The concept of neurogenic control of the cerebral circulation began to develop only as recent as the middle of the 20th century, when it was elucidated that the cerebral blood vessels are supplied by a very dense plexus of adrenergic nerves innervating the vascular bed. After then, already in the course of several decades, more than ten types of neurotransimitters including acetylcholine, serotonin, substance P, and calcitonin gene-related peptide, etc., have been observed in these nerves. To determine the origins and pathways of cerebrovascular parasympathetic nerves and sensory nerves, retrograde axonal tracing with immnohistochemstry has been studied. The cerebrovascular parasympathetic nerves originated 1) in the sphenopalatine ganglion (SPG), and 2) from the internal carotid ganglion, and also 3) from the otic ganglion. While the cerebrovascular sensory nerves originated 1) in the trigeminal ganglion (TG), and 2) from the internal carotid ganglion, and also 3) from the upper cervical dorsal root ganglia. The neurogenic cerebrovascular vasodilatation was demonstrated in vivo, by the electrical stimulation of the cerebraovascular branches of TG or SPG. This vasodilatation was attenuated not by anti-cholinergic agents but triptans as well as anti-CGRP agents. This implicates the mechanism of pathological neurogenic inflammation and vasodilatation during the migraine attacks.
What's involuntary movement? To define the involuntary movement, we should define the voluntary movement. It is, however, difficult to define the voluntariness. The involuntary movement usually indicates some abnormal movement occurring without any movement intention of the subject which excludes any reflex movements, such as tendon reflexes or normal startle response. How to see patients with involuntary movements Classification of involuntary movements entirely depends on clinical features of movements. The method to see the patients, therefore, follows how to describe the movements when explaining those to others. The three main points to care are as follows. Regularity in time or rhythmicity of the movement: regular, mostly regular, irregular or completely irregular. The most rhythmic one is tremor and most irregular one is myoclonus. Conditions inducing involuntary movement: resting, postural, during movement, emotional stress, sensory trick or others. These are important factor to see actual movements in clinical practice. To make an inducing condition in the clinic is sometimes required to see the symptoms. Pattern of involuntary movements: irregular, stereotypical, distribution of moving muscles, right-left difference and others. Several kinds of involuntary movements are presented in my talk.
In the past decade, the therapeutic choices for patients with myasthenia gravis (MG) have not changed, except for the introduction of rituximab. There have been three placebo-controlled randomized trials in the past fifteen years, namely, those on azathioprine (AZP), mycophenolate mofetil (MMF) and tacrolimus. The trial for AZP was carried out on a relatively small number of patients (AZP, 15; placebo, 19), and its outcome showed the therapeutic effectiveness of AZP. The MMF trial was carried out on a large number of patients (MMF, 88; placebo, 88). The result showed no effect on primary and secondary endpoints. The tacrolimus trial was carried out in Japan on a relatively large number of patients (tacrolimus, 40; placebo, 40). Although the study could not reveal an effect on the primary endpoint, several secondary endpoints turned out to be affected. In all three studies, the therapeutic drugs were used in combination with steroid, and the safety and tolerability of the drugs were shown. In diseases with a relatively small affected population, such as MG, successful execution of well-designed clinical trials is difficult. We have to learn how to collect pieces of valuable information wisely from previous studies. The utilization of clinical literacy will be important in this medical practice.
Secondary encephalitis (encephalopathy) causally related with immune response induced by infection, etc., includes encephalitis mediated by innate immunity and adaptive immunity. In the latter, encephalitis mediated by antibodies to molecules at cell-surface of neuron seems to have relatively better outcome. In patients with encephalitis mediated by antibodies to NMDA-type glutamate receptors (NR), mean onset age is 26.5 years old, and the major initial symptoms are limbic symptoms including abnormal behavior, etc. The antibodies are causally related with internalization of NRs, resulting in antagonistic effect of NRs related with symptoms of encephalitis. In patients with encephalitis mediated by antibodies to voltage-gated potassium channel (VGKC), predominant affection of males are observed, and antibodies to leucine-rich glioma-inactivated 1 (LGI1) and contactin-associate protein (CASR) 2 are found as major epitopes. Patients with Hashimoto encephalitis mediated by antibodies to n-terminal of α-enolase (NAE) have broad spectra of clinical characteristics. Antibodies to TPO can be the marker for diagnosis, and thereafter, confirmation of antibodies to NAE is necessary for definitive diagnosis.
Entrapment neuropathy is not uncommon, and surgical treatment is followed by favorite result. Therefore, to obtain an accurate diagnosis based on precise knowledge of the peripheral nervous system is very important. The most popular and useful symptoms and signs of the entrapment neuropathy is paresthesia, dysesthesia and Tinel's like sign at the lesion site. Nerve conduction study is also valuable for the accurate diagnosis. For the last 30years, the author operated on 1,399 lesions of entrapment neuropathy. They consist of 877 carpal tunnel syndrome (63%), 284 tarsal tunnel syndrome (20%), 135 ulnar neuropathy at the elbow (10%), 53 piriformis syndrome (4%), 15 thoracic outlet syndrome (1%), and others. From the pathophysiological point to view, except for the carpal tunnel syndrome, several locations and factors come into play producing the entrapment of the nerve. The author would like to stress that the entrapment neuropathy is not severe disease, though, it strongly insult the patient's quality of life.
Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder characterized by the death of upper and lower motor neurons. In familial ALS kinders with mutations in the SOD1 gene, the age of onset of weakness varies greatly but the duration of illness appears to be characteristic to each mutation. Mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene have been discovered to be associated with familial ALS. In a Japanese family with familial ALS, we found the R521C FUS mutation, which has been reported to be found in various ethnic backgrounds. The family history revealed 23 patients with ALS among 46 family members, suggesting a 100% penetrance rate. They developed muscle weakness at an average age of 35.3 years, and the average age of death was 37.2 years. Neuropathological examination revealed remarkable atrophy of the brainstem tegmentum characterized by cytoplasmic basophilic inclusion bodies in the neurons of the brainstem. The frequency of a hexanucleotide repeat expansion in C9ORF72 with familial ALS has been estimated as approximately 5% in Japan, although the one Japanese patient was identified as a carrier of the C9ORF72 expansion carried the Finnish risk haplotype.
The present state of knowledge of physiological mechanisms underlying nonepileptiform EEG abnormalities is reviewed to clarify the correlation between EEG and neuroimaging. Focal and widespread slow waves, background abnormalities, and bursts of rhythmic slow activity are discussed. EEG phenomena were correlated with lesion size, location, type (white matter vs. gray matter, high density vs. low density), and mass effect. Clinical and experimental accumulated over the past five decades suggest that polymorphic slow activity is generated in cerebral cortex by layers of pyramidal cells and is probably due to partial deafferentation from subcortical areas. Unilateral background activity changes are probably thalamic dysfunction, and bilateral paroxysmal slow activity is due to abnormal thalamocortical circuits combined with cortical pathology. Paroxysmal discharges indicate the presence of epilepsy with possible brain lesion(s). The EEG is a functional test and provides us complementary information to neuroimaging studies.
The concept of mild cognitive impairment (MCI) is clinical condition between normal cognition and dementia. Annual rate of conversion from MCI to dementia is estimated as 10-15%. It must be emphasized that all MCI will not be potential patients of dementing illness. Most studies have been focused on amnestic-MCI as preclinical condition of Alzheimer's disease (AD). Along with the increase number of analyses, MCI is divided in four categories according to clinical presentation such as amnestic-MCI, amnestic-MCI with multiple domains, non amnestic-MCI with single domain and non amnestic-MCI with multiple domains. In general, the underlying disease of amnestic-MCI with multiple domains may be AD, cerebrovascular disorders (CVDs), metabolic disease or depression. Non amnestic-MCI may be frontotemporal dementia, dementia with Lewy body, CVDs and metabolic disorders. In fact, neuropathologic evidence of MCI revealed the presence of various types of pathologic change. Those pathologic changes include an accumulation of tau, amyloid beta, α-synuclein, TDP-43 and FUS protein with various degrees. It is not unusual condition that several different types of pathology are observed in a single individual. Besides neurodegenerative pathology, CVDs and hippocampus sclerosis significantly contribute the cognitive condition of MCI. To realize the complexity of neuropathologic alterations of MCI is important for early intervention of dementia indivisuals.
Epilepsy is a chronic neurological disorder characterized by recurrent seizures that are caused by abnormal and excessive cerebral neuronal discharges. The clinical symptoms are paroxysmal, and may include impaired consciousness and/or motor, sensory, autonomic, or psychic events. Diagnosis of epilepsy is not always straightforward and clear-cut. A seizure is only a symptom that indicates neuronal dysfunction. Other diseases can cause paroxysmal events, which look very much like a seizure but in fact are nonepileptic. Such nonepileptic events include syncope, acute symptomatic seizures, and psychogenic nonepileptic seizures. To identify epileptic seizures and to classify the type of epilepsy, clinical, electroencephalographic (EEG), and/or neuroimaging findings are the fundamentals. Knowledge of the different types of seizures is essential to guide the physician in obtaining the history which leads to the diagnosis of seizure and epilepsy. In real situations, however, it is rare for physicians to actually witness the event of seizure. This lecture provides valuable opportunity to experience "real life" clinical diagnosis of epileptic seizures by showing the video of patient under seizure and EEG data. Representative visual examples of symptoms together with the detailed medical knowledge will greatly enhance the capability of diagnosis, the effectiveness of treatment, and help develop clinical strategies.
Non-motor symptoms including sensory signs have recently been stressed in basal ganglia (BG) disorders. Why do sensory symptoms appear in BG disorders? Four closed loops have been shown between cortex and BG, but no sensory cortical-BG loops. I review two points: fiber connections between the somatosensory cortex and BG to explain sensory symptoms, and pain and basal ganglia. Somatosensory system and BG Many animal studies have shown somatosensory cortex- striatum- globus pallidus- motor thalamus connections, but no connections to the sensory thalamus. This indicates that sensory system may modulate four closed loops between the cortices and BG (motor loop, oculomotor loop, prefrontal loop and limbic loop) as an open loop system. Based on the above findings, two possible mechanisms may explain somatosensory symptoms in BG disorders. Motor modulation abnormalities may be considered as sensory symptoms in patients with BG disorders. Some sensory cognition abnormalities due to abnormal modulation of the prefrontal- BG loop may be considered as sensory symptoms. Pain and dopamine Two systems contribute to pain signs in patients with BG disorders. Descending pain modulation system: several brainstem nuclei send descending pain modulation fibers to the spinal cord mediated by serotonin or noradrenalin. These nuclei are facilitated by D2 neurons from the striatum. Striatal dopamine must suppress the pain information input at the spinal cord. Ascending pain relief system D2 neurons from the ventral tegmental area to anterior cingulate cortex, accumbens and amygdala may reduce pain feeling at the association cortices. In summary, dopamine system will reduce pain at the spinal cord and association cortices. Dopamine depletion, therefore, will enhance the pain sensation.
Chronic headache is caused by several reasons, such as medication over use, psychological stress, depression, anxiety and psychiatric disease. It is often difficult to treat medication over use headache. So it is important to manage the psychological factor before abuse. There are the relationships in migraine and psychiatric disease, especially major depression and panic disorder. In the treatment for chronic headache, it is necessary to assess the personal profile. The Hospital Anxiety and Depression Scale is useful for assess depression and anxiety in patients with painful symptoms.
Progressive muscular dystrophy presents with various complications as the disease progresses, besides decreased motor function. It is critical to make an appropriate and accurate diagnosis and to provide appropriate multidisciplinary medical care continuously from the time of diagnosis, including pharmacotherapy, rehabilitation, orthopedic treatment, respiratory/cardiovascular care, nutritional support and psycho-social care. This will contribute significantly not only to the survival prognosis, but also to improvement of the quality of life of these patients. A comprehensive and proactive posture (result-oriented assessment and coping) toward those therapeutic approaches is important in clinical practice. This concept is common to other rare diseases and neurological intractable diseases and may be applicable to these diseases.
Molecular genetic analyses revealed that most neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and the polyglutamine diseases share a common molecular pathogenesis, namely protein misfolding and aggregation in the brain. Recently, prion-like transmission of these protein aggregates between cells has been suggested to contribute to the spread of neuropathology. To cope with protein aggregation, organisms have protein quality control systems, consisting of molecular chaperones and protein degradation, and therefore, an imbalance between protein aggregation and these systems would lead to neurodegeneration. Mouse models of neurodegenerative diseases exhibit neurological phenotypes before neuronal death, and these phenotypes are unexpectedly reversible, suggesting that neuronal dysfunction rather than death leads to neurological phenotypes. In addition to dysfunctions inside neurons, dysfunctions of the neuronal and neuro-glial networks also contribute to the pathogenesis in a non-cell autonomous fashion. On the other hand, another class of diseases including several spinocerebellar ataxias has been discovered to be caused by a repeat expansion mutation in untranslated RNA resulting in its accumulation, which is called the RNA repeat diseases. Recent discoveries of RNA-binding protein mutations and a repeat expansion mutation in ALS have highlighted the involvement of abnormal RNA metabolism in its pathogenesis. Recently, various researches on molecular-targeted therapies are in progress, which include high throughput chemical screening, RNAi, and gene therapy, etc. Towards development of a therapy for neurodegenerative diseases, sensitive biomarkers suitable for evaluation of therapeutic efficacy in clinical trials are eagerly anticipated.
To neurologists, pregnancy and delivery are major issues in patients with neuroimmunological diseases such as multiple sclerosis (MS), neuromyelitis optica (NMO), and myasthenia gravis (MG). The Pregnancy in Multiple Sclerosis Study reported that the annual relapse rate (ARR) decreases during pregnancy and increases during the first trimester after delivery. Discontinuation of interferon-β (IFNβ) is usually recommended prior to pregnancy. IFNβ exposure is related to lower birth weight, but no fetal complications or development abnormalities have been reported. Regarding pregnancy in NMO, our current study showed that the ARR during pregnancy was same as before pregnancy. A higher ARR was noted after delivery than in patients with MS. The numerous cases of NMO with onset after pregnancy suggest that delivery affects the exacerbation or of NMO. In women with MG, exacerbations occurred during approximately 30% of pregnancies, remission occurred in 30%, and 30% experienced no change. Exacerbations occurred in the first trimester and the three months postpartum. We must consider the risk of transient neonatal MG, because the frequency is 10-20% in infants born of MG mothers. It is especially important to carefully consider anti-MuSK antibody-positive patients because bulbar palsy is a major symptom.
Thrombolytic therapy with intravenous tissue plasminogen activator (IV tPA) is initiated within 3 hours from the onset of ischemic stroke now. Following the publication of the results of ECASS III in 2008, IV tPA treatment has been initiated within 4.5 hours abroad. Expanding the therapeutic time window from 3 to 4.5 hours had been applied, but not approved yet in Japan. Evidence of mechanical intraarterial (IA) thrombectomy within 8 hours is not sufficient. Since a mismatch between PWI and DWI is very attractive for selecting patients for recanalization, the standardization of neuroimaging analysis must be established. For efficacious and safe recanalization, it is necessary to select patients based on accurate information on neuroimages and to establish the most useful therapy (IV tPA and/or IA thrombectomy) for each patient.
Recent clinical management of subacute meningitis is reviewed. Tuberculous meningitis (TbM) and fungal meningitis are the commonest cause of subacute meningitis. Since the delayed treatment in these meningitides is strongly associated with poor outcome, these clinical managements are required to be neurological emergency. Recent clinical guidelines of these meningitides recommended new therapeutic managements. Treatment for TbM should consist of 4 drugs (isoniazid, rifampicin, pyrazinamide, ethambutol) for 2 months followed by 2 drugs (isoniazid, rifampicin) for at least 10 months. Adjunctive corticosteroids should be given to all non-HIV patients with TbM, regardless of disease severity. Treatment for CNS Cryptococcosis and Candidiasis with non-HIV infected and non-transplant hosts is lipid formulation of Amphotericin B combined with flucytosine for at least 4 weeks for induction therapy. This 4-week induction therapy is reserved for patients with meningoencephalitis without neurological complications and CSF yeast culture results that are negative after 2 weeks of treatment. Then, the consolidation with fluconazole for 8 weeks is started. Voriconazole is recommended for the primary treatment of CNS Aspergillosis including meningitis. If the diagnosis is made early, if clinicians adhere to the basic principles of these guidelines, and if the underlying disease is controlled, these meningitides could be managed successfully in the most of patients.
The success of chronic deep brain stimulation (DBS) and electrical neuro-network modulation (ENM) to address neurological and neuropsychiatric disorders has led the Food and Drug Administration (FDA), and also other worldwide regulatory agencies to grant approval for the use of DBS in specific disorders. In the United States, DBS is FDA approved for the treatment of advanced Parkinson's disease (PD), essential tremor (ET), obsessive compulsive disorder (OCD), and for dystonia. OCD and dystonia have been approved under a mechanism referred to as a humanitarian device exemption (HDE). However, as the field of DBS and ENM evolve there has been a shift in practice patterns from targeting diseases to targeting specific and disabling symptoms. This shift has been driving interdisciplinary DBS boards to collect, and to address symptom profiles in all potential DBS candidates. Based on a specific symptom profile, a strategic and personalized medicine approach can be undertaken. The personalized approach will take into consideration the brain target, a unilateral versus a bilateral procedure, and the potential for use of more than one DBS lead per brain hemisphere. Additionally, a personalized approach to DBS will also facilitate improved pre-operative medication adjustments, as well as optimal post-operative medication, behavioral, and device management.
The current clinical trials of gene therapy for Parkinson's disease (PD) are based on three strategies. 1. To restore the local production of dopamine by introducing genes associated with dopamine-synthesizing enzymes into the putamen. 2. To protect nigrostriatal projection by delivering the neurturin gene, a trophic factor for dopaminergic neurons, both in the putamen and the substantia nigra. 3. To modulate the neural activity by transducing the subthalamic nucleus with vectors expressing glutamic acid decarboxylase. A phase I clinical study was initiated in 2007 to determine the safety of intra-putaminal infusion of a recombinant adeno-associated virus (AAV) vector encoding aromatic L-amino acid decarboxylase (AADC). All six patients enrolled in the trial showed improvements from baseline in the Unified Parkinson's Disease Rating Scale motor scores in the OFF medication state at 36 months after treatment. Although this trial was a small, open-label study and the use of a non-blinded, uncontrolled analysis limits interpretation, the efficacy outcomes are encouraging and indicate that the AAV vector-mediated gene transfer of AADC may benefit advanced PD patients. A similar approach, delivering AAV vector carrying AADC gene into the putamen ameliorated the symptoms in children with AADC deficiency.
Ischemic tolerance is as powerful and reproducible for neuro-protection as hypothermia. Several pathways could be involved in acquisition of ischemic tolerance. CREB is an abundant transcription factor in the brain and plays critical role on synaptic plasticity and neuronal survival. CREB activation has been also shown to be involved in ischemic tolerance. Ischemia or oxygen-glucose deprivation leads to release of glutamate, which binds to synaptic NMDA receptor. Then, influx of calcium ions into intracellular space activates calcium-calmodulin dependent protein kinase (CaMK). CaMK I/IV phosphorylates Ser 133 of CREB, and Thr 484 of salt-inducible kinase (SIK). Phosphorylation of SIK2 at Thr 484 triggers degradation of SIK2 through ubiquitin proteasome system. SIK2 maintains the phosphorylation level of CREB-regulated transcriptional co-activator (CRTC). Degradation of SIK2 induces dephosphorylation of CRTC1, and moves CRTC1 from cytoplasm into nucleus. Thus CRTC1 binds to basic ZIP domain of CREB. Both Ser133 phosphorylation and CRTC1 bound to the basic ZIP domain of CREB enhances CRE-mediated transcription, induces gene expression of survival factors, and renders the neurons resistant to subsequent severe ischemia.
Brain white matter lesions (WMLs), which are often observed in patients with ischemic cerebrovascular diseases, contribute to cognitive decline. We analyzed the pathologic and regenerative processes in brain white matter lesions of patients diagnosed with vascular dementia. There was a significant increase in the number of oligodendrocyte progenitor cells (OPCs) in the brains of patients with vascular dementia as well as in rats with cerebral hypoperfusion. WMLs can be induced experimentally by bilateral common carotid artery ligation (BCCAL) of rats to cause chronic cerebral ischemia. After chronic cerebral hypoperfusion injury, oxygen free radicals and activated microglia acting as inflammatory elements contribute to chronic cerebral hypoperfusion-induced WMLs. The cell death of oligodendrocytes (OLGs) contributes directly to WMLs. The activation for intracellular signaling pathway of cAMP responsive element binding protein (CREB) phosphorylation in the white matter was suppressed after BCCAL. Type III phosphodiesterase inhibitor (PDE3-I) has potential therapeutic and brain-protective effects based on multitarget mechanism through cell signaling pathway of CREB phosphorylation. The OPCs subsequently underwent cell death and the number of OLGs decreased. In the rat model, PDE3-I prevented cell death, markedly increased the mature OLGs, and promoted restoration of white matter and recovery of cognitive decline.
We here presented two new neuroprotective agents; a HIF activator and an Akt activator. Hypoxia inducible factor (HIF) plays a pivotal role in the adaptation to ischemic conditions, and its activity is modulated by an oxygen-dependent hydroxylation of proline residues by prolyl hydroxylases (PHD). We discovered a unique compound TM6008, which inhibited PHD and stabilized HIF activity in vitro. Oral administration of TM6008 protected neurons in forebrain as well as focal ischemia. The protection was associated with amelioration of apoptosis but independent of enhanced angiogenesis. Next, elevating Akt activation is an obvious clinical strategy to prevent progressive neuronal death in neurological diseases. We identified a small molecule SC79 that inhibits Akt membrane translocation, but paradoxically activates Akt in the cytosol. SC79 specifically binds to the PH domain of Akt. SC79-bound Akt adopts a conformation favorable for phosphorylation by upstream protein kinases. In a hippocampal neuronal culture system and a mouse model for ischemic stroke, the cytosolic activation of Akt by SC79 is sufficient to recapitulate the primary cellular function of Akt signaling, resulting in augmented neuronal survival. Thus, HIF and Akt activators may be the new therapeutic strategy against cerebral infarction, and be expanded the therapeutic time window for hemolysis.
There are growing experimental and clinical data on the pathophysiological roles of antiganglioside antibodies in Guillain-Barré syndrome (GBS) and Fisher syndrome (FS). Antibodies to a ganglioside complex (GSC) consisting of two different gangliosides are detected in some GBS and FS sera. Recently, anti-GM1/GalNAc-GD1a complex antibodies, anti-GA1/GQ1b antibodies with no reaction against GM1/GQ1b, and anti-GM1/LM1 antibodies have been detected in GBS or FS sera. The anti-GM1/GalNAc-GD1a antibodies correlated with pure motor GBS characterized by antecedent respiratory infection and early CBs at intermediate sites of motor nerves. Complement activation is considered to be a key process causing nerve damage in GBS and FS with antiganglioside antibodies. A recent ex vivo study indicates that antibodies to GM1/GD1a or GM1/GQ1b can induce complement-mediated functional and morphological injury at mouse motor nerve terminals. Complement-independent pathophysiology such as blockade of voltage-gated Ca channels, the apoptotic mechanism of neurons, and alteration of microdomains in the nerve cell membrane should also be considered. Complex glycolipid environments in the cell membrane may govern the accessibility and avidity of antiganglioside antibodies for target gangliosides. Thus, the pathogenic effect of antiganglioside antibodies may depend on the local glycolipid environment in the nerve membrane, as well as on the antibody specificity.
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired, immune-mediated polyradiculoneuropathy. The American Academy of Neurology criteria has been used widely in diagnoses, and has generated clinical and pathological information. Recently, the EFNS/PNS criteria revised the concept of conventional "typical CIDP" and "atypical CIDP", with atypical CIDP including five phenotypes: DADS (distal acquired demyelinating symmetric), MADSAM (multifocal acquired demyelinating sensory and motor), focal, pure motor, and pure sensory neuropathy. However, the concepts of pure sensory, pure motor, and "idiopathic" DADS neuropathy do not have sufficient pathogenic support. MADSAM neuropathy shows significant hypertrophic nerve roots and/or plexuses. Since the characteristic multifocal distribution should correspond to the hypertrophic distribution, MADSAM or "hypertrophic CIDP" may be the promising phenotype of atypical CIDP. Clinical trials indicate that IVIg is more effective in a short time than corticosteroids for the treatment of CIDP, although corticosteroids maintain a longer immune suppression than IVIg. These results suggest that "hybrid therapies", IVIg induction and corticosteroid maintenance, may be effective. A recent study showed that IVIg stabilizes axonal potentials and axonal membranes, and our group showed that juxtaparanodal TAG-1 may be associated with IVIg responsiveness. Although CIDP is a demyelinating disease, the involvement of axon or axon-myelin interactions should be considered.
The diagnosis of multifocal motor neuropathy (MMN) is often missed because MMN disguises itself as a motor neuron disease and is considered relatively rare. Detailed epidemiological studies of MMN have not been undertaken. We therefore conducted a nationwide survey of MMN in comparison with amyotrophic lateral sclerosis (ALS). This retrospective study examined 47 patients with MMN and 1,051 patients with ALS from major neuromuscular centers in Japan from 2005 to 2009. MMN had a younger age of onset and was more common in males than ALS. The ratio of MMN to ALS patients (0-0.10) varied among the centers, but mostly converged to 0.05. The prevalence was estimated to be 0.3 cases for MMN and 6.63 cases for ALS per 100,000 persons. Twenty-five MMN patients (54.2%) showed conduction block. Thirty-four (75%) of 45 MMN patients received intravenous immunoglobulin exhibited a favorable outcome. It is expected that more sensitive indicators of conduction block or focal demyelinating lesions than currently available MMN diagnostic criteria would further increase the ratio of MMN to ALS patients and the total number of MMN patients who can benefit from treatment. MMN is by no means a rare disorder but should be accurately diagnosed in all neuromuscular centers.
POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome is characterized by neuropathy with multiorgan involvement. High-dose chemotherapy with auto-peripheral blood stem cell transplantation (ASCT) and thalidomide, which are new therapeutic approaches to POEMS syndrome could salvage lots of patients with POEMS syndrome and substantially improve the prognosis. However there have been not a few patients who experienced recurrence after ASCT, and part of those patients suffered very mild symptom at the time of the treatment. Indication of ASCT should be reconsidered and different therapeutic strategy such as combined thalidomide with ASCT might decrease risk of recurrence. Moreover we should consider other therapeutic option such as lenalidomide or bortezomib for refractory patients.
All neurologists have to make a differential diagnosis of consciousness loss by EEG. The judgment of epilepsy is especially important. Experts of neurology were also required to determine the level and etiology of the acute or chronic weakness or numbness by EMG with nerve conduction study. Hands on seminar and e-learning would be useful to acquire these tools.
Fist of all, in order to understand the position of neuroimaging, I would like to stree the imaging in neurological practice, being different from neuroradiologist. Neurological examination, and other clinical information are essential to diagnose neurological cases, which provide the anatomical diagnosis of neurological lesion and etiological diagnosis. On the basis of these neurological diagnoses, neurologists can order the appropriate imaging modalities for the diagnosis. On the next step, it is important that the methods, theory and other technical issues should be understood by him/herself. This kind of knowledge will provide the full information obtained from the images. It is usually said that the training of the image of one disorder requires over than 100 cases by own inspection. These training will give the trainee the power to diagnose the neurological disorder appropriately based on neuroimagings.
Neuropathology is essential for neurology since disease concepts of neurological disorders have been based on the neuropathological findings. Amyotrophic lateral sclerosis, Parkinson disease, multiple system atrophy and Alzheimer's disease have been established on the pathological findings. Neuropathology has been still important, even if diagnostic procedure has progressed in neuroimaging and genetic screening. Today neuropathology includes not only morphological findings, but also immunological and molecular biology. Minimum requirements for post-graduate education indicate that autopsy and clinicopathological conference are essential for young doctors for specialists. The practical experience of autopsy procedure promotes further knowledge and understandings of macroscopical findings of central nervous system. CPC provides the training place to compare clinical neurological signs and neuroradiological pictures to pathological findings, and the chance to confirm the clinical diagnosis. These trainings may raise quality of clinical neurology. It is recommended to practice the training courses in specialized neuropathological institutes, or to attend annual and local meetings of Japanese Society of Neuropathology, although the small number of neuropathological educational center and the decreased number of autopsied brains make it difficult for trainee doctors.
The fate of injured motor neurons could be determined by the balance of the protection and death signals, which expressed in the injured motor neuron. However recent studies implied the significances of surrounding non-neuronal cells for the protection of motor neurons in degenerative diseases and nerve injury. In periphery Schwann cell, macrophage and endoneurial fibroblast play crucial roles for the proper nerve regeneration. Schwann cell promotes infiltration of macrophage to remove debris of degenerated myelin and provides a scaffold and several growth factors for axon to elongate. The macrophage phagocytoses myelin debris and stocks lipids, which is re-used for re-myelination by Schwann cell. The fibroblast controls the localization of axon and Schwann cells during nerve regeneration. For those cellular functions several mediators among those cells are expressed. In CNS microglia and astrocytes would be the major players for the protection of motor neurons after injury. After nerve injury the activated microglia adhered to the injured motor neurons for a while and then the astrocyte took over, whereas in the dying motor neurons the initial behavior of the microglia was not observed. Glial behavior in CNS may be associated with the fate of injured motor neurons.
The rapid and efficient induction of neural stem cells (NSCs) from pluripotent stem cells is required for the research of patient-specific iPS cells and regenerative medicine to induce their own neural cells. Here, we induced NSCs from human pluripotent stem cells within 2 weeks and these clonal NSCs were expanded efficiently by their self-renewal ability. Further, we directly induced NSCs from both mouse and human fibroblasts using four reprogramming factors (Oct4, Sox2, Klf4, and cMyc) without the clonal isolation of induced pluripotent stem cells (iPSCs). Since these NSCs rapidly developed into mature gliogenic neural stem cells, we were able to purify these rapidly differentiating NSCs without contamination of differentiation-resistant pluripotent cells. These methods will facilitate high throughput screening of phonotypes appeared in neural cells induced from the somatic cells derived from sporadic neurodegenerative diseases.
Currently, there is no effective treatment for the neuronal loss caused by neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) or ischemic stroke. However, recent studies have shown that endogenous neural progenitor cells continuously generate new neurons in the subventricular zone (SVZ) of the adult mammalian brain. Some of these new neurons migrate to the injured site and differentiate into mature neurons. Such new neurons may be able to replace degenerated neurons and improve or repair neurological deficits. To establish a neuroregenerative therapy using this endogenous system, endogenous regulatory mechanisms must be understood. Here, we review current knowledge on the generation of new neurons in the adult brain and discuss their potential for use in replacing neurons lost to neurodegenerative diseases, including ALS, and to ischemic stroke.
There are four cell types that have specific functions in iron metabolism; duodenal enterocytes, hepatocytes, erythroid cells, and reticuloendothelial macrophages. In these cells, iron absorption, storage, and export are critically regulated by several iron-metabolism proteins, including hepcidin. Iron is abundant in the brain, and iron homeostasis in the brain is relatively independent from that in other tissues because of the presence of the blood-brain barrier. Iron uptake and transport in the brain depends on interactions between the vascular endothelial cells and perivascular astrocytes. Transferrin-bound iron (Tf-Fe3+) binds to the transferrin receptor 1 (TR1) on the luminal membrane of the endothelial cells, and then Tf-Fe3+-TR1 complex is internalized in the endosomes. In the acidic environment of the endosomes, iron is liberated from Tf. The mechanism by which free iron in the endosomes is exported into the interstitial space is still controversial. GPI-anchored ceruloplasmin on the end-foot processes of astrocytes oxidizes newly released Fe2+ to Fe3+, which binds to Tf in brain interstitial fluid, and then Tf-Fe3+ is taken up by neurons. Iron misregulation and abnormal iron accumulation are involved in several genetic and non-genetic neurological diseases through enhanced oxidative stress. Chelation therapy could be an effective disease-modifying approach for these conditions.
Superficial siderosis (SS) of the central nervous system is a rare condition in which hemosiderin is deposited in the subpial layer of the brain and/or spinal cord. It is supposed that hemosiderin deposition is a result of recurrent or persistent hemorrhage in the subarachnoid space. The causes of hemorrhage are tumor, vascular abnormality, injury, dural defect, and others. The source of hemorrhage is not apparent despite of extensive examinations in about a half of the patients with SS. Patients with SS usually reveal slowly progressive and irreversible cerebellar ataxia and/or sensorineural hearing loss. MRI of T2WI or T2*WI demonstrates characteristic linear low intensity along surface of the brain and the spinal cord. There are two types of SS. One is a classical type, in which low intensity of MRI is diffuse and symmetrical. The other is a localized type. We attempted to make a clinical criteria of SS according to the world literature. Then, the criteria was applied to cases (53 cases of classical type and 7 cases of localized type) which are collected from Japanese nationwide questionnaires. The causes and symptoms of Japanese SS are similar with those of Western countries.
Neuroferritinopathy is an autosomal dominant, adult-onset disorder characterized by the deposition of iron and ferritin in the brain and a decreased level of serum ferritin. The disease is caused by mutations of the gene encoding ferritin light chain polypeptide. Seven pathogenic mutations have so far been reported, and two of the mutations were found in Japanese families. The mutations are predicted to affect tertiary structure and stability of the ferritin light chain polypeptide and may cause inappropriate iron release from feritin polymers. The excess iron may cause oxidative stress and lead to cell and tissue damage. The typical clinical features are dystonia and involuntary movement. Some patients may present cerebellar ataxia and cognitive decline. The clinical features appear to be restricted to the nervous system. The variety of MRI findings including T2 hypointense lesions reflecting iron deposits, cystic degeneration of the basal ganglia, and cortical atrophy are characteristic of neuroferritinopathy. Iron depletion therapy by iron chelation in symptomatic patients has not been shown to be beneficial. Recent study shows the iron deposition in neuroferritinopathy begins in early childhood before symptomatic presentation. This finding suggests the importance of early intervention of therapy.
Some fundamental technical aspects of magnetic resonance imaging (MRI) in evaluation of iron deposition were discussed. MRI is an imaging modality sensitive to iron deposition of the brain tissue. T2 weighted imaging (T2WI), T2* weighted imaging (T2*WI), and susceptibility-weighted imaging (SWI) are particularly available for this purpose. They are different in sensitivity and availability, and should be used in the right places respectively. Susceptibility to iron deposition is also dependent on the strength of static magnetic field, which should be taken into account in the interpretation of the images.