitis (ADEM), brainstem encephalitis and cerebral cortical encephalitis. MOG antibodies are thought to be involved in the pathogenesis of these diseases through autoimmune mechanisms, and the same genetic predisposition is expected as in other autoantibody associated diseases. The sensitivity and specificity of MOG antibodies have increased with the development of assay technology and the use of cell–based assays. Although patient serum is commonly used to measure MOG antibodies, MOG antibodies can be positive in cerebrospinal fluid alone.

The pathogenesis of MOGAD is variable, with some MOGAD patients having a monophasic course without relapse. Patients presenting with attacks of optic neuritis or transverse myelitis respond better to acute treatment than patients with aquaporin–4 antibody–positive neuromyelitis optica spectrum disorder, often recovering to their original level of ADL. In children, ADEM is more common and often associated with seizures. Other forms of encephalomyelitis, such as brainstem encephalitis and cortical encephalitis, are less common. Some are very refractory, with recurrent inflammatory attacks and brain atrophy. Retrospective studies have shown that patients with myelitis tend to have a monophasic course. MOG antibody positive–to–negative seroconversion has been reported to be a significant predictor of a monophasic course in children, but it does not necessarily correlate with a monophasic course in adult cases.

Treatment of MOGAD includes steroid pulses in the acute attack phase, as in other CNS inflammatory diseases. There is no drug that is approved in Japan for the prevention of relapses. This review discusses the pathogenesis and treatment of MOGAD.

The cardinal findings of basic and clinical physiology of epileptic seizures have been regarded as “paroxysmal depolarization shifts” (PDS) at the postsynaptic membrane and it correspond to epileptiform discharge in EEG.

In addition, a recent new finding is that the impairment of extracellular K homeostasis in the synaptic cleft. It is mediated by astrocyte dysfunction at tripartite synapses. Namely, decreased expression of Kir 4.1 channel activity in the astrocytes is one of the most responsible factors in both animal and human epilepsy. It is also directly involved in the generator mechanism of ictal DC shifts (Ikeda et al, 1996), and would play a significant role in the propagation mechanisms of focal seizures.

Recent advancement of neurophysiologic and radiologic examinations has enabled us to better define epileptic focus or network. Volumetric evaluation with 3 tesla MRI has made it possible to visualize epileptogenic lesions including very minute changes such as tiny focal cortical dysplasia. Stereo–EEG (SEEG) has prevailed in the United States and Europe in the last decade, thanks to the advancement of MRI, brain navigation system and stereotactic electrode placement techniques. SEEG is superior to evaluation with subdural electrode implantation in 1) its ability to sample EEG from the depth of the brain so that we can visualize and define the epileptic focus and early propagation network in three dimensional way, and 2) less invasiveness (no needs to perform craniotomy). Cortico–cortical evoked potential (CCEP) is a novel connectivity method we have developed to electrically trace the brain connectivity by applying a single–pulse electrical stimulation to a part of the cortices and record brain evoked potentials time–locked to the stimulus. Because of its practicality, good reproducibility and safety with regards to seizure induction, CCEP has been used all over the world to 1) probe the epileptic networks and 2) map and monitor the brain functional networks such as language for brain surgeries.

Vagus nerve stimulation (VNS) is a device therapy for epilepsy that has received considerable attention in recent years. It is indicated for all types of refractory epilepsy and is a relatively minimally invasive treatment that does not require craniotomy. The effect is seen over time, with a seizure reduction rate of approximately 66% reported after 3 years. On the other hand, about 25% of patients do not respond to VNS. In children, there is improvement is noted in emotional and psychological aspects. The complete seizure free rate is about 10%. VNS is a palliative treatment for patients with intractable epilepsy. Although VNS has been approved in Japan for 13 years, it is not yet widely used. It is difficult to predict the effect of treatment on individual patients in advance, so shared decision–making is important for selecting VNS treatment, based on information shared by the patient and family, including the effect of treatment and side effects.

As the pandemic that has swept the globe has passed three years, the theme of the 40th Annual Meeting of the Japanese Society of Neurological Therapeutics was A New Beginning for Neurological therapeutics : Overcoming the Pandemic and Aiming for Further Development. As a medical practitioner who has faced this “pandemic disaster,” I cannot help but think of the difficulty of correctly grasping and dealing with the present, which encompasses the present and future, even though I can look down on the time that has passed. In Symposium 21, the theme of neuroradiological findings in degenerative diseases, we pursued the possibility of diagnosis in the preclinical stage of degenerative diseases by making full use of cutting edge neuroimaging techniques, and explored the genes, etiology, and pathophysiology of the diseases. The presentations were exciting. Among them, the author, from the standpoint of a physician at a city hospital that provides emergency care to the elderly, presented imaging diagnosis in daily practice and the complex pathologies that lie behind the diagnosis, including the correspondence with the background pathology. The course of many neurodegenerative diseases is long, and the imaging findings change with the passage of the disease course. In addition, in diagnosing neurodegenerative diseases in the world, which have entered the hyper–aging society, age–related modifications are added, and complex etiologies and pathologies exist in the background at a high rate. In routine diagnostic imaging, the scope of diagnosis must take into account the time axis from the preclinical stage to the transitional stage, early onset of clinical symptoms, and advanced stages, and the process of searching for the “true nature of the disease” while diagnosing the three– or four–dimensional spread of the disease is required. It takes a long time to “search for the transition of the pathology along with the patient's long clinical course” until the knowledge obtained through the clinical–imaging–pathological linkage is reapplied to clinical practice. More than a year after the conditional approval of disease–modifying drugs for Alzheimer disease (AD) by the U.S. FDA, the possibility of appropriate diagnosis, including the preclinical stage of AD, has been attracting attention, and a newly identified degenerative disease that should be clinically differentiated from early–stage A, has been described. The present study will discuss the imaging–pathological relationships of the newly clarified degenerative diseases that should be clinically differentiated from early AD, such as argyrophilic grain disease/dementia with grains (AGD/DG), primary age–related tauopathy (PART), limbic–predominant age–related TDP–43 encephalopathy (LATE), and hippocampal sclerosis in the elderly, and will serve as a link to the 2nd∼4th presentations that demonstrate the significance and potential of applying the latest neuroimaging technology development and application.

Voxel–based morphometry (VBM) and surface–based morphometry（SBM）done by means of MRI have provided new insights into the neuroanatomical basis for subjects with several conditions. These approaches can detect structural brain changes that appear normal on conventional MRI. Recently, the VBM and SBM has been applied to investigate regional volumetric changes of not only whole brain but also hippocampal subfields. Furthermore, we can acquire structural networks using recently introduced technique of source–based morphometry, which applies an independent component analysis (ICA) to a segmented image, arranges voxels into sets that contain similar information, and acquires common morphological features of the gray matter concentration among individuals at the network level. The aim of this article is to review the recent work using VBM and SBM technique in particular focusing on brain MRI in patients with neurodegenerative disease, including multiple system atrophy, Parkinson disease, and dementia.

The glymphatic system is described as a perivascular brain network that facilitates CSF and interstitial fluid exchange. It has been reported that the activity of the glymphatic system changes dynamically with sleep, aging, alcohol intake, etc., and it is described that it is closely related to the onset of dementia. It has also been suggested that a contribution of an impaired glymphatic system to the accumulation of amyloid–beta (Aβ), which are identified as pathological hallmarks of Alzheimer disease (AD). MRI measurements, such as the diffusivity along the perivascular space (PVS) represented by the ALPS index, the PVS volume, and the fractional volume of free water (FW) in the brain parenchyma, were recently revealed as promising candidates for the evaluation of the glymphatic system function.

Recanalization therapy for acute stroke has become widespread as a treatment with a high level of evidence and continue to develop. We discuss trends in recanalization therapy after the publication of Japanese Stroke Treatment Guideline 2021, the time management, and the role of neurologists.

It is still unclear whether the combination of intravenous thrombolysis (IVT) can be skipped in mechanical thrombectomy (MT) for large vessel occlusion (LVO), although several randomized controlled trials (RCTs) have been reported. The AURORA Database, an analysis of six RCTs that investigated the effects of MT in late presenting stroke, reported two important results : MT was effective in both perfusion mismatch and clinical mismatch profile, and MT was effective in any period between 6 and 24 hours. The RESCUE–Japan LIMIT Clinical Trial in Japan reported a significant increase in the modify Rankin Scale 0–3 at 90 days with MT, the first RCT to report the benefit of MT in LVO with large core infarction. Recently, two RCTs have demonstrated the efficacy of MT for basilar artery occlusion within 12 hours (ATTENTION) and within 6–24 hours (BAOCHE). It is important to confirm the criteria for the trials in which efficacy was demonstrated. There is still no evidence of MT for medium vessel occlusion including M2.

The pre–hospital phase is crucial in shortening the in–hospital time. It is important to be fully prepared prior to patient arrival. Our role is to organize the team as a leader by applying our management skills developed through our IVT treatment.

Neurologists can contribute our knowledge and skills to endovascular treatment, even if we do not perform endovascular treatment ourselves.

Currently, in Japan, the number of patients with intractable neurological diseases (INDs) is increasing due to the aging of the population. Accordingly, it is expected that the number of the patients who receive emergency medical care will also increase. In our hospital, the number of emergency medical department consultations for patients with INDs in 2021 was 147, with 84 for Parkinson disease, 10 for amyotrophic lateral sclerosis, 10 for myasthenia gravis, and 7 for progressive supranuclear palsy, 7 for spinocerebellar degeneration, and 7 for multiple system atrophy. Regarding the symptoms at the time of consultation, the percentage of patients who visited the hospital due to exacerbation of symptoms of neurological disease was relatively small, and the percentage of systemic complications including falls was high. Therefore, it should be noted that emergency care for patients with INDs, many of whom are elderly, has a high risk of complications such as falls, head injuries, infections such as aspiration pneumonia and urinary tract infections, and dehydration. INDs are progressive diseases. Some diseases, such as ALS, progress rapidly and end life in a few years. It is important for attending physicians of emergency medical department to understand how patients with INDs think about how they will spend their recuperative life and how they will face death before providing medical care. Using a tool called ACP (Advanced Care Planning), the patient's life and death views and values are mutually understood by the family and the medical team, and the patient's treatment plan should be shared by the neurologists, the emergency medical doctors, and all other medical staff.

Multiple sclerosis (MS) is characterized by a young onset and an unpredictable prognosis. Although there are multiple effective drugs available, most people with MS eventually will have a clinically progression and a worsening disability. The serious physical and mental problems will be a persistent burden on people with MS and their care givers all their lives, and they have to cope with the condition every day. The disease inevitably affects their daily livings, so those patients will also have to reconstruct their lifestyles according to worsening level of the disorders. Therefore, to keep their good quality of lives, they need daily supports from various medical professions concerning the people's lives as well as the characteristics of the disease, MS. A single function nor a person, even though they have an enough experience and knowledge for the disease, cannot deal with a various problem of people with MS who have various values, characters, living environments and lives they want. We discuss the importance of the role of the medical professions and the team medical care for people with MS, especially focusing on our important role to know both of “the disease” and “the person's live”. We also emphasize a pressing task to resolve medical fee system which appear to impede appropriate medical team cares, especially in outpatient care.

The spread of intravenous tissue plasminogen activator and endovascular therapy, as well as the enactment of the stroke and cardiovascular disease control act have facilitated the building of a team medical system for stroke in Japan. To expand the stroke medical system, primary stroke centers and stroke patient support centers have been established throughout Japan. The target of expansion of stroke medical care has shifted from the acute phase to the chronic phase, and thus collaboration among stroke team medical staff in each center will become more important in enhancing support for survivors of stroke and their caregivers.

The patient was a 45–year–old man who presented with severe right forearm pain after posterior lumbar interbody fusion surgery for lumbar spinal canal stenosis. Two weeks later, along with the improvement of pain, he suffered from multifocal muscle weakness and atrophy in the right upper extremity. MRI showed swelling of the right brachial plexus. A diagnosis of neuralgic amyotrophy (NA) was made. Treatment with intravenous methylprednisolone and intravenous immunoglobulin partially improved his muscle weakness of the upper extremity. However, muscle weakness persisted in the right ulnar nerve area. MRI revealed right cubital tunnel syndrome, and anterior subcutaneous ulnar nerve transposition was performed. Postoperatively, the weakness of the muscles innervated by the ulnar nerve also improved.

In the present case, in addition to mechanical compression of the ulnar nerve due to cubital tunnel syndrome, an immune reaction induced by lumbar surgery may be involved in the mechanism underlying the onset of NA.