The 51st Annual Meeting of the Japanese Society of Neurology was held in Tokyo (Tokyo International Forum) from Thursday, May 20 to Saturday, May 22, 2010 with as many as 5,471 attendants. Our Society has been celebrating its 50th anniversary during the period from 2009 through 2010. At the 51st Annual Meeting in 2010, we looked toward the future, as we celebrate our 50th anniversary together with distinguished guests closely related to our Society. The theme for the 51st Annual Meeting was set as "Future of Neurology-Breakthrough to the next stage-." As represented in the theme, I hope that the Annual Meeting provided an excellent opportunity for all of us to look ahead to the future of Neurology and our Society in the next half-century. We have achieved tremendous advances in better understanding neurological diseases and developing more efficacious treatment over the last half century. Great strides have been made in all areas, of which diagnostic imaging, molecular genetics, immunology and physiology are just a few examples, and understanding of diseases has similarly taken a great leap forward. In Japan, the aging of society coupled with the declining birthrate has placed ever-increasing expectations on neurologists to provide better care for dementia, cerebrovascular disorders and neurodegenerative diseases. Given this situation our Society is required to provide outstanding education in both the pre- and post-graduate context, and, furthermore, to ensure that excellent training programs are available for young neurologists preparing for Board certification. Looking towards the future of neurology, we should continue to anticipate new, ground-breaking achievements for better understanding neurological diseases and establishing more effective treatment through our ongoing endeavors.
Recently, diagnosis and treatment for transient ischemic attack (TIA) and acute stroke is greatly changing in Japan. Now, TIA is closed up because it has been clarified that TIA attack is very high risk for following stroke. Therefore, TIA patients should be immediately evaluated TIA etiology and be treated after TIA attack as soon as possible in order to prevent following stroke. Medical equipment for stroke such as ultrasound and MRI is improving. In particular, development of MRI study including DWI, T2*, FLAIR, and MRA resulted in accurate diagnosis and etiology of super acute ischemic stroke, and paradoxical embolism, arterial dissection, and aortogenic embolism can be diagnosed in acute stroke patients. t-PA therapy has been approved by Japanese government since 1995, October. t-PA therapy can improve patient outcome due to early recanalization of occluded brain artery. The early recanalization rate was approximately 50% of major artery occlusion. We reported that early recanalization depended on time from stroke onset to IV-t-PA administration. Furthermore, we shown that the large ischemic lesions on diffusion-weighted imaging done before-PA infusion and presence of M1 susceptibility vessel sign were predictor for no-early recanalization and poor outcome. Stroke unit consisting stroke doctors, stroke nurse, and rehabilitation staff can improve patient outcome. In this way, management for acute stroke is greatly changing in Japan.
Crow-Fukase syndrome, also called POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome, is a rare cause of demyelinating and axonal mixed neuropathy with multiorgan involvement. The pathogenesis of Crow-Fukase syndrome is not well understood, but overproduction of vascular endothelial growth factor (VEGF), probably mediated by monoclonal proliferation of plasma cells, is likely to be responsible for most of the characteristic symptoms. There is no established treatment regimen. In appropriate candidates, high-dose chemotherapies with autologous peripheral blood stem cell transplantation is highly recommended, because this treatment could result in obvious improvement in neuropathy as well as other symptoms, with a significant decrease in serum VEGF levels. Indication of this treatment has not yet been established, and long-term prognosis is unclear at present. Thalidomide should be considered for patients who are not indicated for transplantation therapy. Treatments that should be considered as future therapy include lenalidomide, bortezomib, and anti-VEGF monoclonal antibody (bevacizumab).
Human prion diseases are classified into 3 categories according to etiologies: idiopathic of unknown cause, acquired of infectious origin, and genetic by PRNP mutation. The surveillance committee have analyzed 2,494 cases and identified 1,402 as prion diseases. Most of them are idiopathic, namely sporadic CJD (77%) with less genetic and acquired prion diseases (17% and 5%, respectively). The number of patients identified by the surveillance committee in these years is about 120 which are less than the number of annual death of prion disease. The difference might be due to partly the fact our surveillance need the consent from patients' family and is not complete. The mean age at onset of prion disease is late 60s while the range is fairly wide. Brain MRIs and increase of CSF 14-3-3 and tau protein levels are very characteristic. Classical sporadic CJD could show completely normal T1WI with patchy high signals in the cerebral cortex and basal ganglia on DWI. In Japan, classical sporadic CJD (MM1) is most popular but there are some rare atypical subtypes. Among them, MM2-thalamic CJD is hardest to diagnose because it shows no high intensity signals on DWI, in addition to frequent absence of CSF and EEG characteristics. In this case, CBF decrease in the thalamus on SPECT is very helpful. Genetic prion diseases in Japan are quite distinct from those in Europe. V180I and M232R mutations are unique to Japan and show sporadic CJD phenotype. Dura graft-associated CJD (dCJD) are composed of 67% of classical sporadic CJD phenotype and 33% of atypical phenotype showing slower progression with amyloid plaques. Trace-back experiments suggested the PrPsc of the atypical dCJD was likely to be modified from infection of abnormal VV2 protein. Although there are some atypical forms of prion diseases as mentioned above, almost all prion cases could be diagnosed with EEG, MRI, genetic test, CSF test and SPECT. We also have some incidents in which brain surgery was done before the diagnosis of prion disease and many other patients were operated using the same operating instruments before their sterilization against prion disease had been done. The explanation of possibility of prion disease infection to the patients and their follow-up was started by the incident committee. It is very important for all the nations to cooperate with each other in order to overcome this intractable disease.
The first post-publication external review of the Japanese Guidelines for the Management of Stroke 2004 had been published in "Stroke" in 2009. Considering to these results, new stroke guidelines 2009 has been published in Japan on November 2009. Main renewed and revised points in guidelines 2009, particularly important for the neurologist were introduced, focusing on acute stroke treatment such as administration of t-PA, management of patients with life-style related diseases as well as new antiplatelet therapy for the secondary stroke prevention.
Varieties of autoantibodies are known to relate to autoimmune neurological disorders as the diagnostic and therapeutic markers. Some of them affected directly to the pathomechanisms of neurological diseases. Recently several autoantibodies with such roles have been reported showing the common characters as recognizing cell surface antigens. Among them, anti-aquaporin 4 antibody (AQP4-Ab) in neuromyelitis optica (NMO) and anti-NMDA receptor antibody (NMDAR-Ab) in non-herpetic limbic encephalitis are drawn considerable attention. The features of NMO with AQP4-Ab are as higher age at onset, extreme women preponderance, severe optic neuritis and myelitis with longitudinary extended spinal cord lesions. AQP4-Ab binds to the astrocytic endfeet extended toward cerebrospinal fluid space or vessel wall, related to the common lesions of NMO, and passive transfer of the antibody with complements to rodents showed NMO pathology. The NMDAR-Ab related encephalitis is seen in young women having ovary teratoma showing memory and consciousness disturbances, agitation, epilepsy, respiratory failure, autonomic disorders and involuntary movements. We showed this antibody really affects to NMDAR specific signal transduction using rodent hippocampal slices with suppression of long-term potentiation induction. The discovery of newly characterized autoantibodies with relation to certain neurological diseases will be expected to expand in the future.
The editorial of the new-year issue of Nature 2010 features "A decade for psychiatric disorders". The DALY estimation clearly shows that psychiatric disorders are the top source for burden of diseases to the individual life and society. Schizophrenia is a most devastating psychiatric disorder in which the onset is usually at youth and the cognitive dysfunction persists for life-long in some patients. Schizophrenia is associated with neurodevelopmental abnormalities. It has been unknown whether post-onset progressive pathology is also present in schizophrenia until the recent sophistication of in vivo neuroimaging techniques. Longitudinal neuroimaging studies on first-episode schizophrenia have shown a progressive deterioration of structure and function of neocortical regions in the early stage of the disorder. Insult to dendritic spines through glutamatergic dysfunction may underlie this process, which may in turn be a promising molecular target for intervention to improve the functional outcome of schizophrenia. More recently, the question of whether early intervention can be targeted at prodromal stage of schizophrenia has called special attention in psychiatry. In University of Tokyo, the integrative neuroimaging studies for schizophrenia targeting early intervention and prevention (IN-STEP) is ongoing. Through these efforts, we would like to contribute to the establishment of "youth mental health", where every youth in the community can know, prevent, and have easy access to needs- and value-based services, and pursue mental well-being and recovery.
The presentation discussed certain issues in the management and research of cerebrovascular diseases in Taiwan. In the first part of the presentation, the acute management of stroke in Taiwan, I have revealed the results of the Taiwan Thrombolytic Therapy for Acute Ischemic Stroke (TTT-AIS) study (rt-PA). TTT-AIS was a multicentre, observational study, which enrolled 244 eligible patients with acute ischemic stroke from 23 hospitals from December 2004 to July 2008. The standard-dose group (0.9mg/kg) had higher rates of symptomatic ICH and mortality within three months, twice that of the lower-dose group. This pattern was more prominent in older patients. Besides, significantly lower independence rate was also observed among patients ≥70 years old receiving standard-dose than lower-dose. This study suggests that the standard dose of alteplase 0.9mg/kg may not be optimal for treating aged Chinese. However, the optimal dose of rt-PA for ischemic stroke in Chinese should be based on more broad and convincing evidences. Randomized trials of lower versus higher dose of rt-PA are needed. The second part of the presentation discussed about the relationship between age-related cerebral white matter lesions (leukoaraiosis) and jugular venous reflux (JVR), one of the plenty researches about cerebral venous insufficiency in Taiwan. The presentation introduced current evidences and rationales favoring venous ischemia as a role in the pathophysiology of leukoaraiosis.
We compared the efficacy and safety of cilostazol and aspirin in 2,672 Japanese patients with non-cardioembolic ischemic stroke. The patients were randomized to be allocated either on cilostazol (200mg/day) group or aspirin (81mg/day) group, and were followed up for one to five years (average 29 months). The primary endpoint was any stroke, and safety endpoint was hemorrhagic stroke or hemorrhage requiring hospitalization. Annual incidence of stroke was significantly lower in the cilostazol group (2.76%) than in the aspirin group (3.71%) (relative risk reduction [RRR] 25.7%, p=0.0357) and annual incidence of hemorrhagic stroke or hemorrhage requiring hospitalization was 0.77% in the cilostazol group and 1.77% in the aspirin group (RRR 54.2%, p=0.0004). The sub-analyses between subtypes of ischemic stroke showed that annual incidence of hemorrhagic stroke was much lower in the cilostazol group (0.36%) than in the aspirin group (1.20%) among patients with lacunar stroke (p=0.003). The results suggest that cilostazol has a favorable risk-benefit profile alternative to aspirin for secondary stroke prevention in patients with non-cardioembolic ischemic stroke, particularly in patients with lacunar stroke, who are at high risk of hemorrhagic stroke.
Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neurodegenerative disease characterized by slowly progressive muscle weakness and atrophy. The cause of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine tract, within the first exon of the androgen receptor (AR) gene. SBMA exclusively occurs in males, whereas both heterozygous and homozygous females are usually asymptomatic. In a transgenic mouse model of SBMA, neuromuscular symptoms are markedly pronounced in the male mice, but far less severe in the female counterparts. Androgen deprivation through both surgical and chemical castration substantially suppresses nuclear accumulation of the pathogenic AR, and thereby improves symptoms in the male mice. Since the nuclear translocation of AR is ligand-dependent, testosterone appears to show toxic effects by accelerating nuclear translocation of the pathogenic AR. In a phase 2 clinical trial, 12-month treatment with leuprorelin significantly diminished the serum level of creatine kinase, and suppressed nuclear accumulation of the pathogenic AR. The ligand-dependent accumulation of the pathogenic AR, an initial step in the neurodegenerative process in SBMA, is followed by several downstream molecular events such as transcriptional dysregulation, axonal transport disruption, and mitochondrial insufficiency, indicating that both upstream and downstream molecular abnormalities should be corrected.
Adult-onset type II citrullinemia (CTLN2) is an autosomal recessive disease characterized by highly elevated plasma levels of citrulline and ammonia due to the urea cycle dysfunction associated with citrin deficiency. Patients with CTLN2 show various neurological symptoms with hyperammonemia closely resembling those of hepatic encephalopathy. Since 1990, 26 CTLN2 patients (17 males and 9 females) have been admitted and treated at Shinshu University Hospital. Twelve of the 26 patients received living related partial liver transplantation (LRLT). After LRLT, neurological symptoms soon disappeared, and all patients returned to their previous social lives. Among the 14 patients that did not undergo LRLT, 6 died of intractable encephalopathy or the development of hepatic cancer, but 8 patients have had relatively good clinical courses (follow-up range 0.5-8 years) with oral intake of L-arginine and low-carbohydrate and relatively protein-rich diet. Six patients have been also given sodium pyruvate and the frequency of attacks of encephalopathy markedly decreased in 5 of 6 patients. Our observations indicated that liver transplantation is a very promising type of therapy but that other therapeutic approaches, including low-carbohydrate diet and pyruvate, are being established.
CARASIL (Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) is the second known single-gene disorder directly affecting cerebral small vessels. The acronym CARASIL was proposed by Bowler and Hachinski (1994), based on its recessive inheritance and resemblance to CADASIL (R instead of D). The first CARASIL patients were most probably described in preliminary reports in 1965-66, and later in Japanese and English articles in 1969-1976. In 1985, the author and colleagues reported on another family of three brothers with strikingly similar clinical features, including not only neurological symptoms but also recurrent acute lumbago and premature alopecia, and cerebral white matter disease on CT scans, proposing that these characteristics can constitute a new systemic syndrome. According to our clinical and pathological/neuroradiological criteria, similar patients have been reported, almost exclusively from Japan, with a total reaching 50 until today. In five consanguineous families including ours, Hara et al. (2009) identified homozygous mutations in the HTRA1 gene on chromosome 10q25. Since no founder haplotype has been identified, the author and allied researchers suspect that this disorder will be found more widely. This review summarizes the historical background, epidemiology, characteristic clinical findings, neuroimaging, and clinical perspectives after the gene identification of this disorder.
Hypertension is a well known risk factor for cerebral small vessel disease (SVD) characterized by MRI white matter hyperintensities called "leukoaraiosis". However, the molecular basis of SVD remains to be elucidated. Both twin and family studies have shown that leukoaraiosis is the most heritable cerebrovascular phenotype with a heritability estimated to be between 55% and 71%, suggesting genetic factors for SVD. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is hereditary SVD lacking hypertension. We have recently identified the causative gene, FHtrA1, for CARASIL by genome-wide linkage study and a candidate gene approach. HtrA1 is a serine protease that represses signaling by TGF-β family members. We found that mutated HtrA1 did not repress signaling by the TGF-β family members (BMP2, BMP4, and TGF-β1), resulting in vascular fibrosis with synthesis of extracellular matrix proteins. Our results indicate that disinhibition of TGF-β signaling underlies the molecular basis of CARASIL. Marfan's syndrome is an autosomal dominant connective tissue disorder caused by disinhibition of TGF-β signaling associated with FBN1 mutations. In a small cohort study, angiotensin II-receptor blockers (ARBs) therapy in patients with Marfan's syndrome significantly slowed the rate of progressive aortic-root dilatation. This study provides a potential for developing a therapy targeting TGF-β signaling for SVD.
Wernicke's encephalopathy is a syndrome characterized by ataxia, ophthalmoplegia, and confusion with thiamine deficiency. We reported on two Japanese brothers with a newly discovered recessively inherited syndrome similar to Wernicke's encephalopathy that developed in the second decade of life; this syndrome was manifested clinically as thiamine-responsive diplopia, ataxia and confusion without serum thiamine deficiency. The patients had complex partial seizure. The administration of high-dose thiamine improved these symptoms. MRI of the brain showed high-intensity signals in the bilateral medial thalamus and periaqueductal region on fluid-attenuated inversion recovery images; these signals were characteristic of findings in Wernicke's encephalopathy. There was no history of chronic alcoholism. The clinical and images features resembling Wernicke's encephalopathy in these patients suggested that the syndrome was caused by a genetic disorder of thiamine metabolism. Genomic analysis of SLC10A3 encoding human thiamine transporter 2 revealed that the patients were compound heterozygotes for the K44E and E320Q mutations. Gene-expression analyses of mammalian culture cells showed that intracellular thiamine uptake activities were decreased significantly. High expression of SLC19A3 RNA in the thalamus may explain the selective thalamic lesions on MRI. The identification of this syndrome proves insight into the thiamine metabolism associated with Wernicke's encephalopathy in humans.
Spinocerebellar ataxia type 6 (SCA6) is one of the common dominantly inherited ataxias in Japan, featuring late-onset ataxia and selective Purkinje cell (PC) degeneration. Molecular pathogenesis of SCA6 has been attracting considerable attention since it is caused by small CAG repeat expansions within the Cav2.1 voltage-gated Ca++ channel gene (CACNA1A). During the past 9 years, efforts have been made to generate and analyze a precise SCA6 model in order to disclose its molecular pathogenesis in vivo. Evidence indicates that the SCA6 mutation does not directly change the basic properties of the channel but rather exerts neurotoxicity through a mechanism associated with age-dependent accumulation of the expanded polyglutamine protein. We envisage further analysis on a knockin model developing PC degeneration at their young age will lead to elucidation of the molecular pathways involved in SCA6 and thus be useful for developing therapeutic strategies against the disease.
Neuromyelitis optica (NMO) is an inflammatory and demyelinating syndrome characterized by severe attacks of myelitis and optic neuritis. A crucial role for humoral immunity in the NMO pathogenesis has been suggested by the detection of a highly specific serum autoantibody NMO immunoglobulin G that binds to aquaporin-4 (AQP4) water channels, and the pronounced deposition of immunoglobulins colocalizing with products of complement activation in a vasculocentric pattern around thickened hyalinized blood vessels in NMO lesions. Moreover, we have recently demonstrated that levels of several cytokines such as interleukin (IL)-6 and IL-1β are increased in the cerebrospinal fluid of NMO patients, and the peripheral white matter-demyelinating cord lesions of NMO were accompanied by infiltration of lymphocytes in the leptomeningeal membrane. These cellular elements in patients with NMO might aid B cells and plasma cells in AQP4 antibody production, and break the blood-brain barrier due to the access of AQP4 antibodies to the extracellular domain of AQP4 at the astrocytic foot process.