I review disease concept and recent developments in understanding and treating 4 repeat tauopathies including corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). PSP and CBD are now considered pathologic diagnoses, with several different and varied clinical phenotypes, that overlap and share features with Parkinson disease, frontotemporal dementia, and spinocerebellar ataxia. New diagnostic criteria have been proposed for CBD and PSP. Because therapeutic interventions that target abnormally–phosphorylated tau have started, further refinement of the diagnostic criteria is needed via biomarker researches with prospective study designs.
We reviewed the recent advances in syringomelia based on nationwide survey on the epidemiology of syringomyelia in Japan. The estimated prevalence of ambulatory syringomyelia patients in Japan was 1.94 per 100,000. The proportion of asymptomatic syringomyelia patients was 22.7%. Chiari type I malformations and idiopathic syringomyelia were the first and second most common etiologies. Approximately 70% patients were performed foramen magnum decompression (FMD) with dural patch grafting and/or dural dissection. Several pedigrees with familial syringomyelia were observed. The progress of genetic analysis study is expected.
Behavioral and psychological symptoms of dementia (BPSD) including agitation, delusion, depression and anxiety have been assumed to impose greater burden on family caregivers than cognitive dysfunction. Treatment of these symptoms often requires urgent interventions involving pharmacotherapy. Psychotropic drugs, antipsychotics in particular, could, however, produce both beneficial and harmful effects on aged patients. Thus there develops a wider trend towards treating BPSD of mild to moderate severity preferentially with a various types of emerging psychosocial methods, which are assumed to be generally effective. Pharmacotherapy using antipsychotics should thus be justified only for the patients with severe BPSD or unsatisfactory response to psychosocial treatment. Although atypical antipsychotics are often chosen for treating BPSD of any degree of severity, cholinesterase inhibitor, tiapride or valproate are first recommended for minimizing adverse events such as dysphagia and fall, if the severity of BPSD is mild to moderate. When the use of antipsychotics is needed, we should attempt to limit their use in dosage and duration with greatest caution with the understanding that short–term, low–dose treatment is sufficient for most patients. Through careful selection of appropriate patients for treatment, education of caregivers, and close monitoring, safety risks can be minimized.
Botulinum toxin has been widely applied to therapeutic and cosmetic uses since 1980's. In Japan two formulations, one type A and one type B, are available under strict official regulations. Off–label use is prohibited, and the reimbursement of national insurance is too much restrictive to encourage clinicians of the next generation to launch the practice of this highly effective treatment. Moreover, many of the doctors in Japan are too busy to learn and perform this relatively time–consuming but financially unrewarded procedure. These hardships may regrettably result in the future decline, both quantitative and qualitative, of practice in the clinical setting, as far as Japan is concerned.
For injection, the author prefers 27–30 gauge thin needles to thicker ones, to minimize patient's agony, and whenever possible tries to accurately identify target muscles under the monitoring with electromyography, electrical stimulation, or ultrasonography, for the treatment of the limb or deep cervical muscles. Especially for the obliquus capitis inferior and semispinalis cervicis muscles, the ultrasound is superior to other monitoring techniques.
In spasticity many patients have anticoagulant or antiplatelet drugs for the secondary prevention of cardio– or cerebro–vascular diseases, and special care should be taken to avoid massive intramuscular bleeding in these patients. The consensus about the adequate use of these drugs still remains to be confirmed.
Antitoxin antibody may abolish the toxin effect, but significant number of patients may show apparent secondary resistance to the therapy due to another reasons than neutralizing antibody. Target sites, dose, and technical issues should be re–assessed before abandoning treatment whenever the toxin effect appears to have diminished.
Essential tremor (ET) is most frequent movement disorder in individuals above 40 years old. The prevalence of ET increases steeply with increasing ages. ET is slowly progressive disorder which is sometimes causing severe disability but is not life–limiting.
Diagnosis of ET is based on clinical examination and neurological history, as a specific biological marker or diagnostic test is not available. Differences among tremor disorders are important in published clinical criteria for ET. In pharmacotherapy, Propranolol and Primidone have level A recommendations. And Topiramate and Gabapentin have level B recommendations. However, drugs for ET is not enough reduction of tremor and side–effects is common. Botulinum toxin is possibly effective. Vim thalamotomy is highly effective but side–effects of surgery should be considered. Noninvasive functional neurosurgery using transcranial MRI guided focus ultrasound is a novel treatment and will become a new option near future.
Guillain–Barré syndrome (GBS) is currently classified into the two major categories ; classical demyelinating form, and axonal form termed acute motor axonal neuropathy (AMAN). AMAN is a pure motor axonal subtype of GBS that was identified in the late 1990s. In Asia and Central and South America, it is the major subtype of GBS, seen in 30–65% of patients. One of the main causes is molecular mimicry of human gangliosides by Campylobacter jejuni lipo–oligosaccharides. In addition to axonal degeneration, electrophysiology shows rapidly reversible nerve conduction blockade or slowing, presumably due to pathological changes at the nodes or paranodes. Autoantibodies that bind to GM1 or GD1a gangliosides at the nodes of Ranvier activate complement and disrupt sodium–channel clusters and axoglial junctions, which leads to nerve conduction failure. Improved understanding of the disease mechanism and pathophysiology might lead to new treatment options. Currently eculizumab (anti–complement C5 monocloncal antibody) is a promising agent, and the phase 2 trial has been finished in Japan.
Fisher syndrome has been regarded peculiar inflammatory neuropathy with ophthalmoplegia, ataxia, and areflexia, whereas Bickerstaff brainstem encephalitis has been considered pure central nervous system disease characterized with ophthalmoplegia, ataxia, and consciousness disturbance. Both disorder share common features including preceding infection, albumin–cytological dissociation, and association with Guillain–Barré syndrome. The discovery of anti–GQ1b IgG antibodies further supports the view that the two disorder represent a single disease spectrum. The lesions in Fisher syndrome and Bickerstaff brainstem encephalitis are presumably determined by expression of ganglioside GQ1b in the human nervous system, either peripheral or central. Bickerstaff brainstem encephalitis is likely to represent a variant of Fisher syndrome with central nervous system involvement.
We need to understand aphasia in terms of two points of view. One is the viewpoint of system of language, and the other is the viewpoint of brain function. Language systems are hierarchically constructed, for instance, acoustic system (hearing and speech), phonetic system (discrimination of language sounds and articulation control), phonemic system and lexical/semantic system. Language impairments can be developed of each system as language symptoms. And there are corresponding lesion sites in the brain for each elementary language symptoms such as anarthrie/apraxia of speech, impairment of discrimination of language sound (word deafness), phonemic paraphasia, word comprehension impairment, word retrieval impairment and so on. Classical aphasia classification are vascular syndromes and can be explained as the syndromes made of the elementary symptoms.
Lower urinary tract dysfunction (LUTD) is very common in neurological disorder. It is essential to evaluate lower urinary tract symptoms (LUTS) by using questionnaire. The pattern of LUTD is determined by the site and nature of the lesion in neurological disorder. The patients with suprapontine lesion show storage dysfunction. Both storage and voiding dysfunctions are found in spinal cord lesion, whereas voiding dysfunctions are predominant in sacral and infrasacral lesion. Measurement of the post–void residual (PVR) volume is necessary for the diagnosis of voiding dysfunction. Urodynamic study is useful for the detailed examination of LUTD and may be helpful for the differential diagnosis of parkinsonism.
Delirium is a common and serious acute neuropsychiatric syndrome and characterized by disturbance in attention and awareness, i.e., reduced ability to direct, focus, sustain, and shift attention and reduced orientation to the environment (Diagnostic and Statistical Manual of Mental Disorders, 5th edition, American Psychiatric Association, DSM–5, 2013). While delirium is associated with higher rates of mortality and institutionalization, it remains underdiagnosed because of its diverse and multifactorial etiologies and widely variable presentation including hyper– and hypoactive subtypes. Multi–component approaches to modifiable risk factors are recommended for prevention of delirium, which include reduction of benzodiazepines and anti–cholinergic agents and environmental approaches towards normal sleep–wake cycle. Recently, a randomized placebo–controlled trial suggests preventive effects of ramelteon, a melatonin agonist, on delirium. Non–pharmacological strategies are central also for therapy of delirium, which focus on treating the triggering factors and addressing patient–specific and environmental risk factors that may contribute to the development or worsening of delirium. Antipsychotics such as risperidone, quetiapine, olanzapine, perospirone, and haloperidol can be used off–label to manage symptoms of delirium (Clinical Guideline for the Treatment of Delirium, 2nd edition, Japanese Society of General Hospital Psychiatry, Practice Guidelines 1, 2015).
The history, working policies, structure and activities of American Society for Experimental NeuroTherapeutics (ASENT), a counterpart of Japanese Society of Neurological Therapeutics (JSNT) were overviewed. A main focus of ASENT is developing new therapeutics and educating young researchers/developers who will be involved in drug development. In the effort of developing better therapeutics for neurological disorders in Japan, JSNT should refer to what ASENT accomplished and reform JSNT more efficient organization.
A Biosimilar is a biotechnology–derived product (biologic) which is comparable to an approved biologic in terms of quality, safety and efficacy. Biosimilars are different from generic drugs, which are bioequivalent to the original with identical active ingredients. Biosimilars are made from proteins which have a much more complicated molecular structure and therefore, exact copies cannot be made. Nowadays, biosimilars are gaining a lot of attention as several major biologic medicines are nearing their patent expiration and real world evidence of usage of biosimilars is accumulating in European countries, where the biosimilar infrastructure is more advanced than in the US and Japan.
Considering that Japan is facing soaring healthcare costs, biosimilars are expected to have a critical role to play in ensuring a sustainable healthcare system. In this respect, swift action should be taken to develop an infrastructure to encourage proper usage of biosimilars by increasing the correct understanding of biosimilars among healthcare providers and developing appropriate policies to promote biosimilar use across society.
Delayed sleep phase disorder (DSPD) comprises a persistent or recurrent pattern of sleep disturbances, sleep disruption that leads to insomnia and/or excessive daytime sleepiness, and impaired functioning in social, occupational, or other spheres. Three techniques are typically used to treat DSPD : chronotherapy, phototherapy, and exogenous melatonin administration. Antipsychotics have not been reported in the treatment of DSPD, aripiprazole (APZ), which is a second generation antipsychotic, manifests a novel mechanism of action by serving as a partial agonist of D2 receptors. Depression is reported to be the most common psychopathology associated with DSPD, and APZ is reported to be effective in major depressive disorder as adjunctive therapy. Therefore, we speculated that APZ might be effective to treat DSPD, and we observed how APZ works for the treatment of DSPD.
Methods : 18 subjects (including 7 women) who are 14–48–year–old (the average is 31.6) were included. The patients were prescribed 0.75–4.5mg APZ at once a day.
Results : We prescribed 1.5–3.0mg/day of APZ, all subject reduced total sleep time (9.6 +/− 2.3h → 7.8 +/− 2.0h, p＝0.03), many cases got up earlier (9.1 +/− 1.9h → 6.7 +/− 1.4h, p＝0.005) in the morning and advanced their sleep phase within one week. The sleep onset was not significantly changed (23.5 +/− 2.0h → 22.9 +/− 1.9h, n.s.).
Conclusion : Low dose of APZ would reduce nocturnal sleep time in the subjects who had prolonged sleep time and DSPD symptoms. The mechanism of action would be dopaminergic up regulation due to dopamine D3 agonistic activity. Since it is difficult for physicians to treat prolonged sleep time and DSPD symptoms, this medication would become a new therapeutic tool for these patients.
Parkinson's disease (PD) is a common neurodegenerative disorder, and lower urinary tract (LUT) dysfunction is one of the most common autonomic disorders, and nocturia is the major LUTS in PD with an estimated incidence rate of 70%. We review the pathophysiology of bladder dysfunction in PD, lower urinary tract symptoms (LUTS), objective assessment, and treatment options. In patients with PD, disruption of the dopamine D1–GABAergic direct pathway may lead to LUTS. Overactive bladder (OAB) is the most common LUT symptom in PD patients, and an objective assessment using urodynamics commonly shows detrusor overactivity (DO) in these patients. The post–void residual (PVR) volume is minimal in PD, which differs significantly from multiple system atrophy (MSA) patients who have a more progressive disease that leads to urinary retention. However, subclinical detrusor weakness during voiding may also occur in PD. Regarding bladder management, there are no large, double–blind, prospective studies in this area. It is well recognised that dopaminergic drugs can improve or worsen LUTS in PD patients. Therefore, an add–on therapy with anticholinergics is required. Beta–3 adrenergic agonists are a potential treatment option because there are little to no central cognitive events. Newer interventions, such as deep brain stimulation (DBS), are expected to improve bladder dysfunction in PD. Botulinum toxin injections can be used to treat intractable urinary incontinence in PD. Transurethral resection of the prostate gland (TURP) for comorbid BPH in PD is now recognised to be not contraindicated if MSA is excluded. Collaboration of urologists with neurologists is highly recommended to maximise a patients' bladder–associated QOL.
Both the intravenous recombinant tissue plasminogen activator (IV rt–PA) and endovascular therapy (EVT) show new insights for hyper–acute stroke care. Prehospital stroke management plays an important role in conducting IV rt–PA and/or EVT immediately after stroke onset. Advertisements of stroke symptoms and adequate behavior for citizens is the first step for onset–to–call bypass. The first, and proper reaction of patients and bystanders at a stroke onset is essential in order to quickly reach the hospital. Public educational systems using TV programs should be recommended.
Secondarily, paramedics must use a prehospital stroke scale in order to establish better, direct transportation to a stroke center for on–set–to call 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 an IV rt–PA/EVT bypass to shorten the interval between onset to treatment. Regarding IV rt–PA bypass, thrombolysis needs to be initiated onsite for a hyper–acute stroke patient. A mobile stroke unit and biomarker may be beneficial. EVT bypass is for a hyper–acute stroke patient with suspected large vessel occlusion (SPLVO) needs to be selectively and preferentially transported from onsite to a comprehensive stroke center. When SPLVO is admitted to a primary stroke center, expeditious transfer to a comprehensive stroke center should be conducted, or in the vernacular…, drip, ship, and retrieve.
We discuss the following aspects in the care of amyotrophic lateral sclerosis (ALS) and multiple system atrophy : key points of the care, maintaining the quality of life (QOL) of patients and their family, selection and decision–making for medical treatments and their planning, transitions to home care, and the end–of–life care. In order to sustain the QOL, it is important to have home care supported by the collaboration of experts in various fields and to have advance care planning (ACP) from an earlier stage of disease and close discussions on the plans of treatments and of coping the end–of–life stage, respecting the patients' will. We consider it necessary to explain, at a satisfactory level, merits and demerits to the patients in deciding medical treatments, especially enteral nutrition and tracheostomy positive pressure ventilation, and also, particularly in the case of ALS, to mention to them the risk of totally locked–in state and frontotemporal lobar degeneration. During transition periods to home care, they should be referred to primary care doctors who are available at any time as soon as possible, and it should be explained not to call an ambulance without consideration if they prefer not to receive life–prolonging treatments. The most important at the end–of–life stage is to ensure the patients and their family to have a sense of ease by placing the highest priority on pain palliation.