Muscular dystrophy is genetic muscle diseases following with progressive muscle weakness. Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy, and the gene responsible for DMD was identified by using a positional cloning technique in 1986. Since the discovery of DMD gene, our understanding on the structure of dystrophin protein, dystrophin–associated protein complexes or pathogenesis has dramatically improved. These knowledges obtained by DMD research have provided the basis for potential therapies, and have particularly contributed to the development of therapies targeting mRNA and genomic DNA. Exon–skipping therapy using antisense nucleic acid (AON) targeting pre–mRNA has been successfully correct out–of–frame mRNAs to produce in–frame transcripts by removing an exon during splicing, with the restoration of functionally preserved dystrophin protein, and is currently approved in US and Japan. Recent advances in genetic analysis techniques including next–generation sequencing (NGS) have made it possible to identify many causative genes and proteins, to diagnose multiple types of muscular dystrophies and to develop potential therapies. In addition to DMD, novel technologies have contributed to the elucidation of pathogenesis in several muscular diseases including myotonic dystrophy (DM), Fukuyama congenital muscular dystrophy (FCMD), GNE myopathy and MELAS, paving the way for clinical research and drug discovery. We hope that further innovation will encourage the progress of basic research, and contribute to breakthrough for the development of therapies for non–curable diseases.

Stroke prevention constitutes antithrombotic treatments and risk control. Atherothrombosis may be treated with dual platelet therapy in the acute phase followed by single therapy with additional cilostazol in high risk group. Cardioembolism and paradoxical embolism should be treated with anticoagulants. Direct oral anticoagulants with dose based on age, renal function and body weight has fewer intracranial hemorrhages than warfarin and is recommended as first choice.

Cerebral small vessel disease is a common disease that affects small vessels in the brain and is associated with stroke, cognitive impairment, and motor dysfunction. The blood–brain barrier and endothelial cell function have been the focus of attention as the etiology of the disease. Recently, the mechanisms of waste removal and neural activity–dependent redistribution of blood flow in the brain have been clarified, and the functions of pericytes, smooth muscle cells, and arterioles have been studied. However, the pathogenesis of the disease is still unknown. Since the prevalence of cerebral small vessel disease increases with age, aging is the most important risk factor. Hypertension is also one of the most important risk factor for cerebral small vessel disease, but even in modern times when antihypertensive therapy is widely available, the onset and progression of symptoms have not been adequately controlled. Recent genome–wide studies have revealed that many genes related to extracellular matrix are included in the risk genes for sporadic cerebral small vessel disease, and their involvement in the pathogenesis is suspected. In addition, HTRA1, the causative gene of hereditary cerebral small vessel disease, is included in the risk genes. This suggests that extracellular matrix changes may be a common pathogenesis of sporadic and hereditary cerebral small vessel disease.

Immune–mediated neuropathy comprises various peripheral neuropathies caused by immune attack against peripheral nerve axon, myelin or vasa nervosum that nourish all components within peripheral nervous system. Guillain–Barré syndrome, most popular acquired demyelinating neuropathy, are caused by attacks of autoantibodies against antigens existing on peripheral nerve. In contrast, precise mechanism of CIDP (chronic inflammatory demyelinating neuropathy), the other popular acquired demyelinating neuropathy, remain vague including evidence of autoantibody. Recently, autoantibodies against various adhesion molecules distributed on node–paranode regions of peripheral nerve fibers are characterized in some patients with CIDP phenotype. Being their symptoms and therapeutic response different from those of CIDP, these patients are classified as different entity, autoimmune nodo–paranodopathy (ANP). In parallel, better therapeutic options for GBS, CIDP, ANP, as well as vasculitic neuropathy have been rapidly gaining．

In this lecture, recent progress of disease basis, new guide lines, therapy and ongoing trials especially biological drug are reviewed.

Human T–cell leukemia virus type I (HTLV–1) causes two diseases in some infected individuals : HTLV–1 associated myelopathy (HAM), a chronic inflammatory disease of the spinal cord, and adult T cell leukemia–lymphoma (ATL), a neoplastic disease. The pathogenesis of HAM is thought to center on the formation and maintenance of chronic inflammatory foci caused by an excessive immune response centered on HTLV–1–infected T cells infiltrating neural tissues, and clarifying the mechanism of pathogenesis is important for personalized medicine based on the pathophysiology of HAM. Based on real–world data obtained from HAM–net, HAM is classified into three major disease activity categories. Furthermore, based on these evidences, the “HAM Clinical Practice Guidelines 2019” established new treatment algorithms, including disease activity classification criteria for HAM and stratified treatment accordingly. More recently, prospective cohort data from HAM–net revealed that the life expectancy (standardized death ratio) of HAM is poor and, surprisingly, ATL is the leading cause of death in HAM patients. These results suggest the importance of medical care based on risk assessment for the development of ATL in patients with HAM. In the future, it will be important to correctly understand the characteristics and status of HTLV–1–infected cells when treating patients with HAM, and further progress in personalized medicine based on biomarkers that reflect the characteristics of each patient is expected.

Clinical practice guidelines are necessary to support clinical and policy decisions for rare disease, although development of guidelines for rare diseases seems to be challenging due to a few high certainty evidence to determine recommendations. This paper draws from the authors' experience on clinical practice guidelines development for rare diseases.

Strategies regarding clinical practice guidelines for rare diseases were identical to ones regarding the other guidelines, aspects from steps that internationally accepted standards by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system or Minds Handbook for clinical practice guidelines development 2020. Even if clinical practice guidelines in poor domains of the evidence, recommendations should be presented by GRADE approach as far as it is possible. At the moment of scoping search or beginning of systematic review at the latest, a guideline developing committee should judge carefully whether you push forward guidelines in progress. Good practice statements and future research questions might be improved clinical practice guideline for any disease affected by a relative lack of evidence.

Rigorous guidelines including innovative evidence elicitation and synthesis methods will benefit for individuals with rare diseases. Further refinement should lead to higher quality clinical practice guidelines in rare diseases.

Multiple System Atrophy (MSA) is a progressive neurodegenerative disease characterized by parkinsonism, autonomic failure, and cerebellar ataxia, with an average course of approximately nine years. Because symptomatic treatment is inefficient, the development of innovative drugs is a worldwide hope. There has been considerable progress in elucidating the structure of α–synuclein in MSA and PD, as well as developing pathophysiological elucidation and differential diagnostic methods based on the structural differences. It is also becoming clear that neuroinflammation and changes in oligodendroglia contribute to the pathogenesis of MSA and PD. In light of these findings, clinical trials of antibody therapy against synuclein, multi–targeted disease–modifying therapies, including mesenchymal stem cell therapies, and various symptomatic therapies steadily have provided new perspectives. We will discuss recent topics in MSA pathophysiology and drug development in this review.

The clinical diagnosis of corticobasal degeneration (CBD) is challenged by the existence of various phenotypes of CBD except corticobasal syndrome (CBS), CBD mimics, and immune–related CBS. Previously, 37% of the pathologically–verified CBD cases only had CBS, while the others presented progressive supranuclear palsy (PSP) syndrome, frontotemporal dementia (FTD), Alzheimer disease (AD)–like dementia or aphasia. Moreover, another report showed that 46% of CBS or CBD cases diagnosed by the clinical criteria were CBD mimics, which includes PSP, AD, FTD, globular glial tauopathy, prion disease, and other tauopathies. Recently, an anti–IgLON5 antibody related disease mimicking CBS was reported. The patient's symptoms were consistent for probable CBS ; however, some clinical and radiological findings were partially improved by immunotherapy. Therefore, the clinicians should be aware that such an anti–IgLON5 antibody related disease exists as a differentiated CBS, and more accurate clinical diagnostic criteria for CBD should be established.

Dementia with Lewy bodies (DLB) is known as one of common dementia disorder in Japan. As well as cognitive symptoms, multifaceted symptoms including movement, psychiatric, sleep and autonomic symptoms are frequently shown in DLB patients. As recent focus on the prodromal state of DLB, new research criteria for the diagnosis of prodromal DLB have been proposed in 2020. Although prodromal DLB has three subtypes including mild cognitive impairment with Lewy bodies (MCI–LB), delirium–onset DLB and psychiatric–onset DLB, there is still insufficient evidence to propose formal criteria for delirium–onset and psychiatric–onset DLB. Further studies including biomarkers for MCI–LB are needed. The DIAMOND–Lewy team developed a Management Toolkit to help clinicians with the management of DLB. Specific management for the five clinical symptoms of DLB is described in this toolkit, it can be expected to be useful in clinical practice.

In Parkinson disease, sleep disturbances are a common non–motor symptom and are associated with a variety of clinical factors. Sleep–related breathing disorders are a major problem in multiple system atrophy, and sleep architecture is significantly impaired in progressive supranuclear palsy. However, there has been little research conducted into sleep disturbances associated with atypical Parkinsonian syndrome, and many aspects remain unclear. Here, I will review sleep disturbances linked to atypical Parkinsonian syndrome, including their clinical implications.

A few years ago, infant–onset SMA patients, who had to make the ultimate choice between spending a lifetime with a ventilator or not, are now treated with the nucleic acid drug, the gene therapy vector formulation, or the small molecule compound. The efficacy and safety of presymptomatic treatment have been recognized, and expectations for newborn screening as an early diagnosis are increasing. 95% of newborns born in the United States have undergone SMA newborn screening, and have been started as an extended newborn mass screening test in seven local governments in Japan. A new era is beginning in which people who are supposed to receive care become caregivers.

With the development of genomic medicine, genetic testing has been implemented in various areas of medical practice in Japan. For intractable hereditary neurological diseases like Huntington's disease, genetic counseling has played a pivotal role for the patient's relatives because of the possibility of future disease onset. In this article, we present a case of presymptomatic diagnosis of Huntington's disease at our hospital and explain the nature and role of genetic counseling to help clients make better choices.

Assisted reproductive technology (ART) in humans was started as a treatment for infertility, but has now become widespread to play a part in maintaining the population in Japan. Advances in ART will radically change the reproductive process, and there is the potential for further development in the era of genetic modification. Along with the history of ART, donated gametes, surrogate pregnancy, uterine transplantation, preimplantation genetic testing, and genetic alteration of germline have been discussed. Common issues in ART and bioethics include the harmony between women's right to self–determination regarding reproduction and ensuring the welfare of their children, consistency with social norms, and the idea of eugenics. In normal medical ethics, patient autonomy and self–determination are most respected. On the other hand, in ART, (1) a person other than the patient is born after using medical technology, and (2) borrows the help of another person in a sense different from organ transplantation–sperm, egg, gamete, uterus, ③ There is a possibility that technology will advance infinitely, ④ Social tolerance, ⑥ It can be a business, etc. It is also a big problem that the legislation for ART in Japan has not been developed yet, and it is carried out only in accordance with the views and guidelines of the Japan Society of Obstetrics and Gynecology.

Recently, public discussions have been held on NIPT and PGT –M. The most important of these two themes is that the true parties to the test are those who have the disease diagnosed by the test, and the couple who are carriers are thinking of having a child.

Comprehensive Cancer Genomic Profiling (CGP) tests were launched into clinical practice in Japan since June 2019 under health insurance coverage in two types of CGP tests (OncoGuide™ NCC Oncopanel System and FoundationOne CDx). In August 2021, FoundationOne Liquid CDx was also launched as a liquid biopsy, analyzing circulating tumor DNA by serum.

Ministry of Health, Labour and Welfare (MLHW) has designated 12 core hospitals, 33 base hospitals, and 189 cooperative hospitals for CGP tests under health insurance in Japan (as of April 2022). The eligibility criteria for CGP tests includes only patients who (almost) finished all the standardized treatment with incurable diseases. Therefore, genome–matched therapies may be difficult due to the poor general condition, even when actionable mutations are detected and specific clinical trials are recommended. In C–CAT (Center for Cancer Genomics and Advanced Therapeutics) database, only 8.1% (607/7,467) received genomically matched treatment. Therefore, more clinical trials are warranted to expand the CGP–based therapies. As germline variants are also detected by CGP test, as well as somatic variants, specific to cancer tissues, genetic counseling is often required to appropriately assess the possibility of hereditary diseases. As whole–genome analysis is ongoing in many solid tumors, establishment of genetic counseling in each hospital is also important to address various types of germline findings.

It has passed 16 years since intravenous thrombolysis (IVT) was approved for acute ischemic stroke in Japan. It is crucial not to delay IVT with the minimum required examination and imaging. According to the Japan Stroke Data Bank, the recent administration rate of IVT in ischemic stroke was 10.8%, and the mean door to needle time (DNT) was 62.7 minutes in 2018, but further improvement is expected. In the recent report from the Czech Republic, the administration rate of IVT was 23.5%, and the median DNT was 25 minutes in 2018 by the national stroke registry and feedback system. In Japan, the Stroke and Cardiovascular Disease Control Act was enacted in 2018, and each prefecture will start the promotion plan in 2022. Recent trials using patients' selection with DWI–FLAIR mismatch or perfusion lesion–ischemic core mismatch revealed the efficacy of IVT in ischemic stroke with unclear onset time, including wake–up stroke. A meta–analysis of individual patient data also showed the efficacy. It is important to adequately add imaging evaluation to detect DWI–FLAIR mismatch or perfusion lesion–ischemic core mismatch in ischemic stroke with unclear onset time.

Mechanical thrombectomy was began by the advent of Merciretriever in 2010. The effectiveness of mechanical thrombectomy was first reported in 2015 and the indication have been expanded recently. Physicians involved in stroke patients need to be indicated for intravenous tissue plasminogen activator and mechanical thrombectomy as hyperacute therapy. We describe the latest evidence and therapeutic indications for mechanical thrombectomy.

For antithrombotic therapy in ischemic stroke patients, selection of an appropriate drug based on early diagnosis of stroke subtype is important especially in the acute phase. In addition, it is necessary to consider the effect of reducing cardiovascular disease including stroke recurrence, and the risk of increasing hemorrhagic complications. The balance of the risk–benefit greatly changes between the acute phase and the chronic phase.

We had shown that hematopoietic stem cell transplantation improves brain function though activating cerebral microvasculature both in experimental stroke model and clinical trial for stroke patients. Recently, we have found that the cause of non–responder of the cell therapy is clot–derived contaminants in cell suspension. Furthermore, we have identified that the key mechanism of the cell therapy is the direct cell–cell interaction via gap junction with supply of energy source, such as glucose, from transplanted stem cell to cerebral endothelium at soon after cell transplantation. Energy source supply activates hypoxia–inducible factor 1 at endothelium followed by induction of angiogenesis. These findings provide significant impact on stem cell biology and encourage development of mechanism–based therapy as the next generation of stem cell therapy.

While inflammation after cerebral infarction is an essential process for removal and repair of the infarcted area, excessive inflammation induces tissue damage. In rodents, damage–associated molecular patterns (DAMPs) released from injured cells in the early ischemic phase induce cytokine and chemokine production by activating microglia, which subsequently induces infiltration of neutrophil and lymphocytes. However, large–scale clinical trials to inhibit neutrophil (ASTIN) and lymphocytes (ACTION II) showed no apparent improvement in functional outcome. In addition, the SCIL–STROKE trial with an IL1 receptor antagonist reduced IL6 expression but did not improve functional prognosis, suggesting that targeting only one molecule may have limitations. In this context, the selection of molecules and cell types that can regulate multiple cytokine production may be important. In a study of autopsy brains of stroke patients, the infiltration of lymphocytes and neutrophils was very low, and the increase and infiltration of activated microglia/macrophages (M/M) was the major pathological changes. Considering that DAMPs/ toll–like receptor (TLR) signaling is the starting point for microglial activation, regulation of TLR signaling in M/M may be an important therapeutic strategy.

We found that (receptor activator of NF–κB ligand) RANKL/RANK signaling expressed in activated M/M suppresses DAMPs/TLR4 signaling, and MHP1, a partial peptide of RANKL, acts on CD14, a co–receptor for RANK and TLRs, and regulates multiple TLR signals. We reported that it suppresses. The peptide showed certain effects in mouse and monkey cerebral infarction models and could be used in combination with tPA. Furthermore, its effects have been observed in psoriasis and pulmonary fibrosis, where TLRs are pathologically relevant. To achieve more effective peptides, modification of the peptides is currently progressing.

Although drug discovery in the field of acute stroke is challenging, continued research on elucidation of molecular mechanisms and development of drugs that differ from existing ones is important for the development of drugs for stroke regulating inflammation.

Spinal muscular atrophy (SMA) is a lower motor neuron disease caused by a deficiency of survival motor neuron (SMN) protein due to deletions or mutations in the SMN1 gene. In SMA patients, SMN protein is produced from the paralogous gene SMN2, but the produced amount of SMN is minimal due to a defect in the splicing process. Nusinersen, an antisense oligonucleotides, and risdiplam, an oral small molecule, have been developed to repair SMN2 splicing failure for full amount of SMN production. Nusinersen has been used in clinical practice in these years and the improvement of clinical score has been observed even in adult patients with long disease duration. Thus, it has led to a dramatic evolution for SMA treatment. Risdiplam has the advantage of oral administration and the accumulation of real–world data on its efficacy in adult patients is now ongoing. In addition, onasemnogene abeparvovec utilizes a nonreplicating adeno–associated virus 9 to provide a copy of the gene encoding the SMN protein and is applicable for patients younger than 2 years of age. Onasemnogene has significantly improved the prognosis of severe cases with SMA. Since these drugs are extremely costly and their treatment responses differ between individuals, discontinuation or replacement with another drug should be considered if they are truly ineffective. However, it is not always easy to determine the efficacy of treatment by clinical scores, especially in adult patients with slow progression of the disease. Therefore, the development of reliable biomarkers is underway that can objectively help to evaluate the treatment efficacy. In addition to the molecular markers such as neurofilament H, creatinine, and cathepsin D, microRNA is attracting attention. SMA therapy is a representative example of a successful treatment for neurodegenerative diseases and is expected to have a major impact on the development of future treatments for many intractable neurological diseases.

Achieving regulation of endogenous gene expression in the central nervous system (CNS) with antisense oligonucleotides (ASOs) administered systemically would facilitate the development of ASO–based therapies for neurological diseases. We demonstrate that DNA/RNA heteroduplex oligonucleotides (HDOs) conjugated to cholesterol or α–tocopherol at the 5′ end of the RNA strand reach the CNS after subcutaneous or intravenous administration in mice and rats. The HDOs distribute throughout the brain, spinal cord and peripheral tissues and suppress the expression of four target genes by up to 90% in the CNS, whereas single–stranded ASOs conjugated to cholesterol have limited activity. Gene knockdown was observed in major CNS cell types and was greatest in neurons and microglial cells. Side effects, such as thrombocytopenia and focal brain necrosis, were limited by using subcutaneous delivery or by dividing intravenous injections. By crossing the blood–brain barrier more effectively, cholesterol–cconjugated HDOs may overcome the limited efficacy of ASOs targeting the CNS without requiring intrathecal administration.

Antisense oligonucleotides (AON) therapy is developed to treat Duchenne muscular dystrophy (DMD) patinets. We have reported that systemic delivery of AONs targeting exon 6 and 8 of the canine DMD gene to a dystrophin–deficient canine animal model, efficiently restored functional dystrophin proteins and improved phenotypes of affected dogs. We, then, optimized AO sequences, which allow exon 53 skipping of the human DMD gene, together with Nippon Shinyaku Co. Ltd. We carried an early phase clinical trial of exon 53 skipping drug among DMD patients with highly effective exon skipping and without serious adverse events, then phase I/II trial in Japan and phase II trial in US were carried by either Nippon Shinyaku Co. Ltd. or NS Pharma, Inc. Based on favorable results in these clinical trials, exon 53 skipping drug, calles as viltolarsen, has been approved both in Japan and in US on March and August in 2020, respectively.

Stroke is a common disease and is probably one of the most frequently encountered diseases by neurologists (especially neurologists working in general hospitals).

The approval of iv tPA in 2005 made stroke a “curable disease,” and the approval of the Merci Retrieval System in 2010 led to the current approval of highly effective stent retrievers and thrombus aspiration catheters for endovascular treatment. The Guidelines 2021 also recommend transvenous fibrinolysis and mechanical thrombectomy as “A” therapy, making acute stroke care a rapidly developing field.

Currently, about 70% of the members of the Stroke Association are neurosurgeons and 30% are neurologists, and it is estimated that less than half of neurologists treat strokes. In addition, only 7.8% of the specialists in the Japanese Society for Neuroendovascular Therapy are neurologists (as of August 2021). The new system is easier to use. In fact, 49 (12.1%) of the 404 certified physicians were neurologists, a higher percentage than that of the membership (9.7%). Although this is an area of growing interest among neurologists, treatment is currently not widespread in some areas, and further inroads into the field are desirable.

However, looking at stroke overall, most patients are not eligible for surgical treatment ; DPC data in 2019 shows that only 5.9% of stroke patients were treated with mechanical thrombectomy and 1.0% with direct surgery. Although attention tends to focus on flashy acute treatment, prevention of recurrence, lifestyle–related disease control, and rehabilitation based on disease type diagnosis are extremely important. A neurologist with broad knowledge and expertise in diagnosis and treatment would be an appropriate leader of a stroke team that manages patients while communicating with other departments, including neurosurgery, and multiple professions.

Acute treatments such as thrombolysis and mechanical thrombectomy are attractive to students and residents because of their dynamic and visible effects. The challenge for the future is to recruit personnel who should become leaders of the stroke team, using acute care as a gateway.

Epilepsy is a common disease in the elderly. About 1.5% of elderly individuals are thought to suffer from epilepsy ; however, the medical system is insufficient to handle this burden, due to the small number of neurologists who specialize in epilepsy. The symptoms of seizures in the elderly tend to be different from those in younger patients. Moreover, accurate diagnosis of seizure in the elderly is not easy, as such patients have more comorbidities and are at higher risk of other disease.

As a major cause of epilepsy in the elderly, management of post–stroke epilepsy (PSE) is important in stroke survivors. Developing PSE is associated with worse clinical outcomes and adversely affects patient quality of life. Good prediction models, such as CAVE or SeLECT score, have recently been developed to identify patients at high risk of late seizure. The use of these scores may help to develop more personalized therapies.

High efficacy and safety are indispensable for antiseizure medications for epilepsy in the elderly. Further, clinicians should consider drug–drug interactions, especially when using older generation antiseizure medications.

Stroke is the leading cause of severe, long–term disability and death in Japan. Its incidence and prevalence are expected to increase significantly with aging of the population. Obstructive sleep apnea is an independent risk factor of stroke and has a high prevalence in stroke patients. However, the effects of continuous positive airway pressure (CPAP) therapy on obstructive sleep apnea after stroke are uncertain, and the subgroup of patients who benefit from CPAP therapy need to be identified.

The relationships between stroke onset and sleep–related diseases other than sleep apnea (e.g., restless legs syndrome and rapid eye movement [REM] sleep behavior disorder) have attracted significant attention, and elucidation of the underlying pathophysiology may provide a new target for stroke prevention. In addition, self–reported short and long sleep times are associated with stroke onset ; this association is particularly strong for long sleep time, which is a marker of chronic illness.

Conversely, sleep–disordered breathing, insomnia, restless legs syndrome, and REM sleep behavior disorder may result in cerebrovascular accidents.

The future challenges for stroke and sleep medicine include thoroughly investigating new treatment strategies for primary and secondary stroke prevention, and establish systematic treatment guidelines.

Sleep disturbance is one of the important non–motor symptoms in Parkinson disease (PD) and affects the quality of life of patients. Early morning off and nighttime motor symptoms can lead to nocturnal and early morning awakenings, and restless legs syndrome can cause difficulty falling asleep. It is also important to screen for sleep apnea, which reduces sleep quality, and rapid eye movement (REM) sleep behavior disorder (RBD), which causes dream–enacting behavior and fragmented nocturnal sleep. PD patients with RBD are associated with characteristic clinical subtypes of PD. In this article, I will discuss the screening of sleep disorders in patients with PD with a focus on RBD and its management.

Migraine is a highly disabling prevalent neurological disease. Cortical spreading depression/depolarization, central sensitization, and neurogenic inflammation in trigemino–vasular system involve the pathophysiology of migraine. Serotonin, dopamine, and calcitonin gene related peptides relate closely these phenomenon.

The relationship between headache disorders and sleep disorders can categorize 1) headaches cause sleep disorders, 2) sleep disorders (disturbances) cause or worse headaches, 3) Somewhat common factor(s) cause both headache and sleep disorders.

In this lecture, I summarized possible relation of migraine and sleep disorders including sleep apnea, somnambulism, restless legs syndrome, narcolepsy.

21st century headache involves new territory and special concern to sleep hygiene are essentially important.