The environment for pharmaceutical regulations regarding the real world data (RWD) and the real world evidence (RWE) that can be evidenced from RWD is undergoing major changes in both the development and post–marketing surveillance.

In terms of drug development, there is the modernisation of the E8 guideline (general guidelines for clinical trials) at the ICH and the ongoing revision of the E6 guideline (ICH–GCP), known as the ‘GCP Renovation’. It is said that the scope of this will include pragmatic clinical trials, randomised controlled trials using patient registry data, and even research using RWD. This movement was taken up as an issue of speeding up pharmaceutical approval through streamlining clinical trials, etc., in the ‘21st Century Act’ in the United States, and the use of real–world data in the approval process is also being promoted.

Although randomised controlled trials (RCTs) have traditionally been the most appropriate research design for evaluating treatment efficacy and safety, there is also a focus on applications for approval using RWD in areas where development is not progressing and where RCTs are difficult, where there is no evidence from conventional RCTs. This article will outline the current trends in domestic and international government and what are actually using RWD, as well as the issues surrounding the use of RWD.

Advance in acute reperfusion therapy: Indications of mechanical thrombectomy (MT) for acute stroke due to large vessel occlusion (LVO) is expanding, especially in patients with large ischemic regions. Six randomized trials (RESCUE–Japan LIMIT, SELECT–2, ANGEL–ASPECTS, TENSION, LASTE, TESLA) has been reported, and five of them revealed the efficacy and safety of MT compared to medical management. However, it should be noted that many patients will be disable even if successful reperfusion was achieved. MR–CLEAN LATE verified efficacy of MT in patients with late presenting stroke due to LVO, without using perfusion images or infarct volume measurements. Regarding the direct MT versus bridging with intravenous thrombolysis, a meta–analysis of six randomized trials (IRIS study) showed non–inferiority of MT, whereas bridging therapy seemed to be more effective within 140 minutes of onset. TRACE–2 clarified non–inferiority of thrombolysis using tenecteplase compared to alteplase in acute stroke patients within 4.5 hours of onset. The ARAMIS trial showed non–inferiority of dual antiplatelet therapy compared to thrombolysis using alteplase in patients with mild neurological symptoms.

Advance in antithrombotic therapy: In the RESCUE BT2 trial, tirofiban (glycoprotein IIb/IIIa inhibitor) is more effective in acute ischemic stroke patients without LVO or medium vessel occlusions compared to aspirin. ELAN is a randomized trial of direct oral anticoagulant (DOAC) initiation for the composite endpoint of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization. Participants were randomly assigned early or later anticoagulation based on stroke severity, and the incidence of composite endpoint was similar between two groups.

The hot topic of treatment of neurocognitive disorder in 2023 is undoubtedly the approval of lecanemab and its use in patients with early Alzheimer disease (AD) in clinical settings in Japan. This is a paradigm shift in treatment of neurodegenerative diseases : we can use the disease–modifying drug for patients with AD and it is expected that efforts to resolve unmet medical needs in dementia treatment will accelerate. A number of agents are in development that target the causative proteins of neurodegenerative diseases such as tau, α–synuclein in addition to amyloid–β. In this article, we describe the results or plans of clinical studies relevant to amyloid–β, tau and α–synuclein that have been newly reported in 2023.

Recent advances and new knowledge in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) were reviewed.

In NMOSD, subgroup analyses of the N–MOmentum study in Asian participants reported similar efficacy and safety of inebilizumab between the Asian and non–Asian subgroups. An interim analysis of the post–marketing surveillance of eculizumab in Japan provided real–world evidence of the long–term safety and efficacy of eculizumab in patients with aquaporin–4 antibody (AQP4 Ab)–positive NMOSD, consistent with the results of the PREVENT study. Analyses based on the SAkuraSky and SAkuraStar studies, including the double–blind and open–label extension periods, demonstrated the long–term efficacy of satralizumab in AQP4 Ab–positive NMOSD. CHAMPION–NMOSD (NCT04201262), a Phase 3, open–label, externally controlled interventional study, reported on the efficacy and safety of ravulizumab in adult patients with AQP4 Ab–positive NMOSD.

Diagnostic criteria for MOGAD have been proposed by an international panel. In these criteria, diagnosis of MOGAD is required to fulfill 1) One or more core clinical demyelinating events, including optic neuritis, myelitis, acute disseminated encephalomyelitis (ADEM), cerebral monofocal or polyfocal deficits, brainstem or cerebellar deficits, and cerebral cortical encephalitis often with seizures 2) Positive MOG IgG test 3) Supporting clinical or MRI features including optic neuritis, myelitis, and brain, brainstem, or cerebral syndrome 4) Exclusion of better diagnoses including multiple sclerosis. The nationwide survey in Japan reported the estimated prevalence and incidence (1.34/100,000 and 0.39/100,000, respectively), the predominance of ADEM in younger patients and that of brainstem encephalitis, encephalitis, and myelitis in older patients at onset, and the high efficacy of immunotherapy at both onset and relapse. These findings were similar to those reported in other countries. Another study reported the association of early immunotherapy with longer corticosteroid treatment and lower risk of relapse in pediatric MOGAD.

We reviewed autoimmune encephalitis (AE) articles published in 2023. A meta–analysis was conducted to determine the effect of ovarian teratoma resection on patients with N–methyl–D–aspartate receptor (NMDAR) antibody encephalitis. However, the data were insufficient to provide a recommendation regarding teratoma resection. Recently, a fusion protein containing the Fc part of immunoglobulin G and NMDAR subunits was developed. This construct can neutralize NMDAR antibodies and inhibit the binding of NMDAR antibodies to receptors. Chimeric autoantibody receptor (CAAR)–T cells were also developed as a potential treatment for NMDAR encephalitis. CAAR–T cells express an extracellular NMDAR antigen and an intracellular signaling domain, which is cytotoxic only to B cells producing NMDAR antibodies. A retrospective study of anti–leucine–rich glioma–inactivated 1 (LGI1) encephalitis showed that a minority of patients experienced poor functional outcomes and relapse. Advanced age, cognitive impairment, and LGI1 antibody positivity in the cerebrospinal fluid were associated with poor outcomes. Another retrospective analysis of patients with anti–immunoglobulin–like cell adhesion molecule 5 disease showed that 41% had clinical improvement after short–term immunotherapy. Low pre–treatment serum neurofilament light chain levels and long–term immunotherapy initiation within the first year of disease onset were significant predictors of treatment response. A recent study analyzed the effect of long–term immunotherapy using rituximab and found that it was associated with a reduced hazard for time to first relapse and recurring relapses. Another study showed that immunotherapy was effective for most patients with seronegative as well as seropositive AE. In a study of patients with immunotherapy–refractory AE, escalation therapy with bortezomib and/or daratumumab improved functional outcomes, despite high disease severity at maximum disease. A study of AE patients treated with mycophenolate mofetil as a long–term immunotherapy reported that the beneficial effects of oral corticosteroid treatment do not persist beyond 12 months and the risk of adverse effects may be increased.

The molecular basis and pathogenesis of Parkinson disease (PD) and related disorders have been elucidated by accumulated research, leading to the identification of potential therapeutic targets and the development of therapies. In 2023, foslevodopa/foscarbidopa subcutaneous injection, a new device–assisted therapy for PD, was marketed in Japan, providing a new therapeutic option for patients with advanced PD. In addition to symptomatic therapies, disease–modifying therapies that slow progression of the diseases are being developed around the world.

Here, we review papers published in 2023 on clinical trials, focusing primarily on randomized controlled trials (RCTs) on pharmacotherapy for PD. Results of RCTs on venglustat (GBA–related PD), ursodeoxycholic acid, buntanetap and transdermal nicotine have been reported as candidates for disease–modifying therapy. Venglustat and transdermal nicotine failed to demonstrate beneficial effects compared with placebo. Ursodeoxycholic acid and buntanetap showed some promise and need further investigation. Results of RCTs on focused ultrasound ablation of globus pallidus internus (GPi–FUSA) and Kw–6356 have been reported as candidates for symptomatic treatment of motor symptoms. GPi–FUSA met its primary endpoint, improving motor function and/or reducing dyskinesia at a higher rate than a sham procedure, but was associated with adverse events. Thus, longer and larger trials are required for further evaluation. Kw–6356 may be more effective than placebo for PD symptoms, but development has been halted. Results of RCTs on fecal microbiota transplantation (FMT), probiotics, SYN120, candesartan, clonidine, and sodium oxybate have been reported as candidates for symptomatic treatment of non–motor symptoms. FMT and probiotics significantly improved non–motor symptoms compared with placebo. SYN120 and candesartan failed to show beneficial effects on cognitive impairment, but might ameliorate apathy. Although the primary endpoint was not met, the results support further investigation of the effects of clonidine on impulse control disorders in PD and of oxybate on rapid–eye–movement sleep behavior disorder (RBD).

Spinocerebellar ataxia (SCA) and multiple system atrophy (MSA) are two neurodegenerative disorders with limited treatment options. Recent advancements in therapeutic strategies for these conditions have shown promising results. In the case of MSA, therapies targeting α–synuclein aggregation, neuroinflammation, and energy metabolism, along with cell–based therapies like mesenchymal stem cells, are under investigation. For SCA, novel molecular genetic approaches such as CRISPR/Cas9 gene editing, RNA interference (RNAi), and antisense oligonucleotides (ASO) are being developed to target the underlying genetic mutations. This paper reviews the current state of therapeutic development for SCA and MSA, including the latest clinical trial data and potential future directions. The ongoing research aims to slow disease progression and improve the quality of life for patients affected by these debilitating conditions.

Motor neuron diseases (MND) are devastating neurodegenerative disorders that primarily affect motor neurons, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal bulbar muscular atrophy (SBMA). In 2023, the FDA approved tofersen, an antisense nucleotide targeting the SOD1 mutation, based on results from an open–label extension of VALOR trial and the observed reduction in neurofilament light chain levels in plasma, despite the VALOR trial not reaching its primary endpoint. This review provides a comprehensive overview of the clinical advancements in MND research and summarizes key literature on therapeutic approaches from 2023.

This article reviews the novel promising therapies and clinical researches of peripheral neuropathy, focusing on four diseases which substantial development have been made recently. The results of an international collaborative study on Guillain–Barré syndrome (GBS) and new practice guidelines were published in 2023. The development of new therapeutic agents for GBS is actively underway, particularly targeting the inhibition of the complement cascade. Clinical trials of complement– and antibody–targeted agents are also ongoing for chronic inflammatory demyelinating peripheral neuropathy (CIDP). Results of clinical trials on subcutaneous IgG (SCIg) that may extend dosing intervals beyond the conventional products for CIDP have also been published. Autologous Hematopoietic Stem Cell Transplantation may be a fundamental therapy for CIDP. For IgM–related neuropathy, a study design for a prospective collaborative study to analyze prognosis was published in 2023. Clinical trials of rituximab and Bruton's tyrosine kinase (BTK) inhibitors are in progress in this disease. For ATTRv amyloidosis, a number of new nucleic acid medicines are available in clinical practice.

The management of generalized myasthenia gravis (gMG) has been improved due to immunotherapy advances, but 20% of individuals with MG are refractory to the conventional therapy. To provide better management of refractory MG patients, new biological drugs are necessary. The Japanese clinical guidelines for MG published in May 2022 include the concept that treatment is often lifelong and should aim to maintain a sufficient quality of life (QOL) and mental health. Minimal manifestations (MM) or better status with an oral prednisolone dose of 5 mg/day or less (MM–5 mg) is recommended as the first goal to achieve favorable QOL. Japan MG study group conducted the fourth largest multi–center survey in 2021, obtained detailed clinical information from 1,710 consecutive MG patients all over Japan. This review summarizes the clinical efficacy, safety, and tolerability of the biological drugs including anti–complement and anti–neonatal Fc receptor inhibitors for generalized MG based on the real–world date of Japan MG study group. Eculizumab was administered in only 3.3% of anti–acetylcholine receptor–positive gMG patients, although 5 years had passed since the approval of eculizumab for gMG in Japan. Eculizumab was preferentially used in severe and refractory gMG patients. The duration of eculizumab treatment was 35 months in average. MG–ADL improved from 9.4±4.9 to 5.9±5.1, and 25 (70%) of the 36 gMG patients were responders. Postintervention status was markedly improved after the eculizumab treatment. In contrast, 36 (2.7%) started efgartigimod among 1,343 gMG patients. Twenty–six patients (72%) had refractory MG. Twenty–one (62%) patients were responders. Efgartigimod can be considered for the treatment of patients with generalized MG who do not achieve minimal manifestations, with a broad flexibility of patient selection and treatment schedules.

Recent advances in the field of neurological diseases have led to an increase in treatable conditions and significant changes in treatment approaches. Among the diseases characterized by autonomic dysfunction, hereditary ATTR amyloidosis and Parkinson disease have shown notable treatment progress.

Hereditary ATTR amyloidosis is caused by abnormal folding of the transthyretin (TTR) protein, leading to amyloid deposits in tissues and organs. Autonomic dysfunction, such as cardiovascular, gastrointestinal, and urinary issues, is a prominent early symptom. Treatment options have evolved from liver transplantation to TTR–stabilizing drugs like tafamidis, which prevents TTR misfolding and amyloid formation, and RNA interference therapies like patisiran and vutrisiran, which reduce TTR production. These disease–modifying therapies have shown improvements in autonomic symptoms, gastrointestinal function, and quality of life.

Parkinson disease treatment initially focused on motor symptoms, but recent advancements have addressed non–motor symptoms, including autonomic dysfunctions such as orthostatic hypotension and gastrointestinal issues. Deep brain stimulation (DBS) has improved autonomic functions like heart rate variability and gastrointestinal motility. Continuous Levodopa–Carbidopa Intestinal Gel (LCIG) therapy stabilizes blood levels of levodopa, reducing fluctuations in symptoms and improving autonomic functions such as constipation and orthostatic hypotension. These are considered disease–modifying therapies as they offer more comprehensive management of Parkinson disease.

Future treatment prospects for autonomic diseases include gene therapy, stem cell therapy, and advanced deep brain stimulation techniques. Research on immunotherapy and antibody therapy targeting α–synuclein in Parkinson disease and other neurodegenerative diseases is ongoing, despite challenges in clinical trials. These advancements hold promise for further improving the quality of life for patients with autonomic dysfunction.

In conclusion, the continuous evolution of treatment methods for hereditary ATTR amyloidosis and Parkinson disease represents a significant step forward in managing autonomic dysfunction. The development and implementation of disease–modifying therapies are pivotal in this progress. Ongoing research and clinical trials are expected to bring even more innovative therapies to the forefront, offering hope for better management and improved outcomes for patients suffering from these debilitating conditions.

We reviewed advancements in the treatment of headache and epilepsy, primarily focusing on literature published in 2023.

Recent advancements in epilepsy treatment include deep brain stimulation (DBS) of the thalamus, which has been approved by the FDA and recently in Japan. DBS significantly reduces seizure frequency, particularly effective for patients resistant to multiple anti–seizure medications. Observational studies in Europe also revealed its efficacy in 2023.

Post–stroke epilepsy is increasingly important due to aging populations. The SeLECT2.0 score helps predict epilepsy risk post–stroke, emphasizing the importance of status epilepticus as early seizure.

Fenfluramine hydrochloride is now approved for Lennox–Gastaut syndrome in addition to Dravet syndrome. It reduces seizures by enhancing serotonin and modulating specific receptors.

Recent studies on anti–seizure medications and pregnancy show that valproate increases the risk of psychiatric disorders in children. Other medications like lamotrigine and carbamazepine did not show similar risks. Lacosamide's use during pregnancy does not indicate significant safety concerns, but more data is needed for a conclusive evaluation.

As for migrane, Recent developments in migraine treatment include the use of calcitonin gene–related peptide (CGRP) therapies and selective 5–HT1F receptor agonists. Four CGRP antibodies―Galcanezumab, Eptinezumab, Fremanezumab, and Erenumab―are available, with the three other than Eptinezumab already marketed in Japan. The European Headache Federation (EHF) 2022 guidelines recommend CGRP antibodies as a first–line preventive treatment for migraine.

A study in 2023 showed that early use of Erenumab significantly reduced migraine days and had a higher responder rate compared to oral preventive medications. Acute migraine treatments traditionally use triptans, but new selective 5–HT1F receptor agonists like Lasmiditan and CGRP receptor antagonists (gepants) like Ubrogepant are gaining attention due to their lack of vasoconstrictive effects.

Ubrogepant effectively prevents migraines when taken during aura, and Atogepant has shown efficacy and safety in phase 3 trials for chronic migraine prevention. Zavegepant, another gepant, also demonstrated significant headache relief in trials. These oral medications, alongside CGRP antibodies with subcutaneous injection, offer promising advancements in migraine therapy.

The transition from pediatric to adult health care for individuals with childhood–onset neurological conditions can be challenging, partly because many physicians are inexperienced in treating people with intellectual and physical disabilities. We investigated the impact of working at a medical and rehabilitation center on physicians' perceptions of disabilities medicine. Participants were part–time physicians who worked four half–days per week at the Tokyo Metropolitan Kita Medical and Rehabilitation Center for the Disabled. After a four half–days working stint, participants were asked via a questionnaire to rate their understanding of 11 items related to medical care for people with disabilities before and after the said work period. In total, seven physicians answered these questions. The items that they were less familiar with before their stint were the daily lives of people with disabilities, an overview of medical facilities for people with disabilities, and methods of physical examination and communication. After having worked at the Center, respondents' awareness of 8 items related to medical care for people with disabilities had improved significantly compared to the pre–work period. Opportunities to practice at hospitals for people with disabilities may deepen physicians' understanding of disabilities medicine for patients with childhood–onset diseases.

Objective : To evaluate the effectiveness of rehabilitation using a hybrid assistive limb (HAL) in two patients with inclusion body myositis (IBM)

Methods : A male in his 60s had lower limb muscle weakness and difficulty standing (Case 1). The rehabilitation goal was to improve standing movements, and the HAL was set to “STAND” mode. A female in her 60s had lower limb muscle weakness and difficulty in climbing stairs and standing (Case 2). The rehabilitation goal was to improve walking and stair climbing, and the HAL was set to “WALK” mode. Each patient underwent two courses of nine 60–minute HAL sessions over 4 weeks, with a 3–month interval between the two courses.

Results : Case 1 showed reduction of minimum seat height required for standing, increase of walking speed, decrease of serum creatine kinase (CK) levels, and same or better European Quality of Life 5 Dimensions 3 Level Version (EQ–5D–3L) scores. Case 2 showed increase of walking speed, increased 2–minute walking distance, decrease of serum CK levels, and maintenance of EQ–5D–3L scores.

Conclusions : Rehabilitation using HAL may be not only temporary improvement in walking ability in patients with IBM but also in maintaining their quality of life.