The nested polymerase chain reaction (PCR) and the loop-mediated isothermal amplification (LAMP) assay were performed to detect and identify toxoplasma parasites in human cerebrospinal fluid (CSF). The performed nested PCR targeting the 18S rDNA using primers generated by Dr. L.D. Sibley instead of the conventionally used primers that target the B1 gene. Toxoplasma gondii-specific LAMP primers targeting both genes were also designed. The clinical sensitivity and specificity were evaluated using clinical CSF samples from 16 patients with toxoplasmic encephalitis (TE) and from 12 patients with other diseases. The 18S rDNA nested PCR showed the highest detection sensitivity limit with a minimum of 1.0 × 10^–8 ng/μl. However, sensitivity and specificity of nested PCR with clinical specimens were 50% and 100%, respectively. The sensitivity of molecular diagnosis of TE is not sufficient; therefore, patients clinically suspected of having TE should be treated promptly. This molecular diagnostic tool would restrictively facilitate a definitive diagnosis of TE at an early stage in approximately 50% of patients.

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We established a new disease autosomal dominant hereditary motor and sensory neuropathy with proximal dominant involvement (HMSNP) in 1997, in Okinawa, Japan. This disease is characterized by proximal dominant neurogenic atrophy with fasciculations, painful muscle cramp, obvious sensory nerve involvement, areflexia, high incidence of elevated creatine kinase levels, hyperlipidemia and hyperglycemia. (MIM %604484). HMSNP is so called or HMSNO (HMSN OKINAWA type),. These clinical features resembled those of Kennedy-Alter-Sung syndrome. Most HMSNP patients have severe muscle atrophy and finally the tracheostomy and artificial ventilation are required. Therefore, we initially thought to classify HMSNP into a subtype of motor neuron disease (MND) like familial amyotrophic lateral sclerosis (FALS) or spinal muscular atrophy (SMA). However, the general consensus for MND was no sensory involvement. Therefore, as the disease showed severe sensory involvement, we categorized HMSNP in subtype of HMSN at that time. We also reported the pathology of HMSNP, showing severely decreased anterior horn cells, decreased posterior horn cells, and loss of posterior funiculus in the spinal cord.

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Mutations in TFG gene have been demonstrated in hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) and hereditary spastic paraplegia (HSP). A broad spectrum of TFG pathology is suspected in motor neuron diseases including amyotrophic lateral sclerosis (ALS). We performed mutation screening of TFG gene in ALS cases and evaluated the biological functions of mutant TFG by expression experiment in cultured cells. Two missense mutations associated with sporadic ALS were discovered. Mislocalization of ALS-related proteins, including TDP-43 and optineurin, was demonstrated. These results indicate that mistrafficking of ALS-related proteins by mutant TFG might be a biological cascade leading to motor neuron death.

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Neuropathology of a case of Shiga pedigree with proximal-dominant hereditary motor and sensory neuropathy (HMSN-P) is reported. In the spinal cord, marked atrophy of anterior and posterior roots was found. Histologically, severe neuronal loss and gliosis were evident in the spinal anterior horns. Bunina bodies and hyaline inclusions were not seen. Neuronal loss and gliosis were mild in the hypoglossal and facial nuclei. Myelin pallor was evident in the posterior and lateral columns of the spinal cord. The posterior column, corticospinal tract and spinocerebellar tract showed loss of myelinated fibres and gliosis. In Clarke’s nucleus, neuronal loss and gliosis were found. Dorsal root ganglion showed mild neuronal loss with a few Nageotte’s nodules. In the precentral gyrus, mild loss of Betz cells and gliosis together with neurophagia were observed. In the iliopsoas muscle, islands of isolated muscle fibres can be seen against a background of fatty tissue. The sural nerve showed a markedly decreased number of large and small myelinated fibres without onion-bulb formation. Small infarctions were seen in the subcortical white matter, the basal ganglia, the brainstem and the cerebellum. Immunohistochemistry revealed ubiquitin-positive, TAR DNA-binding 43 kDa-positive, TFG-positive inclusions in the remaining LMNs.

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Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is an autosomal dominant neurodegenerative disease characterized by proximal predominant weakness and muscle atrophy accompanied by distal sensory disturbance. Linkage analysis using 4 families identified a region on chromosome 3 showing a LOD score exceeding 4. Further refinement of candidate region was performed by haplotype analysis using high-density SNP data, resulting in a minimum candidate region spanning 3.3 Mb. Exome analysis of an HMSN-P patient revealed a mutation (c.854C>T, p.Pro285Leu) in TRK-fused gene (TFG). The identical mutation was found in the four families, which cosegregated with the disease. The mutation was neither found in Japanese control subjects nor public databases. Detailed haplotype analysis suggested two independent origins of the mutation. These findings indicate that the mutation in TFG causes HMSN-P.

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The diagnosis of amyotrophic lateral sclerosis (ALS) is frequently challenging, and needle EMG plays a central role to assess lower motor neuron dysfunction. Ultrasonography can clearly visualize fasciculation, one of characteristic features of ALS, and could contribute to the diagnosis of ALS. Echogenicity might be useful to assess chronic denervated changes of muscles, although there are some issues to be solved with regard to establishing methods and normal values. Attempts to utilize ultrasound to diagnose ALS have been just started. However, ultrasound has an advantage of non-invasiveness over EMG or nerve conduction study. Ultrasound could become a new tool to evaluate neuromuscular disease without pain in the near future.

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Ultrasonographic nerve enlargement has been reported in patients with demyelinating Charcot-Marie-Tooth disease, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy and POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome. Reference nerve sizes are needed at evaluation sites to determine nerve enlargement. However, neither site-based differences nor associations between the reference nerve sizes and several physical characteristics had been sufficiently verified. In our study, the reference nerve sizes of the median and ulnar nerves and the cervical nerve roots were determined in healthy Japanese adults. Site-based differences in the nerve sizes were observed. The stratification of reference nerve sizes according to gender is reasonable for practical use, as these differences reflect physical characteristics. The cross-sectional areas of the peripheral nerves were markedly larger at all evaluation sites in patients with demyelinating CMT than in patients with CIDP. However, the nerve sizes of the cervical nerve roots were not significantly different between patients with either disease. We also observed that the number of sites exhibiting nerve enlargement in the intermediate region of the median and ulnar nerves was useful to distinguish demyelinating CMT from CIDP. Thus, nerve ultrasonography is a promising diagnostic supportive tool for demyelinating neuropathy.

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Muscle ultrasound is a useful tool of the neuromuscular disease. On muscle ultrasound, we can detect the affected muscle as increase of muscle echo intensity because of the fibrosis and fatty infiltration. Muscle atrophy and thickened muscle fascia are also visualized with muscle ultrasound. Another advantage of muscle ultrasound compared to other imaging technique is to visualize muscle movement, such as fasciculation. In this paper we review the findings of muscle ultrasound in normal muscle and affected muscle and discuss the possibilities and limitations of muscle ultrasound.

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High-resolution ultrasound allowed for more detailed morphological assessment peripheral nerves and muscles. It is important to elucidate ultrasound features of peripheral nerves or muscles in various neuromuscular diseases because ultrasound is a widely used, non-invasive and easily accessible diagnostic tool. We attempted to demonstrate characteristic findings of nerve ultrasound in patients with Charcot-Marie-Tooth disease (CMT), Amyotrophic lateral sclerosis (ALS), and Cervical radiculopathy. In patients with CMT1A, cross sectional areas (CSAs) of all the nerves we examined were significantly larger than those in normal controls. Additionally, median nerve CSA had positive correlation with CMT neuropathy score, and negative correlation with nerve conduction velocity. In patients with ALS, increased CSA forearm/upper arm ratio of the median nerve was a characteristic finding to support the diagnosis. In patients with cervical radiculopathy, we could observe that decreased CSA and diameter of the nerve root corresponding to the findings of MRI and electromyography. These results demonstrate that the combination of electrophysiological study, diagnostic imaging, and nerve ultrasound could lead to accurate diagnosis of various neuromuscular diseases.

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Ultrasonography is useful for the management of carpal tunnel syndrome. It aids in the diagnosis of idiopathic cases, screening of local pathologies(space-occupying lesions, tenosynovitis, and bone and joint abnormalities), incomplete release, and anatomic variations, and performance of low-invasive surgery

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In approximately 3％ of migraineurs, migraine evolves into more protracted and severe conditions annually. Meanwhile, approximately 26％ of chronic migraine cases regain the episodic nature of migraine headaches in two years. The prevalence of chronic migraine is estimated to be approximately 1％. Although the pathophysiology of migraine chronification is poorly understood, several studies have demonstrated abnormalities in pain processing mechanisms. Of note, the descending pain inhibitory system has been found to be defective in chronic migraine patients. Topiramate appears to ameliorate the disease conditions by correcting such abnormalities in the pain processing mechanisms. Neurogenic inflammation around the dural trigeminal afferents is known to play an important role in the generation of migraine attacks. Botulinum neurotoxins inhibit regulated exocytosis at the nerve terminals by cleaving the SNARE protein, SNAP25. As a result, release of migraine-related neuropeptides, calcitonin gene-related peptide and substance P, is reduced. Moreover, the insertion of transient receptor potential vanilloid subfamily, member 1 (TRPV1) into the plasma membrane is hindered by BoNT-A. We have demonstrated that the inability of TRPV1 to translocate to the plasma membrane results in its proteasome-mediated degradation within the trigeminal ganglion neurons, which may be relevant to the efficacy of BoNT-A against chronic migraine.

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Chronification of migraine headache is one of the major issues to resolve urgently. The prevalence of chronic migraine is close to 2％, and the chronification occurs in approximately 2.5％ of episodic cases annually.
The pathophysiology of transformation from episodic to chronic migraine is still unclear. It is considered that there are several risk factors for migraine chronification; 1) non-modifiable: age, low education/socioeconomic status, and head injury, 2) modifiable: attack frequency, obesity, medication overuse, stressful life events, caffeine overuse, snoring, and other pain syndrome, 3) currently putative: allodynia, proinflammatory states, prothrombotic states, and specific genes.
There were a few clinical reports concerning to the migraine transformation from abroad, but few data from Japan. The prevalence of chronic daily headache in our headache clinic in Japan was 20-30％. The medication overuse headache was the most prevalent form in the highest attack frequency (>15 days/month) grope. Discontinuation of overused medication and administration of prophylactic medication were effective, and 40％ of followed cases kept out of MOH at two years later.

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Migraine is a common neurological disorder that produces substantial disability for sufferers. Chronic migraine (≧15 headache days/month; CM) was significantly more disabling than episodic migraine (< 15 headache days/month; EM). CM was associated with greater impairment of occupational and social aspects of quality of life. Lost productivity time was substantially higher among CM participants than persons with EM. Full time employment was lower in CM participants because of medical leave. The medical costs were two or three times higher for CM than EM. These results suggest that migraine chronification is associated with substantial economic burden.

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The Japanese Headache Society and the Japanese Society of Neurology has published the 2013 guidelines for the diagnosis and treatment of chronic headache. A new CQ has been set up in the guidelines on the topic of “How to treat chronic migraine.” In the past, lomerizine was the only prophylactic medication of migraine that was eligible under insurance coverage. However, afterward in 2010, valproate was added to the list of antimigraine medications approved under insurance coverage, followed by propranolol, amitriptyline, and verapamil, with rapid advances in the treatment of migraine. Valproate, topiramate (not approved under insurance coverage until date), and amitriptyline could potentially be used in the treatment of chronic migraine in Japan; further, considering the clinical outcomes thus far, lomerizine could also be added to the list. As a drug for migraine prophylaxis, valproate is contraindicated in pregnant women and needs to be used with caution.

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Cognitive impairment is a part of neurological findings. Localization of each cognitive function, however, is not as straightforward as motor or sensory functions. Individual differences in premorbid abilities and functional network, in addition to the hierarchical organization of cognitive functions, make functional localization highly complicated. Brain-behavior relationships have been studied in patients with focal lesions, such as cerebrovascular diseases or brain tumor. Nowadays, distribution of brain atrophy in relation to cognitive performance is also investigated in neurodegenerative disorders using various neuroimaging techniques. Neurologists can take the pathological processes in each disease into account when they explore the distribution of impaired neural networks. Integrating sophisticated lesion analysis with deficit analysis based on knowledge of normal cognitive function would clarify brain-behavior relationships.

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Memory can be divided into several types, although all of them involve three successive processes: encoding, storage, and retrieval. In terms of the duration of retention, neurologists classify memory into immediate, recent, and remote memories, whereas psychologists classify memory into short-term and long-term memories. In terms of the content, episodic, semantic, and procedural memories are considered to be different types of memory. Furthermore, researchers on memory have proposed relatively new concepts of memory, i.e., working memory and prospective memory. This article first provides explanations for these several types of memory. Next, neuropsychological characteristics of amnesic syndrome are briefly outlined. Finally, how several different types of memory are affected (or preserved) in patients with amnesic syndrome is described.

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Alajouanine (1956) established a concept of jargon as a speech symptom of aphasia and gave clinical descriptions of three types of jargon—undifferentiated, asemantic (neologistic) and paraphasic (semantic) jargon. Several case-reports of undifferentiated jargon in Japanese language have been published in clinical aphasiology. On the other hand language development of jargon-type in normal children was reprorted in developmental psychology. We point out a phenomenological similarity of clinical language symptoms of jargon with language development of jargon-type considering its neuropsychological implications.

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The nature of the relation between neuropsychology and consciousness has become a major issue. DB had a left lower quadrant hemianopia. When questioned about his vision in the left lower field, DB reported that he saw nothing. When DB was asked to point to locations in the impaired field in which spots of light were turned on briefly, he was surprisingly accurate. Apparently, even though DB could not consciously perceive a light in his blind region, his brain knew where it had appeared. This phenomenon has become known as blindsight. DF suffered carbon monoxide poisoning. The result in DF was an extensive lesion of the lateral occipital region, including cortical tissue in the ventral visual pathway. The principal deficit that DF experienced was a severe inability to recognize objects, which is known as visual form agnosia. Despite her inability to identify objects or to estimate their size and orientation, DF still retained the capacity to appropriately shape her hand when reaching out to grasp something. The anoxic episode affected her vision for perception, but left her vision for action largely unscathed. These patients lack conscious awareness about some subset of information, even though he or she processes that information unconsciously.

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Prion disease is developed by changing normal prion protein to transmissible abnormal prion protein and its accumulation in the brain. Drug development project using small chemical molecules is now progressing based on constitutional analysis of prion proteins, and a domestic network for clinical trial is consolidating. Prion disease is classified into 3 types, and the Japanese Prion Disease Surveillance Committee has identified 2,026 patients with prion diseases during 14 years from 1999 (sporadic: 77％, genetic: 19％, environmentally acquired: 4％). Compare with patients in other countries, relatively larger amount of patients with dura mater graft-associated Creutzfeldt-Jakob disease (CJD) and genetic prion diseases have been characteristically identified. Sporadic classical CJD patients, which present rapid progressive dementia, are identified in most of the cases. Genetic prion disease are classified into 3 major phenotypes such as genetic CJD, Gerstmann-Straeussler-Scheinker disease (GSS) mainly showing spinocerebellar ataxia, and fatal familial insomunia. All the 83 cases but 1 case of variant CJD were dura-grafted CJD in environmentally acquired prion disease. Accurate diagnosis and prevention of secondary infection are important according to those surveillance data and systems.

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In Japan, prion diseases are classified into 76.6％ with sporadic Creutzfeldt-Jakob disease (sCJD), 19.6％ with genetic prion diseases, and 4.9％ with acquired prion disease. In sCJD, MM1 type sCJD, which show typical clinical course of CJD, is the most common. Among atypical sCJD cases, MM2 type sCJD is the most common. In genetic prion diseases, the most common mutation of prion protein gene is V180I. All cases with acquired prion diseases except for one case of variant CJD are dura mater graft-associated CJD (dCJD), and the number of dCJD in Japan is account for more than 60％ of all patients with dCJD all over the world. The remarkable frequency of dura mater graft use in Japan might contribute to the elevated incidence of dCJD, but the possible reasons for the disproportionate use of this procedure in Japan remain unclear. Our recent study revealed that differences in the medical conditions precipitating dura mater graft might contribute to the frequent use of cadaveric dura mater and the higher incidence of dCJD in Japan.

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MRI including diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) is useful for the diagnosis of prion disease, particularly Creutzfeldt-Jakob disease (CJD). Hyperintensity lesions are predominant on DWI, and are often seen in the cerebral cortex (“cortical ribboning”) or both in the cerebral cortex and striatum (anterior dominant). However, clinical and MRI findings of CJD can be mimicked by those of many other dementing conditions, including autoimmune encephalitis. Non-prion diagnosis should be considered when hyperintensity is predominant on FLAIR, apparent diffusion coefficient (ADC) is increased early, the lesion is symmetric, the limbic region is most affected, or ADC is decreased in the white matter.

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Hsich et al reported 14-3-3 protein in CSF supports a diagnosis of human prion disease, and 14-3-3 protein is one of supportive diagnostic criteria on WHO (1998). In the presence of 14-3-3 protein and total tau protein is widely used as a surrogate marker in the pre-mortem diagnosis of human prion disease and other rapidly progressive dementia. Most recent research report that the sensitivity of 14-3-3 protein was 43%–100%, and the specificity of 14-3-3 protein was 47%–97%. And the sensitivity of total tau protein was 43%–100%, and the specificity of total tau protein was 47%–97%. In other hand we recently developed a new in vitro amplification technology, designated “RT-QUIC assay”, for the detection of PrP^Sc in CSF of sCJD. Other group reported that CSF RT-QUIC method analysis has the potential to be a more specific diagnostic test for sCJD than current CSF tests, but their method is different from our method and their study was not enough. Now we are analyzing for the sensitivity and specificity of biomarkers and RT-QUIC method in CSF of definite cases of human prion disease, the number of definite cases of human prion disease is larger than that of other studies.

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[in Japanese]

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The beneficial effects of rehabilitation are known to plateau around 6 months after stroke. But there are some reports that motor functions are improved with using botulinum neurotoxin A (BoNT-A) for limb spasticity in the maintenance stage of stroke. Though it has been thought that BoNT-A works in the peripheral nerves so far, Caleo showed BoNT-A can affect the central nervous system. We suspected BoNT-A affected the spinal cord directly following retrograde transsynaptic transport from his reports. We deduce the abnormal stretch reflex is made a modification by affecting the spinal cord, and it follows that motor function.
We suggest it is important BoNT-A injection immediately followed by intensive rehabilitation to regain active motor function, because BoNT-A has a specific affinity to cleave certain proteins involved in the mechanism of acetylcholine exocytosis. We propose BoNT-A treatment at 3-month interval should be set.

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In rehabilitation medicine, botulinum toxin (BTX) as adjunct to other interventions for spasticity can result in a useful and effective therapeutic tool treating disabled stroke patientswith spasticity. Other than spasticity, non-reflex motor disorders (muscle stiffness, shortness and contracture) can complicate clinical course and hamper rehabilitative process of stroke patients. After treating spasticity by BTX, the paralysis might be improved by changing muscular imbalance following stroke. We also have to face unique and difficult to treat clinical conditions abnormal posture and movement disorders due to chronic severe stroke patients. The effectiveness of BTX in treating some of these conditions is also provided. Since, neurologically disabled stroke patients can show complex dysfunction, prior to initiating BTX therapy, specific functional limitations, goals and expected outcomes of treatment should be evaluated and discussed with family and caregivers. BTX also might improve not only care, passive function, but also improve active function in stroke patients with intensive rehabilitation with rTMS, tDC, electrical stimulation, stretching and other rehabilitation strategy. Therefore BTX might change rehabilitation medicine.

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NEURO (NovEl intervention Using Repetitive TMS and intensive Occupational therapy) have been recently reported to be clinically beneficial for post-stroke patients with upper limb hemiparesis. We confirmed the safety and feasibility of the protocol in 1,008 post-stroke patients from different institutions, and identify predictors of the clinical response to the treatment. And in our randomized controlled study of NEURO and constraint-induced movement therapy, NEURO showed the superiority of NEURO relative to constraint-induced movement therapy; NEURO improved the motion of the whole upper limb and resulted. We have investigated the recovery mechanism using electrophysiological examination and functional magnetic resonance imaging. Low-frequency rTMS applied to the non-lesional hemisphere in post-stroke patients significantly decreased the F-wave frequency and amplitude in the affected upper limb, suggesting that this modality has an anti-spastic effect in post-stroke patients. Serial functional magnetic resonance imaging indicated that our proposed treatment can induce functional cortical reorganization, leading to motor functional recovery of the affected upper limb. Especially, it seems that neural activation in the lesional hemisphere plays an important role in such recovery in poststroke hemiparetic patients.

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Repetitive facilitative exercise (RFE), a combination of high-dose (high frequency) of repetitions and neurofacilitation, is a recently developed approach to the rehabilitation of stroke-related limb impairment. We conducted a randomized controlled evaluation of RFE compared with a duration-matched conventional rehabilitation program in the treatment of subacute stroke-related upper extremity impairment (Shimodozono et al. 2013). RFE demonstrated both statistically and clinically significant benefits over conventional rehabilitation both on the Action Research Arm Test, which is designed to measure dexterity and function, and on the Fugl-Meyer Arm scores, which was chosen as measure of motor control. In the case-series study, the beneficial effect of RFE is also reported in the treatment of chronic phase of stroke. More research is needed, but RFE could conceivably be integrated with other approaches such as vibration, neuromuscular electrical stimulation, repetitive transcranial magnetic stimulation, botulinum toxin, and robotics to achieve further improvement in its capabilities.

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Unilateral spatial neglect (USN) is defined as a failure to pay attention to the contralesional space due to the brain damage. As this symptom affects on many aspect of activities of daily living, a lots of therapeutic approaches were developed so far. Among them, prism adaptation (PA) technique is one of the most promising methods because it could produce generalized and long lasting after-effect and is effective even for chronic USN patients. It is, however, true that there are USN patients showing no PA effect. Unfortunately, we cannot tell in advance who can adapt to prisms and show improvement of their neglect symptom at this moment. In further studies, to know who is more likely to adapt to prisms we should analyze clinical data from USN patients showing improvement by PA. In addition, to be an effective PA technique for much more patients with USN we should clarify what it the best condition in PA task.

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This issue is a kind introduction for the next three speakers who will give lectures about three considerably pathophysiology-known involuntary movements: tremor, myoclonus and dystonia.
What’s involuntary movement? This question relies on what is a voluntary movement. Some movements may include voluntary components and involuntary components. It usually excludes normal reflex movements, but they are sometimes included in the involuntary when much enhanced and cause some problems for the patients.
Classification of involuntary movements. Clinical classification is based on clinical features, and it is, therefore, the same as how we explain some unknown movements to others. The rhythmicity, rapidness, pattern, stereotypy, part of the body involved, trigger factors are main features we use.
How to record them. Video recording is the best method to record and show them to others. EEG, evoked potentials, polygraphs and some other physiological studies may help you to analyze their pathophysiology.

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Clinical manifestation of dystonia features involuntary muscle contraction or spasm resulting in postural and movement disorders. Depending on the distribution and spreading pattern of dystonia, four patterns have been described, including focal, segmental, multifocal and generalized dystonia. Dystonia can be seen as one of additional clinical features in a more severe neurologic condition. Most of pathophysiology in dystonia remains to be elucidated. Considering the pathology in secondary dystonia, basal ganglia is mostly involved, especially putamen. Dysfunctions of the cerebello-thalamo-cortical loop would result in development of dystonia. Stereotactic and functional neurosurgery has been demonstrated to provide clinical benefits to dystonia patients. In addition, involvement of other neuronal circuit or tissue has been revealed, including cerebello-thalamo-cortical loop, brainstem, spinal cord and peripheral nervous system. Elucidation of pathophysiology, molecular genetics, and functional neuroanatomy would further contribute to developing therapeutic strategy in dystonia.

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Tremor is a rhythmic involuntary movement of any body parts. Some peripheral and central mechanisms can produce it. The former includes peripheral mechanical oscillations and oscillations due to spinal reflexes. The latter includes central oscillations originated from some central pacemakers or network loops through cerebellum, basal ganglia or others.
Weight loading on a body part is one method for differentiation between the peripheral and central mechanisms. In peripheral tremor, the weight load usually changes the tremor frequency. In contrast, it is not affected by the load in the central tremor. Both mechanisms relate to produce essential tremor and enhanced physiological tremor.
Basal ganglia, sensory-motor cortex, cerebellum, red nucleus and inferior olive nucleus could be the central pacemakers or involved in the central loops for tremor.
The facilitation and inhibition imbalance within a pacemaker or imbalance between feed-forward and feedback regulations within central loops may generate some rhythms.

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Myoclonus is one of the common movement disorders in clinical practice, and its differential diagnosis is important. Usually, myoclonus can be classified into cortical, subcortical, brain stem, spinal and peripheral, based on its pathogenesis. Especially, cortical myoclonus is closely associated with epilepsy (myoclonic epilepsy) and has been studied extensively so far. Here, we will review the pathogenesis of cortical myoclonus from the viewpoint of clinical neurophysiology.

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The progress has been made in research on rare and intractable diseases, for which new drug development has long been limited due to rarity, by establishing a global network in recent years. In Japan, the countermeasure of rare and intractable diseases has been implemented under national policy outline as an integrated strategy since 1972, including surveys and research, construction of medical facilities, reducing burden of medical expenses for patients, and enhancement of welfare and improving QOL of patients. Along with legislation or regulation of orphan drugs development, treatment and care for rare diseases have been emphasized in each national healthcare system globally. In the US, the Office of Rare Diseases was established under NIH in 1989 and European countries also started collaboration for rare disease projects with their own national plans in 1999. As a platform of rare diseases patients, healthcare professionals, researchers, pharmaceutical industry, and policy makers, Orphanet has a well-designed website which networks them. In Japan, there are urgent needs for global standard patient registration system and strengthening global collaboration for developing treatment and care for the patients of rare and intractable diseases, which needs more cooperative relations with patient organizations and pharmaceutical industry within country.

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NANBYO policy which has practiced since 1972 has been discussing for making fundamental reform. As a part of a plan to reform, “Total Supports for Persons with Disabilities Act” executed. The target of this act is included with NANBYO patients. Regarding to the enforcement of the act, there are major changes as follows; 1) Regional government has a responsibility to set up the support project for NANBYO patients, 2) Welfare policy will be altered by a change in the definition of disability (the target of welfare for the disabled is not only patients who have fixed disabilities but have changed (e.g. NANBYO), 3) NANBYO patients will be regarded as a target for job assistance under the act. In this abstract, the author raises the fundamental issues as “Society where NANBYO patients can live is equal to that where all people can live”, from patient’s perspective.

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Nutritional intervention in neurological diseases including amyotrophic lateral sclerosis (ALS) has drawn attention in recent years. Malnutrition or progressive weight loss in the early stage of ALS has been reported as a predictor of poor survival prognosis. Percutaneous endoscopic gastrostomy (PEG) is recommended in the early stage of ALS to stabilize the body weight and possibly to improve patients’ quality of life (QOL) or survival prognosis. Clinicians should be precisely aware of clinical significance and purposes, and optimal timing of PEG in ALS. PEG should be performed in the stages with preserved respiratory function (forced vital capacity > 50%, and arterial carbon dioxide pressure < 45 mmHg), to avoid early death after PEG and to maintain QOL with nutritional intervention through PEG. Although appropriate amount of energy to be administered is yet to be established, high calorie diet is expected to be effective for potential improvement of survival. PEG is also necessary as a safe administration route of opioids for palliative and end-of-life care.

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As Japan has been confronting rapid aging of the population, the government is promoting home medical care, with reforming medical service policy, offering subsidies, and revising payment system of medical service. Hereafter, home medical care will play an important role in order to build the integrated community care system by cooperating with long-term care services. More physicians, not only of specialized clinics, but also of general ones, are expected to visit home to provide medical service to their own immobile patients.

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Presently, myasthenia gravis (MG) is seldom lethal. However, full remission without immune treatment is not common, and many patients still find it difficult to maintain daily activities. To both determine factors affecting health-related quality of life (QOL) and propose an appropriate treatment target for patients with MG, we evaluated 640 consecutive patients with MG seen at 11 neurological centers. Two-year follow-up data were obtained for 282 patients. Correlations between detailed clinical facotrs and the Japanese version of the 15-item MG-specific QOL scale were analyzed.
In the cross-sectional analysis of 640 MG patients, multivariate regression revealed that disease severity as evaluated by MG Composite (p < 0.0001), but not quantitative MG score, total dose of oral prednisolone (p = 0.002), but not current dose, and Cushingoid appearance index (p = 0.0004) showed significant negative effects on QOL. Achieving status of Minimal Manifestations or better with prednisolone ≤5 mg/day was found to exert a major positive impact on QOL in both the cross-sectional and 2-year follow-up patient samples and can be recommended as a treatment target.

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Autoimmune myasthenia gravis (MG), affecting both ocular and generalized muscles, results in various symptoms. Ocular myasthenia (OM) is a form of MG that is clinically restricted to extrinsic ocular muscles. Clinical signs of OM can be highly variable, ranging from mild unilateral ptosis to complete opthalmoplegia. There is no clear evidence supporting corticosteroid use for OM. We studied 123 patients whose symptoms were limited to ocular muscles with duration of illness ≥ 2 years. We classified them into two groups: 36 patients with ptosis alone (the ptosis group) and 87 with diplopia with or without ptosis (the diplopia group). Prednisolone (PSL) and immunosuppressants were less frequently used in the ptosis group. There were no significant differences in the post-treatment condition and quality-of-life (QOL) impairment between the two groups. Forty-seven (38%) patients who failed to gain minimal manifestation or better status with PSL ≤ 5 mg/day (the unfavorable condition) showed severe QOL impairment. Ocular-QMG score was a factor associated with the unfavorable condition. A treatment strategy, discriminated by ptosis or diplopia, is necessary to improve the ocular symptoms and QOL in OM patients with the unfavorable condition.

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The aim of this study was to delineate the status of oral corticosteroid therapy in myasthenia gravis (MG), and to elucidate the effectiveness of oral corticosteroids according to dosing regimen. We evaluated 472 MG patients from 11 neurological centers in Japan. Disease severity was determined according to MGFA, QMG and MG composite. Clinical state following treatment was categorized according to MGFA postintervention status. We also completed the Japanese version of the 15-item MG-specific QOL scale (MG-QOL15-J). The statistical analysis revealed that achievement of minimal manifestation (MM) or better status using maximum prednisolone (PSL) dose or reduced PSL dose by 25% or more after adding calcineurin inhibitors had significantly positive effects on the present QMG, MG composite and MG-QOL15-J. The maximum dose and administration period of PSL did not influence present disease severity, but administration period of PSL ≥20 mg mg/day had negative effects on the present QOL. Achieving a status of MM or better by maximum PSL dose or reduced PSL dose combined with other agent may improve the present MG status and QOL.

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Calcineurin inhibitors (CNIs) and intravenous immunoglobulin (IVIg) are immunomodulatory treatments used to treat patients with myasthenia gravis (MG). The objective of this study was to describe the clinical features of MG treated with CNIs or IVIg. To characterise the clinical features of myasthenic symptoms in MG treated with CNIs compared with MG treated without CNIs. Patients with MG (676 cases) underwent a multidisciplinary clinical examination (quantitative MG score for disease severity (QMG score), MG composite, etc), and we extensively reviewed the case histories with current clinical and laboratory evaluations. We confirmed CNIs were safe and effective in the treatment of MG in association with reduction of corticosteroids. IVIg have efficacy in reducing QMG score in patients with moderate to severe MG.

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Rituximab (RTX) is a chimeric murine/human monoclonal antibody directed against the CD20 surface antigen of B cells. RTX has been for the treatment of non-Hodikin lymphoma. Recently, RTX was shown to be effective in treating patients with myasthenia gravis (MG) who did not show improvement with other immunomodulation treatments. However, the evidence of its efficacy is mostly limited to a few case series or open-label trials. At the present stage, RTX may be permitted to be used in patients who understand the risk of its side effects and provide consent for its use in treatment. In future, it will be necessary to establish an effective and safe medication protocol of RTX in Japan.

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The prognosis of Guillain-Barré syndrome (GBS) is not as good as might be expected. Among GBS patients, 30% do not respond to intravenous immunoglobulin therapy (IVIg) and 10% may worsen after initial treatment (treatment-related fluctuation). Recent prospective trials show that 16% of GBS patients are unable to walk independently a year after onset of the disease. The prognosis of GBS is influenced by clinical, electrophysiological and biological factors, of which the clinical factors are most important. The Erasmus GBS Respiratory Insufficiency Score (EGRIS) and the modified EGOS (Erasmus GBS Outcome Score) are very useful for prediction of mechanical ventilation or aided walking. A small increase in serum IgG (delta IgG) two weeks after IVIg treatment is useful as a biological prognostic marker that is significantly associated with slow recovery and aided walking at 6 months. Use of these factors makes it possible to predict the prognosis of GBS patients, and to identify patients with a poor prognosis in the early phase of the disease and provide these patients with intensive treatment. An accurate prediction of the level of disability is important for improvement of the prognosis of GBS.

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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-Barre syndrome. The discovery of anti-GQ1b IgG antibodies further supports the view that the two disorder represent a single disease spectrum. Currently Bickerstaff brainstem encephalitis can be regarded as a variant of Fisher syndrome with central nervous system involvement.

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Bickerstaff brainstem encephalitis (BBE) is characterized by acutely progressive bilateral ophthalmoparesis and ataxia with impaired consciousness or pyramidal signs, or both; all of which are followed by a monophasic course with good recovery. Alike Guillain-Barré syndrome (GBS), BBE is proposed to have an autoimmune mechanism triggered by antecedent infection. The nationwide epidemiologic survey for BBE, which the author had performed in Japan, suggests that BBE consists of typical and atypical cases. Typical BBE has similar neurological and serological features to Fisher syndrome and shows good recovery, whereas atypical BBE is characterized by delayed recovery, negative anti-GQ1b antibodies, and abnormal cerebrospinal fluid and brain MRI findings with other possible pathogeneses.

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