Neuroprotection is essential for potential therapy not only in acute stage of stroke but also in chronic progressive neurodegenerative diseases such as ALS, Parkinson's disease (PD), and Alzheimer's disease (AD). Free radical scavenger can be such a neuroprotective candidate with inhibiting death signals and potentiating survival signals under cerebral ischemia and even neurodegenerative cellular processes. Edaravone is one such free radical scavenger, which is the first clinical drug for neuroprotection in the world and has been used from 2001 in most ischemic stroke patients in Japan.
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease caused by selective death of motor neurons. Among our own 390 ALS patients, 4.1% show familial ALS (FALS), in which 50% is associated with missense mutations of SOD1, 25% were TDP43 and FUS mutations, and 6.3% is an optineurin mutation. Although the underlying mechanism of ALS has not yet been fully clarified, several reports have implicated the involvement of oxidative stress under selective death of motor neurons in both ALS patients and animal models.
A recent multicenter prospective double–blind placebo–control clinical trial with edaravone for ALS patients conducted in Japan showed a positive effect for delaying the clinical score (ALSFRS–R) during the course of examination (24 weeks). Serious or critical adverse effect was not noted in this clinical trial. Of particular was that this clinical benefit of edaravone was shown as an add–on therapy after anti–glutamatergic riluzole. These data strongly suggest a potential underlying mechanism of oxidative stress both in acute ischemic stroke and in ALS by a free radical scavenger. Edaravone is approved for ALS on 2015 in Japan, 2016 in Korea, and 2017 in USA.
Autoantibodies are frequently detected in the sera or the cerebrospinal fluid from patients with neuroimmunological diseases. Anti–aquaporin 4 antibodies are specifically detected in neuromyelitis optica. Antibodies against NMDA receptor, LGI1 and CASPR2 are associated with autoimmune encephalitis. In autoimmune neuropathies, such as Guillain–Barré syndrome and IgM paraproteinemic neuropathy, antibodies specifically recognizing carbohydrate epitopes of glycolipids are frequently present in the sera from patients. Recently, presence of antibodies against paranodal proteins such as neurofascin 155 has been reported in the sera from a subset of patients with chronic inflammatory demyelinating polyneuropathy. Autoantibodies are useful diagnostic markers and some of them are directly involved in the pathogenetic mechanisms. Further investigation on autoantibodies may lead to better understanding of neuroimmunological diseases and development of novel therapeutic strategies.
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. In Japan, interferon–beta, glatiramer acetate, fingolimod, dimethyl fumarate, and natalizumab are approved treatments for MS. These disease–modifying drugs (DMDs) are efficacious for reducing the frequency of relapses in relapsing remitting MS, but they are generally not effective for progressive MS. Because MS is heterogeneous in its clinical manifestations and disability progression, DMDs must be chosen carefully in consideration of each patient's condition and life stage. In this review, I discuss how to choose DMDs according to the following five standpoints of view on MS treatment : (1) window of opportunity (early initiation) of DMDs in the disease course of MS, (2) presence of benign MS, (3) cortical lesions and cognitive impairment, (4) atypical cases, and (5) occurrence of progressive multifocal leukoencephalopathy. In addition, it is important to monitor disease activity and emergence of atypical lesions suggestive of progressive multifocal leukoencephalopathy after introduction of DMDs by regularly conducting magnetic resonance imaging of the brain and spinal cord.
Inflammatory myopathies are a heterogeneous group of immune–mediated diseases that involve skeletal muscle as well as many other organs. The classification of inflammatory myopathies has been based on clinical diagnoses, pathological diagnoses, and autoantibodies, independently. The clinical phenotypes of inflammatory myopathies are characterized by various autoantibodies that are originally detected by RNA or protein immunoprecipitation. However, since the correlation between histological features and autoantibodies had not been fully elucidated, we created the “Integrated Diagnosis Project for Inflammatory Myopathies” in October 2010. Based on our work and previous studies, the three major subsets of inflammatory myopathies defined by autoantibodies are immune–mediated necrotizing myopathy (IMNM), antisynthetase syndrome, and dermatomyositis. IMNM is the pathological entity, characterized by significant necrotic and regeneration muscle fibers with minimal or no inflammatory cell infiltration. The detection of autoantibodies against signal recognition particles or 3–hydroxy–3–methylglutaryl–coenzyme A reductase is important for the diagnosis of IMNM. Antisynthetase syndrome, characterized by myositis, interstitial lung disease, skin rash, arthropathy, and Raynaud phenomenon, is the clinical entity based on the presence of aminoacyl transfer RNA synthetase antibodies. Perifascicular necrosis is a distinctive hallmark of antisynthetase syndrome in muscle pathology. The diagnosis of dermatomyositis is usually based on clinical features of typical skin rash. Several autoantibodies are associated with specific subsets of dermatomyositis. Myxovirus resistance A expression in the myofiber cytoplasm has a better sensitivity for the diagnosis of dermatomyositis compared to perifascicular atrophy. The screening of autoantibodies has clinical relevance for managing patients with inflammatory myopathies.
In this manuscript, I will mention two topics as the update of electrodiagnostic examinations. One is the clinical and electrophysiological diagnosis of amyotrophic lateral sclerosis (ALS), and the other is electrodiagnosis of plexopathies including true neurogenic thoracic outlet syndrome (TN–TOS).
Revised El–Escorial criteria (R–EEC), the most famous diagnostic criteria for ALS, was criticized by its low sensitivity and its disrespect for the fasciculation potentials. Awaji criteria have been proposed, which reappraised the fasciculation potentials and introduced the interoperability between clinical and electrical findings. However, some studies including ours documented lower sensitivity of Awaji criteria than R–EEC, which was due to the fact that two regions with upper motor neuron (UMN) signs were required in the Awaji criteria to become study eligible. Modified or updated Awaji criteria have been proposed, which achieved the highest sensitivity. However, patients lacking UMN signs cannot be diagnosed using any of the existing criteria. As the more sensitive and specific signs, we investigated the fasciculation potentials themselves, spontaneous activities in the trapezius muscle, and the decremental response in repetitive nerve stimulation test in the trapezius muscle.
For the electrodiagnosis of brachial plexopathies, combination of sensory conduction studies is promising. Among brachial plexopathies, the concept of thoracic outlet syndrome (TOS) has been the topic of debate. Professor Wilbourn in Cleveland clinic argued that the true neurogenic TOS (TN–TOS) is the only established disorder among neurogenic TOS, and criticized the concept of classical TOS that has been frequently treated surgically, naming it as the disputed neurogenic TOS. TN–TOS is a motor–dominant disorder presenting with thenar atrophy and impaired skilled movement of digits. Sensory symptoms are usually minimal. Nerve conduction studies clearly document the lower trunk lesion dominant in the T1 component.
Neuropathy is a common disease. Recent progress of neurotherapeutics enabled us to treat and cure some intractable neuropathies ; this means that neurologists are required to diagnose and pick–up “treatable neuropathy” patients properly, and to catch–up the recent progress of neuropathy treatment. In this article, I briefly present practical points of diagnosis and treatment in representative treatable neuropathies. In Guillain–Barré syndrome (GBS), first line treatments (plasmapheresis and IVIg) were established in 1980s and 1990s, respectively, and no novel therapeutic regimen has been proposed in these 25 years. However, because a substantial number of patients, especially with severe disease, showed poor recovery and residual deficits, a breakthrough therapeutic strategy has eagerly been awaited. In 2016, Japanese neurologists completed a prospective, multi–center, placebo–controlled double–blinded, randomized phase–II study to evaluate the efficacy of eculizumab in GBS and got favorable results. Future phase–III trials are expected. In chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), three first line treatments (corticosteroids, plasmapheresis, and IVIg) were already established. However, nobody knows which therapeutic regimen is most appropriate in individual patient. Recent discovery of autoantibodies in CIDP (e.g. anti–neurofascin 155) may subdivide CIDP patients, and enable us to choose best therapy in each patient. Vasculitic neuropathy needs prompt diagnosis and rapid commencement of immunotherapy. Pathological confirmation of vasculitis is most important in the diagnosis of this disorder and most of the patients show multiple mononeuropathy, but patients presenting polyneuropathy are not rare. Neuropathy due to vitamin B1 deficiency (beriberi) shows motor–dominant acute polyneuropathy and sometimes misdiagnosed as GBS.
Outstanding progress in functional neuroimaging has been recently achieved prominently in molecular imaging using nuclear medicine techniques. Amyloid PET, tau PET, and dopamine transporter SPECT have been applied to dementia and movement disorders for early diagnosis, differential diagnosis, and evaluation of effects of disease modifying drugs not only in clinical research or trial but also in routine clinical studies. Quantification of amyloid and tau deposition or striatal dopamine transporter is necessary for diagnosis.
RCVS comprise a group of disorders characterized by prolonged but reversible vasoconstriction of the cerebral arteries, usually associated with acute–onset, severe, recurrent headaches, with or without additional neurologic symptoms and signs. Recurrent thunderclap headaches, seizures, transient ischemic attacks, brain infarctions, brain hemorrhages and non–aneurysmal subarachnoid hemorrhages can all reveal RCVS.
Stroke can occur a few days after initial normal imaging, and cerebral vasoconstriction is at a maximum on angiograms 2–3 weeks after clinical onset. Segmental constrictions of cerebral arteries resolve within 3 months. RCVS is supposedly due to a transient disturbance in the control of cerebrovascular tone.
Brain white matter lesions are frequently observed changes in older adults. Traditionally, white matter lesions were considered to be caused by peripheral circulation disorders due to stenosis of large blood vessels. However, the discovery of small blood vessel diseases with only small blood vessels indicates that in some situations, small blood vessels are affected primarily and have a different molecular mechanism from large blood vessels. Hereditary cerebellar small vessel diseases are caused by mutations of genes ubiquitously expressed in many tissues, but the pathological changes of small vessels are different from organ to organ. This fact indicates that small blood vessels can be characterized by each organ. Furthermore, recently, cerebral small vessels have been found to function as a mechanism of excretion from the brain and as a mechanism of blood flow redistribution depending on nerve activity. The neurological symptoms which are suggested by these new mechanisms cannot be understood by the traditional concept of clinical neurology based on functional localization theory. Neurological symptoms due to cerebral small vessels should be understood from a whole new perspective. It is also suggested that there is a close relationship between dysfunction of cerebral small vessels and degenerative diseases. For this understanding, the molecular mechanism of the hereditary cerebrovascular disease is considered to be useful. Pathology of small vessels is characteristic of each cerebral small vessel disease. The affected lesions in cerebellar small vessel disease are anatomically limited to specific cells or structures in vessels. The study of cerebral small vessel diseases will open a new understanding of cerebral small vessel disease in sporadic cases and new therapeutic strategy for dementia.
Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular degenerative disease characterized by slowly progressive muscle weakness and atrophy. The cause of SBMA is the expansion of a trinucleotide CAG repeat encoding a polyglutamine tract within the first exon of the androgen receptor (AR) gene. The ligand–dependent nuclear accumulation of the polyglutamine–expanded AR protein is central to the gender–specific pathogenesis of SBMA. The pathogenic AR–mediated neurodegeneration is suppressed by androgen inactivation, the efficacy of which has been tested in randomized controlled trials. Decreases in serum creatinine, a biomarker of SBMA, occurred approximately 15 years before the onset of subjective muscle weakness. The mean serum creatinine concentration is ∼0.6mg/dl and ∼0.8mg/dl at the onset of weakness and hand tremor, respectively. The low serum creatinine concentration in subjects with SBMA is caused by impaired muscle uptake of creatine due to the pathogenic AR–mediated down–regulation of creatine transporter SLC6A8, in addition to being caused by neurogenic atrophy.
Orthostatic hypotension (OH), anhidrosis, and pupil abnormalities are clinically common autonomic symptoms. Subjective symptoms of orthostatic hypotension include lightheadedness, fainting, and pale vision. The degree of OH can be measured at the bedside in patients lying supine or standing, using a sphygmomanometer. The pathogenesis of OH can be indicated by assessing positionally related changes in blood pressure and heart rate. Anhidrosis can be indicated by measuring body temperature under warm or hot conditions. Sweating that is insufficient to compensate for increases in body temperature produces unpleasant feelings and abnormally increased body temperature. A poor ability to sweat can be estimated simply by touching dry skin and more precisely determined by generalized thermal sweating tests using the Minor method. Pupil abnormalities can be identified by close examination of the eyes under light and dark conditions. Myosis, ptosis, and anhidrosis in the affected side of a face are the triadic symptoms of Horner syndrome, in which the sympathetic tract from the upper thoracic spinal cord to the eye is disturbed. Remarkable mydriasis can be determined under conditions of light in patients with Adie syndrome, in whom the accommodation reflex remains preserved. These symptoms can be easily assessed at the bedside and should be interpreted appropriately to solve clinical problems associated with the autonomic nervous system.
Stroke is a disease with a high risk of recurrence. Annual recurrence rate of stroke is 5% on average for 10 years, and this rate is higher immediately after stroke and in the case of cardioembolism. Recent advance of stroke prevention strategy includes introduction of novel drugs such as PCSK9 inhibitor and direct oral anticoagulants (DOAC), and revision of standards for antithrombotic therapy during peri–surgical period or in the presence of cryptogenic stroke or multiple cerebral microbleeds. This review overviews therapeutic strategy for stroke, focusing especially on the recent advancement.
Acupuncture and moxibustion therapy are part of traditional oriental medicine, which has a history of more than 2000 years, and can have effects on many diseases and symptoms.
Our department was established in 1984, and has been engaged in medical treatment and research/education in our university. We have received requests for acupuncture and moxibustion therapy from many departments, and have demonstrated the great effectiveness of acupuncture and moxibustion therapy in patients with intractable pain, paralysis or a series of unidentified complaints. Acupuncture treatment has also contributed to improvement in the physical and mental QOL of these patients, and it has objectively supported the idea of oriental medicine described in classic textbooks.
Our department has also investigated the effects of acupuncture treatment on various organs, and has initiated the scientification of traditional medicine. As a result, it was suggested that acupuncture treatment contributed to alleviation of symptoms not only by mere local reactions but also through the central nervous system. Furthermore, the responses of the body to acupuncture treatment differ between individuals with diseases and symptoms and healthy people, suggesting the possibility of acupuncture treatment being involved in the recovery of the body's homeostasis. We believe that these normalizing effects of acupuncture treatment are characteristics of traditional medicine.
Thus, the clinical practice and the research on the effect and mechanisms of acupuncture treatment on neurological disorder such as the primary headaches and stroke have been promoted in cooperation with neurology.
From these results, we believe that traditional medicine, acupuncture and moxibustion therapy will be established as a new era of medicine by fusing with modern Western medicine by further developing medical collaboration.
According to the World Health Organization, about 15 million people suffer a stroke each year with roughly one–third resulting in death and another one–third sustaining severe permanent disability. Even in developed nations such as Japan, stroke is the third leading cause of death with more than 100,000 fatalities each year from approximately 3,000,000 stroke cases. Stroke can occur at any age but 75% of all strokes occur in people over the age of 65. Ischemic stroke, which accounts for about 70–80% of all strokes, is caused by an occlusion of a blood vessel by a blood clot stopping blood supply to a particular area of the brain. The effects of a stroke can be catastrophic because cessation of cerebral blood flow leads to energy failure and eventually cell death through necrosis as well as apoptosis, and triggers immune responses and inflammatory cell activation and infiltration. Recombinant tissue plasminogen activator (rtPA) can only be given within a narrow time window (4.5h) following stroke onset and carries the risk of inducing haemorrhage. Despite efforts to increase the use of such reperfusion therapies, only 4–5% of stroke patients receive intravenous thrombolysis. The worldwide percentage is even lower when developing nations are included. Among those who undergo reperfusion treatment, 25–30% have successful arterial recanalization. In addition, more recently introduced endovascular thrombectomy can achieve considerably higher recanalization rates approaching 90% in acute ischemic stroke patients. However, not all patients with recanalization have sustained clinical improvements, and not always is a treatment possible within the narrow time window required for thrombolysis and thrombectomy. Therefore, seeking effective treatment for stroke remains an urgent priority. To achieve success in developing more effective management of stroke, a better understanding of all aspects of stroke including prevention, diagnosis, treatment, and post–stroke recovery and complications is needed.
Even with optimal management with drug and surgical therapies, patients with Parkinson's disease (PD) are faced with progressively increasing motor and non–motor problems. Rehabilitation combined with the treatment have a possibility of the further improvement of the symptoms of PD. It is necessary for physicians to know the intervention methods of rehabilitation for Parkinson's disease. In this presentation, I introduce new intervention methods of rehabilitation including the evidence shown with “Parkinson's disease treatment guidelines 2011 and the new” by Societas Neurologica Japonica including a new method to evaluate PD gait and severity using a portable gait rhythmogram (PGR) and music therapy.
Exercise and motor training are effective for health related QOL, muscular strength, balance, walking speed, UPDRS–III, reaching performance. Walk training with the treadmill and Nordic events walking are also effective. The frequency of the fall decreases with physiotherapy.
It is important for PD rehabilitation to choose an appropriate intervention method for their severity. Disused syndrome is also an important problem in PD. In an early stage, education is very important to keep their life–style. In middle stage, exercise and motor training is necessary for motor function, for example, gait problems as well as speech and swallowing disturbance. Lee–Silverman Voice Treatment improves speech and swallowing function. Tai chi exercise improves the stability of the posture. And a cue strategy method, for example, the walk training using the external auditory stimulation is effective including music therapy.
Furthermore, I make a presentation about a new evaluation method using an acceleration sensor (PGR). Finally, it is necessary to make high evidence intervention methods from the multidirectional points of view including an evaluation of compliance such as continuity and motivation in order to offer better rehabilitation.
Secondary headache refers to a headache associated with the underlying disease causing it and is a generic term for headache compared to primary headache where headache itself is disease such as migraine, tension–type headache, and trigeminal autonomic cephalalgia. According to “Clinical Practice Guideline for Chronic Headache 2013”, in the following cases : (1) headache with sudden onset, (2) headache never experienced before, (3) headache different from the customary headache, (4) headache that has increased in frequency and intensity, (5) headache begins after age 50, (6) headache with neurological deficit, (7) headache in a patient with cancer or immunodeficiency, (8) headache in a patient with psychiatric symptoms, (9) headache in a patient with fever, neck stiffness or meningeal irritation, it is recommended that an aggressive search is necessary in doubt of secondary headache.
Recent advances in imaging diagnostic techniques, especially MR imaging, make head and neck MR examinations a powerful tool to advance the differential diagnosis of organic diseases that cause secondary headache. It is important to keep in mind the characteristics and accompanying symptoms of headaches to search.
In everyday headache medical examination, it is important to always pay attention to that secondary headache should not be overlooked.
I review diagnosis and treatments against sleep–related breathing disorder (SRBD) observed in neuromuscular diseases including amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA). SRBD includes sleep apnea syndrome, nocturnal stridor, hypoventilation, and central respiratory disturbance. These conditions cause frequent awakening, nocturnal pollakiuria, morning headache, and hypersomnia. Clinical examination followed in selected patients by nocturnal saturation monitoring and polysomnography is essential for correct diagnosis and treatments.
Headache is the most common chief complaint among the patients visiting neurology out–patient clinic. A survey done at Tatsuoka Neurology Clinic showed 84.0% were given an IHS diagnosis of migraine, 3.0% cluster headache and 7.0% tension–type headache at our clinic. Therefor it is important to understand the diagnosis and the treatment of these primary headaches for the paramedical staffs of neurology clinic.
The diagnosis of each headache is carried out according to criteria for The International Classification of Headache Disorders, 3rd edition (beta version). The diagnostic criteria of migraine without aura, infrequent episodic tension type headache and cluster headache were shown in the tables.
The treatment of migraine includes acute treatment and prophylactic therapy. Clinical Practice Guideline for Chronic Headache 2013 recommends NSAIDs for mild to moderate headache, and triptans for moderate to severe headache, or even mild to moderate headache when NSAIDs were ineffective. For acute treatment, attention has to be paid to medication–overuse headache of which diagnostic criteria is shown in Table 5. Prophylactic therapy is recommended for patients with migraine attacks two times or more or 6 days or more a month, for patients with poor response of acute treatment, and for patient with contraindication of acute treatment. The guideline recommends valproic acid, propranolol, amitriptyline and lomerizine for prophylactic treatment.
Frequent episodic tension–type headache and chronic tension–type headache require acute or prophylactic treatment. NSAIDs are recommended for acute treatment and amitriptyline for prophylactic treatment.
For cluster headache, subcutaneous injection of sumatriptan and pure oxygen delivered via a side tube of a face mask at 7L/minute for 15 minutes are recommended. Sumatriptan nasal spray and oral zolmitriptan are also useful. For prophylactic treatment of cluster headache verapamil and corticosteroids are recommended.
Elderly patients usually have specific geriatric problems, including cognitive impairment, depression, falls, gait disturbance, incontinence, eating and swallowing difficulties, malnutrition, and visual and auditory difficulties, in addition to comorbid medical illnesses. Therefore, comprehensive geriatric assessment (CGA) might be effective for preventing diseases or complications and for maintaining the health status of elderly patients with various neurological diseases. Frailty increases the risks of adverse health outcomes, including falls, disability, hospitalization, institutionalization and even death. Physical frailty is common in old patients with neurological diseases, especially dementia. Several studies suggest that physical frailty and dementia might interact in old age. Since elderly patients with dementia underlie multiple pathologies in the brain, including Alzheimer pathology, cerebrovascular disease, and Lewy body pathology, they unlikely show typical symptoms and clinical courses. Geriatric assessment and intervention may be necessary for considering an exact diagnosis and appropriate therapy and care for elderly patients with neurological diseases.
Multiple sclerosis (MS) is a chronic disease that attacks the central nervous system. It affects the brain, spinal cord, and optic nerves. MS symptoms and signs depend on where the nerves are demyelinated and may include : visual changes including double vision or loss of vision, numbness, tingling or weakness (weakness may range from mild to severe), paralysis, vertigo or dizziness, erectile dysfunction (ED, impotence), pregnancy problems, incontinence (or conversely, urinary retention), muscle spasticity, incoordination of muscles, tremor, painful involuntary muscle contractions, slurred speech, fatigue. No single test can confirm a diagnosis, so several strategies are needed when deciding whether a patient meets the criteria for a diagnosis. There will be a neurologic exam, imaging scans, a test to measure the electrical activity of the brain, a cerebrospinal fluid (CSF) analysis, and possibly other tests. These can help rule out other possible causes of the symptoms. The McDonald diagnostic criteria, which was originally proposed in 2005, was updated at European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2017 and will allow earlier diagnosis. This new criteria includes the presence of oligoclonal bands (OB) in CSF in patients with a first symptom, as an alternative to waiting for additional symptoms or lesions to present. In a patient with a typical clinical isolated syndrome (CIS) and fulfillment of clinical or MRI criteria for “dissemination in space” and no better explanation for the clinical presentation, demonstration of CSF–specific OB allows an MS diagnosis to be made without the previously required “dissemination in time.” There is no cure for MS, so treatment focuses on suppressing the autoimmune response and managing symptoms. Corticosteroids are the most commonly prescribed drugs for MS at acute phase. They reduce inflammation and suppress the immune system. Several disease–modifying drugs (DMD) are approved for the relapsing forms of MS.
Accumulating evidence strongly suggest that amyotrophic lateral sclerosis (ALS) is linked to protein misfolding. TAR DNA–binding protein 43kDa (TDP–43) is nuclear RNA–binding protein, which is also implicated in the pathogenic cascades sporadic ALS by forming various aggregates. TDP–43 aggregates, as well as fused–in sarcoma (FUS) protein, are tightly linked to stress–granules, and the aberrant liquid phase separation attracts huge attention as a direct cause of aggregate toxicity. Therefore, the elimination of pathogenic forms of TDP–43 is a rational and a promising strategy to prevent motor neurons from degeneration. We previously generated a mouse monoclonal antibody (MAb), 3B12A raised against peptides containing E246/D247 located in the nucleus export signal (NES), which are exposed in the misfolded states of TDP–43. 3B12A MAb recognizes mislocalized and aggregated forms of TDP–43, but not non–aggregated WT TDP–43 in the nucleus. Using cDNA derived from mRNA of 3B12A hybridoma, we generated a single chain of variable fragments (scFv), aiming to eliminate intracellular pathogenic aggregates of TDP–43 in ALS. In the transfected cells, the 3B12A scFv showed the similar binding profiles to FL MAb, in which mislocalized or aggregated TDP–43, but not nuclear WT TDP–43 colocalized or co–immunoprecipitated with 3B12A MAb. Moreover, 3B12A scFv contains PEST–like motif at CDR2 of VH, which promotes the proteasome degradation of aberrant TDP–43, concomitant merit that the scFv alone was unstable in the absence of the antigen. To increase the degradation efficacy, we also tested the fusion of chaperone–mediated autophagy (CMA) signal to the 3B12A to provide dual proteolytic machinery. The 3B12A CMA–scFv acquired increased efficacy to shorten the half–life as well as to eliminate the TDP–43 aggregates in the transfected cells, estimated by the pulse–chase assay and time–lapse fluorescent microscope analysis, respectively. The scavenging of the intracellular aggregates by 3B12A CMA scFv also depressed the toxicity in HEK293A and Neuro2a cells. Notably, the interaction of CMA–scFv with the aggregates transcriptionally induced heat–shock chaperone, HSP70, which concomitantly refolded the misfolded TDP–43. In vivo evaluation of the neuroprotection of the intrabody, using the in utero electroporated mice pup brain, revealed that TDP–43 aggregates in the brain were significantly suppressed by the co–introduced intrabody, while expression levels of WT TDP–43 showed no significant change with or without the intrabody.
These results indicate that the misfolding–specific intrabodies with dual proteolytic signals promise molecular targeting therapy for TDP–43–linked ALS, although further estimation is required toward clinical application.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder leading to respiratory muscle paralysis a few years after the onset because of motor neuron death. After the discovery of the SOD1 gene in 1993 as the causative gene, more than 20 genes, such as FUS, the second most frequent Japanese, and C9ORF72, the most frequent in Europe and America, have been clarified. Our research group developed an ALS rat model with SOD1 mutation, which recapitulates the motor neuron pathology found in human ALS cases. A continuous administration of hepatocyte growth factor (HGF) using the osmotic pump into the intrathecal cavity of ALS rat model showed a significant prolongation of disease duration at 63%. In 2014, the phase I study of intrathecal administration of HGF for patients with ALS at Tohoku University Hospital was conducted to confirm safety and pharmacokinetics. Currently, phase II clinical trials are being conducted with the aim of obtaining a proof of concept. In the current placebo–controlled double–blind study, the total number of cases is 48 at the Tohoku University and Osaka University. The primary endpoint is the reduction in the ALSFRS–R score evaluated for 24 weeks. On the basis of a 3–month observation period, patients with similar progression are involved. We have mentioned the candidate therapeutic targets that have been clarified through rodent models, such as pathological analysis of nerve axon in the early stage of ALS mouse model and abnormalities in immune mechanism of C9ORF72–deficient mice.
Cybernic functional regeneration treatment using Hybrid Assistive Limb (HAL) may become a new standard treatment for all neurological ambulation disorders such as neuromuscular. The NCY–3001 clinical trial for neuromuscular diseases including spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy (SBMA), amyotrophic lateral sclerosis (ALS), muscular dystrophy, Charcot–Marie Tooth disease (CMT), distal myopathy, sporadic inclusion body myositis, and congenital myopathy was completed, and HAL was approved as a new medical device in 2015. According to the results of this RCT to test the short–term efficacy and safety, cybernic treatment using HAL started to be covered by Japanese health insurance in April 2016, and Cyberdyne Inc. released this system in September 2016. Clinical trials for the other neurological disorders including spastic paraplegia (NCY–2001). We have much experience of long–term efficacy of cybernic treatment in the neuromuscular diseases in the real world data. This cybernic treatment can be combined with other treatments including drug, oligonucleotide, antibody and stem cell therapies.
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) and the pathogenesis leading to demyelination includes 3 major processes. The first step is establishment of autoimmunity to CNS myelin components. The second step is entry of immune cells into the CNS via the blood–brain barrier (BBB). Activated T cells can easily cross the BBB using surface α4–integrin as a ligand to VCAM–1, which is expressed on endothelial cells in the CNS. As the third step, immune reactions occur within the CNS when activated T cells encounter specific antigens presented by microglia. Of the helper T cells re–stimulated by autoantigens, Th1 cells producing interferon–γ and Th17 cells secreting interleukin–17 play major roles in propagating inflammation, while Th2 cells producing IL–4, and regulatory T cells secreting IL–10 and TGF–β suppress pathological processes. Final demyelination is rendered either by macrophages recruited from the bloodstream across the BBB, or by TNF–α and nitric oxide, which are secreted by Th1 cells and macrophages, and toxic to CNS myelin. With these immunopathgenesis of MS in mind, physicians should decide to choose one among the 6 disease–modifying drugs (DMDs), including interferon–β1b, interferon–β1a, glatiramer acetate, fingolimod, natalizumab, and dimethyl fumarate. The first 3 drugs are regarded as a baseline one preventing disease activation through Th2–predominant immune effect (Th2 shift) with long–term safety profile. Fingolimod and natalizumab render more potent suppression to MS via marked reduction of immune cells entering the CNS. The former is placed as second–line drug as is the latter for JC virus–negative patients, while natalizumab for JC virus–infected patients is placed in the third, because of the risk for the development of progressive multifocal leukoencephalopathy. The position of dimethyl fumarate has not been established. Usually, escalation therapy is chosen, however, induction therapy may be necessary for patients with highly active disease. Physicians should obtain informed consent from patients with MS after full explanation of risk and benefit of those DMDs.
Multiple sclerosis (MS) is an inflammatory demyelinating disease of central nervous system. It has been reported that Japanese MS patients have milder disease than those in Western countries and have less risk of developing progressive disease. Even though, some Japanese MS patients do show brain atrophy and develop progressive disease. We should differentiate the patients who show brain atrophy from the beginning of the disease and should use disease modifying drugs that have potential to prevent the atrophy.
Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system caused by JC polyomavirus (JCV). In Japan, the incidence of PML has been investigated by us, a Health and Labour Sciences Research Grant for Research on Measures for Intractable Diseases (Prion Disease and Slow Virus Infections) from the Ministry of Health, Labour and Welfare of the Japanese government. Recently, we have established registration system on PML Surveillance Committee. This system makes epidemiological investigation effective and exact. In Japan the basic disease of PML are changing variously. The major basic diseases are hematologic disease/malignancy such as lymphoma, collagen disease/autoimmune disease as SLE, HIV infection, MS and kidney disease. Four fingolimod–associated PML cases and one natalizumab–associated PML are reported in Japan. Next, we have established new criteria for the diagnosis of PML by PML Practice guideline 2017. Clinical diagnosis criteria consist of clinical feature, neuroradiographic imaging, excluded criteria, and the presence of the virus in the CSF compartment. In histopathological diagnosis criteria, Definitive diagnosis of PML requires neuropathologic demonstration of the typical histopathologic triad (demyelination, bizarre astrocytes, and enlarged oligodendroglial nuclei) coupled with the techniques to show the presence of JC virus. Furthermore, Nakamichi et al established ultrasensitive PCR assay in detection of JCV DNA in the cerebrospinal fluid. Shishido–Hara et al are accepting of consultation of pathological examination form attending doctors and pathologists. These measures will be helpful for the new DMD–associated PML.
Prehospital stroke management plays an important role in conducting intravenous recombinant tissue plasminogen activator (IV rt–PA) and/or endovascular therapy (EVT) immediately after stroke onset because these hyper–acute therapies show new insights for stroke care. Firstly, proper reaction of patients and bystanders at a stroke onset is essential in order to start IV rt–PA and EVT, rapidly. Advertisement and education of stroke symptoms and adequate behavior for citizens are the great step for hyper–acute stroke therapy.
Secondarily, paramedics should use a prehospital stroke scale in order to establish direct transportation to a stroke center for stroke bypass. The requirements of prehospital stroke scales are sufficiently accurate straightforward enough for paramedics tasked with selecting stroke patients from mimic strokes.
Finally, it is important that we make shortening the interval between admission to treatment. A mobile stroke unit and biomarker may be beneficial. Expeditious transfer to a comprehensive stroke center should be conducted. Information and communication technology and expert stroke nurses yield extreme advantage for stroke service among medical staffs.
Cybernic functional regeneration treatment using Hybrid Assistive Limb (HAL) may become a new standard treatment for all neurological ambulation disorders including neuromuscular and cerebrovascular diseases. The NCY–3001 clinical trial for neuromuscular diseases including has been completed, and HAL was approved as a new medical device in 2015. Cybernic treatment using HAL started to be covered by Japanese health insurance in April 2016, and Cyberdyne Inc. released this system in September 2016. Clinical trials for the other neurological disorders including spastic paraplegia (NCY–2001) and recovery phase of stroke (HIT–2016) are now being conducted. In the design of HIT–2016, cybernic treatment starts at almost plateau levels following conventional physiotherapy, and cybernic treatment using HAL enhances the treatment effect. After this study, the next clinical trial plan is to move the starting point much earlier, that is in acute phase, so that the effect might be more pronounced. This cybernic treatment can be combined with other treatments including drug, oligonucleotide, antibody and stem cell therapies.
Prompt recognition and treatment of herpes simplex virus encephalitis (HSVE) is potentially lifesaving in the care of patients. However, no new antiviral drugs have been introduced in nearly 30 years. Although acyclovir treatment for HSVE is highly effective, the rate of poor outcomes, including advanced sequelae, remains high at 33–53%, and the rate of return to normal living is less than 50%. Clinical care guidelines around a simple algorithm, supported by an evidence base, would improve the outcomes of patients with HSVE. In Japan, the guidelines for the clinical management of HSVE were revised in 2017. Three major points were revised in the guidelines. First, a simple algorithm for examination and treatment has been presented at the beginning of the guidelines, to enable prompt management of encephalitis as an emergency. Second, the guidelines in Japan recommend that initiation of therapy should not be delayed beyond 6 hours of the patient's arrival at the hospital. Third, the management of clinically resistant herpes simplex virus has been clarified. We review here the revisions of the Japanese guidelines for the clinical management of HSVE, that were revised in 2017.