The aggregation and deposition of α–synuclein (αS) are major pathologic features of Parkinson's disease, dementia with Lewy bodies, and other α–synucleinopathies. The αS aggregation and its propagation play a key role in the onset and progression of clinical phenotypes. Thus, there is increasing interest in developing strategies that attenuate them. Based on cumulative evidence that αS oligomers are neurotoxic and critical species in the pathogenesis of α–synucleinopathies, we previously reported that polyphenols such as myricetin inhibit αS aggregation including oligomerization, thereby ameliorating αS oligomer–induced cellular and synaptic toxicities.

Heterogeneity in gut microbiota may influence the efficacy of dietary polyphenol metabolism. We recently showed that brain–penetrating polyphenolic acids 3–hydroxybenzoic acid (3–HBA), 3,4–dihydroxybenzoic acid (3,4–diHBA), and 3–hydroxyphenylacetic acid (3–HPPA), which are gut microbiota–based metabolites of dietary polyphenols, had an in vitro ability to inhibit αS oligomerization and mediate αS aggregates–induced neurotoxicity. Additionally, 3–HPPA, 3,4–diHBA, 3–HBA, and 4–HBA significantly attenuated intracellular αS seeding aggregation in a cell–based system. Here, we focus on recent research developments regarding the significance of αS aggregation and anti–αS aggregation effects of phenolic compounds and their metabolites by the gut microbiome, including our findings in the pathogenesis of α–synucleinopathies.

Currently, exon skipping using antisense oligonucleotides (ASO) is the most promising treatment for Duchenne muscular dystrophy (DMD), an X–linked severe muscle disorder caused by mutations in the DMD gene. In this context, the screening of efficient ASO sequences before clinical trials is laborious. We have recently reported efficient cellular skeletal muscle modeling of DMD by using myogenic differentiation 1 (MYOD1)–transduced urine–derived cells (MYOD1–UDCs) obtained from DMD patients. However, there are several obstacles to applying this model directly for the screening of exon skipping drugs. First, we have no robust evidence that exon skipping efficacy in vitro reflects the efficacy in vivo. Second, dystrophin restoration levels vary in MYOD1–UDCs due to their cellular heterogeneity. To overcome the obstacles, the DMD subjects enrolled in our ongoing exon 44 skipping trial will be evaluated in two ways : one is using myotubes differentiated from patient–derived myoblasts, fibroblasts and UDCs, and the other is using skeletal muscle tissue from the same patients. Furthermore, we have obtained preliminary data using a single cell analysis of RNAseq in normal human UDCs. As a result, we identified some renal stem cell markers expressed on a specific subpopulation of the UDCs. Further study will be needed to confirm whether those markers could be promising targets of MYOD1–induction and subsequent dystrophin expression.

Simultaneously, we also challenge creating neurons from UDCs by introducing several transcription factors. If successful, our study should pave the way for the development of precision medicine to treat various neuromuscular diseases, including amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy.

Recent technological advancements in genetic analysis have allowed for the consecutive discovery and elucidation of repeat expansion disorders : diseases caused by the abnormal expansion of repeat sequences in the genome. Many of these repeat expansion disorders are neurodegenerative disorders. Radical cures for these disorders have yet to be established. Although conventional treatments for repeat expansion disorders have mainly targeted the abnormal mRNA and proteins encoded by the affected genes, therapeutic approaches targeting repeat DNA, the root cause of repeat dis–orders, is also being explored in current research. In particular, a small molecule has been found that binds to abnormally expanded CAG repeats, the cause of Huntington's disease, and shortens them. Such small molecules targeting nucleic acids are expected to be developed into groundbreaking treatment drugs capable of ameliorating the symptoms of repeat expansion disorders and preventing their onset.

Steroids are one of the primary therapies for myasthenia gravis (MG) patients. Oral or intravenous pulse administration of steroids should be recognized as having different effects on MG. Intravenous methylprednisolone therapy (IVMP) is used in the early stage as a fast–acting treatment. Oral steroids should be kept to small doses because higher and longer steroid treatments do not ensure better outcomes. Initial exacerbation induced by IVMP is a possible event, but IVMP considering the characteristics of effects and the adverse event can lead to improvement of symptom. In this review, effective steroid use, mainly IVMP, and its adverse events will be discussed.

In Japan, the early fast–acting treatment strategy (EFT) has been proposed to reduce the side effects of steroids as well as to improve myasthenic symptoms ; as part of EFT, the use of non–steroidal immunosuppressive drugs is recommended early after the diagnosis of myasthenia gravis (MG).

Two types of calcineurin inhibitors (CNIs) are available in Japan : cyclosporine and tacrolimus. There are several randomized controlled trials suggesting a steroid–sparing effect, improvement of MG symptoms, and reduction of anti–acetylcholine receptor antibody titers by CNIs. CNIs are limited to the dose used for MG, but it is well tolerated without serious side effects.

In other countries, azathioprine and mycophenolate mofetil are used as non–steroidal immunosuppressants. These drugs are also options for refractory cases, but they are not indicated for use in Japan.

Eculizumab is the first drug to be developed and approved as anti–complement therapy for the treatment of paroxysmal nocturnal hemoglobinuria and secondarily for the treatment of atypical hemolytic uremic syndrome, both hematologic diseases associated with the complement system. Eculizumab is a humanized monoclonal antibody that inhibits the cleavage of C5 to C5a and C5b by C5 convertase, preventing the generation of the terminal complement complex C5b–9 (membrane attack complex : MAC). Anti–complement therapy has been clinically used in autoantibody– and complement–related neuroimmunological diseases. Anti–acetylcholine receptor antibody–positive (AChR⁺)–generalized myasthenia gravis (gMG) is a disease that could be treated with eculizumab.

AChR autoantibodies are mainly of the IgG1 and IgG3 subtypes ; thus, they are divalent and complement–activating. The binding of these antibodies to AChRs results in the activation of the classical complement pathway, with MAC assembly. The MAC causes local damage to the membrane, resulting in the loss of AChRs ; the damaged postsynaptic membrane shows diminished response to acetylcholine as expressed electrophysiologically by the reduced amplitudes of the endplate potential. The role of the complement system in damage to the neuromuscular junction is supported by experimental animal models of MG. Additionally, evidence showing that functional blockade of C5 protects against severe disease in preclinical studies suggests that complement inhibition might be a potential therapeutic approach for MG. Eculizumab was shown to have efficacy (60% of patients with AchR⁺gMG) and was well tolerated in a 6–month randomized, double–blind, placebo–controlled study (REGAIN). Therefore, it was approved for the treatment of AChR⁺gMG. Approximately 90% of all responders have a good response within 12 weeks after the start of anti–C5 therapy.

There is no consensus on the kind of patients with gMG who are selected to preferentially receive eculizumab, although the indication criteria of eculizumab for AChR⁺gMG includes refractory patients who have a poor response to intravenous immunoglobulin or plasma exchange in Japan. In contrast, practical clinical data have been collected over three years on the market.

Here, we present a review of the role of eculizumab, an anti–complement component C5 therapy in AChR⁺gMG, as well as clinical trial data.

Myasthenia gravis (MG) is an autoimmune neuromuscular disorder mediated by autoantibodies to acetylcholine receptors or muscle–specific tyrosine kinases. Whereas mild cases can be treated with small doses of oral corticosteroids and immunosuppressive drugs, moderate and severe cases require intravenous immunoglobulin and plasmapheresis therapy. In Japan, eculizumab (a complement component 5 inhibitor) has been approved for the treatment of refractory MG. However, despite the combination of available therapies, there continue to be cases of refractory MG and those wherein patients never achieve complete remission. Currently, several clinical trials are underway to evaluate the efficacy of targeted agents against molecules critical to the pathogenesis of MG. Herein, I summarize the progress of clinical trials on targeted agents against neonatal fragment crystallizable receptor antibodies and against clusters of differentiation 19 and 20.

Intractable disease nursing is an approach that supports the reconstruction of life/life planning and maintains and/or improves the quality of life (QOL) in response to the worsening of a treatment. In other words, it supports “living with a disease that cannot be cured.” Intractable diseases are rare and their symptoms are highly individualized which makes it difficult to accumulate support experience. In anticipation of the enactment of the Act on Medical Care for Patients with Intractable Diseases, along with the support of the Ministry of Health, Labour and Welfare's research team and the hospitals involved, momentum grew to train specialists in intractable disease nursing. In 2013, the Japan Intractable Illness Nursing Society established a system for nurses certified by the Society.

As of 2020, there are 433 intractable disease certified nurses (first to eighth certified nurses by the Society), of which 320 (73.0%) work in hospitals, 94 (21.7%) in visiting nurses, and 19 (4.3%) in other facilities. The nurses per regions were : 98 in Hokkaido/Tohoku (22.6%), 138 in Kanto (31.8%), 66 in Hokuriku/Chubu (15.2%), 55 in Kinki (12.7%), 23 in Chugoku/Shikoku (5.3%), and 62 in Kyushu/Okinawa (14.3%).

The results of the survey suggested that intractable disease certified nurses were active as “information hubs” for intractable diseases within their respective affiliations, but it was difficult for them to generate activity time due to lack of recognition. This indicated the importance of improving the environment. In Japan, specialization of intractable disease nursing has been cultivated through a unique system of supporting intractable diseases, and is characterized by the pursuit of common knowledge based on intractable disease nursing rather than on a disease basis. One of the appeals of intractable disease nursing is that it is closely related to systems and policies and responds to social situations. The authors hope that the nurses who carry and play the role of an escort runner of the medical treatment will increase.

Japanese “Intractable Neurological Diseases” are dedined as 1) diseases with unknown pathogenic mechanism, 2) diseases with no established treatment, 3) rare diseases, and 4) diseases that require prolonged medical treatment. In Europe and the United States, there is no equivalent term for Japanese “Intractable Neurological Disease.” Although the activities of nurse specialists overseas are useful for the future efforts in Japan, there are various differences in culture, religion, and health care systems, in addition to the unique Japanese perspectives on 1), 2), and 4). The greatest unmet needs of patients with intractable neurological diseases are the development of desease–modifying therapies to suppress the progression of the disease. At the present time, it is necessary to learn from “patients living with the disease” on a daily basis and continue to be involved in medical care from the time of diagnosis to the advanced stage of the disease, with a basic stance of “patient-centered medicine”.

Although Parkinson's disease (PD) is classified as a movement disorder, the concept of the disease has changed dramatically with a wide variety of non–motor symptoms in most patients. The symptomatic treatment of PD is extensive and has become very complex, with frequent use of multiple anti–PD drugs other than oral medications (patches and subcutaneous injection) and device–aided therapy. Therefore, the multidisciplinary team of experts for PD patients is essential. The provision of optimal medical and nursing care requires a high level of expertise, and various challenges are required in the PD medical care.

The PD nurse specialists (PDNS) are expected to play a central role in the comprehensive multidisciplinary medical care team for patients and caregivers with specialized knowledge of all aspects of PD treatment. The importance of PDNS has been described in the clinical guidelines produced by the National Institute for Health and Care Excellence (NICE) in the UK (2006, 2017).

Pure autonomic failure (PAF) and multiple system atrophy (MSA) are neurodegenerative disease that present with severe autonomic dysfunction, and their diagnosis is often difficult. According to the current MSA diagnostic criteria, probable MSA requires a sporadic, progressive adult–onset disorder including rigorously defined autonomic failure and poorly levodopa–responsive parkinsonism (MSA–P) or cerebellar ataxia (MSA–C). MSA–P is thought to be almost the same as striatal substantia nigra degeneration (SND), MSA–C is thought to be almost the same as olivopontocerebellar atrophy (OPCA). On the other hand, there is no “MSA-A” equivalent to Shy–Drager syndrome. Even in case that autonomic failure is the main symptom and it is difficult to distinguish from PAF, it is necessary to diagnose MSA–P or MSA–C from slight motor symptoms.

PAF and MSA present with severe systemic autonomic dysfunction in the urinary system, cardiovascular system, gastrointestinal tract, skin, sweat glands, etc., and the autonomic failure worsens as the stage progresses. Pathologically, PAF mainly consists of sympathetic ganglion and postganglionic lesion, whereas MSA has central or preganglionic lesions such as vagal nerve lateral nucleus, locus coeruleus, spinal cord medial lateral nucleus, and sacral Onuf nucleus.

Therefore, it is effective to evaluate the lesion of autonomic dysfunction to diagnose PAF and MSA. In general, cardiovascular autonomic nervous function and urinary autonomic nervous function test are often used in combination. However, the diagnostic sensitivity is not particularly high in the early stage of the disease. So, we make a comprehensive diagnosis while evaluating other autonomic nerve function such as cutaneous sympathetic function and electrogastrrogram.

The histological hallmark of Lewy body disease (LBD), which encompasses Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, and pure autonomic failure with Lewy bodies, is neuronal α–synuclein aggregates called Lewy bodies and Lewy neurites. Neuronal α–synuclein aggregates are distributed throughout the nervous system, including not only the central nervous system (CNS) including substantia nigra, locus ceruleus, dorsal motor nucleus of the vagus, intermediolateral nucleus of thoracic cord and hypothalamus, but also sympathetic ganglia, enteric nervous system, cardiac and pelvic plexuses, submandibular gland, adrenal medulla and skin. Involvement of central and peripheral autonomic nervous system is characteristic feature of LBD. Non–motor symptoms of LBD closely related to the pathological α–synuclein aggregates in central and peripheral autonomic nervous system. The long duration of pure autonomic failure with Lewy bodies may suggest that development of α–synuclein aggregates from peripheral autonomic nervous system to CNS is not always the same as those among LBD.

Trigeminal autonomic cephalalgias (TACs) is a concept introduced in the 2nd edition of the International Headache Classification, and has since been continued in the 3rd edition. Types of headaches in TACs include cluster headache, paroxysmal hemicrania, short–lasting unilateral neuralgiform headache attacks, hemicrania continua, and probable trigeminal autonomic cephalalgia.

Headaches classified as TACs share the clinical features of unilateral headache and, usually, prominent cranial parasympathetic autonomic features, such as 1) conjunctival injection and/or lacrimation, 2) nasal congestion and/or rhinorrhea, 3) eyelid oedema, 4) forehead and facial sweating, 5) miosis and/or ptosis, which are lateralized and ipsilateral to the headache.

Currently, the pathophysiology of TACs is suggested that activation of the hypothalamus, activation of the trigeminal–autonomic nerve reflex, internal carotid artery dilation, and some neuropeptides are involved in, but it is not unequivocal. There are many points for further studies are awaited.

Migraine is a highly prevalent and disabling disorder. Recent surveys have demonstrated the large global burden of disease in people with migraine. Their quality of life is heavily disturbed. There are unmet needs for migraine in terms of sufficient and appropriate diagnosis, and better management and therapies for treatment of migraine. In this review, I discussed the current state of unmet needs of migraine management and possible solutions.

Migraine is known to have a profound effect on daily and social life due to a headache attack. Previously, there was no satisfactory migraine treatment experience, but since the emergence of an acute treatment, triptan, has brought about a revolutionary change in migraine treatment. Nevertheless, in a recent report, the years of life lived with disability for people with migraine is second in the world and fourth in Japan, and thus they are forced to live in poor health. Migraine preventative treatment has been using antiepileptic drugs, β–blockers, and antidepressants. However, treatment failure and safety concerns associated with long–term use are a challenge. Therefore, many new drugs have been developed. Calcitonin gene–related peptide (CGRP) has been shown to play an important role in the pathophysiology of migraine. Overseas, anti–CGRP and anti–CGRP receptor antibodies have been developed and marketed as a treatment for migraine. In Japan, an anti–CGRP antibody (galcanezumab) will also be launched as a preventive treatment for migraine in the first half of 2021, followed by other drugs. This paper describes an anti–CGRP antibodies (galcanezumab, fremanezumab, and eptinezumab) and anti–CGRP receptor antibody (erenumab), which are expected as a preventive treatment for migraine.

Migraine therapy is classified into two categories : attack–aborting and prophylactic treatments. Triptans are very efficacious in alleviating migraine attacks. Nevertheless, the vasoconstrictive properties of triptans restrict their clinical utility. Because simple analgesics and NSAIDs are suboptimal for the acute therapy of migraine, there have been demands for alternative non–vasoconstrictive drugs. Calcitonin gene–related peptide (CGRP) is known to play a pivotal role in the pathogenesis of migraine. Migraine–like attacks are induced in a delayed manner by CGRP administration exclusively in migraine sufferers. BIBN 4096 BS, a first CGRP receptor antagonist, was shown to be effective in ameliorating migraine attacks in a dose–dependent manner, thus demonstrating that CGRP was a bona fide therapeutic target of migraine. It was also revealed that CGRP receptor blockade did not entail any significant cardiovascular risk. There has been much progress in the development of CGRP receptor antagonist in the last decade. Consequently, three CGRP receptor antagonists (gepants) have been approved and marketed globally.

Triptan, a class of serotonin 5–HT_1B/1D receptor agonists, are currently the first choice for acute migraine treatment. Triptans cause vasoconstriction by activation of 5–HT1B receptors, and are contraindicated in patients with certain cardiovascular conditions and events. Lasmiditan is a selective 5–HT_1F agonist, so called ditan, without causing vasoconstriction. Lasmiditan was approved by the U.S. Food and Drug Administration (FDA) on October 11, 2019, and is the only ditan currently in clinical use. This article reviews both preclinical and clinical studies on lasmiditan as a potential acute therapy for migraine, as well as pharmacokinetic and pharmacodynamic features.

Non–invasive neuromodulation devices for migraine have been launched recently, such as external trigeminal nerve stimulation (eTNS), non–invasive vagal nerve stimulation (nVNS), and single–pulse transcranial magnetic stimulation (sTMS). These devices have been well–studied in the randomized sham–controlled pivotal trials or open label studies. In this review, we describe the efficacy of these devices as well as their mechanism of actions and adverse events including our experience with eTNS in Japan.

Chemotherapy–induced peripheral neuropathy (CIPN) is a common dose–limiting side effect for cancer treatment and affect long–term function and quality of life in cancer survivors. It is important for neurologists to understand the pathophysiology and clinical picture of CIPN and evaluate and treat it appropriately.

The common drugs which cause CIPN were Platinum analogs, Vinca–alkaloids, Taxol and proteosome inhibitors. The neurotoxicity of the drugs is usually dose–dependent and symptoms of neuropathy become apparent as chemotherapy repeated. Typically, CIPN is sensory dominant polyneuropathy, characterized by numbness, tingling, often neuropathic pain in stocking and glove distribution. If the symptoms or medical history are atypical, it is necessary to perform blood test, nerve conduction testo or neuroimaging study for making the different diagnosis.

Accurate assessment for CIPN is difficult and several outcome scores were developed. The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI–CTCAE) remains the most common assessment tool and is utilized to decide whether drug to reduced/discontinue the drug. Total neuropathy score (TNS) has been used to monitor objective evidence of neurotoxicity. Patients–Reported outcomes measures such as European Organization for Research and Treatment of Cancer (EORTC) chemotherapy–induced peripheral neuropathy questionnaire (CIPN–20) and Functional Assessment of Cancer Therapy/Gynecological Cancer group Neurotoxicity questionnaire (FACT/GOG NTX), are also used for identifying the impact of neuropathic symptoms on daily life.

To date, the treatment for CIPN is limited and relies on reducing or discontinuing the offending agent. There is a lack of good quality clinical trials on the treatment of existing CIPN or painful CIPN. Nonpharmacological treatment, such as exercise, cryotherapy and nutritional interventions, may also be useful, although there is no clear evidence of its effect. Further research on CIPN is needed.

The effect of immune checkpoint inhibitors has become clear, and its indication is expanding. Contrary to its effects, immune related adverse events (irAE) have become a problem. Neurologic irAE are relatively rare, yet potentially fatal. Neurologists should make appropriate diagnoses and treatments.

Pneumonia is the most common cause of death in Parkinson's disease (PD), with dysphagia as the presumed cause of death. Patients with PD, who are older than 63.5 years and take more than 475mg/day of L–dopa, are at risk for dysphagia in the pharyngeal phase. However, silent aspiration is common in PD ; thus, patients may not be not aware of the risk of dysphagia. In light of this, these patients must be screened for dysphagia–related complications. Patients with PD complicated by severe oropharyngeal dysphagia have three clinical characteristics : higher modified Hoehn and Yahr stage, low body mass index, and increased difficulty in keeping food or drink in the mouth. Moreover, PD patients with severe oropharyngeal dysphagia are more likely to respond affirmatively to the following questions : “Have you lost weight in the past year?,” “Do you cough when you take some medicines?,” and “Do you have difficulty moving the food in your mouth while eating?” The Swallowing disturbance questionnaire is also useful in identifying PD patients with dysphagia. In the treatment of dysphagia in PD patients, those with poor motor symptoms should first be treated with medication. However, dysphagia in PD is not only an extrapyramidal system abnormality, but also the result of a combination of multiple causes, and does not improve with drug treatment alone. One treatment option is the chine down posture, which is useful in improving swallowing in PD patients, and is more effective when combined with expiratory muscle strength training. Further, some motor swallowing exercises on swallowing dynamic may reduce the difficulty in moving food in the mouth when chewing. Patients who have poor laryngeal elevation should be trained to strengthen the swallowing muscles, whereas those with delayed swallowing reflex onset, liquid food should be thickened to slow its passage through the pharynx. Additionally, PD patients with severe dysphagia should be considered for gastrostomy, for medication and nutritional management.

In both Japan and the US, dysphagia rehabilitation for individuals with neurodegenerative diseases had focused on compensatory strategies such as diet modification, postural changes, use of special utensils, and/or non–oral feeding, rather than therapeutic intervention which aims at physiological changes in the muscles and neural pathways. Recently, however, research findings indicate positive influence of certain types of exercises and stimulations on swallowing. This article highlights novel approaches suitable for individuals with Parkinson's disease and ALS in two countries.

近年，地域在住高齢者の介護予防として，口腔構音機能の維持，改善を目指した口腔機能向上プログラムが行われ，高齢者のオーラルフレイルに対する効果が報告されている．しかし，口腔機能低下と認知機能の関連が示唆されているにも関わらず，口腔機能向上プログラムが認知機能や意欲に及ぼす影響は明らかではない．本研究では，高齢者における口腔機能向上プログラムの効果を検証するため，地域在住高齢者に口腔機能向上プログラムを実施し，口腔構音機能，認知機能，意欲に与える影響を検討した．その結果，プログラムの実施前後で，口腔構音機能に有意な変化を認めなかったが，認知機能のうち，実行機能で有意な変化が認められた．この要因として，高齢者の口腔機能向上プログラム参加による社会的交流の活発化や自主訓練実施の意識づけが，実行機能の改善につながったと考えられた．

症例は74歳，男性．3年前stage IAの上皮成長因子受容体（epidermal growth factor receptor：EGFR）遺伝子変異陽性の肺腺癌の手術歴があり再発なく経過した．2か月前から頭痛，羞明とADL低下を示し前医に入院後，急速な意識障害を認めた．当院に転院し，MRIと髄液細胞診により髄膜癌腫症と診断した．緊急腰椎ドレナージ術を行い，第三世代EGFRチロシンキナーゼ阻害薬osimertinibが奏効し，診断から20か月後も独歩での通院を維持できた．osimertinibはEGFR遺伝子変異陽性肺癌に伴う重症の髄膜癌腫症の一次治療として有効な可能性がある．また，原発巣の病期が早期でも髄膜癌腫症の発症に留意すべきである．