Post–stroke epilepsy (PSE) is divided into two categories. Early seizures (ES) typically occur within one week after stroke onset and are also termed ‘acute symptomatic seizures’, whereas late seizures (LS) have a peak within 6–12 months with a higher recurrence rate. PSE is about 10% as a stroke complication, but its rate is as high as 30 to 40% in the cause of elderly–onset epilepsy. Although there is no evidence for the treatment of post–stroke epilepsy, antiepileptic drug treatment should be considered in the event of an unprovoked first seizure. We hope that new antiepileptic drugs will be effective as the evidence accumulates. This review provides a comprehensive perspective of PSE, including the definition, diagnostic criteria, examination tool, and treatment of PSE.

In Parkinson's disease, the progression of the clarification of cortico–basal ganglia loop based on the firing rate model has dramatically contributed to the development of not only medical and surgical treatments but also an understanding of side effects. On the other hand, progress in recent research has clarified the limitations of the firing frequency model and has shown the relationship between abnormal β band oscillations and pathological conditions that complements the limitations of the firing rate model. Besides, research on the elucidation of new pathological conditions using resting–state functional MRI analysis has also been in progress. This review summarizes recent advances in treatment strategies for Parkinson's disease that take into account brain network abnormalities.

Chronic levodopa treatment often leads to problematic levodopa–induced dyskinesia (LID) in patients with Parkinson disease. There are two distinct factors that lower LID threshold, dopaminergic denervation and repeated L–dopa treatment. The emergence of LID is determined by excessive GABA release from terminals of striatal spiny projection neurons composing the direct pathway (dSPN) into the output nuclei. The GABA release from dSPN receives negative feedback by GABAb receptors located on terminals of dSPN. Dopaminergic denervation disables the negative feedback for the GABA release. Then, in the brains with severe dopaminergic denervation, D1 receptor stimulation to dSPN triggers excessive GABA release into the output nuclei. Thus, dopaminergic denervation itself lowers dyskinesia threshold. In addition, along with dopamine neuron loss, serotonin neurons become to convert L–dopa to dopamine and release the dopamine into the striatum. However, unlike dopamine neurons, serotonin neurons cannot control synaptic dopamine levels because they lack D2 receptors and dopamine transporters. As the results, the striatal dopamine levels fluctuate markedly after L–dopa intake, resulting in pulsatile stimulation of dopamine receptors in the striatum. The pulsatile stimulation makes corticostsital synapses at dSPN more sensitive and induces hyperactivity of signal transduction of dSPN. Then, GABA synthesis rises in dSPN after L–dopa and repeated L–dopa treatment gradually increases GABA pool in axon terminals of dSPN. Thus, L–dopa treatment gives a rise to a gradual increase in GABA release into GPi/SNr, reflecting worsening of dyskinesia and lowering of LID threshold. That is to say, the priming of dyskinesia is the GABA storage process, and the emergence of dyskinesia is determined by the amount of the GABA release triggered by each L–dopa intake.

• In the field of large clinical trials, the term “intracranial hemorrhage” includes not only hemorrhagic stroke but subdural hematoma. Each interpreter of trial results should pay an attention for the confusion of definitions, otherwise it may cause misunderstanding.

• In the field of large clinical trials, the term “intracranial hemorrhage” includes not only hemorrhagic stroke but subdural hematoma. Each interpreter of trial results should pay attention to the confusion of definitions, otherwise, it may cause misunderstanding.

• Recently, the bleeding complication during antithrombotic treatment becomes more important and serious due to the wide spreading of its usage.

The speaker revealed that the risk of intracerebral hemorrhage during aspirin therapy for secondary stroke prevention is significantly higher among patients with lacunar stroke. For patients with lacunar stroke or multiple microbleeds, neurologists must avoid aspirin or dual–antiplatelet therapy including aspirin.

Interestingly, the content of intracranial hemorrhage during DOAC anticoagulation is different among DOAC subtype, i.e. subdural hematoma is common in the patients with the thrombin inhibitor, whereas the intracerebral hemorrhage is much frequent among those with factor Xa inhibitors. The neurologists should select more suitable DOAC according to their patients' background and risk factors.

• At late years, some new drugs have been developed for the anticoagulation–rerated bleeding. Idarucizumab is the specific antidote (antibody Fc fragment) for dabigatran, and prothrombin complex concentrate (PCC) can be used for rapid warfarin neutralization. Andexanet alpha for factor Xa Inhibitors is just approved in the United States, and the clinical trial was completed also in Japan. Nevertheless, the immediate control of blood pressure is the still most important issue against a neurological deterioration for the patients with antithrombotic therapy–related intracranial hemorrhage.

Neuromuscular adverse events (AEs) associated with cancer treatment with immune checkpoint inhibitors (ICIs) include diverse clinical subsets. The general features of neuromuscular AEs have not been elucidated because the frequency is generally low, ranging from 1%–2% of cancer patients undergoing ICIs therapy. The diseases affect the central nervous system, peripheral nerves, neuromuscular junction, and muscle. Disease onset and progression may be rapid with a critical clinical course. The clinical presentation may be different from that of patients unrelated to drugs. Headache, dizziness, and dysgeusia were relatively common and mild treatment–related AEs. In contrast, representative immune–related AEs such as autoimmune encephalitis, demyelinating polyneuropathy, myasthenia, and myositis were serious. There was a tight association between myasthenia, myositis, and myocarditis. There are guidelines for the treatment of neuromuscular immune–mediated AEs. For all but the minimum neurological symptoms, checkpoint inhibitor therapy should be withheld until the nature of the AEs is defined. Immune–modulating medication is generally effective for neuromuscular AEs. Both CD8+ cytotoxic T–cells and autoantibodies are involved in the pathogenesis of neuromuscular AEs. Correct understanding of neuromuscular AEs is required for the best management of cancer patients.

Neuromyelitis optica spectrum disorder (NMOSD) is diagnosed using international consensus criteria, a conceptual change from the original neuromyelitis optica (NMO) and considered beneficial for patients positive for the anti–aquaporin–4 (AQP4) antibody. When a diagnosis of NMOSD is confirmed, an established strategy for long–term immunosuppressive therapy will be chosen. Recent advances in understanding of the NMOSD pathomechanism have revealed that the anti–AQP4 antibody is likely the first to cause damage to astrocytes in the central nervous system (CNS) via complement activation, which then results in formation of a membrane attack complex. Another pathological process is an antibody–dependent cell–mediated cytotoxicity (ADCC) mechanism rendered by natural killer cells. Use of mild immunosuppression with corticosteroids and/or azathioprine has resulted in remarkable improvement in patient prognosis, with mycophenolate mofetil and tacrolimus also administered for this purpose. However, a substantial proportion of patients are refractory to those treatments, thus development of novel therapeutic options is mandatory. In this regard, repeated plasmapheresis for removal of pathological autoantibodies is an interesting candidate. Although anti–complement (C5) monoclonal antibody (MoAb) treatment is expensive, it is now available in Japan and has been shown to be a highly efficacious reagent that can largely prevent relapse. Furthermore, anti–IL–6 MoAb, which suppresses immune–mediated inflammation in the CNS, and anti–CD20 MoAb, which deletes B cells, i.e., a precursor of plasma cells, are promising treatment options. It should be noted that anti–AQP4 seronegative patients who are diagnosed in agreement with the NMOSD criteria have heterogenous etiologies. They may show an anti–myelin oligodendrocyte glycoprotein (MOG)–antibody syndrome that has good response to corticosteroids, while there is also a possibility that they are affected by opticospinal multiple sclerosis (MS), which should be controlled by disease–modifying drugs for MS. It is important to note that seronegative NMOSD patients require careful assessment of both neurological status and radiological findings irrespective of treatment selection.

The idiopathic inflammatory myopathies (IIMs, also known as myositis) are a heterogeneous group of autoimmune disorders involving skeletal muscle. IIMs are mainly characterized with associated clinical complications, pathological findings, and myositis autoantibodies. It has been known that about 70 percent of patients have myositis autoantibodies ; myositis–specific autoantibodies (MSAs) or myositis–associated autoantibodies (MAAs). Because a number of MSAs/MAAs correlate with specific clinical features of patients with IIMs, and only one of MSAs is detected in individual patients, it is presumed that autoantibodies or their target molecules correlate with underlying pathomechanisms of IIMs.

For the treatment of IIM, high–dose oral corticosteroid therapy is used for the first–line therapy mainly based on experience. As second–line therapies, immunosuppressants are used as steroid–sparing agents or when the disease is refractory. Intravenous immunoglobulin therapy is considered in the patients who failed to respond to first–line therapy. Therefore, at present, most of the immunotherapies applied to IIMs patients are nonspecific in spite of heterogeneity of underlying pathological mechanisms. Currently, numerous synthetic and biological immunosuppressive agents are available to treat rheumatic diseases including IIMs. To develop more specific therapies targeting underlying pathogenic pathways, further studies on better classification of IIMs and further therapeutic studies on subsets of classified IIM patients should be necessary.

Deep vein thrombosis (DVT) is a condition in which a blood clot forms in a vein, usually in the legs or pelvis. When DVT occurs, urgent care is required. Here, we describe the diagnosis and treatment of DVT in patients with neurological disease.

Stroke and DVT

Patients with stroke may lose the ability to maintain a sitting position, stand, or walk due to sudden hemiplegia or quadriplegia. They may be forced to remain in bed during the acute period, which can make them more susceptible to the development of DVT in the leg on the affected side. Anticoagulant therapy may also lead to the concurrent prevention of DVT depending on the type of cerebral infarction, especially in cases of cardiogenic cerebral embolism, and care is taken in the selection and dosage of the anticoagulant.

Cerebral infarction from DVT

It is important to understand that DVT can cause cerebral infarction. Emboli are sometimes produced in the cerebral arteries when there is a right–to–left shunt due to the existence of a patent foramen ovale, interatrial septal aneurysm, pulmonary arteriovenous fistula, or other condition. During diagnosis, the presence of a right–to–left shunt is confirmed with transesophageal echocardiography.

Other neurological diseases and DVT

The frequency of DVT also increases in conditions where lower limb paralysis is seen, such as peripheral neuropathy or neurodegenerative disease. Unlike stroke, the onset is not sudden and the progressive nature makes the initial determination difficult. DVT can occur due to decreased physical activity from staying in bed or lower limb paralysis cause by secondary impairment to venous return. Consequently, regular evaluation and prevention of DVT is important in patients with neurological disease who have paralysis.

Conclusion

Early discovery of DVT and appropriate treatment are important in patients with neurological disease.

For an accurate diagnosis of neuromuscular disorders, neurological examination based on intensive history taking is definitely important to figure out the distribution of muscle wasting and weakness, as well as accompanying findings including muscle pain, fasciculation, tremorous movement, myotonia, and dermatological changes. Moreover, further medical work–up, such as myogenic enzymes, myositis–specific and –associated autoantibodies, radiology, and electrophysiology, should be conducted to determine application of genetic and muscle histological examination. Muscle biopsy must be performed on adequate region for suspected diseases, and the samples must be collected and treated properly because the operation is invasive. We here focus on frequently encountered neuromuscular disorders for neurologists, and illustrate the cases that can be preferentially conducted muscle biopsy or genetic analysis with specific examples. We present representative histological features of inflammatory myopathies, muscular dystrophies, distal myopathies, neurogenic atrophies, and others. Comprehensive knowledge of muscle histological findings is essential for systematic diagnostic procedure for neuromuscular disorders.

Now Intravenous rt–PA and endovascular therapy are performed in patients with acute stroke. Intravenous rt–PA therapy has been approved in Japan for more than 10 years, and it can be said that rt–PA intravenous therapy is now the standard treatment. Recently, efficacy of endovascular therapy is proved and patient outcomes have changed dramatically from bad outcome to good outcome. We sometimes experience the large vessel occluded patients treated with endovascular therapy, who are walking and being discharged from the hospital. The time windows of endovascular therapy will be prolonged, in the future, which may extend beyond 24 hours onset. We will discuss the advantages and disadvantages of rt–PA and endovascular therapy.

In immune–mediated peripheral neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP) and Guillain–Barré syndrome (GBS), intravenous immunoglobulin therapy (IVIg), plasmapheresis therapy, and corticosteroids therapy had been established by the 1990s and have achieved a certain success. However, there is a need for more effective treatment of long–term neurological decline in severe GBS cases or CIDP cases with recurrent exacerbations. In addition, for MAG antibody–associated neuropathy, there is no treatment with sufficiently established efficacy. In response to these treatment demands, new treatment approaches have recently been put into practical use, or movements toward practical use in the future have been progressing. These movements can be broadly divided into the following three categories : (1) modifying existing treatment methods to improve the quality of treatment as a whole, including patient quality of life ; (2) expanding of indications of existing medicines, (3) new therapeutic approaches. As (1), the indication for maintenance IVIg in CIDP has been introduced, and the administration time has been shortened by high–concentration γ–globulin preparation, and self–injection (subcutaneous injection) at home has also become possible. As (2), the long–term prognosis improving effect of GBS of eculizumab which is an anti–complement drug was reported. There is also a demand for expanding the coverage of rituximab for MAG antibody–positive neuropathy. As (3), degradation of immunoglobulin degrading enzymes (IdeS : IgG degrading enzymes of Streptococcus pyogenes) in GBS and synthetic HNK–1 sugar chain epitope polymers for MAG antibody–associated neuropathy have been under development. In addition to these, there have been reports of the application of biomarkers such as anti–neurofascin155 antibody and anti–contactin–1 antibody in CIDP for treatment selection.

Aphasia is one of the most common cognitive symptoms in brain–damaged patients. Examination of language and related functions is an important part of the neurological examination. To understand symptoms of aphasia, basic knowledge of neuroanatomy is necessary. I propose a four axes theory of functional neuroanatomy of the brain ; anterior–posterior axis (output vs. input), left–right axis (temporal/analytic vs. spatial/synthetic), dorsal–ventral axis (sensory to motor vs. sensory to semantic), and inner–outer axis (basic/innate vs. complex/acquired). This simple theory allows us to estimate the clinical features of each aphasia type. For instance, the Broca's area is located in the left inferior frontal gyrus that corresponds to the anterior, left, dorsal and outer area. The location of the Broca's area suggests the clinical features of Broca's aphasia. For the screening of language functions we observe spontaneous speech, listening comprehension, repetition, naming, reading and writing abilities. The types of aphasia can be determined mainly by the performance on speech fluency, listening comprehension and repetition. The classic aphasia types were based on the clinical syndromes that result from cerebral infarction in the territory of the left middle cerebral artery. In contrast, three variants of primary progressive aphasia are associated with the underlying neurodegenerative diseases. Thus, these two types of aphasia classification are different with each other, which may confuse clinicians. Linguistic features of each type of aphasia, however, could be understood by the functional neuroanatomy of language.

There is increasing evidence that rehabilitation is useful for Parkinson's disease (PD). In–hospital rehabilitation is reported to be effective. However, because of the small number of medical facilities capable of performing intensive rehabilitation and the inconvenience of health insurance system in Japan, not all the PD patients can receive in–hospital rehabilitation. Therefore, we need to make good use of outpatient rehabilitation.

The important point is that rehabilitation is the only method that patients themselves participate positively and are responsible for the results. As a key to the success of continuous rehabilitation, we need to provide a cheerful rehabilitation program and need to let the patients consider the exercise as a part of usual daily life.

Appropriate rehabilitation program for PD patients is composed of a mixture of the following 4 parts ; 1 : aerobic exercise to keep physical strength better, 2 : stretch exercise, 3 : muscular exercise, and 4 : rehabilitation programs to relieve PD–specific problems including abnormal posture, freezing of gait, etc. Paradoxical movement induced by external cue is frequently utilized as PD–specific rehabilitation. In addition, cognitive movement strategy is also often used and is sometimes very effective.

Falling is one of the important troublesome matters in PD. Not only the rehabilitation but confirmation of the falling pattern and the preparation of housing environment are also important to protect patients from falling.

Apart from rehabilitation, various methods such as dances, yoga, music therapy, and vibration therapy are tried and some are reported to be effective. Among these, we have been interested in whole body vibration therapy. Assuming that slow gentle vibration to the whole body may be effective, we loaded whole body vibration with 0.3Hz frequency for 10min to 12 PD patients and found a significant improvement in PD symptoms. Although precise mechanism of the vibration effect and the optimal stimulation parameters are still unknown, we believe that whole body vibration therapy could be one of the future devices to cure PD.

Regular physical activity is one of most important things to improve health. Although types and amounts of recommended physical activity may differ, patients with chronic neurological disabilities benefit from physical activity. On the view point of Sports Neurology, traumatic brain injury (TBI) is a serious problem. Recurrent concussion within several weeks may occur second impact syndrome (SIS) which is rare but sometimes lethal in youth. SIS can occur with any two events involving head trauma. Repeated concussive or subconcussive blows to the head can lead to a progressive neurodegeneration known as chronic traumatic encephalopathy (CTE).

In this lecture, there are 3 key–points : 1) summarizing proper intensity of exercise for healthy adults from physical activity guidelines for Americans, second edition, 2) discussing both of management of mild TBI including concussion and concept of CTE, and 3) featuring of some new methodology of neurological rehabilitation using motor imagery.

In the past, medical treatment was left to specialists. In recent years, after informed consent was established, it has been recommended that advance care be considered as advance care planning (ACP). However, research shows that 75.5% of the general population does not know about ACP. It is recommended that medical care teams make policy decisions based on the choices of their patients. However, patients may still seek physician initiative at university hospitals. Therefore, doctors at university hospitals need to know the general public's awareness of ACP. In March 2018, A questionnaire was conducted to the general public assuming three cases of terminal cancer, severe heart disease, and dementia. Among them, there was a tendency for all three conditions typically did not want medical treatment that would prolong their lives. In the last stage of their life, they want to receive medical care at home for terminal cancer, at medical facility for severe heart disease, and at nursing home for dementia. The disease trajectory of intractable neurological diseases without the use of a respirator is very similar to the disease trajectory of severe heart disease. With the use of a respirator, such neurological diseases have a similar disease trajectory to dementia. When considering where to want to reach the end, it was important to consider, in order, that their families would not be burdened, that the patient would not suffer mental or physical pain, and that the financial burden would be small.

Of the 108 inpatients admitted to Department of Neurology at The Jikei University School of Medicine, Katsushika Medical Center in 2018, 75 were discharged, and more than half of them introduced new home–visiting care. This occurred because they were unable to enter the medical facility economically and had to return home. In addition to this, there are various other decisions to consider for neurological diseases, such as the need for a gastrostoma or ventilator. It is necessary to provide appropriate decision support at the right time, keeping in mind the trajectory of each disease. Because many home–visiting physicians and institutional physicians are not neurologists, it is difficult to visualize disease trajectories. Also, at the time of a patient's transfer from a medical facility to home–visiting care, a patient–physician relationship has yet not been established. For this reason, if it becomes difficult for a patient to go to or remain at a university hospital, there is an obligation to make a decision about ACP prior to leaving the university hospital, steer, and send it out.

It is a crucial decision making for ALS patients whether or not receive tracheostomy and artificial ventilation (TPPV). ALS patients are referred from university hospital to home care doctor when the patient can no longer visit the hospital because of deterioration of motor function. Although patients did not wish to receive TPPV when interviewed at university hospital, many of them are still wondering for TPPV at home.

During 12 years at Yoshino Neurology Clinic, author has been involved for decision making process for TPPV in 169 ALS patients. Among these, 80 patients received TPPV. ALS patients who received TPPV are younger than those who did not receive TPPV, more frequently use facility for care, and more frequently accompanied by spouse.

For decision making process, it is important to correlate with multidiscipline staffs including visiting nurses, care manager, rehabilitation staffs. It is also important to divide enough home care support for patients to make decision under better QOL. Finally, we need to interview continuously as patients usually could not decide their mind until the last moment.

In order for hospital neurologists to support home care patients and their families in making decisions in collaboration with their home doctors and other medical staff, it is important that they do the following:

1) provide the home doctor detailed hospital records including the decision–making process.

2) clarify the division of roles between the hospital doctor and the home doctor.

3) communicate with the home doctor at the right time.

4) make sure that medical staff are comfortable working together.

Each and every neurologist should try hard to help patients and their families make medical decisions that they will not regret later.

Pharmacological therapy of Parkinson's disease was historically initiated with anti–cholinergic agent. The dopamine replacement therapy using with dopa was established in 1960s and followed by dopamine agonists and monoamine oxidase B. Based on the therapeutic strategic concept of continuous dopaminergic stimulation, catechol–o–methyltransferase inhibitors, sustained–release oral agents and patch in dopamine agonists, and L–dopa carbidopa intestinal gel appeared one after another. In Japan, zonisamide and istradefylline were developed ahead of the world, which are anti–epileptic drug and non–dopaminergic drug, respectively. In 2019, two new anti–parkinsonian drugs were added in the lineup, which were ropinirole patch and sufinamide. One clinical trial of opicapone was completed and two clinical trials of novel adenosine A2A receptor antagonist and novel non–ergot dopamine agonist are ongoing. Development of anti–parkinsonian drugs is still in progress, which can offer many treatment options in future. In contrast, because the number of patients with Parkinson's disease is estimated to increase like a pandemic, aged patient issues and medical economics issues also become important in pharmaceutical therapy in Parkinson's disease in near future.

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. The pathological hallmark of PD is loss of dopaminergic neurons in the substantia nigra and the appearance of Lewy bodies, which are mainly composed of aggregated α–synuclein (αS). Dopamine replenishment therapy can alleviate motor symptoms of PD, but there is currently no available treatment which can halt or reverse disease progression. Thus, there is an urgent need for disease modification targeting the build–up of cytotoxic αS in the nervous system. Furthermore, emerging evidence has suggested that aggregated αS can transfer from one cell to another, thereby affecting the normal physiological state of the neighboring neurons in a prion–like manner. These transmissible, extracellular αS species are ideal targets for the disease–modifying treatment including immunotherapy. In this review, I will overview the molecular structure and function of αS, its relevance to PD pathogenesis and will discuss the current status and future prospective of disease–modifying strategies targeting αS in PD.

Parkinson's disease is regarded as the second most prevalent neurodegenerative disorder after Alzheimer's disease. The characteristic pathological finding in cases of Parkinson's disease is dopaminergic neuronal degeneration with Lewy body. Braak et al hypothesized that Parkinson's disease might be distributed from peripheral autonomic neurons to the central nervous system. The progression of Parkinson's disease might be caused by prion–like dissemination of alpha–synuclein, which is known as the main component of Lewy body. Thus, it might be expected that prevention of alpha–synuclein aggregation is possible through disease–modifying therapy. Alpha–synuclein is associated with lipids and the perturbation of the association is caused by the aggregation of alpha–synuclein. Furthermore, genetic dysfunction of phospholipid and glucolipid enzymes, such as GBA mutation and PLA2G6 mutations, is associated with Parkinson's disease with Lewy body. Therefore, elucidation of the pathomechanisms in Parkinson's disease related to the perturbation of lipid metabolism might shed light on the development of disease–modifying therapy.

Parkinson's disease is a progressive neurodegenerative disease and motor complications such as wearing–off and the dyskinesia become problematic with disease progression. For the appropriate treatment, it is necessary to detect precisely the change of symptoms at home as well as in clinic. There is, however, no effective method other than depending on the subjective report of the patients such as a symptom diary for obtaining information of the symptom at home. To obtain objective information, there are several trial using the information and communication technology (ICT), which consists of telemedicine, electric medical record, and monitoring devices. Monitoring device can be divided to “wearable” monitoring device and “non-wearable” devices. In this manuscript current situation and future of application of monitoring device for Parkinson's disease will be reviewed.

Parkinson's Disease (PD) is a progressive degenerative neurological disorder characterized by resting tremor, bradykinesia, cogwheel rigidity, and postural instability. These symptoms result primarily from the loss of dopaminergic neurons in the substantia nigra. Positron emission tomography (PET) has enabled the acquisition of in vivo images of dopamine metabolism in patients with PD. Human endogenous dopamine level peaks at around 20 years old, and is decreased in 10 to 13% per decade of life. Some studies indicated that 80% loss of dopaminergic neurons in the substantia nigra was needed to develop symptoms of Parkinson's disease. Because many compensation systems are working against the decrease of dopamine. One of the most famous systems is acetylcholine. The striatal medium spiny neuron is regulated by dopaminergic input from substantia nigra pars compacta and cholinergic ineterneurons. Cholinergic interneurons occupy 1 to 2% of the neurons in the striatum. Nigral dopaminergic neurons suppress cholinergic interneurons in the striatum. In Parkinson's disease, the cholinergic system is relatively dominant because of degeneration of dopaminergic neurons. Anticholinergic reverses the balance of acetylcholine dominance. Using PET, we have shown that sigma₁ and adenosine A_2A receptors are involved in the compensation of dopamine deficiency.

In Lewy body disease including Parkinson's disease and dementia with Lewy bodies (DLB), dopamine neurons in the substantia nigra and various neurons in the brain degenerate, resulting in the appearance of motor and various non–motor symptoms. Lewy bodies are observed in the remaining neurons of the brain, which play an important role in neuronal degeneration. After that, there has been accumulating evidence that Lewy bodies are found in neurons of the peripheral autonomic system, resulting in the appearance of various autonomic symptoms. Cardiac meta–iodobenzylguanidine (MIBG) uptake on ¹²³I–MIBG myocardial scintigraphy is reduced in patients with Lewy body disease, suggesting disturbance of the postganglionic sympathetic nerve in Lewy body disease. Postmortem studies have shown that the number of tyrosine hydroxylase–immunoreactive nerve fibers of the heart was decreased in pathologically–confirmed Lewy body disease, supporting the findings of the reduced cardiac MIBG uptake in Lewy body diseases. These clinical and pathological evidence have confirmed the involvement of the peripheral autonomic nervous system in Lewy body disease. Thus, the concept of “Lewy body disease is a systemic disease” has been established.

Lewy bodies, Lewy neurites, and glial cytoplasmic inclusion in the brain constitute the main histopathological features of α–synucleinopathies including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy. They comprise amyloid–like fibrils composed of α–synuclein (αS), a small protein (～14kDa). Because the aggregation of αS in the brain has been implicated as a critical step in the development of α–synucleinopathies, the researches for biomarkers and disease–modifying therapies (DMT) have focused on the pathogenesis of αS and its aggregation process in the brain. We previously found that αS and amyloid β–protein (Aβ) acted as seeds and affected each other's aggregation pathways in vitro. In addition, we recently reported that cerebrospinal fluid (CSF) levels of αS are correlated with some clinical symptoms and CSF levels of other pathogenic proteins such as Aβ1–42, tau, and phosphorylated tau in drug–naïve PD patients.

Although αS aggregates from a monomer to assemblies such as oligomers, protofibrils and mature fibrils, the early intermediate aggregates, that is, oligomers have been considered to be most toxic species in the pathogenesis of α–synucleinopathies. We previously reported that phenolic metabolites by gut microbiota inhibited αS oligomerization and were effective in modulating the development and progression of motor dysfunction in a Drosophila model of α–synucleinopathy. The elucidation of αS pathogenesis is expected to develop biomarkers and DMT for α–synucleinopathies.

Clinicians need reliable diagnostic and prognostic biomarkers for synucleinopathies including Parkinson's disease. The diagnosis of Parkinson's disease mostly depends on clinical findings, and recent research identified that the potential diagnostic and prognostic value of CSF and blood biomarkers closely reflecting the pathophysiology of Parkinson's disease, such as α–synuclein. And recent research developed the detection methods based on amplification of synuclein seeds (e.g. RT–QuIC or PMCA). So we introduced that αSyn seeding activity may serve as a novel biomarker for antemortem diagnoses of PD and other synucleinopathies.

In synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), accumulation and aggregation of α–synuclein (SNCA) trigger cytotoxicity and neurodegeneration. When treating synucleinopathies, a therapy to exogenously compensate for dopamine deficiency in the brain due to the degeneration of dopaminergic neurons, has become most common. However, the treatment is not immune to decreased drug efficacy with disease progression. In contrast, if a therapy targeting SNCA, which constitutes the essential disease condition for synucleinopathies, became available, it could be a fundamental treatment that suppresses the progression of neuronal degeneration. In line with the rapid progress in nucleic acid modification techniques, a therapeutic approach that prevents the production of target proteins using nucleic acids medicine has become available. Our group is attempting to treat PD using nucleic acid medicine targeting SNCA. We use Gamper–type antisense oligonucleotides (ASOs) that incorporate a novel nucleic acid modification, amino–bridged nucleic acids (AmNA). These AmNA–ASOs have the advantages of enhanced binding capacity and stability, as well as reduced toxicity. In our previous studies, we optimized the sequence and structure of ASOs that most effectively suppresses SNCA mRNA. By administration into lateral ventricles in mouse models of PD, the ASO was efficiently delivered into mouse brains. Furthermore, the ASO suppressed the levels of SNCA in the striatum of mouse models and improved their motor symptoms. We are currently testing the efficacy and safety of the ASO in non–human primate to proceed this therapeutic approach to clinic, especially for familial PD (PARK4) that is caused by SNCA overexpression. If we can establish an SNCA suppression treatment for PARK4 using ASO, this therapy might eventually be applied to all kinds of synucleinopathies and serve as a groundbreaking disease–modifying therapy.

Autoimmune encephalopathies are clinically and immunologically heterogeneous disorders. Many different types of autoimmune encephalopathy have been discovered, and most common type may be Hashimoto encephalopathy in it. In clinical situations, we often recognize that patients with autoimmune encephalopathy are misdiagnosed as exhibiting functional psychogenic movement, conversion, or somatoform disorders. Most patients with autoimmune encephalopathy showed motor disturbance mostly with unsustained and/or give–way weakness. About 70% of patients showed sensory abnormalities that was not explainable anatomically. One–fourth of patients exhibited involuntary movements such as tremor entrainment, dystonia, or coarse involuntary movement. Although give–way weakness, anatomically unexplainable pain, and strange involuntary movements were thought to be psychogenic, the presence of one of these three symptoms was indicative of autoimmune encephalopathy. As autoimmune encephalitis exhibits diffuse involvement with the whole brain, these symptoms were entirely understandable. Except for the presence of organic disease, most patients were classified into somatoform disorders or functional movement disorders. Without first excluding autoimmune encephalopathy, physicians should not diagnose somatoform disorders.

In the fall of 2015, acute flaccid paralysis (AFP) occurred frequently. As a result of an active epidemiological survey based on the Infectious Diseases Control Law, 115 cases were confirmed between August and December 2015. A secondary survey found that 58 patients met the case definition for acute flaccid myelitis (AFM).

Japan was the only country in the WHO Western Pacific Region not carrying out an AFP surveillance. Due to the frequent occurrence of AFM in 2015, “Acute flaccid paralysis (excluding poliomyelitis)” has been reported as a notifiable infectious disease, by National Epidemiological Surveillance of Infectious Diseases based on the Infectious Diseases Control Law since May 2018 (week 18). Accordingly, all physicians are required to notify a Public Health Center within seven days of a diagnosis of AFP (including GBS) involving a patient under the age of 15 years.

The number of AFP cases has increased since week 39 of 2018, with 139 reported by week 52, and the number of reports peaking in October (51 cases in October). The median age was 3 years (interquartile range, 2–7 years). In 2019, 36 cases were reported by week 26 (up to June 30). The search for causative pathogens can be performed by storing clinical specimens (respiratory specimens, stool, serum, and cerebrospinal fluid) early in the onset of paralysis, subdivided into several at −70°C or lower. For more information on diagnostic treatment, see “Guidance on Surveillance, Diagnosis, Testing, and Treatment of Diseases with Acute Flaccid Paralysis” (https://www.niid.go.jp/niid/images/idsc/disease/AFP/AFP-guide.pdf). An electrophysiological examination of the peripheral nerves and an MRI of the cerebrospinal cord are important for a pathological judgment. MRI imaging requires imaging of the entire spinal cord, even for uniparalysis. The treatment is being analyzed based on a 2018 case study, but may be targeted at protecting the horn cells of the spinal cord.

This research study was conducted under the Grant–in–Aid for Scientific Research on the Ministry of Health, Labor and Welfare Research Project for Emerging and Re–emerging Infectious Diseases and Vaccination Policies, “Clinical epidemiology research to contribute to the investigation of causes and pathologies, including a comprehensive pathogen search, for neurological diseases such as acute flaccid paralysis, acute encephalitis, and encephalopathy, and the establishment of therapeutic methods (Research Representative : Dr. Keiko Tanaka-Taya),” undertaken by Dr. Ryutaro Kira, Dr. Pin Fee Chong, Dr. Hiroyuki Torisu, Dr. Akihisa Okumura, Dr. Harushi Mori, Dr. Sawa Yasumoto, and Dr. Masato Yashiro, as Joint research with Dr. Mitsuaki Hosoya, Dr. Satoshi Kamei, Dr. Makoto Hara, Dr. Hiroyuki Shimizu, Dr. Reiko Shimbashi, Dr. Satoru Arai, Dr. Takahiro Maeki, Dr. Chang–Kweng Lim, Dr. Hiroto Shinomiya, Dr. Tsuguto Fujimoto, and Dr. Nozomu Hanaoka.