In my clinic, working time consists of home care medicine (80%) and out–patient clinic (20%). Ninety percent of out–patients have neurodegenerative diseases or neuromuscular disorders and seventy in home care medicine. Only 10% of the home calls required the specialization that neurologists have. And when neurological specialization was required it was limited to the examination because neurological treatment often requires specialized equipment or medicine that is only available at large hospitals or universities. Moreover, it is difficult to maintain the knowledge and skill of neurology for a neurology specialist in home care medicine.
The Japanese Society of Neurological Therapeutics decided to start a new working group for community medicine (named by the president Nakashima and headed by the administration officer Suzuki) for the member doctors working in community medicine. The role of neurology specialists in home care medicine is still not concretely determined. I hope the working group will help neurology specialists build a community in which they can share collective knowledge and skill to ultimately improve the quality of the care they provide in home care medicine.
After the meta–analysis of 5 major randomized controlled trials (ESCAPE, EXTEND–IA, SWIFT–PRIME, MR–CLEAN, REVASCAT), adding mechanical thrombectomy on the t–PA therapy will become the standard therapy. However, the emergency transport system for acute stroke patients are not operated well in Japan. With the elongation of t–PA therapy to 4.5h after onset of the ischemic stroke, the new era started for the acute stroke therapy. We should make new systems in which how to select the stroke patients for such new therapy. For subacute ~ chronic phase of embolic stroke patients, we can now select 5 anticoagulant therapy, however the way how to select those drugs for which type of patients are not well established.
Dementia affects over 35 million people in the world with a rapidly increasing prevalence. Alzheimer's disease (AD) is the most common form of dementia. No fundamental treatment for AD has been established, and novel therapeutic strategies are under investigation. This progress has led to the development of numerous therapeutic strategies in the clinical testing. Immunotherapy against Aβ has been pursued extensively as a therapeutic approach to Alzheimer's disease, and several other promising trials are currently ongoing. In addition, new therapeutic strategies have been reported in Huntington's disease and frontotemporal dementia. This review overviews recent advances in basic and clinical research in dementia.
Recent advances in the treatment of neurological infections are described based on reports published in 2016.
According to the European cohort study of community–acquired bacterial meningitis, the incidence of adult bacterial meningitis has decreased substantially, which is partly explained by herd protection by pediatric conjugate vaccines. Also, adjunctive dexamethasone treatment was associated with substantially improved outcome. Streptococcus pneumonia is the most common pathogen in adult. Patients with active cancer, however, present with lower CSF leukocyte counts, are more likely to be infected with Listeria monocytogenes, and are at high risk of unfavorable outcome.
The plasma–cell–depleting proteasome inhibitor bortezomib could be useful for severe and therapy–refractory cases of anti–NMDAR encephalitis. Bortezomib treatment showed clinical improvement or disease remission in 5 severely affected patients with anti–NMDAR encephalitis with resistance to standard immunosuppressive therapy (corticosteroids, IVIG, plasma exchange, immunoadsorption, rituximab, cyclophosphamide). Autoimmune encephalitis including anti–NMDAR encephalitis often poses a therapeutic challenge. The Korea study reported the efficacy and safety of rituximab treatment as a second–line immunotherapy treatment for autoimmune limbic encephalitis. Functional improvement occurred more frequently in the rituximab group compared to the control group, regardless of autoantibody status. In a prospective observational case control study, treatment effects of plasma exchange and immunoadsorption were evaluated in 21 patients with autoimmune encephalitis associated with NMDAR, LGI1, CASPR2, GAD, mGluR5 and Hu antibodies. Apheresis is well tolerated and effective also as first–line therapy in autoimmune encephalitis, particularly in patients with antibodies targeting neuronal surfaces.
Cochrane Database Systemic Review reported the effect of adjuvant corticosteroid therapy in tuberculous meningitis. There is high quality evidence of the benefit of corticosteroids in preventing death in people with tuberculous meningitis. For HIV–positive people with TB meningitis, there is uncertainty about whether or not corticosteroids are beneficial due to the lack of direct evidence in this group. However, corticosteroids may not be associated with increased risk of adverse events. On the other hand, adjuvant corticosteroid therapy did not reduce mortality among patients with HIV–associated cryptococcal meningitis and was associated with more adverse events and disability than was placebo.
We reviewed recent advances and new evidence related to treatment for immune–mediated central nervous system disorders particularly multiple sclerosis (MS) and neuromyelitis optica (NMO).
In Japan, new disease modifying drugs (DMDs) for MS were approved every year for the last three years, therefor we should know the efficacy and safety about each DMD and how to use it for MS patients. DMDs reduce the relapse rate in MS patients but some DMDs are associated with a risk of progressive multifocal leukoencephalopathy (PML). Because of the frequently poor prognosis of PML, it is importance to establish this diagnosis at an early asymptomatic stageusing the basis of magnetic resonance imaging (MRI) and JCV DNA. Additionally pregnancy and the use of DMDs, rebound syndrome, lateral and escalation therapy in relapsing remitting MS were reviewed.
We also reviewed neuromyeltisoptica (NMO). It is difficult to diagnose a patient with aquaporin 4 (AQP4) IgGseronegative NMO. MOG–Ig G seropositive NMO is one of the AQP4 IgGseronegative NMO, It's clinical presentation, radiological and laboratory features, treatment response and so on were reported in details in 2016.
We review reports published in 2016 providing new information on the management of Parkinson's disease (PD) and related disorders. In 2016, the Japanese Public Health Ministry authorized the use of levodopa/carbidopa intestinal gel for PD.
We report here the outcome of this new medical management of PD. Rivastigmine improved gait stability. Exercise trainings such as resistance training and cognitive motor intervention, were shown to be effective for muscle strength, parkinsonian motor symptoms and gait stability. A wearable technology such as inertial measurement units combined with a smartphone application (CuPiD–system) was useful for gait training. Modafinil improved excessive daytime sleepiness and exogenous melatonin improved quality of sleep and REM sleep behavior disorder. Rotigotine improved quality of sleep. Doxepin and Yang–Xue–Qing–Nao granules may be effective for sleep disturbance. Probiotics and prebiotic fiber relieved constipation in PD. Dipraglurant, a metabotropic glutamate receptor 5–negative allosteric modulator, but AQW051, a nicotinic acetylcholine receptor α7 agonist, reduced levodopa induced peak dose dyskinesia. Preladenant, an adenosine 2A antagonist, could not reduce off time in Japanese PD patients with wearing off. Phase 1 trial of PRX002, an anti–α–synuclein monoclonal antibody, resulted in safe and supported continued development of PRX002. Nilotinib, a tyrosine kinase Abelson inhibitor, was suggested to have beneficial effect on motor and cognitive function in PD and Dementia with Lewy bodies. For PD–related disorders of progressive supranuclear palsy, infusion of mesenchymal stroma cells into the cerebral arteries reduced progress of motor symptoms for at least 6 months. Rasagiline, a monoamine oxidase type B inhibitor, failed to reduce deterioration of motor and cognitive dysfunctions.
We reviewed the recent advances in therapeutics of spinocerebellar degeneration and multiple system atrophy that were published in 2016. Various clinical trials were carried out in 2012, mainly in FRDA. However, the therapeutic reports did not provide much evidence. Some interesting clinical trials were reported, and further developments are expected. The therapeutic studies investigating a new pathomechanism were reported in animal and/or cell culture studies. We expect that these results will be translated to patients with these disorders.
Amyotrophic lateral sclerosis (ALS) is the progressive motor neuron disease (MND) in adults, characterized by the selective death of motor neurons in the motor cortex, brainstem and spinal cord. This review provides a general overview of preclinical and clinical advances in 2016 and summarizes the literature regarding emerging therapeutic approaches. The topics include research using next–generation sequencing, progress in the pathomechanism of C9ORF72–mutated ALS, therapeutic strategies on mitochondrial pathology, neuroinflammation, autophagy, growth factor supplementation, axonal pathology in ALS. Clinical trials for ALS targeting on these pathomechanisms are on–going including intrathecal administration of hepatocyte growth factor (HGF).
The aim of this paragraph is to introduce recent advances in the studies of, intravascular lymphoma, lymphomatoid granulomatosis and neurosarcoidosis to neurological clinicians based on reports published in 2016. Any three are very rare, and their neurological manifestations are non–specific, hence they are difficult to diagnose, in early phases. Gliomatosis cerebri has been deleted from the 2016 central nervous system (CNS) World Health Organization (WHO) classification as a distinct entity, rather being considered a growth pattern found in many gliomas.
Regarding Intravascular lymphoma, a comprehensive meta–analysis of 654 cases of intravascular lymphoma patients published between 1957 and 2012 was reported in 2016. In their results, there were no significant differences between Asian and non–Asian populations in clinical features. Lymphomatoid granulomatosis (LYG) sometimes suffer from lesions of the CNS, although the pathogenesis of LYG is still unknown. A review describing pathological feature of CNS–LYG was reported in 2016. There are also case reports of successfully treatment of CNS–LYG with rituximab plus cyclophosphamide, vincristine, and prednisolone therapy. A systematic review and meta–analysis of studies on neurosarcoidosis identifying 29 articles describing 1088 patients diagnosed between 1965 and 2015 and a cross–sectional cohort study including 52 patients were reported in 2016. The recommended treatment of neurosarcoidosis consisits of corticosteroids (first line), methotrexate or azathioprine (second line), or monoclonal antibodies (third line).
Zika virus infection became epidemic in many countries in South or Central America in 2015–2016. Guillain–Barré syndrome (GBS) after Zika virus infection in French Polynesia was reported. The duration to peak from neurological onset was 6 days (range 4–9), and 12 patients (29%) required mechanical ventilation in 42 GBS patients after Zika virus infection. The electrophysiological study showed decline of distal compound muscle action potential. Zika virus is a possible trigger of GBS. The result regarding Inhibition of Complement in GBS study (ICA–GBS study) was reported from UK. However, the number of enrolled patients was not enough for evaluation of the efficacy of eculizumab. A similar study was also performed in Japan, in which the target number of patients was already enrolled. Safety and efficacy of thalidomide in patients with POEMS syndrome were reported. Oral thalidomide (200mg/day) or placebo for six cycles (24 weeks) was randomly administered in 25 patients (thalidomide ; n＝13, placebo ; n＝12) with POEMS syndrome. These patients were not eligible for autotransplantation. One patient in placebo group was excluded, and the remaining patients were analyzed. For primary endpoint, the reduction rate of serum VEGF were 0.39 in the thalidomide group and −0.02 in the placebo group (p＝0.04). Thalidomide significantly reduced serum VEGF levels and improved the motor nerve velocity during 72 weeks including open–label period. Thalidomide is effective for POEMS syndrome patients who are not eligible for autotransplantation.
Until recently, there had been no cure for many of muscle diseases. However, now several lines of clinical trials are being conducted for Duchenne muscular dystrophy (DMD) and other muscle disorders. Among them, exon skipping therapy seems a most promising strategy that targets DMD patients with deletions. Eterplirsen was approved by U.S. Food and Drug Administrations with conditions. Read–through agent, ataluren, has obtained a conditional approval from European Medicines Agency. In Japan, phase 2 clinical trial is being conducted using arbekacin based upon its read–through activity higher than that of gentamycin. An anti–myostatin monoclonal antibody, PF–06252616, which is expected to increase muscle volume, is under phase 2 clinical trial. Another hypertrophying agent, bimagrumab, a monoclonal antibody to type IIB activin receptor, did not reach the primary end point of global clinical trial against inclusion body myositis, for which no efficacious therapy has been known. GNE myopathy is caused by missense in GNE gene that encodes a protein with enzymatic activities of UDP–GlcNAc 2–epimerase and ManNAc kinase. Accordingly, sialic acid production is reduced and cells are hyposialylated. This hyposialylation status can be recovered by simply giving sialic acid. Furthermore, myopathic phenotype in the mouse is almost completely suppressed by oral administration of sialic acid. Based upon these in vitro and in vivo results, slow release tablets of sialic acid (SA–ER) is now under phase III clinical trial in North America and European countries. In diagnostic point of view, immune–mediated necrotizing myopathy and sporadic late onset nemline myopathy should be considered. Patient registry and natural history of the disease need to be established for clinical trials for rare disorders to be successful.
Article on novel development of neurological treatment published in 2016 were reviewed.
1. Orthostatic hypotension (OH) : Droxidopa had the long–term safety and durability of efficacy in patients with symptomatic neurogenic OH. It reduced fall rates in Parkinson's disease (PD) patients with symptomatic neurogenic OH.
2. Postural tachycardia syndrome (POTS) : Adolescents with POTS demonstrated a significant increase in overall functional ability and significant reductions in depression and catastrophizing by an interdisciplinary rehabilitation program.
3. Vasovagal syncope : Non–pharmacological treatments such as increasing fluid and salt intake and physical counter maneuvers were first–line treatments. Pharmacological treatments including β–blockers, α–agonists and anti–cholinergic medications, etc. and pacemaker therapy were required when syncope was severe and refractory to conservative treatment.
4. Constipation : Abdominal massage was beneficial in relieving symptoms of constipation in patients with PD. STN–DBS improved gastric motility as well as gastrointestinal symptoms in PD. Fingolimod reduced synucleinopathy and improved gut motility in A53T mice.
5. Urinary disturbance : Mirabegron demonstrated low adherence and persistence similar to anticholinergic therapies. Electrical stimulation on overactive bladder was safe, efficacious, and worthy of clinical use.
We reviewed major bibliographic references pertaining to headache (migraine and cluster headache) and epilepsy treatments, which were predominantly published in 2016. Headache is the most common neurological disorder and the third leading cause of disability worldwide. Calcitonin gene–related peptide (CGRP) plays a major role in the pathophysiology of migraine headaches. In 2016, most migraine preventive studies of the monoclonal anti–CGRP antibodies are now in phase 3. AMG 334 leave no doubt that, unlike current preventive treatments, short–term tolerability is very good. On the other hand, TEV–48125 has been proven safety and tolerability for chronic migraine only in phase 2b. In present, further development of TEV–48125 for the preventive treatment of chronic migraine in a phase 3 trial. Migraine with aura has been consistently associated with increased risk of stroke. Both migraine and CAD have a strong genetic determination, and recent genome–wide association studies have identified risk variants for each.
Cluster headache is one of the most painful disorders. There have been reports on the effectiveness of sphenopalatine ganglion (SPG) stimulation in patients with medically refractory, chronic cluster headache. In this study, SPG stimulation is an effective acute therapy in 45% of patients, offering sustained effectiveness over 24 months of observation.
Genetic study is regarded important in the treatment of epilepsy. Carbamazepine–induced SJS–TEN is strongly associated with the HLA B*1502 allele. SJS–TEN did not develop in any of the HLA–B*1502–negative subjects receiving carbamazepine. Therefore, the HLA B*1502 allele was shown to be a biomarker for carbamazepine–induced SJS–TEN. Hemispheric surgery has been proven to be an effective treatment for patients with medically intractable epilepsy. However temporal plus epilepsy, characterized by a primary temporal lobe epileptogenic zone extending to neighbored regions, there are surgery failures. So, there are necessary for sufficient preoperative examinations.