In May 2023, the Amyotrophic Lateral Sclerosis (ALS) treatment guidelines supervised by the Japanese Society of Neurology were revised for the first time in about 10 years. Riluzole and edaravone are the only two treatment methods (disease–modifying therapy) with established evidence for improving prognosis described therein. Recently, a phase III trial of high–dose methylcobalamin was successful in Japan. Accelerated approval of tofelsen for familial ALS associated with SOD1 gene mutation was granted in the United States, and sodium phenylbutyrate–taurursodiol was approved in the United States and Canada. In Japan as well, there is a demand for the development of a system for conducting clinical trials more rapidly than ever before, and it is important to establish a registry based on patient registration and to understand the natural history of the disease. The Japanese Consortium for Amyotrophic Lateral Sclerosis research (JaCALS) has been established and has already achieved various results. The development of disease models using iPS cells is also progressing, and the development of therapeutic agents associated with it is also progressing. Furthermore, nutritional therapy may also improve the prognosis, and is attracting attention.

Advance in acute recanalization therapy : Mechanical thrombectomy (MT) for acute large vessel occlusion become a standard therapy. In 2022, RESCUE–Japan LIMIT revealed that the efficacy of MT among patients with large ischemic core (ASPECTS 3–5). Furthermore, ATTENTION and BAOCHE trials extended the MT indication to the posterior circulation stroke. Regarding the direct MT versus bridging with thrombolysis, final results of SWIFT–DIRECT and DIRECT SAFE were published. The integrated analysis of the 6 trials by the European Stroke Organization–European Society for Minimally Invasive Neurological Therapy (ESO–ESMIT), did not show non–inferiority of direct MT. CHOICE verified the efficacy of intra–arterial alteplase after effective recanalization and showed an increase in the number of patients with a good outcome at 90 days. AURORA was an integrated analysis of late time window MT, and showed 2.54 times better outcome for the MT group. The AcT trial compared the mRS 0–1 at 90 days after tenecteplase (0.25 mg/kg) and alteplase (0.9 mg/kg) in patients with stroke within 4.5 hours, and showed non–inferiority of tenecteplase versus alteplase.

Advance in antithrombotic therapy : TIMING is a randomized controlled trial of DOAC initiation for cerebral infarction with NVAF, which demonstrated non–inferiority of early initiation to late initiation for the composite endpoint of recurrent stroke, symptomatic intracranial hemorrhage, or all–cause mortality during a 90–day observation period. An integrated analysis of the SAMURAI–NVAF and RELAXED studies was reported from Japan. As a result, the 1–2–3–4 days rule was proposed as the timing for starting DOAC for transient ischemic attack, mild stroke (NIHSS ≤7), moderate stroke (8–15), and severe stroke (≥16), respectively.

Blood pressure control : A meta–analysis conducted by the Blood Pressure in Acute Stroke investigators showed no improvement in outcome with enhanced antihypertensive therapy, but did show some inhibition of hematoma expansion and limited improvement in outcome.

Perhaps the most significant topic in 2022 concerning the treatment of dementia was the report at the Clinical Trials on Alzheimer's Disease (CTAD) conference at the end of November of that year that lecanemab had shown favorable effects in early Alzheimer disease (AD). Based on these results, the drug received expedited approval from the U.S. Food and Drug Administration (FDA) on January 6, 2023. Against this backdrop, expectations for the development of disease–modifying drugs for various neurodegenerative diseases, including AD, are increasing. In the field of dementia, in addition to agents targeting amyloid, a number of agents are in development that target the causative proteins of each neurodegenerative disease, including agents targeting tau and α–synuclein. In this article, we will follow suit, organizing by causative protein and drug lineage, and pick up on the results of relatively large clinical studies that have been newly reported in 2022, as well as on clinical studies that have moved forward.

Influenza is an infectious disease that spreads every year ; however, it remains a disease with a high fatality rate and the potential for serious sequelae. It often presents with rapid exacerbations, diffuse cerebral edema, multiple organ damage, coagulation abnormalities, and requires treatment to suppress inflammatory cytokine production, manage vascular endothelial disorder, and prevent apoptosis in various organs. Treatment involves systemic management and specific approaches, such as antiviral, steroid, and gamma globulin therapies. In some cases, specialized treatment may be necessary.

The incidence of herpes zoster is also on the rise. When herpes zoster is complicated by central nervous system disorders, it can lead to severe and refractory cases, emphasizing the need for early diagnosis and treatment. Detecting VZV–DNA by cerebrospinal fluid PCR is a useful diagnostic tool, but it may not always be detected immediately after VZV reactivation. Recently, the use of the multiplex PCR method with high sensitivity and specificity has been recommended, providing test results within hours. In cases of suspected VZV central nervous system disorders, early administration of acyclovir is recommended.

In Japan, there has been a significant increase in syphilis, becoming a social issue. Untreated syphilis can progress to neurosyphilis, increasing the likelihood of encountering such cases in the future. Neurosyphilis can develop at any stage, and cerebrospinal fluid is crucial for diagnosis, while early treatment intervention with penicillin G plays a decisive role in determining the prognosis. Moreover, with benzylpenicillin becoming available in Japan in September 2021, the treatment of latent syphilis has become possible. Our future goals include preventing infection spread through preventive measures and minimizing sequelae through early diagnosis and intervention with timely treatment.

Recent advances and new findings relating to multiple sclerosis (MS) and other inflammatory disorders in the central nervous system including neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein–associated disease (MOGAD) were reviewed. The following topics were discussed : the association between Epstein–Barr virus infection and MS development, the relevance of serum neurofilament light chain measurement in MS, the association between brain atrophy and progression independent of relapse activity in MS, the efficacy and safety of extended interval dosing of natalizumab for MS, the initial immune mechanism in NMOSD, the decrease of retinal vessels in NMOSD, the neuroaxonal damage and astrocytic injury in MOGAD, and the effectiveness of maintenance intravenous immunoglobulin for MOGAD.

At present, there has been a significant increase in the global prevalence of Parkinson's disease (PD), underscoring the critical need for the development of foundational treatments. In 2022, various disease–modifying therapies were reported, including antibody treatments targeting α–synuclein, iron chelators, and statins. However, no drugs have definitively demonstrated disease–modifying effects for PD as of yet. Nonetheless, numerous candidate drugs for modifying PD are actively under development, fostering hope for the discovery of effective treatments.

While symptomatic therapy continues to be the primary approach in treating PD, there has been a growing number of reports on innovative treatments for motor complications like wearing–off phenomena and levodopa–induced dyskinesia. Furthermore, there are reports on therapeutic drugs aimed at gut bacteria, which may not only address non–motor symptoms but also enhance our understanding of the underlying mechanisms of PD. Additionally, there have been reports on novel approaches to treat previously challenging symptoms such as insomnia and excessive drooling.

To advance PD treatment, the development of both disease–modifying therapies and symptomatic treatments is deemed crucial. This paper primarily reviews reports from double–blind, randomized controlled trials published in 2022, with a specific focus on potential candidates for disease–modifying PD therapy and reports showcasing the effectiveness of symptomatic therapy for both motor and non–motor symptoms.

We will review the recent therapeutic advances in spinocerebellar degeneration (SCD) that were published in 2022. This article provides an overview of therapies including riluzole/troriluzole, omaveloxolone, mesenchymal stem cells, Coenzyme Q10, erythropoietin, cinpanemab, prasinezumab, cerebello–spinal transcranial direct current stimulation (tDCS), and rehabilitation. We anticipate that these treatments will contribute to improving motor dysfunction and ataxia in patients with cerebellar disorders.

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 2022, results of phase 3 trial of ultra–high dose methylcobalamin (JETALS) and tofersen, an antisense nucleotide for SOD1 mutation (VALOR) were published. Ultra–high dose methylcobalamine was effective for ALS–patient 1–year within the onset. VALOR trial did not reach the primary endpoint, although open label extension trial suggested the positive efficacy.

This review provides an overview of clinical advances in MND research and summarizes selected key literature on therapeutic approaches in 2022.

Peripheral neuropathies are very common neurological disorders that are caused by various etiologies. This review focuses on four neuropathies which substantial advances have been made recently. In Guillain–Barré syndrome, treatment for severe cases is still a challenge. Clinical trials of several anti–complement drugs are currently underway and results are awaited. In CIDP (Chronic inflammatory demyelinating polyneuropathy), subcutaneous immunoglobulin has been added as a standard maintainace therapy. The efficacy of rituximab or neonatal Fc receptor (FcRn) for CIDP patients has been investigated. It is also interesting from the point of view of elucidating the pathology, and the publication of the results is awaited. Currently, the treatment for the patients with MMN (Multifocal motor neuropathy) is only IVIg and novel treatments for advanced cases are desired. Based on the findings that IgM anti–GM1 antibodies, which are highly positive in MMN patients, bind to motorneurons and activate complement pathway, a trial of AGX722, an antibody against C2, is currently underway. Therapeutic advances in ATTR amyloidosis have been remarkable : in addition to stabilizers of transthyretine, interference therapeutic agents are becoming the main treatment. Phase I trials with gene–editing therapeutics have also been underway and further developments are expected. Compared to other autoimmune diseases such as Myathenia Gravis or Neuromyelitis Optica, autoimmune peripheral neuropathies currently have limited treatment options. However, the development of these novel therapies may lead to new treatment options. While keeping a close eye on the development of new treatments, efforts should be made to accurately diagnose these diseases at an early stage and provide appropriate treatment to patients.

We reviewed articles on the novel development of treatment for autonomic disorders published in 2022. Hypovitaminosis D is significantly associated with orthostatic hypotension (OH) in older adults but another study does not support use of vitamin D3 supplementation as an intervention to prevent OH. Long–term studies are still needed on the efficacy of vitamin D supplementation in treating OH. Among patients with recurrent vasovagal syncope (VVS), a supervised program of tilt training and aerobic exercise reduced syncopal recurrence. Patients with refractory VVS undergoing regular psychotherapeutic intervention had less recurrence of events. Yoga as adjunctive therapy is superior to standard therapy alone in reducing the symptomatic burden in patients with recurrent VVS. Midodrine is effective in preventing syncope induced by head–up tilt testing. Posterior tibial nerve stimulation is a beneficial treatment option for neurogenic over active bladder symptoms in males with multiple sclerosis. Intradetrusor abobotulinumtoxinA is an effective treatment and alternative option for patients with neurogenic detrusor overactivity incontinence. Prune intake significantly decreased hard and lumpy stools and not increasing loose and watery stools. The probiotics were effective in improving the symptoms of functional constipation and constipation of Parkinson disease patients. Prucalopride improves not only constipation but also abdominal bloating. Two gold kiwifruit daily are effective in treating constipation. Daily dietary fibre supplementation by using partially hydrolyzed guar gum for 4 weeks in long term care facility residents results in significantly less laxative use than placebo. Use of topical glycopyrronium tosylate improved the symptoms of primary axillary hyperhidrosis.

We reviewed advancements in the treatment of headache and epilepsy, primarily focusing on literature published in 2022.

CGRP (calcitonin gene–related peptide) agents like Galcanezumab, Eptinezumab, Fremamezumab, and Erenumab have shown promise for patients unresponsive to conventional treatments. The European Headache Foundation guidelines recommend CGRP antibodies as a first–line preventive treatment for migraine. Furthermore, emerging studies explore super–responders and non–responders to CGRP antibodies, indicating varying effectiveness and characteristic patient profiles. The text also highlights new acute migraine treatments, such as selective 5–HT1F receptor agonists (ditan drugs) and CGRP receptor antagonists (gepant drugs). Lasmiditan, a selective 5–HT1F agonist, avoids vasoconstriction side effects seen with triptans. Gepant drugs like zavegepant are redeveloped with improved safety profiles. Both classes of drugs hold potential for migraine treatment.

As for epilepsy, Deep brain stimulation (DBS) targeting the thalamus, especially the anterior nucleus, is explored for epilepsy management. DBS has gained FDA approval for drug–resistant focal seizures. The treatment showed a 75% seizure frequency reduction over seven years, and another observational study also showed a significantly decreased seizure frequency. DBS has shown efficacy not only for epilepsy but also for psychiatric conditions like depression. Additionally, levetiracetam was approved for status epilepticus in 2022. One Japanese study showed the non–inferiority of levetiracetam to phenytoin in convulsive status epilepticus. Fenfluramine hydrochloride for Dravet syndrome was also approved in the last year. Although its precise mechanism remains unclear, activation of the 5–HT receptor or modulation of the opioid receptor may be associated with seizure reduction.

Zonisamide was developed as an antiepileptic drug, and its usefulness in Parkinson's disease was reported from Japan¹⁾. Its mechanism of action has been suggested to include monoamine oxidase B inhibition and enhancement of levodopa effect, but a clear mechanism of action has not been elucidated. To evaluate the effect of Zonisamide, on motor symptoms over time and quantitatively, we conducted a retrospective analysis using outpatients at our hospital.

A 33–year–old woman with synovitis–acne–pustulosis–hyperostosis–osteitis (SAPHO) syndrome developed non–throbbing headache. She was permitted to take a tablet of naproxen by her doctor in advance when being febrile or having a headache due to SAPHO syndrome. She took a tablet of naproxen as usual, but her headache was getting worse. In the next day, she developed not only severer headache, but also impaired consciousness, nausea, and vomiting. Neurological examinations revealed abnormal fluctuation of consciousness level and meningeal signs. Blood tests showed severe inflammatory reaction, and cerebrospinal fluid tests showed pleocytosis with polymorphonuclear predominancy and an elevated level of protein. Discontinuation of naproxen rapidly diminished her symptoms and signs. After exclusion of other possible diagnoses, we finally diagnosed her as naproxen–induced aseptic meningitis. Nonsteroidal anti–inflammatory drugs are recognized as a possible cause of drug induced aseptic meningitis (DIAM), but naproxen–induced aseptic meningitis is extremely rare in Japan. Allergic reaction against the dura associated with the autoimmune abnormality based on SAPHO syndrome is suggested as the main mechanism of DIAM in this case.

A 16–year–old male patient was hospitalized due to Duchenne muscular dystrophy. At the age of 18 years, he underwent tracheotomy in order to be placed on a ventilator due to the acute exacerbation of respiratory failure. One year and 9 months after the tracheotomy (20 years of age), a sudden, large–volume hemorrhage was noted and the patient went into a state of shock. Suspecting a tracheoinnominate artery fistula, the tracheal cannula cuff was over–inflated causing the bleeding to stop and the patient's vital signs to stabilize. The tracheal defect was closed and artificial vascular bypass surgery was successfully completed at an advanced treatment hospital. At the age of 25 years, the precordial surgical wound expanded, and when the artificial blood vessel was checked macroscopically, an air leak within the respiratory air supply was confirmed with contrast–enhanced computed tomography, thus establishing the diagnosis of tracheocutaneous fistula. However, reoperative surgery was not indicated and the patient was treated conservatively. The patient died from heart failure 6 years and 2 months after surgery. A life–saving case of Duchenne muscular dystrophy in conjunction with tracheal artery fistula is rare. This is a case that could be followed up for a long time after surgical treatment.