About a quarter–century ago, I encountered rat model of experimental autoimmune neuritis (EAN) for the first time in my life in Philadelphia where I stayed as a visiting scholar. Since then, I explored several experiments on EAN. As a president of the 38th annual meeting of the Japanese Society of Neurological Therapeutics, I would like to present what I had learned from rats with EAN and indicate the future perspective of developing new therapeutics for immune–mediated neuropathy (IMN).
Despite rapid progress of therapeutics for IMN, severe neurological sequelae or intractability still exist. To resolve these, EAN ; an animal model for IMN, is used. EAN is usually induced in Lewis rats to obtain uniform temporal profile of motor sign. About 10 days after immunization with peripheral nerve–related antigen, usually a synthetic peptide of bovine myelin P2 protein, monophasic motor paralysis develops, peaks about 5 days later and gradually recovers for next 10～15 days to reach mild sequelae. Activation of EAN is characterized by Th1 activity and at the peak of the disease Th1 to Th2 switching occurs, that finally results in spontaneous recovery. At peak stage of EAN, peripheral nerves are histologically characterized by severely infiltrated mononuclear phagocytes and lymphocyte and patchy foci of demyelination, that resolves considerably later.
To intervening pathological process of EAN, we tried several drugs that are already approved in treatment for non–neurological disorders, such as hyperlipidemia, hypertension or vasodilator, including hydroxymethylglutaryl–CoA reductase inhibitors (statins), angiotensin II receptor blockers (ARBs) and phosphodiesterase inhibitors (PDE–I).
We employed atorvastatin (ATO) ; one of strong statin that is able to suppress animal model of multiple sclerosis, various ARBs (candesartan ; CAN, losartan ; LO and irbesartan ; IRB), PDE3–I ; cilostazol (CLZ) and PDE5–I sildenafil (SIL).
ATO suppressed motor paralysis of EAN mildly and intraneural proinflammatory Th1 cytokine expression. But peak of anti–inflammatory Th2 cytokine expression was also suppressed and delayed, indicating ATO might suppress Th1 activity only.
IRB suppressed motor paralysis through entire EAN course while CAN did not suppress and LO delayed onset and accelerated recovery mildly. These differences clearly depended on the ARB's affinity to C–C chemokine receptor 2b.
CLZ suppressed EAN severity in entire course clinically and histologically via Th1 to Th2 deviation, while SIL facilitated recovery from motor paralysis indicating remyelination and regeneration of the peripheral nerve.
The disease modifying ability of all the drugs I depicted above seems insufficient to treat human patients when used single, however these drugs might be useful if used in combination with any other treatment. Further study is needed to elucidating this point in future.
The neurological disease was thought not to be able to get over even if the diagnosis is possible, however, treatment is enabled.
This report is made from the president view and describes it about as of a thing of the Japanese society of neurological therapeutics (JSNT) which I walked with members and the future prospects.
In other words, the neurotherapeutics guidelines that should be able to be called the axis on this society add it to result such as standard neurotherapeutics guideline publishing, in addition, globalization committee, an innovative drug development committee, regional clinician working group, the medical needs investigation working group might be well performed.
As the future prospects, we JSNT have to perform not only disease–modifying therapy but the complete drug for neurological disease based on big data and genetical analysis by AI with all member.
Multiple Sclerosis (MS) is a chronic demyelinating disease in the central nervous system. The pathogenesis of MS is mainly by cellular and humoral immunity against myelin sheaths. The main cause of disability is derived from secondary progressive phase of MS, which could induce chronic demyelinating slowly expanded lesions together with axonal damage and neuronal loss. Recently, it is considered that the chronic activity of phagocytic macrophages is induced by antibody–producing B cells and T cells in lymphoid tissue in the CNS, which could be the molecular targets of treatment. Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease caused by anti–aquaporin 4 antibody. One of the main cause of tissue injury is mediated by complement–dependent cytotoxicity against astrocytes. Now humoral immunity is the main target in NMOSD, there is several antibody medicines including eculizumab, satralizumab, inebilizumab, and rituximab. In this issue, I would like to focus on the therapeutic strategy of MS and NMOSD by recently developing drugs.
It has been demonstrated that neuronal surface (NS) antibodies play an important role in the pathophysiology of various neurological and neuropsychiatric disorders, including non–infectious/post–infectious encephalitis, first–episode psychosis, epileptic and non–epileptic seizures, atypical demyelinating syndrome, post–partum psychosis, progressive dementia, involuntary movements (orofacial–limb dyskinesias, faciobrachial dystonic seizures, catatonia, rigidity, stiffness, tremors, myoclonus, chorea, stereotypies, oculomotor abnormalities), and non–REM/REM sleep disorder. IgG NS antibodies are considered more likely to be pathogenic, accordingly the presence of NS antibodies supports early initiation of immunotherapy. In 2016, a practical diagnostic approach to autoimmune encephalitis (AE) was proposed to achieve prompt immunotherapy at 3 levels of evidence for AE (possible, probable, and definite) with diagnostic criteria for possible AE, probable AE, probable and definite anti–NMDAR encephalitis, autoimmune limbic encephalitis, ADEM, and Hashimoto encephalopathy. Identification of autoantibodies against NS or intracellular antigens is crucial in making a diagnosis ; however, the antibody testing results should be carefully assessed especially when measured with commercial assay alone.
In this lecture, I focus on recent progress in AE, and its related disorder including cryptogenic new–onset refractory status epilepticus.
We describe here our results of epidemiological survey for fatigue in Japan, and our recent findings found in chronic fatigue syndrome (CFS) patients. In 1999, our epidemiological survey of 3,015 Japanese people revealed that 35.6% of them had chronic fatigue and 16.8% had a deterioration of daily physical activities. Eight people (0.26%) were diagnosed as CFS according to CDC 1994 criteria. Our recent studies revealed that the existence of neuroinflammation in patients with CFS by the positron emission tomography. We also found that CFS patients exhibited significant differences in intermediate metabolite concentrations in the tricarboxylic acid and urea cycles, and that the identification of actin network proteins in circulating extracellular vesicles were useful as the blood biomarkers for CFS.
The intracellular antigens have been known to involve in several forms of encephalitis/encephalopathy. Anti–Hu and other onco–neuronal autoantibodies against intra–cellular antigens have been identified since 1960s. The autoimmune cerebellar ataxia consists of paraneoplastic ataxia (anti–Yo et al.), anti–GAD–autoantibodies associated ataxia, gluten ataxia (anti–gliadin and TG2) and Hashimoto's encephalopathy (anti–NAE).
Recently, various autoantibodies against antigens in cell surface or inter–synaptic spaces, the NMDA receptor, the AMPA receptor or the VGKC complex (LGI1 and Caspr2) etc., have been also identified in association with several forms of encephalitis/encephalopathy, especially limbic encephalitis. The target antigens are receptors or channels that play crucial roles in synaptic transmission and neural plasticity.
Immuno–precipitation and peptide sequence analysis of the target protein (proteomics) provided the identification of the antigens corresponding to autoantibodies in autoantibody–mediated encephalitis/encephalopathy. Appropriate preparation of antigens (synthesized peptides, or recombinant proteins prepared in E.coli or cultured mammalian cells) and assay systems (immunoblot, ELISA, immunoprecipitation or cell–based assay [CBA]) should be selected for the detection of each autoantibodies.
The early and accurate diagnosis of autoantibody–mediated encephalitis/encephalopathy is important because most patients show responses to immunotherapy. The treatments of autoantibody–mediated encephalitis consist of steroid, immunosuppressants (cyclophosphamide), plasma exchange, intravenous administration of immunoglobulin (IVIg), rituximab and tumor removal. A careful screening of neoplasms is a critical point in both the diagnosis and treatment in autoantibody–mediated encephalitis.
Further studies on the effects of autoantibodies in animal models that recapitulate the disease and the process of recovery, and clinical trials to search for the appropriate treatments are necessary to fully understand autantibody–mediated encephalitis.
New evidences are being accumulated year by year regarding therapeutic concept and methodology of stroke. Dramatical change had occurred even on grade A–therapies especially for acute reperfusion. Variety of mechanical thrombectomy (MT) devices (5 stents and 4 aspirators) are available nowadays. Treatment indication is determined by advanced brain imaging, i.e. penumbral mismatch or DWI–FLAIR mismatch. So–called “Tissue-based strategy” is the current standard for decision making in patients with late time window (＞6h) or unclear onset time. DIRECT–MT study revealed direct MT without rt–PA pre–infusion showed non–inferiority to those combined with rt–PA.
For non–cardioembolic stroke, dual antiplatelet therapy (DAPT) using aspirin and clopidogrel became current standard therapy during the acute phase. Optimal DAPT duration is suggested as 21 days by pooled analysis of CHANCE and POINT trials. Long–term DAPT for more than 1 year is usually harmful with bleeding risk. However, cilostazol–based DAPT in combination with clopidogrel or aspirin might be a good option as shown in CSPS.com study.
For patients with non–valvular atrial fibrillation, anti–coagulation therapy is highly recommended for secondary prevention of stroke. RELAXED study showed that initiation within 14 days of onset seems effective and safe, should the patient be able to swallow rivaroxaban early after stroke. Another topic of anti–coagulation is the introduction of effective antidotes : 4–factor prothrombin complex concentrate for warfarin and Idarucizumab for dabigatran.
Migraine is characterized by recurrent headache attacks of moderate to severe intensity accompanied by nausea, vomiting, and photophobia/phonophobia. This disabling headache disease causes an enormous financial burden on society. Although the pathophysiology of migraine remains largely unknown, it is now much appreciated that migraine is primarily a neural disease. Migraine headache is caused by abnormal activation of the trigeminal system with calcitonin gene–related peptide (CGRP) playing a pivotal role in the development of sensitization. Triptans, 5–HT1B/1D/1F agonists, are the mainstay of migraine acute therapy. For prophylaxis, calcium channel blockers, anti–epileptic drugs, and tricyclic antidepressants are used with a view to rectifying abnormal neural activity. In addition, CGRP–targeted therapy, which consists of CGRP–related monoclonal antibodies and small–molecule CGRP receptor antagonists, has been launched into migraine management. In particular, CGRP–related antibodies are shown to exert efficacy even in difficult–to–treat cases.
Guillain–Barré syndrome (GBS) is a monophasic immune–mediated neuropathy. Approximately 20% of GBS patients can't walk without aid at one year from onset. The effectiveness of second IVIg couldn't be shown in the recent SID–GBS trial. Thus, novel therapies are required for improvement of the prognosis in GBS. Complement inhibitors are notable as the novel therapies for GBS. The inhibitor of C5, eculizumab, is expected for the improvements of long–term prognosis in GBS. In addition, the inhibitor of C1q also possibly has an effectiveness as well as C5 inhibitor. Previous in vitro and in vivo studies have shown that IgG–degrading enzyme of Streptococcus pyogenes (IdeS) inhibits deposition of complement and prevents axonal degeneration. At present, several trials regarding those complement inhibitors are in progress.
Immune mediated nervous system disorders are female–predominate diseases that often first presents during a women's childbearing years. We cannot treat their diseases without thinking their pregnancy and delivery. We focus on the pregnancy and delivery of a patient who have immune mediated nervous system disorders especially multiple sclerosis (MS), Neuromyelitis optica spectrum disorder (NMOSD) and myasthenia gravis (MG). Immunity of the pregnancy is performed on human maternal–fetal interface from early pregnancy. There are many decidual immune cells at maternal portion of placenta and they are the basis of maternal–fetal tolerance. The main components of them are NK cells, T cells, macrophages, dendritic cells. Decidual CD4＋T cells are shifted Th2 and Treg cells from Th1 and Th17 cells as it becomes in late pregnancy, so that most of the MS patients don't have a relapse. But after delivery, immune system changes and relapse rate returns to a state before the pregnancy. On the other hand, anti AQP4 anti body production increases during pregnancy. AQP4 was found on fetal villous surfaces in placenta. When NMO patients are not treated with immunosuppressive drugs, anti AQP4 antibodies bind AQP4 molecules and they cause placental inflammation and fetal death. Pregnancy outcomes of MG patients are quite better when their conditions are stable. NMO and MG patients should be treated during pregnancy. Most of the drugs are safe. Breast feeding should be considered by the factor which influences a mother's milk shift to a baby.
The clinical outcomes of neurogenic lower urinary tract dysfunction are improvement as well as prevention of urinary tract complications (renal impairment, symptomatic urinary tract infection and so on), attainment of social urinary continence, and improvement as well as maintenance of quality of life. To this end, appropriate urinary management that maintains low pressure in lower urinary tract throughout the storage as well as emptying phase plays a pivotal role in achieving these clinical outcomes. When outcomes are not achieved despite appropriate urinary management with or without pharmacotherapy, adjustments to urinary management including pharmacotherapy and/or surgical therapy should be considered.
Dysphagia refers to a series of movement failures that prevent uptake of food and passage of food to the stomach. When it is caused by neurological disease, the patient rarely complains of dysphagia. Dysphagia is first assessed in these patients by bedside observation and is suspected if any of the following are present : an increase in sputum, choking, a wet husky voice, food mixing with sputum, a sense of discomfort in the pharynx, decreased appetite, fatigue during eating, prolongation of mealtime, a change in eating performance, and weight loss. Further evaluation of deglutition can then be performed at the time of the first medical examination or at the time of hospitalization. These examinations include the repetitive saliva swallowing test and modified water swallowing test ; videofluoroscopy, in which the deglutition–related organic state and movement are assessed ; and videoendoscopy, which enables serial evaluation at the bedside. A treatment strategy is then decided to prevent aspiration of food and food from remaining in the pharynx after swallowing. Dysphagia also affects the intake of medicine, and can interfere with medical treatment. Medicine in any form, including tablets, capsules, orally disintegrating tablets, and powdered medicine, can leave behind residue in the oral or pharyngeal cavity when taken by patients with dysphagia. Accordingly, careful observation is required.
One fifth of populations had sleep problems such as insomnia, sleep apnea syndrome (SAS), REM sleep behavior disorder (RBD), and hypersomnia. Sleep disturbances frequently complicated with neurological disorders. Also, some sleep disturbances proceed neurological disorders.
SAS is not only one of risk factors but also complication of cerebral vascular disorders. Also, SAS is one of risk factors of vascular dementia.
Patients with Alzheimer disease (AD) often have sleep disturbance on early stage of the disorder. Also, sleep disturbance is one of risk factors of behavioral and psychological symptoms of dementia. Recently, insomnia is supposed as one of risk factors of AD. On the other hand, hypnotics also is one of risk factors of dementia.
RBD is related with dementia with Lewy bodies and Parkinson's disease (PD). Especially, RBD proceed synucleinopathies including multiple system atrophy. Questionnaires are useful for screening RBD. If Patients with RBD had other symptoms such as urinary dysfunction, color discrimination, cognitive impairment, and progressive motor symptoms, they might progress synucleinopathies.
Hypersomnia is related with lesions of hypothalamus such as stroke, brain tumor, demyelinating disease.
Many sleep disorders are associated with neurological disorders. Neurologists need to pay more attention to sleep disturbance.
In Setagaya, regional hospitals and medical associations cooperated in formulating the Setagaya Regional Cooperative Critical Path for Diagnosis of Dementia, and put this system into practice in 2008. At the same time Setagaya Dementia Network Study Groupe, in which we discuss the operation of path and conduct case studies and special lectures, was launched. In this critical path, a physician in a clinic refers his/her patient to a regional hospital in the critical path network, using a patient record form prepared by the clinic. The doctor who receives the referral in the network hospital examines the patient for the presence/absence of dementia, determines the underlying cause of dementia, and returns the patient to the referring doctor in the clinic with the therapeutic strategies decided upon. The patient is then followed by the referring doctor in the clinic while being given drug therapy or other necessary treatments, and is examined in the hospital regularly at intervals of about 6–12 months. The introduction of this critical path system has facilitated smooth cooperation among hospital physicians, primary care physicians and staff involved in the care of patients with dementia.
Further formulation of a system to support patients with dementia involving the whole community through cooperation among patients and their families, primary care physicians, regional hospitals, administrative authorities, and regional comprehensive support centers is awaited. Such a system would facilitate reaching the future goal of construction a community that allows people to live with peace of mind even after becoming demented.
The staff, who work for hospitals or clinics with beds in Setagaya Ward, meet up regularly to discuss bed control in acute care hospital etc. This work shop is named Setagaya Hospital Renkei Network (SHRN), which is an advisory panel of Hospital Directors' Conference in Setagaya. For regional medical cooperation, not only hospitals–clinics but also hospitals–hospitals cooperation is very important and collaboration practitioners are involved in this cooperation. Some members of SHRN played an important role in launching and operating Setagaya Dementia Network Study Group (SDNSG). The secretariat of SDNSG consists of nurses and collaboration practitioners including medical social workers (MSW) and clerks. The secretariat helps to collaborate with the Setagaya Medical Association, Tamagawa Medical Association, and Setagaya Word to support the activities of SDNSG as well as to hold official liaison meetings and special lectures. In 2020, the secretariat of SDNSG have prepared for the regular lecture in February, but it has been suspended due to preventing the spread of COVID–19 infection. In this way, the collaboration practitioners not only practice in hospitals–clinics and hospitals–hospitals cooperation but also help activities of SDNSG.
Setagaya dementia network workshop was established for the purpose of performing cooperation of the dementia treatment between a specialized hospital and the family doctor of the Setagaya district. The network is useful for cooperation with the family doctor. In the medical care of dementia, a right diagnosis and the maintenance of the quality of life are important to a patient. Therefore, the cooperation with medical care, care and community supports people with dementia and their families. Strengthening cooperation is a step toward establishing a community where people with dementia and their families can spend their daily lives with hope.
Since 1987, the Setagaya Medical Association has been conducting a home–visit medical project with the aim of ensuring appropriate medical care in the community for patients suffering from intractable neurological diseases. In this project, a specialist visits the patient's home, along with members of the Setagaya Medical Association, to examine the patient and explain the current medical condition, disease–specific symptoms, and expected course in the future to the patient and his/her family. Based on this, family doctors, visiting nurses, public health nurses, life counselors, etc. will consider subsequent medical treatment and care works. At this symposium, I would like to consider the past efforts and future issues of this project from the standpoint of a family doctor.
The purpose of this research is, to examine the effect of coordination training on salivary cortisol response with SOMA–Cube–Reader (Oral Swab®). 18 children in the 4th grade at elementary school in Japan performed light or moderate intensity rhythm exercises for 40 minutes. The results showed that the Cortisol level after exercise decreased significantly by carrying out short term coordination exercise [t(17)＝2.543, p＜.05].
The results showed that the Cortisol level after exercise decreased significantly by carrying out short term coordination exercise [t(17)＝2.543, p＜.05]. For the physical education, it is necessary to apply coordination exercise with a view of stress management.
Diminished regulatory component of the immune system are reported in multiple sclerosis (MS). Synthetic glycolipid OCH acts on iNKT cells to selectively produce IL–4, alleviating experimental autoimmune encephalomyelitis an MS animal model. The first–in–human Phase I investigator–initiated clinical trial was conducted at our hospital during 2012–2017. We have confirmed tolerability of OCH in both HS and MS patients. Pharmacokinetics study revealed that absorption of OCH from intestine was better in human than primates and rodents. Moreover, we have observed several immune–related changes in the blood of the HS and MS. Phase II clinical trials were started in November 2019. We herein outline a single–center, two–group, randomized, double–blind, phase II clinical trial among 30 patients with recurrent multiple sclerosis (RMS) who received weekly, repeated oral administration (24 weeks). Test drug (0.3–g granules ; containing 3.0mg OCH–NCNP1) or a control drug (placebo) is administered to examine drug efficacy and safety. As of January 2021, 25 patients participated in the trial.
Oligonucleotide therapeutics belong to molecularly–targeted therapy as well as antibody drugs and gene therapy drugs do, and directly bind target molecule without gene expression. They can bind nuclear RNA and work in the cell, though the antibody drug targets are limited to cell surface molecules. Antisense oligonucleotides, small interfering RNA, decoy, aptamer, and CpG ologonucleotides are mojor subtypes of oligonucleotide therapeutics which are classifed by the mechnism of action. The improvement of chemical modifications such as backbone modificatins and sugar modifications have increased thier stability. As a result, many of FDA approved oligonucleotide therapeutics have been developed in past five years. In 2020, viltolarsen was approved by FDA as a first antisense oligonucleotide developed in Japan. In this abstract, we review the characteristics, classification, and chemical modifications of oligonucleotide therapeutics. Moreover, we outline their current status in clinical practice.
Aggregation of α–synuclein (αSyn) plays a central role in the pathogenesis of Parkinson's disease (PD). Reduction of αSyn production may provide a disease–modifying therapy in PD. ASOs designed against human SNCA have the potential to be a disease–modifying therapeutic target for PD patients. PARK4 patients with a duplication or triplication of the αSyn gene, without any pathological mutation, are healthy before onset, although their symptoms develop relatively early. PARK4 might be a useful target to investigate the mechanism through which DA neurons regulate αSyn aggregation before the clinical onset of PD and could lead to the development of new therapies for patients with PARK4. Inhibition of leucine–rich repeat kinase 2 (LRRK2) activity also represents one of the most promising therapeutic strategies. A phase I clinical study evaluating the safety and tolerability is currently enrolling 82 subjects in Europe. For the development of these therapies, it is important to provide an accurate diagnosis at a very early stage of the disease and it is necessary to develop accurate biomarkers that can be used to assess the degree of the accumulation of α–synuclein aggregates in the brain of patients to evaluate the efficacy of those treatments.
Duchenne muscular dystrophy (DMD) is a fatal, inherited progressive muscle degenerative disorder and a prototypical rare disease for the development of advanced precision medicines. There is currently no cure and therefore, an urgent need for new therapies to extend lifespan and improve quality–of–life for DMD patients. Currently, exon skipping therapy by antisense oligonucleotide is a promising approach to treat DMD. We have reported the proof of concept of exon skipping, using dystrophic mouse or dog models in addition to DMD patient–derived cells. Based on those preclinical findings, National Center of Neurology and Psychiatry and Nippon Shinyaku Co., Ltd. have achieved marketing approvals of viltolarsen, phosphorodiamidate morpholino–based oligonucleotide drug, for DMD in Japan and the USA in 2020. As the next step, to address psychiatric symptoms in DMD, we characterize the absence and impact of brain dystrophin isoforms in DMD mouse models.
Fukuyama congenital muscular dystrophy is an autosomal recessive disease that is characterized by congenital muscular dystrophy with abnormalities in central nervous system and/or cardiomyopathy. The responsible gene is Fukutin and its mutations lead to abnormal glycosylation of dystroglycan, a receptor for matrix proteins. We identified a novel post–translational moiety in the sugar chain of dystroglycan, namely, tandemly–connected ribitol–phosphate, and showed that Fukutin encodes an enzyme synthesizing the ribitol–phosphate moiety. Furthermore, we have revealed the pathogenesis how glycosylation defects cause muscular dystrophy, central nervous system abnormalities, and cardiomyopathy using Fukutin conditional knock out mice. In this report, we summarize structure of dystroglycan sugar chain and enzymes responsible for its biosynthesis. We also discuss therapeutic strategies for Fukuyama congenital muscular dystrophy and related diseases.
Mutations in dysferlin are responsible for a group of progressive, recessively inherited muscular dystrophies known as dysferlinopathies. Using recombinant proteins and affinity purification methods combined with LC/MS/MS, we found that AMPKγ1 was bound to a region of dysferlin located between the third and fourth C2 domains. Using ex vivo laser injury experiments, we demonstrated that the AMPK complex was vital for the sarcolemmal damage repair of skeletal muscle fibers. Injury–induced AMPK complex accumulation was dependent on the presence of Ca2+ and the rate of accumulation was regulated by dysferlin. Furthermore, it was found that the phosphorylation of AMPKα was essential for plasma membrane repair, and treatment with an AMPK activator rescued the membrane–repair impairment observed in immortalized human myotubes with reduced expression of dysferlin and dysferlin–null mouse fibers. Finally, it was determined that treatment with the AMPK activator metformin improved the muscle phenotype in zebrafish and mouse models of dysferlin deficiency. These findings indicate that the AMPK complex is essential for plasma membrane repair and is a potential therapeutic target for dysferlinopathy.