It remains uncertain how brain circulation has effects on cognitive function in aging. Cerebral blood flow (CBF) decreases with advancing ages and in cognitive decline, apparently in vascular dementia and modestly in Alzheimer disease. Brain is an organ which requires enormous amount of CBF and metabolism compared to the other organs, and therefore, cerebral circulation is protected through autoregulation and subsequently, enhancement of oxygen extraction by neuronal structures even when CBF is decreased due to stenosis or obstruction of cerebral vessels.

The damages in the grey matter is relatively mild, but the white matter becomes rarefied with gliosis and nerve fiber loss, if the decrease of CBF remains for a long duration at the level ranging from 50 to 70% of the baseline. In the long run, the patients may exhibit brain atrophy and cognitive decline. The mechanism of dementia in cerebrovascular disease, including small vessel dementia, is relatively straightforward, whereas in Alzheimer disease, it remains unclear how chronic cerebral hypoperfusion may lead to cognitive dysfunction and dementia. Apparently, chronic cerebral hypoperfusion induces neuro–inflammation, disintegration of blood–brain barrier (BBB) and altered excretion of amyloid beta via dysfunction of periarterial drainage pathway and glymphatic system. This review overviews the relationship between cerebral circulation disturbance and cognitive decline with advancing ages.

The concept of time window for acute thrombolytic therapy has changed based on the tissue–based selection. Patients of more than 4.5 hours of stroke onset require penumbral mismatch to achieve significant improvement with alteplase therapy. The EXTEND trial showed significant improvement (adjusted Odds ratio 1.44, p＝0.04) over placebo in patients with 4.5–9 hours and wake–up strokes. This finding was further confirmed by combined analysis using EXTEND, ECASS4–EXTEND and EPITHET data. How to utilize perfusion imaging in Japan is our task for future.

Several new data regarding prehospital (RIGHT–2 for NTG patch) and acute in–hospital management (SHINE for glucose management ; ENCHANTED for blood pressure management after thrombolysis) were disclosed in 2019. However, none showed significant effect to alter our current guideline.

Long term dual antiplatelet therapy (DAPT) using cilostazol is effective and safer than aspirin or clopidogrel monotherapy. CSPS.com offers new treatment option for high–risk non–cardioembolic ischemic stroke.

RESPECT–ESUS compared the efficacy and safety of dabigatran and aspirin in patients with embolic stroke of undetermined source (ESUS). The study failed to show the usefulness of DOAC, that is in line with NAVIGATE ESUS. We need to re–consider the ESUS concept, as such to differentiate atrial cardiopathy and arteriogenic embolism, etc.

Regarding hemorrhagic stroke, 2 topics are documented. Antedotes for Xa inhibitors, Andexanet Alfa became available in United States. The drug is now awaited in Japan. MISTIE–III trial showed the evidence of acute hematoma evacuation. Survival outcome significantly improved by MISTIE therapy (stereotactic hematoma aspiration, followed by intra–cavity tPA) compared to medical therapy (Hazard 0.67, p＝0.037).

Dementia affects over 46 million people in the world with a rapidly increasing prevalence. The global number of people living with dementia is expected to increase to 130 million in 2050. However, drug development for dementia is difficult. No approved disease–modifying treatment for AD has been established, and novel experimental studies are under investigation for preclinical and prodromal AD, as well as AD dementia. These situations, therefore, resulted in necessity of more sensitive biomarkers and more precise classification of stages of AD. This progress has led to the development of numerous therapeutic strategies in the clinical testing. Immunotherapy against Aβ has been pursued extensively as a therapeutic approach to AD dementia, and several other promising trials are currently ongoing. On the other side, it is estimated that about 30% of dementia cased may be attributable to potentially modifiable risk factors including hypertension. This suggests that interventions targeting these factors could perhaps delay or prevent the onset of dementia.

In 2019, these outcomes including verubecestat, crenezumab which are amyloid–based immunotherapy in patients with AD, acetylcholinesterase inhibitors and memantine which are used for present AD treatments (meta–analysis of randomized controlled trials), and other drugs have been reported. This review overviewed recent advances in these larger clinical researches of treatment for dementia and relation between antihypertensive treatment and dementia.

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 significance of silent progression in disability progression of MS, the association between the initial disease modifying therapies and the risk of developing secondary progressive MS, the risk of progressive multifocal leukoencephalopathy in MS patients receiving extended interval dosing of natalizumab, the efficacy and safety of three randomized controlled trials of novel biotherapies for relapse prevention of neuromyelitis optica spectrum disorder, such as eculizumab (anti–complement therapy), inebilizumab (B–cell depleting therapy), and satralizumab (interleukin–6/interleukin–6 receptor axis blockage therapy), and the relapse prevention therapy for myelin oligodendrocyte glycoprotein antibody–associated disease.

We review reports published in 2019 providing new information on the management of Parkinson's disease (PD). L–dopa inhalation powder and sublingual apomorphine are effective on the motor symptom of off–state of PD patients. Rasagiline is safe and effective in monotherapy for patients with early–stage of PD. Zonisamide is effective against parkinsonism in patients with dementia with Lewy bodies (DLB). An oral preparation of nicotine has a significant improvement in scores of falls and freezing gait. Nicotine gum is effective for hypotension in PD patients. Fesoterodine improved nocturia and urinary urgency in PD patients. Percutaneous vagal nerve stimulation for PD patients with gastrointestinal complaints is a potential device for the non–invasive improvement of gastrointestinal symptoms. Incobotulinumotoxin A is effective on PD hypersalivation. Vinpocetine and intranasal insulin are effective for symptoms of cognitive impairment of PD. Aerobic exercise using gamed–virtual reality software and body weight supported treadmill training (BWSTT) were reported to be effective for PD. Probiotics significantly improved PD symptoms, and a significant improvement effect of licorice on motor symptoms was also reported. Treatment methods using medical devices are also advancing, such as Proprioceptive Focal Stimulation (Equistasi^®) by nanotechnology equipment, high–frequency repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS) have been reported. Simultaneous stimulation of the subthalamic nucleus (STN) and substantia nigra reticulata (SNr) is effective for restless leg syndrome and nocturnal motor symptoms. A method that directly targets the dentatoruburothamic tract (DRTT) under the guidance of diffusion tensor imaging and tractography (DTIT) improves the tremor of PD patients. Finally, caloric vestibular stimulation (CVS) using a device called Thermo Neuro Modulation (TNM™) improves motor and non–motor symptoms of PD.

We reviewed the recent advances in therapeutics of spinocerebellar degeneration (SCD) that were published in 2019. Ion channel modulation may contribute to recover for Purkinje neuron dysfunction and motor impairment in a variety of cerebellar ataxias. The role of RNA–binding proteins as RNA chaperones may lead to the development of new treatments for SCA31. Aminopyridines and acetyl–DL–leucine will provide new therapeutic strategies of cerebellar disorders. We expect that these treatments will contribute to patients with cerebellar motor dysfunction and ataxia.

Motor neuron diseases (MND), including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal bulbar muscular atrophy (SBMA) are devastating neurodegenerative diseases that primary affect motor neurons. Nucleic acid–based therapeutics and gene transduction therapies are novel treatment methods for MND, which have the potential to transform these incurable diseases into treatable diseases. This review provides an overview of preclinical and clinical advances in MND research, future issues and prospects, and also summarizes selected key literature on therapeutic approaches in 2019.

The treatment of brain tumors and granulomatous disease in the brain represents a serious unmet medical need in the field of neuro–oncology. Eventhough many effective compounds have demonstrated success in treatingperipheral tumors with targeted agents, one aspect of this lack of success inthe brain may be related to poor delivery of otherwise effective compounds. Thisreview discusses some issues that are pertinent to precision medicine for glioma, brain metastases and neurosarcoidosis with some reports published in 2019. Inaddition, we introduce the promising results in clinical trials of new–targetedimmunotherapies for these diseases.

Various clinical trials for peripheral neuropathy were published in 2019. Systematic review was performed using terms, “neuropathy”, “peripheral neuropathy”, “treatment” and “clinical trials” with the time lock from January 1, 2019 through December 31, 2019. A total of 19 trials were reviewed in this article on diabetic neuropathy (DPN ; n＝7), chemotherapy–induced peripheral neuropathy (CIPN ; n＝5), carpal tunnel syndrome (n＝4), hereditary ATTR amyloidosis (n＝1), chronic inflammatory demyelinating polyneuropathy (CIDP ; n＝1), and multifocal motor neuropathy (n＝1). For painful DPN, milogabalin, exercise, curcumin, deep tissue laser stimulation, and bio–feedback were found to be effective for pain relief. For CIPN, efficacy of pregabalin and duloxetine was confirmed, but muscle stimulatyion, cryotherapy, and topical agents did not show significant efficacy. For ATTR amyloidosis, a tolcapone trial revealed a short–term efficacy on TTR stabilization. For immune–mediated neuropathies, subcutaneous immunoglobulin as a maintenance therapy for CIDP, and multifocal motor neuropath were published. These results showed sustained research activity to develop new therapies for a number of peripheral nerve disorders.

This article reviewed the representative papers of treatment of myasthenia gravis (MG) published in 2019. We focused on novel molecular target drugs for MG treatment. Rituximab has shown to be a remarkable effective drug for MG, especially seropositive for autoantibodies against muscle–specific kinase. Unfortunately, rituximab is not available for MG treatment in Japan. Eculizumab was effective and well tolerated in patients with anti–acetylcholine receptor (AChR) antibody–positive refractory generalized MG (REGAIN study). Eculizumab is now approved by the Japanese government for the treatment of AChR refractory MG. Eculizumab is expected to have treatment benefits for refractory and generalized MG patients, although Eculizumab is the most expensive treatment for MG in Japan. In addition, improvements with eculizumab in activities of daily living, muscle strength, functional ability, and quality of life in REGAIN were maintained through 3 years ; 56% of patients achieved minimal manifestations or pharmacological remission. Efgartigimod is designed as a first–in–class investigational antibody fragment to target the neonatal Fc receptor (FcRn). Phase II clinical trials revealed that efgartigimod was well–tolerated in MG patients, with no serious or severe adverse events reported. All patients treated with efgartigimod showed a rapid decrease in total IgG and anti–AChR autoantibody levels, and assessment using all 4 efficacy scales consistently demonstrated that 75% showed a rapid and long–lasting disease improvement.

We reviewed articles on novel development of neurological treatment published in 2019. The combination of pyridostigmine and atomoxetine was reported to have a synergistic effect on improvement in neurogenic orthostatic hypotension. It was reported that lixisenatide and metformin have a potential to improve post prandial hypotension. Studies on pacemaker treatment for vasovagal syncope was systematically reviewed, and closed–loop stimulation evidenced a statistically meaningful reduction in syncopal burden. A meta–analysis showed that intradetrusor injection of botulinum toxin A was effective and safe for neurogenic detrusor overactivity. The different treatment methods in management of neurogenic bladder in patients with Parkinson's disease was systematically reviewed, but at present there is little or no evidence that treatment improves. Phase III randomized, double–blind, placebo–controlled study indicated that a linaclotide was effective and safe in Japanese patients with chronic constipation. Glycopyrronium tosylate applied topically was reported to improve primary axillary hyperhidrosis. Oral pilocarpine was reported to alleviate heat retention and cholinergic urticaria in patients with acquired idiopathic generalized anhidrosis.

Delirium is a common and distressful mental syndrome. Persistent delirium in hospital patients may be poor prognosis.

A retrospective study in (258 beds) Saiseikai–Otaru Hospital revealed that 527 patients (13.4%) in admission 3956 patients developed delirium on each three months from November to January in 2014, 2016 and 2018. Patients identified with delirium criteria of DSM5, were associated with bone fracture/falling out, malignancy, gastrointestinal diseases, central nervous system disorders and chest diseases. Median duration (days) of delirium on each medical background were not significantly changed with log rank test (p＝0.09). Symptoms of delirium defined by stuff included “screaming” and “attachment removing behavior” at 60%, and “consciousness impairment” was defined at only 10%.

The survival of patients with delirium from the day of their hospital admission with BPSD was longer than the patients without BPSD in the Kaplan–Meier plots (log rank test p＜0.01). Proportion of coexisted dementia to delirium patients recognized by ward stuffs was 10.7–21.3% in the delirium patient group.

The group of discharged patients had shorter periods of delirium than the group of nursing home or chronic hospitalization (4.3 days vs 9.6 days or 9.4 days, Mann–Whitney U test p＜0.05, Bonferroni method).

Comparison of the long delirious periods (21 days–) and the short periods (–20 days) groups revealed a much shorter survival in the long periods group by the survival analysis (log rank test, p＜0.01).

Survival of delirium patients might be dependent on the duration of delirium and coexistence of BPSD.

We present a case of long–term gait training using a hybrid assistive limb (HAL) for myotonic dystrophy type 1 (DM1). The patient was a 62–year–old man diagnosed with DM1. To improve his gait function, we performed intermittent gait training using a HAL (20minutes/day × 9days/2 weeks). During the course, we reduced the number of training days to 5days/week ; however, his gait function continued to improve without adverse events. As the variability of CTG repeat length in the DMPK gene leads to the heterogeneity of the clinical features, it is important to optimize the HAL conditions for each DM1 patients.

Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant polyglutamine disease that mainly affects the cerebellum, characterized by a late–onset, slowly progression. Although SCA6 has been thought to exhibit preserved generally swallowing function and thereby relatively good prognosis, we already reported that some patients with SCA6 had severe dysphagia. No established treatment for dysphagia has been reported in this disease. In the present report, imidapril hydrochloride, one of the angiotensin–converting enzyme (ACE) inhibitor, was administered to a 69–year–old man who had SCA6 with mild hypertension and cerebral ischemic changes. He did not recognize dysphagia, but video fluoroscopic examination of swallowing (VF) revealed that he had severe pharyngeal dysphagia with silent aspiration. Because ACE inhibitor treatments have been reported to reduce the risk of aspiration pneumonia in hypertensive patients with stroke and improve swallowing function in elderly people with aspiration pneumonia, we selected imidapril hydrochloride as an antihypertensive drug. After administration of imidapril hydrochloride, VF showed improved swallowing functions with no silent aspiration. He did not develop aspiration pneumonia during one–year of imidapril hydrochloride treatment. Possible pharmacological mechanisms included promotion swallowing reflex by increased substance P in the pharyngeal mucosa and improvement of cerebral microcirculatory perfusion. ACE inhibitors may be a candidate for treatment of dysphagia in neurodegenerative diseases with hypertension.