Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder characterized by degeneration of the anterior horn of the spinal cord and muscle atrophy, most commonly caused by the survival motor neuron 1 (SMN1) on chromosome 5 (5q13). The severity ranges according to time of onset and is classified as type 0–4. SMN2 is paralogous to SMN1, and the copy number of the SMN2 is an important determinant of SMA severity. That is, a greater number of SMN2 copies can generate more SMN protein and presents milder SMA phenotypes. A series of novel therapies have been approved for SMA in recent years, which include nusinersen, a nucleic acid drug using antisense oligonucleotides ; onasemnogene abeparvovec–xioi, a gene therapy drug ; and risidiplam, a small molecule drug. Each has different routes and intervals of administration, but all are designed to increase SMN protein. Clinical trials have shown positive effect on survival, respiratory function, as well as motor function. In order to achieve higher efficacy, evidences have shown that initiation of the treatment as early as possible is essential. In this term, a newborn screening system is being developed for early diagnosis. The further accumulation of data to assess the long–term efficacy and safety of these drugs are needed.

Advance in acute recanalization therapy: The most significant topic in 2021 was the validation of the significance of pre–intravenous administration of alteplase in patients of large vessel occlusion (LVO) planned to mechanical thrombectomy. An integrated analysis of 1,633 patients from DIRECT–MT, DEVT, SKIP, and MR CLEAN–NO IV studies, was performed. The risk difference for functional independence was 1% (95% CI −4–5%) and for symptomatic intracranial bleeding 1% (95% CI −1–3%), suggesting non–inferiority of MT alone to MT plus alteplase in several respects. Another meta–analysis of 433 patients in 4 trials of tenecteplase (TNK) found that effective recanalization with TNK was increased 3.05 (95% CI 1.73–5.40) times compared to those with alteplase. TNK also reduces the time required to recanalize the occluded vessel.

Advance in antithrombotic therapy: Dabigatran did not prove efficacy over aspirin among east Asian patients with ESUS (Embolic Stroke of Undetermined Source). Sub–group analysis of CSPS.com study revealed that add–on effect of cilostazol is greater with patients treated with clopidogrel than those with aspirin. Dual antiplatelet therapy (DAPT) using cilostazol might be a potential solution to the genetic polymorphisms in CYP2C19 poor metabolizer.cover poor metabolizer. Cilostazol based DAPT is effective for non–cardioembolic ischemic stroke patients with intracranial arterial stenosis.

Blood pressure control: Hypertension is the most powerful risk factor of stroke, even for the patients with ischemic stroke. A meta–analysis of Boncorago et al. revealed that anti–hypertensive therapy reduces the risk of ischemic stroke/TIA (HR 0.79, 95%CI 0.66–0.94). A post–hoc analysis of ATACH–2 reaffirmed that the blood pressure drop should not exceed 90mmHg to avoid acute kidney injury.

New desease associated with COVID–19: It is the Thrombosis with Thrombocytopenia Syndrome (TTS). Similar to Heparin–induced Thrombocytopenia, heparin aggravates TTS. Intravenous immunoglobulin and non–heparin anticoagulants should be started as soon as possible.

For those of us involved in dementia care, 2021 was a big year. In June, the U.S. Food and Drug Administration (FDA) conditionally approved aducanumab. It is the first disease–modifying drug to be approved. Meanwhile, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a negative opinion in December. Subsequently, in Japan, where a review was conducted at the end of the same year, the decision was made to “continue deliberations,” resulting in a split decision in each country.

In addition, there was the pandemic of the new coronavirus (SARS–CoV–2) infection, which affected not only acute care facilities but also all medical and nursing care facilities, including those for dementia.

Although it has been an eventful year, this report focuses on the results of relatively large clinical studies on dementia treatment reported in 2021. As far as we could find, most of them were related to Alzheimer disease, and only a few were related to dementia with Lewy bodies. Here we report a summary of these studies.

COVID–19, which has been raging in Japan since 2020, has been reported to cause various syndromes and neurological disorders, including stroke, Guillain–Barré syndrome (GBS), encephalitis/encephalopathy, and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as sequelae. These mechanisms are mainly immune–mediated mechanisms rather than direct viral effects, and GBS and encephalitis/encephalopathy have slightly different characteristics from the conventional COVID–19 non–associated course. In addition, in stroke, not only neurological damage but also multi–organ damage may occur, and rehabilitation may be time–consuming. Furthermore, 14.3% of patients with sequelae of COVID–19 infection develop ME/CFS. Since no treatment for ME/CFS has been established, patients are forced to seek treatment by hand, such as rTMS therapy and carnitine replacement, and future treatment methods are awaited.

In infectious meningoencephalitis, Multiplex PCR, although not approved by insurance in Japan, has the potential to rapidly identify the pathogen and is expected to be utilized in clinical practice as soon as possible. Although no new drugs have been introduced, meta–analysis has shown the usefulness of naloxone combination therapy for viral meningitis, dexamethasone combination therapy for tuberculous meningitis, and a single high–dose amphotericin B liposome regimen for HIV–positive cryptococcal meningitis, respectively.

The recent widespread use of biologics for neuroimmune diseases has focused attention on progressive multifocal leukoencephalopathy (PML), a serious complication of some agents. However, since this therapy may result in brain damage, it is no longer recommended, and the focus is on discontinuation of the causative agent and symptomatic treatment.

In HTLV–1–associated myelopathy (HAM), the pathogenesis has become clearer over the years, and CXCL–10 and neopterin are already established biomarkers of disease activity. Oral steroids and interferon–alpha have been shown to improve motor function and are already being utilized in clinical practice, but the development of HAM–specific therapeutic agents that affect CXCL–10 and neopterin levels is also underway daily, and we look forward to future drug discovery efforts.

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 DMT initiation strategy and MS disability progression, the real world data on MS DMT and pregnancy, the association between expansion of chronic lesions and disease progression in relapsing–remitting MS, the efficacy of prednisolone monotherapy for neuromyelitis optica spectrum disorder (NMOSD), the clinical features and risk of relapse in children and adults with myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD), and the brain structural alterations in MOGAD measured by multimodal MRI.

We review reports published in 2021 providing new information on the management of Parkinson disease (PD) and its related disorder. Several clinical trials of drugs for disease–modifying therapy (DMT) are also underway, but no drug has yet been reported that has clearly demonstrated efficacy in either PD or secondary parkinsonism.

We would like to review the recent therapeutic advances of spinocerebellar degeneration (SCD) that were published in 2021. Currently, SCD treatment is limited only to symptomatic mitigation, and no therapy is available to stop or delay the disease progression. Various pre–clinical and clinical trials were carried out in 2021. Some interesting trials have been reported, and further developments are expected. This article introduces the outline of therapies with rovatirelin, riluzole/troriluzole, leriglitazone, sodium valproate, CRISPR/Cas9 gene editing, antisense oligonucleotides (ASOs), mesenchymal stem cells (MSCs), and cerebello–spinal transcranial direct current stimulation (tDCS). We expect that these treatments will benefit the patients with SCD.

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 2021, results of open–label extension study of sodium phenylbutyrate–taurursodiol and long–term observational study of masitinib were published, which both studies proved the positive effects for survival of ALS. As for SMA, risdiplam was approved in Japan. And 5 years observational study of onasemnogene abeparvovec showed lasting effect.

This review provides an overview of clinical advances in MND research and summarizes selected key literature on therapeutic approaches in 2021.

In recent years, new treatments such as molecular targeted drugs and tumor vaccine therapy have appeared and progressed rapidly. However the treatment of brain tumors and granulomatous disease in the brain represents serious unmet needs due to lethal progression and the blood–brain barrier. The improvements in clinical trial designs and therapeutic drugs overcome these problems. In this article we will focus on glioma, brain metastases and neurosarcoidosis and introduce the promising results in clinical trials of new–targeted therapies with some reports published in 2021.

Peripheral neuropathies are very common neurological disorders that are caused by various etiologies. This review focuses on four neuropathies where substantial advances have been made recently. In Guillain–Barré syndrome, treatment for severe cases is still a challenge. Unfortunately, the efficacy of immunoglobulin re–administration has not been proven. Clinical trials of several anti–complement drugs are currently underway and results are awaited. In CIDP (chronic inflammatory demyelinating polyneuropathy), European Academy of Neurolog/Peripheral Nerve Society published updated guidelines. The classification of CIDP subtypes has been changed and autoimmune nodopathies are divided from CIDP. Subcutaneeous immunoglobulin has been added as a standard maintainace therapy. In addition, knowledge is accumulation regarding optimization of globulin dosing for maintenance therapy and the efficacy of rituximab for autoimmune nodopathies has been investigated. For ATTR amyloidosis, remarkable treatment progress has been made. In addtion to stabilizers of transthyretine, RNA interference therapeutic agents have become the main treatment. Chemotherapy induced peripheral neuropathy (CIPN) is a very common complication of anti–cancer treatment. However, no drugs have been successfully developed for CIPN treatment. Researches on new drugs such as GM1 and calmangafodipir are ongoing and non–pharmacologic interventions have been investigated. With advances in cancer treatment and the increasing number of cancer survivors, CIPN patients are increasing and future developments are expected.

We reviewed articles on the novel development of treatment for autonomic disorders published in 2021. Thigh–length elastic pressure socks may prevent orthostatic hypotension (OH) that could develop after spinal surgery. A randomized double–blind and controlled study indicated that ampreloxetine improved OH. A meta–analysis revealed that commonly prescribed drugs causing sympathetic inhibition were associated with significantly increased odds of OH. Caffeine might be a treatment option for OH if other evidence–based treatments are ineffective. Abdominal and lower body compression, high dietary sodium intake, and ivabradine reduced heart rate and improved symptoms during standing in adult patients with postural orthostatic tachycardia syndrome. Acarbose may avoid the occurrence of postprandial hypotension. For patients with recurrent vasovagal syncope (VVS), there is a possibility that yoga exercise improves postural symptoms and QOL. Increased salt and water intake may reduce syncope recurrence rates in pediatric patients with VVS. Tibial nerve stimulation may be as effective as anticholinergic drugs for overactive bladder (OBA) and more tolerable. Transcutaneous tibial nerve stimulation may be as effective as percutaneous tibial nerve stimulation for OAB. Sacral neuromodulation may be effective as well as onabotulinumtoxin A for OAB, and safety. A randomized double–blind and controlled study indicated that vibegron (75mg/day) was more effective for OAB than tolterodine (4mg/day). Treatment with a cinnamon patch might improve OAB. Tenapanor may improve irritable bowel syndrome with constipation symptoms. A randomized double–blind and controlled study showed that plecanatide relieved the symptoms of chronic idiopathic constipation with a relatively low incidence of diarrhea. Probiotics treatment may be effective for constipation in patients with Parkinson disease. Rhubarb, a Chinese traditional medicine, may be effective for chronic idiopathic constipation.

We reviewed treatments for headaches (migraine and cluster headaches) and epilepsy, mainly published in 2021. Headache is the most common neurological disorder and the third leading cause of disability worldwide. Recently, calcitonin gene–related peptide (CGRP) has been highlighted for its role in the pathophysiology of migraine headaches. Therefore, since 2021, monoclonal anti–CGRP antibodies have been approved in Japan. They have been shown to improve the frequency of headache attacks compared with placebo or previous medications. Furthermore, they did not show significant adverse effects in the clinical trials. In addition to these antibodies, a selective 5–HT1F receptor agonist (ditans) was also approved in 2021 and was shown to resolve pain in the acute phase of migraine.

Recently, one study showed a difference in survival between patients treated with enzyme–inducing antiseizure medications and lamotrigine or levetiracetam for post–stroke epilepsy. These results can be due to the increased metabolism of drugs used in secondary prevention after stroke or directly associated with markers of vascular diseases, such as lipid abnormalities. The mechanistic target of rapamycin (mTOR) is a ubiquitous regulator of cell metabolism, growth, proliferation, and survival. Pathogenic variants of genes associated with mTOR cause epilepsy or neurodevelopmental disorders, such as tuberous sclerosis. In addition, focal cortical dysplasia type II results from somatic brain mutations of mTOR pathway activators. Therefore, substances associated with mTOR can be therapeutically used to treat drug–resistant seizures.

Objective : During the third wave of the coronavirus disease 2019 (COVID–19) pandemic in Japan in December 2020, vaccination programs had not yet begun. Many elderly people in aged care facilities were infected and hospitalized. Many of them were too sick to be discharged from the hospital, resulting in fewer hospital beds for newly admitted COVID–19 patients. Our hospital had already been collaborating in accepting patients in the recovery phase of COVID–19 from a designated medical facility for infectious diseases since the first wave in April 2020, and we had accepted many elderly patients in the third wave. In this study, we evaluated the outcomes of dysphagia treatment in the recovery phase of elderly COVID–19 patients with underlying diseases.

Methods : The courses of disease and treatment of 14 elderly COVID–19 patients were examined retrospectively. They were infected in aged care facilities, hospitalized in a designated medical facility for infectious diseases and transferred to our hospital after acute treatment. Dysphagia treatment was initiated by doctors, nurses and physiotherapists, and speech–language and hearing therapists were involved after patients completed a period of quarantine.

Results : Fourteen patients were aged 86±7 (mean±SD, range 72–95) years, 8 had dementia and 2 had neurodegenerative diseases. Of the COVID–19 patients, 86% showed pneumonia, and 64% required oxygen. All patients were able to eat orally before the onset of COVID–19. On admission to our hospital 18.2±5.6 (11–33) days after onset, 9 (63%) patients were unable to eat orally. After admission, five patients recovered enough to be able to feed orally after undergoing a swallowing assessment and dysphagia treatment. However, two patients with neurodegenerative diseases did not recover from their dysphagia, one patient with dementia did not recover enough to feed due to a disability in his pre–oral stage, and another patient died.

Conclusion : Feeding and swallowing function was restored in 83% of elderly people who recovered from COVID–19. Swallowing assessment and successful dysphagia treatment may have contributed to improving patient prognosis.

Introduction : Spinocerebellar degeneration (SCD) is a disease that presents with slowly progressive cerebellar ataxia symptoms. Protirelin and taltirelin are often used to treat with this disorder. There are few reports about assessing therapeutic effects using Scale for the Assessment and Rating of Ataxia (SARA) and International Cooperative Ataxia Rating Scale (ICARS). We investigated therapeutic effectiveness of protirelin, using SARA and ICARS for assessment.

Method : Ten SCD patients treated with protirelin were included in this study. We analyzed the scores of SARA and ICARS before and after treatment with protirelin for two weeks. Statistical analysis was performed using Wilcoxon signed rank test.

Results : Improvements of both total SARA and total ICARS scores were observed (total SARA scores before 16.25, after 12.90, p＝0.0176 : total ICARS scores before 41.50, after 32.75, p＝0.0020). The scores of kinetic functions and posture and gait disturbance were improved significantly. However improvement of the scores of speech disorders and oculomotor disorders were not observed.

Conclusion : Protirelin was found to be effective against SCD, using SARA and ICARS.

Purpose. No fixed method has been established for postoperative drug use in deep brain stimulation (DBS) therapy for Parkinson's disease (PD). This study aims to examine the relationship between drug use and prognosis after 1 year of treatment and to optimize postoperative drug therapy. Method. The relationship between drug use and motor function changes was examined after 1 year of treatment. Result. The mean age and disease duration were 62.7 years and 13.4 years, respectively. The mean L–dopa and L–dopa equivalent daily doses were 470 and 897mg, respectively. A significant difference in the Movement Disorder Society–Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III improvement rate was observed when examined with and without monoamine oxidase type B (MAO–B) inhibitors (9 with MAO–B inhibitors (selegiline 5 and rasagiline 4) and 14 without MAO–B inhibitors) at 1 year (77 vs. 35%, p＝0.012). Conclusion. Concomitant use of MAO–B inhibitors may improve the off status after the DBS of the subthalamic nucleus in PD.

A 29–year–old woman presented with schizophrenic features, such as paranoia, hallucinations, and disorganized speech, and catatonia features such as agitation, stupor, mutism, stereotypes, and posturing after an injection of ceftriaxone sodium against Streptococcus pneumoniae pneumonia. The diagnosis of ceftriaxone sodium–associated encephalopathy was suspected, as these findings improved after the discontinuation of ceftriaxone sodium. Patients with this disease present with psychological and neurological symptoms such as disturbance of consciousness, seizures, and myoclonus. However, details of the former are unknown. Based on previous reports, we note that schizophrenic and catatonic features are distinctive psychological symptoms of this disease. The pathophysiology of schizophrenia and catatonia involves dysfunction of the gamma–aminobutyric acid (GABA) system. We hypothesized that antagonism at the GABA_A receptor in ceftriaxone sodium might induce these symptoms due to a dysfunction of the GABA systems. Therefore, ceftriaxone sodium–associated encephalopathy should be considered in psychological symptoms during administration.

An 80–year–old man was admitted because of an attack of disturbance of consciousness (DOC). He had moderate difficulty in performing the activities of daily living and was carted off wheelchair–bounded for the past 4 years. On admission, he showed unresponsiveness with Japan Coma Scale Il score of 30. Caloric vestibular–ocular response was evoked with ice water, and his eyes were fully and conjugately deviated toward the irrigated ear. Electroencephalography (EEG) revealed diffuse 5Hz background activity. However, the cause of DOC was unknown.

His DOC lasted for about 7 hours after admission. When he became alert without treatment, he reported recurrent hallucinations of human faces for the past 5 years. In addition, neurological examination disclosed progressing dementia and marked parkinsonism with severe microphonia. EEG showed 7～8Hz activity.

Thus, a diagnosis of dementia with Lewy bodies (DLB) was made. However, he experienced two siinilar DOC attacks on day 6 after admission. The attacks lasted for a few hours and disappeared without treatment. Oral amantadine (AD）at a dose of 50mg/day was initiated on the 7th day after admission. The attack did not recur for next 4 months following AD administration; after that, the patient was lost to follow up. It is hypothesized that AD could inhibit nicotinic receptor function of DLB with DOC and may have prevented the recurrence of DOC. Further studies to determine the efficacy of AD are recommended.