Japan's population is aging at a rate never before experienced by humankind. In this context, neurologists are expected to have a wide range of skills, including ability to comprehensively understand and deal with patients who has multimorbidity, complex decision support, promotion of drug discovery and clinical trials, and medical care that supports patients who live, all of which have not been covered in undergraduate education to date. I have looked ahead to the next 20 years as a neurology department that is more useful to society.

Among patients with emergent large vessel occlusion (LVO), mechanical thrombectomy (MT) is now become first–line therapy. It is unclear whether preceding alteplase is mandatory or not. DIRECT–MT study showed non–inferiority of MT alone in terms of achieving good clinical outcome compared to combined therapy with alteplase and MT. This clinical question will be answered when other ongoing similar trials' data become available.

New generation P2Y₁₂ antagonists, ticagrelor and prasugrel, announced promising results in 2020. Dual antiplatelet therapy (DAPT) using ticagrelor reduced stroke or death in patients with minor ischemic stroke or high–risk TIA. Although overall benefit was cancelled by increase of severe bleeding. Prasugrel showed good safety profile among Japanese high risk patients (age ＞75y or weight ＜50kg) with lacunar and atherothrombotic stroke.

The concept of embolic stroke of undetermined source (ESUS) is now entered re–consideration phase. Japanese subgroup analysis of RE–SPECT ESUS disclosed that dabigatran significantly reduced the risk of recurrent stroke (HR 0.55, 95%CI 0.32–0.94). Furthermore, no difference was observed about the risk of major bleeding. Japanese subgroup was older and more CKD patients are enrolled. Prevalence of covert atrial fibrillation may be higher than the other.

Treat Stroke to Target (TST) trial investigated whether aggressive LDL lowering (＜70mg/dL) result in reduction of cardiovascular events among patients with recent ischemic stroke with atherosclerotic plaque. Indeed, lower–target group (LDL ＜70mg/dL) revealed 22% risk reduction compared to higher–target group (LDL 90–110mg/dL).

Finally, COVID–19 pandemic dramatically changed our stroke triage and emergency protocol. Top priority is the perfect defense of medical staff from COVID–19 infection. Making each hospital's own Protected Code Stroke is essential. COVID–19 itself seems to cause stroke. ESUS, LVO, young stroke, and hypercoagulable state are the key words of COVID–19 related stroke.

With the aging of society, the number of dementia patients in Japan continues to increase, with the Ministry of Health, Labor and Welfare predicting 4.62 million dementia patients in 2012 and another 4 million patients with mild cognitive impairment. In other words, about 8.6 million people have dementia or are in the preliminary stages of the disease. When this number is compared with the number of patients with other diseases announced by the ministry in 2014, it is not as high as the number of patients with hypertension (10.1 million), but it is much higher than the number of patients with diabetes (3.16 million). This increase is not limited to Japan, the same trend is observed worldwide, and many research results have been reported in response to this trend.

We summarized and reported the results of the relatively large–scale studies on dementia treatment reported in 2020.

Recent advances and new findings relating to multiple sclerosis (MS) and other inflammatory disorders in the central nervous system were reviewed. The following topics were discussed : the association between disease modifying therapy (DMT) of MS and coronavirus infectious disease–19 (COVID–19), the association between initial DMT and MS disability progression, the efficacy of extended interval dosing of rituximab in treatment for RRMS, the efficacy and safety of ofatumumab for RRMS, the characteristic relapse patterns of neuromyelitis optica spectrum disorder (NMOSD), the efficacy and safety of satralizumab monotherapy for relapse prevention of NMOSD, the characteristic MRI findings of myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD), the pathological characteristics of MOGAD, and the use of rituximab for relapse prevention of NMOSD and MOGAD.

We review reports published in 2020 providing new information on the management of Parkinson disease (PD) and its related disorder.

Motor neuron diseases (MND) are devastating neurodegenerative disorder which primary affects motor neurons : amyotrophic lateral sclerosis (ALS), spinal bulbar muscular atrophy (SBMA), and spinal muscular atrophy (SMA). In 2020, positive results of several clinical trials including novel antisense oligonucleotide treatment on SOD1–ALS (tofersen) were published. As for SMA, novel gene–replacement treatment (zolgensma) was approved in Japan. These novel drugs will bring a promising future for MND patients.

This review provides an overview of clinical advances in MND research and summarizes selected key literature on therapeutic approaches in 2020.

The treatment of brain tumors and granulomatous disease in the brain represents a serious unmet medical need in the field of neuro–oncology. Even though many effective compounds have demonstrated success in treating peripheral tumors with targeted agents, one aspect of this lack of success in the brain may be related to poor delivery of otherwise effective compounds. This review discusses some issues that are pertinent to precision medicine for glioma, brain metastases and neurosarcoidosis with some reports published in 2020. In addition, we introduce the promising results in clinical trials of new–targeted immunotherapies for these diseases.

Evidence is being generated and new treatments are being developed in various neuropathies. This paper discusses about recent progresses that clinicians should be aware of : In Guillain–Barré syndrome, a randomized controlled trial failed to show the efficacy of a second administration of immunoglobulin. Development of new therapies to inhibit complement activation is underway. European Association of Neurological Societies/Peripheral Nerve Society published updated guidelines of CIDP. Clinical subtypes have been organized and subcutaneous immunoglobulin has been added as a recommended treatment. For POEMS syndrome, thalidomide was approved after an investigator–led clinical trial. Moreover, ELISA kit for vascular endotherial growth factor was also approved for diagnosis and evaluation of therapeutic response. ATTRv amyloidosis is an autosomal dominant inherited disorder for which innovative treatments have been implemented. Although ATTRv amyloidosis is rare, it should be kept in mind as a differential diagnosis to provide patients with appropriate treatment as early as possible.

We reviewed articles on novel development of neurological treatment published in 2020. Atomoxetine improved orthostatic blood pressure changes as much as midodrine and was better in terms of ameliorating orthostatic hypotension symptoms. One meta–analysis provides low–quality evidence of a short–term improvement in orthostatic intolerance with increased salt intake. Another meta–analysis showed no significant effect to orthostatic hypotension of resistance exercise, electrical stimulation, and lower limb compression bandaging. Splanchnic venous compression alone did not improve tachycardia or symptoms, but the combination with propranolol was more effective in improving symptoms than either alone. Pharmacological norepinephrine transporter inhibition prevented severe vasovagal reactions and syncope induced by head up–tilt testing in patients with vasovagal syncope. Overactive bladder (OAB) symptoms were significantly improved in older adults with Parkinson's disease under fesoterodine fumarate treatment. One meta–analysis indicated that the safety and efficacy profile of mirabegron remains favorable compared with anti–muscarinics among older adults. Vibegron provided significant reductions in micturitions, urgency episodes and urge incontinence in patients with OAB. Daily consumption of sterilized probiotic containing L. helveticus with or without polydextrose alleviated constipation–related symptoms. Flaxseed flour was more effective at increasing defecation frequency than lactulose, patients with chronic functional constipation. Linaclotide significantly improved opioid–induced constipation symptoms. Electro–acupuncture could effectively improve bowel function, mental states and QOL of functional constipation patients. Plecanatide, tenapanor and minesapride were well–tolerated and effective treatment option for patients with constipation–predominant irritable bowel syndrome or functional constipation.

We reviewed treatments for headaches (migraine and cluster headaches) and epilepsy, mainly published in 2020. Headache is the most common neurological disorder and the third leading cause of disability worldwide. Recently, Calcitonin gene–related peptide (CGRP) has been shed light on because of its role in the pathophysiology of migraine headaches. In 2020, the monoclonal anti–CGRP antibodies were approved in Japan. They were shown to improve the frequency of headache attacks compared to the placebo or previous medications. Furthermore, they did not show significant adverse effects in the clinical trials. Other than these antibodies, selective 5–HT_1F receptor agonist (ditans) or CGRP antagonists (gepants) are also under clinical trials. Cluster headache is one of the most painful disorders. Although the precise protocols were not determined, one study showed that the gradual decrement protocols of prednisolone improve the frequency of headache attacks.

Recently, the number of patients with epilepsy in the elderly has been gradually increasing because of the aging society. Since the cause of late–onset epilepsy was mainly cerebrovascular diseases and dementia, the cross–talks between epilepsy and dementia were reported. Patients with Alzheimer's disease had a 6–times higher odds ratio of complications of seizures. Meanwhile, cognitive functions of minimal cognitive impairment cases with epileptic seizures worsened compared to those without epileptic seizures. Autoimmune encephalitis is one of the crucial causes of late–onset epilepsy. However, autoimmune encephalitis such as anti LGI1 antibody–associated encephalitis was often misdiagnosed because it mimics epilepsy or dementia. It responses to immunological treatments like methylprednisone pulse or IVIg.

Other advances were reported below. 1) The use of continuous electroencephalogram (cEEG) was revealed to improve the prognosis of critical care patients. As a result, the American Clinical Neurophysiology Society recommended its use to diagnose nonconvulsive seizures in the neuro–intensive care unit. 2) Oromucosal solution containing the active substance midazolam was approved in Japan to treat prolonged, acute convulsive seizures in children and adolescents less than 18 years of age. 3) The treatment with responsive neurostimulation (RNS) in the USA was shown to provide significant reductions in the frequency of focal onset seizures through 9 years of follow–up. In addition, there could be longer–term neuromodulatory effects of neurostimulation that resulted in continued improvement in outcomes.

A 48–year–old woman with schizophrenia presented with catatonic features, including fever, stupor, immobility, mutism, and staring, after a routine aripiprazole intramuscular injection. Fever and rigidity worsened after discontinuance of antipsychotics and benzodiazepines. Although the symptoms met the diagnostic criteria for neuroleptic malignant syndrome, a diagnosis of malignant catatonia was confirmed because treatment with diazepam infusion was dramatically effective, whereas dantrolene and bromocriptine were not beneficial. Malignant catatonia presents with fever and autonomic disturbance, in addition to catatonic features. Although the clinical presentation of antipsychotic–induced malignant catatonia and neuroleptic malignant syndrome is similar, the pathogenesis of the former is unclear. This case suggests that discontinuance of antipsychotics and benzodiazepines may induce malignant catatonia by the dysfunction of dopamine and GABA systems and the feedback pathway between the two systems. Antipsychotics and benzodiazepines are often used in combination. Malignant catatonia may be misdiagnosed as neuroleptic malignant syndrome.

A 56–year–old man underwent treatment for severe atopic dermatitis at the department of dermatology at our hospital in 2016. Left hemiparesis appeared in 2017, causing a progressively worsening gait disturbance and by late 2018, he could not walk by himself. In January 2019, he was found in a coma at home and was hospitalized. Physical examination showed disturbance of consciousness, left pyramidal signs, and generalized lichen. Blood examination revealed severe dehydration and IgE elevation of 81,399U/ml. In brain magnetic resonance images, acute and old cerebral infarctions coexisted in the cerebral cortex, white matter, cerebellum, and brainstem. There was no apparent arterial lesion, cardiac embolic source, coagulopathy, or connective tissue disease ; he was diagnosed with multiple cerebral infarctions associated with atopic dermatitis. After we administered cilostazol, rupatadine, and steroid ointments, the skin lesions were ameliorated dramatically. There was no clinical relapse of cerebral infarction for one year. Atopic dermatitis is reported to increase the risk of cerebral infarction. There are several case reports on infections or inflammation due to atopic dermatitis leading to embolization. We considered that skin treatment prevented cerebral infarction from recurring and reported this case as a valuable clinical lesson.

The patient was a 16–year–old female. Two weeks after the onset of fever and headache, she began to have fluctuating disturbances of consciousness, presenting monologues, and became unable to follow instructions. MRI of the head showed no abnormalities, and there was no complication of ovarian tumor as well. Based on the clinical course, we diagnosed her condition as anti–NMDA receptor encephalitis uncomplicated by tumor, and administered multidisciplinary immunotherapy with steroid pulse, plasma exchange, intravenous gamma globulin, and immunosuppressive drugs. At the most severe stage of the disease, she required intubation and deteriorated to a state requiring ICU management. However, with repeated immunotherapy from the early stage of the disease, she improved to a level with a good functional prognosis within about 2 months after the onset of consciousness disturbance. In a long–term prognostic study of anti–NMDA receptor encephalitis, 81% of patients were reported to have a good functional prognosis (mRS 0–2) after 24 months, but it took a long time for them to recover. We suggest that early and aggressive multidisciplinary immunotherapy may be successful in anti–NMDA receptor encephalitis.