In 2018, a new treatment concept of tissue–based strategy was established. The two late time window thrombectomy trials, DAWN (6–24 hours) and DEFUSE3 (6–16 hours), showed dramatical improvement of outcome in patients with emergent large vessel occlusion (LVO). Both used RAPID software to select candidates who have small core with clinical–imaging mismatch or target mismatch. Revised AHA/ASA and Japanese guidelines now recommend mechanical thrombectomy as late as 16/24 hours after onset. In addition, patients with unknown onset time or wake–up stroke are now candidates for thrombolytic therapy using alteplase if diffusion–FLAIR mismatch is confirmed.

In patients with non–cardioembolic stroke, dual anti–platelet therapy (DAPT) using clopidogrel and aspirin is recommended up to 21 days. The POINT trial further evaluated intensive DAPT starting as early as <12 hours with higher loading dose and continued until 90 days. Though POINT disclosed better efficacy on preventing recurrence of stroke, but increased bleeding events denied clinical application of the intensive DAPT therapy.

NAVIGATE ESUS compared the efficacy and safety of rivaroxaban and aspirin in patients with embolic stroke of undetermined source (ESUS). This study was terminated prematurely because of the increased bleeding risk assigned to rivaroxaban treatment. Although efficacy was identical between the two groups. This ESUS concept was attracting and could offer better treatment option, however, it was not a case. It is time to consider refinement of ESUS concept or treatment strategy.

Dementia affects over 46 million people in the world with a rapidly increasing prevalence. No fundamental treatment for AD has been established, and novel experimental studies are under investigation. 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 and other dementias, and several other promising trials are currently ongoing.

In 2018, these outcomes including solanezumab, verubecestat, LMTM, idalopirdine, pimavanserin and so on have been reported. This review overviewed recent advances in these larger clinical researches in dementia.

Recent advances and new findings relating to multiple sclerosis (MS) and other inflammatory disorders in the central nervous system were reviewed. We adopted the studies regarding serum neurofilament light chain as an efficient biomarker for axonal damage in patients with MS, B cell targeted therapies for MS, the MRI technique that distinguishes MS from neuromyelitis optica spectrum disorder (NMOSD), plasma exchange as an acute–phase treatment for NMOSD, and cumulative information about myelin oligodendrocyte glycoprotein immunoglobulin G–positive disorder.

We review reports published in 2018 providing new information on the management of Parkinson's disease (PD) and its related disorder. Adjunct zonisamide to levodopa improved parkinsonism in dementia with Lewy body, without worsening cognitive function or psychiatric symptoms. Camicinal, a gastroprokinetic resulted in significant reduction of off–time and significant decrease in motor symptom in patients with PD, which occurred in parallel with more rapid absorption of levodopa. Subcutaneous apomorphine infusion during waking hours (16 hour a day) significantly reduced off–time. Sodium oxybate, a first–line treatment in narcolepsy, improved excessive daytime sleepiness (EDS) and Epworth Sleepiness Scale (ESS) score in patients with PD. Rasagiline also showed beneficial effects on sleep quality in patients with PD with sleep disturbances. Safinamide improved PD chronic pain in the long term (2–year). Subthalamic nucleus (STN) deep brain stimulation (DBS) slowed rest tremor progression in early PD. STN–DBS decreased restless legs syndrome symptoms in patients with PD and the improvement was sustained over a 2–year period. STN–DBS was effective in improving impulse control disorders and neuropsychiatric fluctuations in the long term. The first randomised blinded evaluation of DBS in the caudal zona incerta (cZi) showed its efficacy on PD symptoms, especially for tremor. The doses of dopaminergic medications did not decrease. PRX002 is a humanized monoclonal antibody designed to target aggregated forms of α–synuclein. Multicenter, randomized, double–blind, placebo–controlled, multiple ascending–dose trial (phase Ib) in 80 patients with PD showed that single and multiple doses of PRX002 were generally safe and well tolerated and resulted in robust binding of peripheral α–synuclein. ProSavin is a lentiviral vector–based gene therapy that delivers local and continuous dopamine. Long–term follow up of a Phase I/II Study of ProSavin showed a significant reduction of off–time in patients with PD. ProSavin continued to be safe and well tolerated.

We reviewed the recent advances in therapeutics of spinocerebellar degeneration (SCD) that were published in 2018. This article introduces the outline of therapies with mesenchymal stem cells, cerebello–spinal tDCS, betamethasone, and cyclodextrin. We expect that these treatments will contribute to patients with cerebellar motor dysfunction and ataxia.

Motor neuron diseases (MND) are devastating neurodegenerative disorder which primary affects motor neurons. Amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal bulbar muscular atrophy (SBMA) are representative MND. Since the advent of novel drugs of SMA (Nusinersen) and SBMA (Leuprorelin) in 2017, the treatment of MND has changed dramatically and the door of new hope has opened. This review provides an overview of preclinical and clinical advances in MND research, future issues and prospects, and summarizes selected key literature on therapeutic approaches in 2018.

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 2018. In addition, we introduce the promising results in clinical trials of new–targeted immunetherapies for these diseases.

Various clinical trials for peripheral neuropathy were published in 2018. Systematic PubMed search using terms, “neuropathy”, “peripheral neuropathy”, and “clinical trials” was performed with the time lock from January 1, 2018 through December 31, 2018. A total of 22 trials were found on diabetic neuropathy (DPN ; n=10), chemotherapy–induced peripheral neuropathy (CIPN ; n=7), hereditary ATTR amyloidosis (n=2), Guillain–Barre syndrome (GBS ; n=1), chronic inflammatory demyelinating polyneuropathy (CIDP ; n=1), and multifocal motor neuropathy (n=1). For painful DPN, exercise, pregabalin, alpha–lipoic acid, and spinal cord electric stimulation were effective for pain relief. For CIPN, exercise Calmangafodipir and Sigma–1 receptor ligand treatment showed possible beneficial effects. For ATTR amyloidosis, a tafimidis trial revealed a significantly beneficial effects on cardiomyopathy, and an anti–sense oligonucleotide, inotersen, showed improvedment in neuropathy and QOL scores. For immune–mediated neuropathies, clinical trials on eculizumab for GBS, subcutaneous immunoglobulin as a maintenance therapy for CIDP, and intravenous immunoblobulin as a maintenance therapy for 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 immune–mediated muscular disorder published in 2018. We focused on molecular target drugs for treatment of myasthenia gravis and inflammatory myopathies. Eculizumab was approved by the Japanese government for the treatment of acetylcholine receptor antibodies–positive refractory MG in December 2017. Eculizumab is expected to have treatment benefits for refractory and generalized MG patients, although Eculizumab is the most expensive treatment for MG in Japan. Neuromuscular experts should keep the appropriate indication of eculizumab for refractory MG in mind. 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. Randomized phase 2 clinical study demonstrated that belimumab did not have significant efficacy compared with placebo in generalized MG. In contrast, abatacept and infliximab were well tolerated and potentially effective for treatment of refractory polymyositis and dermatomyositis.

We reviewed articles on novel development of neurological treatment published in 2018. Treatment algorism of orthostatic hypotension was indicated in a JACC State–of–the–Art Review. In regard to cardiovascular autonomic dysfunction, consensus statement on the definition of neurogenic supine hypertension in autonomic failure was proposed by the American Autonomic Society (AAS) and the European Federation of Autonomic Societies (EFAS). It was reported that propranolol, bisoprolol and a combination of pyridostigmine and propranolol or bisoprolol showed effectiveness for postural tachycardia syndrome. Therapy for vasovagal syncope was also updated. For over active bladder, effectiveness of gabapentin and phytomedicine extracts were reported, and several confirmative studies were also performed. Safety and efficacy of elobixibat and linaclotide for chronic idiopathic constipation were shown by the phase 3 trials. Safety and efficacy of plecanatide (unapproved in Japan), a guanylate cyclase agonist, for irritable bowel syndrome was also shown by the phase 3 trial. A meta–analysis showed efficacy of naldemedine and naloxone for the treatment of opioid–induced constipation. Topical botulinum toxin type A liposomal cream significantly was reported to improve axillary hyperhidrosis. It was reported that a combination of topical agents and oxybutynin reduced focal hyperhidrosis. Percutaneous radiofrequency thoracic sympathectomy was reported to improve palmar hyperhidrosis.

Hybrid Assistive Limb医療用下肢タイプ（HAL^®）による歩行運動療法を継続した筋萎縮性側索硬化症（amyotrophic lateral sclerosis：ALS）の1例を報告する．症例は61歳女性．4点杖による介助歩行が可能で，座位・立位姿勢にて頸部と体幹の前屈を認めていた．Edaravoneの経静脈的投与と並行して，歩行能力の維持を目的として1クールあたり20分/日×9日を基本とするHAL^®による歩行運動療法を開始した．1クール目の終了時には歩行機能が改善し，14～31日のインターバルをおきながら歩行運動療法を継続した．経過を通じて歩行機能は緩徐に低下したが，歩行運動療法の各クール終了時には歩行機能の改善が認められた．また，座位での頸部・体幹の前屈が一過性に改善した．HAL^®による歩行運動療法を継続することにより，短期的ではあるが，歩行機能と体幹機能の改善が期待できることが示唆された．

オンライン診療は利便性が高いものの，対面診療と異なる診療方法となるため抵抗感を持つ患者も少なからず存在する．今回我々は神経疾患患者を対象にオンライン診療に対する意識調査を行った．回収された調査票は215例で，多発性硬化症/視神経脊髄炎，てんかんで遠隔医療を「利用したい」「利用してもいい」割合が高かった．70歳代以降で「利用したくない」割合は増加するが，通院所要時間やactivity of daily living（ADL）との関連はみられなかった．好発年齢の若い多発性硬化症やてんかんにはオンライン診療は導入しやすい可能性があるが，脳血管障害などの高齢者への急速な普及には課題が多いことが考えられる．

症例は67歳女性で進行性腎細胞癌に対して血管内皮増殖因子（vascular endothelial growth factor；VEGF）受容体阻害薬であるaxitinibの内服が開始されたが，投与開始7日目に著明な高血圧と強直間代性痙攣を呈し救命救急センターに搬送された．頭部MRIでは両側の後頭葉皮質下と小脳半球に高信号病変を認めた．降圧療法とaxitinibの中止により速やかに症状は改善し，約2週間でMRI高信号病変も消失し，可逆性後頭葉白質脳症（posterior reversible encephalopathy syndrome；PRES）と診断した．1ヶ月後より厳重な血圧管理下でaxitinibを少量から漸増して再開し，PRESの再発なく経過した．PRES発症後の被疑薬再開の是非と血圧管理の重要性について，文献的考察を加え報告する．