Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system and combined with various clinical symptoms. The invisible/hidden symptoms of MS, that pain and numbness, fatigue, dysuria, depression, and cognitive dysfunction other than MS motor dysfunction are hard to detect and understand from the outside. Therefore, it is easy to misunderstand at family life and employment. It might be significantly hindrance the patient's quality of life (QOL). In the daily medical care of MS patients, not only the effect of suppressing relapse and/or progression by disease modifying drug, but also understanding the various those complications of the patient and taking appropriate measures will lead to the improvement of QOL by responding to the unmet medical needs of the patient. This paper outlines about the treatment of MS complications based on 「Multiple sclerosis / neuromyelitis optica clinical practice guidelines 2017」.

Parkinson's disease (PD) is a chronically progressive neurodegenerative disease with a prevalence of about 100 to 180 per 100,000 in Japan, which is increasing with aging. Focusing on the Parkinson's disease clinical practice guideline 2018 supervised by the Japanese Society of Neurology, we will outline the drug treatment algorithm in early and advanced PD and the points to be noted in drug treatment in PD patients with comorbidities.

Deep brain stimulation (DBS) for Parkinson's disease (PD) has been approved since the year 2000, and more than 9,000 patients with PD have been received in Japan. Controlling the stimulation parameters with anti–PD drugs should be performed simultaneously. Therefore, it is important to understand the therapeutic characteristics and mechanisms of DBS. Recent developments in DBS devices, such as directional lead and closed–loop stimulation, enable us to control symptoms precisely than previous devices. Using closed–loop stimulation, we can evaluate the neuronal activity of the basal ganglia and monitor it continuously. This is the first therapy for PD using real–time biological markers of the brain. Further development of both medication and device–aided therapy is expected to establish disease–modifying effects on PD.

Neurological and muscular immune–related adverse events (irAEs) associated with cancer treatment with immune checkpoint inhibitors (ICIs) include diverse clinical subsets. The frequency seems to be higher than previously recognized, ranging from 3%–5% of cancer patients undergoing ICIs therapy. The diseases affect the central nervous system, peripheral nerves, neuromuscular junction, and muscle. Disease onset and progression may be rapid with a critical clinical course. The clinical presentation may be different from that of patients unrelated to drugs. Representative irAEs such as autoimmune encephalitis, aseptic meningitis, myelitis, polyradiculoneuropathy, myasthenia gravis, and myositis are usually serious. There is a tight association between myasthenia gravis and myositis, termed as “PD-1 myopathy”. There are guidelines for the diagnosis and treatment of neurological irAEs. For all but the minimum neurological symptoms, ICIs therapy should be withheld until the nature of the irAEs is defined. Immune–modulating medication is generally effective for neurological irAEs. Contribution of neurologists is required for the best management of cancer patients.

Gait disorders are among the most frequent disorders that can impair functional independence and quality of life in patients with movement disorders, such as Parkinson's disease (PD). The core manifestation of gait disorders in PD is a “bradykinetic/hypokinetic gait,” which is characterized by reduced stride length, step width, and gait speed. The leg lifting height and arm swing are also reduced. Additionally, gait asymmetry is observed as seen in other movement disorders. Patients with advanced PD may develop freezing of gait (FOG) and a festinating gait. L–dopa is the standard pharmacotherapy for gait disorders in PD. It has been reported that L–dopa can extend the range of motion of the pelvis and lower limb joints and improve stride length and gait speed. However, the effects of L–dopa on gait parameters are inconsistent and its effects on postural control are limited. In addition, cholinesterase inhibitors has been reported to decrease the incidence of falls in PD patients with a history of falls. The dose adjustment of antiparkinsonian drugs such as L–dopa and management of wearing–off are the first–line therapy for FOG. The dose of L–dopa is set considering that the treatment threshold for FOG may be higher than that for other movement symptoms. Recently, istradefylline has been reported to be effective in reducing FOG in patients with advanced PD who are refractory to conventional therapy.

Routine MRI images of the spinal cord in clinical practice have not changed significantly from the past, and even with 3T MRI systems, it is difficult to say that the image quality has improved significantly compared to past MR images. In addition, the spatial resolution of images cannot be significantly improved due to the nature of MRI. Moreover, even when abnormal findings are observed on MRI images, they are often non–specific. Symptoms and other clinical information are of course important in differentiating between patients, but it is also important to make a comprehensive judgment that includes findings other than localized abnormalities in the spinal cord. In addition, methods for analyzing objective MRI images of the spinal cord, such as the Spinal Cord Toolbox, are expected to be useful in clinical research and practice in the future. In any case, further development of MRI for spinal cord diseases, including imaging and analysis methods, is needed and expected.

In the super–aging society like Japan, neurologists are highly expected to treat patients with epilepsy, which incident and prevalence has bimodal peaks in the young and elderly population. In year 2020, various old and new generation anti–epileptic drugs (AEDs) become available. Monotherapy is recommended, but rational polypharmacy is the second choice when a few monotherapy trials fail. Medical treatment should be tailored to each patient by taking account of epilepsy/seizure classification, comorbidity such as cognitive impairment, psychiatric symptoms and visceral impairment, drug–interaction profile, side–effect profile, and medical cost, in reference to the available guidelines. When the patient is considered medically intractable, neurologists should refer the patient to epileptologists in the epilepsy center for the re–evaluation of the diagnosis and the work–up for epilepsy surgery using the state–of–the art examinations such as the long–term video–EEG monitoring.

Peripheral vestibular disorders can be diagnosed by characteristic nystagmus, whereas central vestibular disorders can be diagnosed by neurologic signs/symptoms other than vertigo/dizziness. Thus, in the differential diagnosis of vertigo/dizziness, both nystagmus and neurological symptoms should be examined. When a diagnosis of benign paroxysmal positional vertigo is made, the canalith repositioning maneuver should be attempted by all practitioners. Vertigo/dizziness usually dose not persist for a long period of time due to vestibular compensation. However, some of dizziness may persist because of collapsed vestibular compensation mechanism or central sensitization. In the treatment of dizziness, it is useful to know the mechanism of chronicity.

In the 1970s and 1990s, thymectomy and high–dose oral prednisolone (PSL) were the only treatment options for myasthenia gravis (MG). Immunosuppressive agents and intravenous immunoglobulin therapy for MG were introduced in 2000. In 2016, a randomized controlled trial was conducted to evaluate the efficacy of thymectomy in non–thymoma patients, and the treatment was found to be effective in patients with acetylcholine receptor (AChR) antibody–positive early onset MG. In 2017, eculizumab, a component C5 inhibitor, was introduced for AChR antibody–positive refractory patients who relapse despite standard therapy. New molecularly targeted agents for MG are under development and clinical trials. However, the remission rate of MG remains low, and treatment is aimed at improving patients' quality of life (QOL). To maximize QOL improvement, PSL use should be minimized. Early treatment with a combination of plasmapheresis, intravenous methylprednisolone therapy, and immunosuppressive drugs is the fastest and most effective way to achieve good QOL and is recommended for the treatment of generalized MG.

Nutritional therapy for neurodegenerative diseases is described, using amyotrophic lateral sclerosis (ALS) as an example. Several clinical trials are underway to test whether the prevention of body weight loss can improve outcomes. A formula for predicting the appropriate caloric requirement in ALS is also reported. In addition, three approaches to managing the nutrition of patients with ALS need to be considered : increasing the number of calories consumed, using tools to support the diet and nursing. During the advanced stages of the disease, it is important to monitor respiratory function frequently and to avoid missing the timing of percutaneous gastrostomy.

Lifestyle disease and social inactivity used to be considered as the principal cause of aging–related cognitive decline in our country. More recently, however, research emphasis has shifted to studies of neurodegenerative disease. It is now widely accepted that lifestyle disease accelerated the onset and progress of Alzheimer's disease (AD). No curative treatment is available, but epidemiological research provides a substantial amount of evidence of modifiable risk and protective factors that can be addressed to prevent or delay onset of AD and dementia. Risk of late–life dementia is determined by exposures to multiple factors experienced over the life course, and the effect of specific risk/protective factors depends largely on age. Medical and lifestyle interventions and promote social, mental, and physical activities aimed at increasing the cognitive reserve. The treatments for lifestyle disease represent an important avenue of approach to help slow or prevent the onset and progression of AD.

Parkinson's disease nurse is a nurse who has expert knowledge and skills in the care of Parkinson's disease patients. The rapid increase in the number of patients with Parkinson's disease, comprehensive assessment of various motor and nonmotor symptoms and complicated therapeutic strategies including the development of the device aided therapy and the non–oral dopaminergic therapies have increased the need for Parkinson's disease nurses in recent years. Together with the physicians, Parkinson's disease nurses are expected to play important roles in the multidisciplinary team for the care of Parkinson's disease patients. In several foreign countries, the educational and training systems for developing Parkinson's disease nurses are well established and several guidelines for Parkinson's disease nurses are available for clinical practice. The educational courses for developing Parkinson's disease nurses are recently held also in Japan, however the training system remains to be well organized. In this article, the current situation in the foreign countries and a variety of role of Parkinson's disease nurses are discussed.

ALS multidisciplinary clinics (MDCs) are also provided in Japan, but unlike the MDCs in Europe and the United States, there are only a limited number of facilities where multiple occupations gather at the same place on the same day. For ALS patients who progress quickly and have difficulty moving, it is a great help to be able to solve many problems with one outpatient visit, and it is great for clinical research and clinical trials to gather many patients at once. We established this Western–style ALS MDC (ALS Clinic) in March 2017. At the time of its establishment, there were only three people, the author (neurologist), a rehabilitation doctor, and an outpatient nurse, but now, with the cooperation of many professionals, a “one team” consisting of more than 10 staff members. We Introduce the history of ALS MDC, which has become the standard form of medical care in Western countries in ALS medical care, the current progression of our ALS clinic, and the ALS Café (patient association) that we are conducting as part of our social contribution activities.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy induced by anti–aquaporin4 (AQP4) antibody and complement. Recently, it is revealed that there is a group of myelin oligodendrocyte glycoprotein (MOG) antibody positive cases in seronegative NMOSD and this MOG antibody associated disease (MOGAD) is now considered as a new disease entity. I would like to focus on the relationship between NMOSD and MOGAD especially on the pathomechanism and future treatment strategy in this symposium.

Neuropathic pain often impairs quality of life in patients and becomes a global health issue. Recently, interaction between neuropathic pain and autoantibodies have been attracting much attention. Because autoantibody–mediated neuropathic pain is often a good response to immunotherapy, the detection of pain–generating autoantibodies may lead to clinical improvement in patients with intractable neuropathic pain.

In this review, we describe the clinical features of autoantibody–mediated neuropathic pain and novel candidate neuropathic pain–related autoantibodies.

Selection of appropriate treatment from the early stage of the disease is important for better prognosis of patients with multiple sclerosis (MS). Although various kinds of disease modifying drugs (DMDs) have been approved for MS, there is no appropriate biomarker to predict treatment responsiveness. We have identified serum Sema4A as a biomarker predicting treatment efficacy of IFN–β therapy. One–third of patients with MS show high serum Sema4A level. These patients tend to have higher EDSS score, and possess immune characteristics of Th17–skewing condition. Interestingly, these patients do not respond effectively to IFN–β therapy. However, retrospective analysis of our MS cohort demonstrated that those with high serum Sema4A level show favorable response to fingolimod therapy. Efficacy of fingolimod was observed even in patients who later switched to fingolimod due to recurrent attacks under IFN–β therapy. Our observations suggest that fingolimod could be a better candidate for managing the disease activity of MS patients with high Sema4A level. Considering the fact that the efficacy of other DMDs still remains elusive among MS patients with varying Sema4A profile, further investigation is required to clarify the role of serum Sema4A as a biomarker in making appropriate decision of DMD choices. Regarding patients with NMOSD, we found that certain proportion of patients show high level of serum Sema4A. In the present review, we would discuss the current advances in the field of MS research focusing on the role of Sema4A, and further present the clinical features of patients of NMOSD with high Sema4A level.

Given that immune–mediated neurological disorders are caused by inadequate immune response, manipulating the functions of immune cells represents a promising treatment. Monoclonal antibody therapy and oligonucleotide therapy target specific molecules via different mechanisms of action.

Some clinical studies for immune–mediated disorders of antisense oligonucleotides (ASO), short interfering RNA, and oligonucleotide aptamers have been already initiated. Though lymphocytes are important players in immune–mediated disorders, regulating these functions is challenging because lymphocytes are highly resistant to transfection. Therefore, efficient drug delivery technology for conventional oligonucleotides is required. We developed DNA/RNA heteroduplex oligonucleotide (HDO), which is comprised of ASO and delivery ligand conjugated–complementary RNA. Notably, α–tocopherol (vitamin E) binding HDO has achieved efficient delivery into hepatocytes and brain microvascular endothelial cells compared with the parent ASO.

Although some monoclonal antibody drugs are approved for immune–mediated neurological disorders, these drugs can't control the intracellular molecules of immune cells, such as lymphocytes and microglia. Unlike monoclonal antibody drugs, oligonucleotide drugs have the potential to manipulate the functions of immune cells by modulating the endogenous gene expression including non–coding RNAs, such as some micro–RNAs, involved in pathophysiological processes. The development of oligonucleotide therapy with high potency for immune–mediated neurological disorders is desired.

“Insomnia” has come to a turning point globally. Firstly, a major change has been made to its nosology ; the distinction between “primary insomnia” and “secondary insomnia” has been discarded in the latest Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Sleep Disorders (ICSD), and they have been integrated as “insomnia disorder” as an independent diagnostic entity. This is based on the recognition that insomnia can have an independent course even with comorbid conditions, and also has a bidirectional relationship with them. The second major change is the global and ongoing transition of treatment priority from pharmacotherapy to cognitive behavioral therapy for insomnia (CBT–I). The accumulation of the broad range of evidence of CBT–I is striking, and most of the latest guidelines in western countries positioned CBT–I as the first–line treatment. It is also astonishing that it has been suggested that CBT–I can improve not only insomnia but also reduce or even prevent depression. Although its availability is a major issue, digital technology might be one of the solutions. The third major change is regarding the classes of hypnotics. Conventional benzodiazepine receptor agonists (BZRA) have become emphasized to be tapered or discontinued because of dependence and cognitive and motor side effects. Instead, melatonin receptor agonists and orexin receptor antagonists have been developed and focused, as for their reduced side effects like BZRA. The fourth potential major change might be emerged as to the insomnia subtyping. The latest ICSD also discarded conventional subtypes, such as psychophysiological insomnia or idiopathic insomnia, due to lack of stability in their diagnosis. Robust and practical subtyping covering predictability for depression or treatment response would be expected. Accordingly, further knowledge as to the pathophysiology of insomnia would also be needed.

Hypoglossal nerve stimulation (HNS) is a novel therapy in treating moderate and severe obstructive sleep apnea (OSA) in patients who cannot tolerate continuous positive airway pressure (CPAP) therapy. Studies showed that HNS decreased apnea–hypopnea index decreased by 68%, and that the device was effective even after five years. HNS has become a therapeutic option for OSA. More studies may be needed to ensure the highest safety profile.

Restless legs syndrome (RLS) is a sensory–motor disorder that causes insomnia due to abnormal sensations in the lower limbs and is frequently associated with periodic leg movements during sleep or resting wakefulness. RLS is associated with neurological disorders such as migraine and Parkinson's disease as well as peripheral neuropathy, which can also mimic RLS. RLS is diagnosed by interviewing patients to confirm the 4 essential features (URGE) : U＝urge to move the legs ; R＝rest induces symptoms ; G＝getting active brings relief ; and E＝evening and night make symptoms worse. In addition, it is necessary to exclude RLS mimics such as leg cramps, arthritis and peripheral neuropathy. For treatment, iron is administered in patients with low serum ferritin (＜50µg/L), and the main pharmacotherapies used are dopamine agonists and alpha–2 delta ligands. Intermittent administration of levodopa may be an option for daytime symptoms triggered at rest. In this article, I will review the pathophysiology, diagnosis and treatment of RLS.

Even though we are currently in the midst of pandemic from coronavirus infection, the new influenza (H1N1) epidemic in 2009–2010 was unforgettable. Concurrently with the H1N1, narcolepsy surged in post–affected children in China. In Northern Europe, narcolepsy surged in children after H1N1 vaccination. Although there were many cases of H1N1 in Japan, there was no change in the incidence of narcolepsy because anti–influenza drugs prevented the disease from becoming more severe and the vaccine did not contain an adjuvant. It has recently become clear that the Spanish flu that prevailed about 100 years ago was also H1N1. Economo's encephalitis lethargica, which was prevalent at the same time, is thought to be autoimmune encephalitis rather than H1N1–induced influenza encephalitis. It has been reported that Economo's encephalitis caused damage to the hypothalamus, including the orexin system, resulting in lethargic symptoms.

Since the 2010s, the number of patients with neurodevelopmental disorders (ADHD, ASD) has been increasing among the patients who complain of hypersomnolence. Consideration of the course of symptoms revealed that the patient was originally below the threshold of the diagnostic criteria for neurodevelopmental disease, that hypersomnolence occurred from around adolescence, and that the case also met the criteria for neurodevelopmental disease. Although hypersomnolence was not noticeable in early childhood and inattention was the main symptom, the diagnostic criteria were not met. Hypersomnolence, on the other hand, increased from around adolescence, was added, and attention deficit was exacerbated. Therefore, it is considered that there are many cases that satisfy both the diagnosis of ADHD and central hypersomnia. ADHD characteristics such as attention deficit, hyperactivity, and poor impulsivity may be observed in children who have recovered from Economo's encephalitis and are called post–encephalitis behavioral disorders. The pathophysiology of Economo's encephalitis is presumed to be a disorder of the hypothalamus, including the orexin system, but it is possible that the disorder remained even after recovery.

We believe that impaired attention, and restlessness caused by the hypersomnolence in neurodevelopmental disorders can be explained by dysfunctions of the orexin system and its arousal system. H1N1 morbidity may trigger neurodevelopmental disorders accompanied by hypersomnolence.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by dream enactment behaviors. Patients often experience unpleasant dreams with anger or fear, such as “fighting” or “being chased by a bear,” and often experience violent movement and injury related to the dream. RBD has been recognized as a precursor to neurodegenerative diseases such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. In the treatment of RBD, it is necessary not only to deal with dream enactment behaviors but also to consider the future progression to neurodegenerative diseases.

Polysomnography is essential for the diagnosis of RBD, and REM without atonia is important for RBD diagnosis.

In a systematic review and meta–analysis of RBD longitudinal studies, the progression rate from idiopathic RBD to neurodegenerative diseases (phenoconversion) was 33.5% at five years, 82.4% at 10.5 years, and 96.6% at 14 years from the first visit.

As non–pharmacological interventions for dream enactment behaviors, it is vital to make a bedroom environment safe. Coping with stress and reducing alcohol consumption are also effective. As for medication, clonazepam is effective in most cases but has a risk of confusion and falls. Ramelteon and Yokukansan (Yi–Gan San) have been reported to be useful for dream enactment behaviors in RBD.

There is insufficient evidence for therapeutic interventions in the long–term course of RBD. To improve the quality of treatment for RBD comorbid with Parkinson's disease or dementia with Lewy bodies, it is necessary to conduct a survey and establish the evidence about the incidence of injury due to dream enactment behaviors and adverse drug effects.

Among neurodegenerative diseases, “What kind of disease should we know now?” is the theme given to me at the 38th Annual Meeting of the Japanese Society of Neurological Therapeutics. In recent years, neuroimaging have been actively incorporated as objective biomarkers into diagnostic criteria for neurodegenerative diseases, and there are a wide variety of issues to be addressed. In this paper, in the limited space, the characteristic MRI findings of diffusion–enhanced images trigger the diagnosis of intranuclear inclusion disease, hereditary diffuse leukoencephalopathy with axonal spheroids–CSF1R and their differential diagnoses. In addition, as the development of Alzheimer's disease modifiers progresses, it is important to distinguish diseases other than Alzheimer's disease, which develop due to forgetfulness and show the first imaging findings of hippocampal atrophy. I will describe argyrophilic grain disease/dementia of grains (AGD/DG), primary age–related tauopathy (PART), limbic–predominant age–related TDP–43 encephalopathy (LATE) and their differential diagnoses, and hope that it would be a useful step for the treatment of neurodegenerative diseases in the near future.

Alzheimer's disease (AD) is neuropathologically characterized by the deposition of amyloid–β (Aβ) plaques and neurofibrillary tangles. Imaging biomarkers for these protein deposits play a key role in the accurate diagnosis of neurodegenerative dementia and in the development of anti–dementia drugs. Recent advances of AD biomarkers have clarified the dynamic pathological changes underlying AD. Amyloid and tau PET have been widely used for the assessment of Aβ and tau pathology in the living brain. ¹⁸F–labeled amyloid PET probes are commercially available. In addition, several tau probes have been successfully developed. Longitudinal examination of Aβ and tau pathology will clarify the effect of these protein deposits on neurodegenerative process and cognitive impairment in AD.

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the CNS. With the discovery of specific serum marker of anti–aquaporin 4 (AQP4) antibody, NMO is now considered to be a distinct disease spectrum from multiple sclerosis (MS). Pathological studies showed that in NMO lesions MBP–stained myelinated fibers were relatively preserved though the AQP4 and GFAP staining are severely lost. The pathogenicity of AQP4–antibody in the pathogenesis of NMO was demonstrated in animal models where patient–derived immunoglobulins were passively transferred. These in vivo studies have shown that AQP4–antibody are capable of inducing astrocyte injury in a complement–dependent manner. Accumulating evidence obtained from further researches utilizing animal models has clarified the involvement of additional type of cells such as T cells, neutrophils, eosinophils, monocytes and microglia in the disease mechanism of NMO. The essential roles of IL–1β and IL–6 have also been demonstrated in several literatures. Based upon these observations obtained by in vivo studies, several novel drugs such as Eculizumab, Inebilizumab, and Satralizumab have been currently proven to be highly effective for the prevention of NMO relapses. Here we discuss the potential role of animal models for the development of future therapeutic targets of NMO.

Several animal models of Guillain–Barré syndrome (GBS) which is an acute immune–mediated polyneuropathy have been reported. The detailed analysis of the animal models revealed that complement activation is associated with the pathogenesis of GBS, and recently complement inhibitors are notable as novel therapies in GBS. Recent studies using the animal models have shown the efficacy of complement inhibitors such as eculizumab, C1q inhibitor, and IgG–degrading enzyme of Streptococcus pyogenes. At present, several trials regarding these drugs are in progress. Animal models have an important role for development of novel therapies.

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disorder of the CNS. Perception of cognitive functioning in patients with MS has increased exponentially over 30 years. Cognitive impairment might occur even in early course of MS, and it could become more frequent and moderate to severe in progressive course. Moreover, it may force a burden on patients with MS, their family members and society, due to the negative impact of workplace performance, daily life and social engagement. Cognitive functioning of MS could routinely be assessed by using some validated tools. A meta–analysis has highlighted that disease–modifying therapies exert positive effects on cognitive functioning in patients with MS. It is hoped that medical professions including neurologists or nurses, and social community would recognize the impact of cognition in patients with MS.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system. The assessment of neurodegeneration in terms of brain atrophy is of high clinical relevance because it has substantial predictive value with respect to long–term physical disability, cognitive decline and disease progression. Here, we discuss several methods to assess the degree of neurodegeneration in MS.

The hallmark of early multiple sclerosis (MS) pathology is “inflammatory demyelination”, whereas neurodegeneration leading to brain atrophy begins unexpectedly early in the course, at least subclinically. Oxidative stress caused by inflammation and remyelination failure are two major mechanisms underlying neurodegeneration, while B cells and neuroinflammation as well as aging process may also contribute during the progressive phase. For the brain health of MS, early diagnosis and adequate treatment from the beginning of disease course is mandatory. After “MS domino” started to run, its pathology becomes far more complicated and multimodal approach may be necessary to halt the disease progression.

Progressive multifocal leukoencephalopathy (PML) is a JC virus infection that is an inapparent infection under normal immune conditions ; however, the JC virus is pathologically reactivated when the immunocompetence of the host declines, causing infectious demyelinating encephalopathy. There are three types of disease–modifying drugs (DMDs) associated with PML in multiple sclerosis treatment. Fingolimod (FGM) and siponimod (SPM) are sphingosine–1–phosphate receptor agonists. Natalizumab (NTZ) is an antibody against the integrin alpha–4 beta–1 subunit of T lymphocytes. Dimethyl fumarate (DMF) is a nuclear factor (erythroid–derived 2)–related factor 2 that has antioxidant and anti–inflammatory effects that are thought to be mediated by the activation of the transcription pathway. The risk of NTZ–related PML depends on the JC virus antibody index, history of immunosuppressant use, and duration of NTZ administration. In recent years, extended interval dosing therapy, which extends the NTZ administration interval, has attracted attention as an optional treatment method that maintains adequate blood levels of NTZ while reducing the risk of PML. The mechanism of FGM–related PML is unknown, but FGM and SPM cause a decrease in lymphocytes in the blood, and administration in elderly patients and the long–term use of these drugs are associated with a high risk of PML. The frequency of PML in Japan may be statistically higher than that worldwide. It has been pointed out that the risk factors of DMF–related PML include a persistent decrease in the blood lymphocyte count (less than 500/mm³) and age older than 50 years.

Since immune reconstitution inflammatory syndrome (IRIS) is nearly inevitable in cases of DMD–related PML, it is important to administer steroids according to the conditions to control central nervous inflammation after IRIS onset. It is also important to adjust the imaging interval according to the risk of detecting the asymptomatic stage of PML and to avoid the development of IRIS, and if a physician considers it necessary, the cerebrospinal fluid should be checked as well.

No diagnostic test can substitute for a detailed history in the diagnosis of epilepsy. Obtaining eyewitness reports is imperative as patients can be unaware of their seizures. Past similar episodes should be identified to elucidate the characteristics of seizures. Alternative diagnoses such as cardiogenic causes should be ruled out. If the events are suggestive of epileptic seizures, patients should be evaluated for underlying etiology.

Electroencephalography (EEG) may show interictal epileptiform discharges when the history is suggestive of epileptic seizure. It is also useful to exclude or identify seizure activity, especially nonconvulsive status epilepticus, in older patients in the hospital for altered mental status of unclear etiology, and their neurological prognosis may be improved. A routine interictal EEG has limited diagnostic utility for older patients when the history is more suggestive of syncope.

A brain imaging study should be obtained in older individuals with possible seizures or epilepsy, given the higher frequency of stroke and other structural disease as possible etiologies. Magnetic resonance imaging, more sensitive than computed tomography, is preferred especially when ictal symptoms are focal, or neurological examination or EEG shows abnormal findings. Contrast–enhanced imaging increases the ability to identify tumors, inflammatory disease, and abscesses.

Because metabolic abnormalities can precipitate seizures in patients with and without epilepsy, patients with acute seizures should have blood analyzed for levels of electrolytes including calcium and magnesium, renal and liver function tests, and glucose. Metabolic causes should be excluded with laboratory evaluation also in older individuals suspected of epileptic seizures or epilepsy. Complete blood count with differential should be also performed in anticipation of initiating antiseizure drugs.

Because of the atypical symptomatology, seizures in older patients are frequently misdiagnosed, or the diagnosis is delayed.

It has long been argued that epilepsy surgery is one of the most underutilized therapeutic intervention in medicine. Based on the health insurance claims, the annual number of epilepsy surgery performed in Japan is about half of that in the United States. It is important to consider surgical indication promptly when drug–resistant epilepsy (DRE) is suspected. When patients with DRE have surgically remediable etiology such as unilateral hippocampal sclerosis and low–grade epilepsy associated tumors, surgical indication should be considered at early stage of treatment. The chance of seizure control by the next drug becomes smaller as the number of previously–failed antiepileptic drugs increases. Surgical treatment should be considered when many antiepileptic drugs failed to control patient's seizures.

Less invasive approaches are increasingly utilized in epilepsy surgery. Stereotactic insertion of depth electrodes assisted by the robotic system was recently covered by insurance in Japan. This will accelerate the use of stereoelectroencephalogprahy (SEEG) for pre–surgical evaluation of epilepsy. SEEG enables the exploration of deep structures, including the hippocampus, insula, and cingulum, and may improve diagnostic accuracy and surgical outcome. Magnetic resonance–guided laser interstitial thermal therapy and brain–responsive neurostimulation have not been introduced in Japan. Deep brain stimulation (DBS) of the thalamus is known to be effective in reducing seizures in patients with DRE, although the use of DBS is not approved for epilepsy in Japan. All of these new approaches eliminate the need for craniotomy or the need for brain resection. The introduction of the less invasive procedures will reduce the burden on patients and may expand the indications for surgical treatment.

Epilepsy rehabilitation is a comprehensive, holistic approach to treating patients with epilepsy for their seizure control as well as comorbidities and psychosocial issues. The goal is to minimize the effects of seizures and associated disabilities, thereby maximizing the potential for patient's independence in life. In order to achieve this goal, multidisciplinary professionals must collaborate across medical and social disciplines to engage efficiently and effectively over the course of patients' lifespan. While the concept of epilepsy rehabilitation has been proposed since the 1980s in Japan, it is one important framework to be readdressed in the current epilepsy care system. In this paper, the conceptual framework of epilepsy rehabilitation is discussed first, followed by the importance of comprehensive assessment and intervention. A study at the Tohoku University Hospital inpatient evaluation program illustrated the practical implementation of epilepsy rehabilitation, with regard to both the comprehensive evaluation of patients' needs and the patient–reported evaluation. Lastly, the current social system and welfare services that are available for patients with epilepsy is discussed.